JPS609753B2 - Novel sulfamphthalein compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel chemical compounds for use in optical processing in photographic processing, more particularly for protecting exposed light-sensitive materials from post-exposure fog during development in the presence of ambient light. The present invention relates to novel sulfamphthaleins useful as filter agents and filter agent precursor materials.

Many diffusion transfer methods are available that produce photographic images in both black and white and color.

A method of particular interest is the diffusion transfer method in which the image-receiving layer carrying the transferred image is not separated from the developed photosensitive layer(s) after processing, but both elements are held together as a permanent laminate. Such a laminate includes as part of it a layer of light-reflecting material, preferably titanium dioxide, between the image-bearing layer and the developed photosensitive layer. A light-reflecting layer separate from the image-bearing element and the photosensitive element provides a white background for the transferred image and also masks the developed photosensitive layer. In addition to these layers, the laminate usually includes dimensionally stable outer layers or support layers, at least one of which the resulting transferred image is visible by reflection against the background provided by the light-reflective layer. As transparent as possible. Diffusion transfer methods for forming visible images without separation of the photosensitive element and receiver element and positive film units useful in such methods, i.e., negative or photosensitive elements and positive or A film unit which retains the image-receptive element as a permanent laminate after processing is published by Edwin H., December 10, 196. U.S. Patent Nos. 3,415,644 and 3,415 issued to Eduuin Land.
No. 645 and No. 3415646: Edwin H. March 30, 1971. U.S. Patent Nos. 3,573,043 and 35,730 issued to Rand
No. 44; and Howard G., July 20, 1971. U.S. Patent Nos. 3,594,164 and 35 issued to Howard G. Roger Dai.
No. 94165. Edwin H.
U.S. Pat. No. 3,647,437, issued March 7, 1972, also relates to a diffusion transfer process in which the photograph produced is one part of a permanent laminate.
It consists of a developed photosensitive layer which carries as part an image-receiving layer.

In the method described in this patent, a photographic film unit containing a light-sensitive element is developed under ambient light, but further undesired exposure during processing is due to the light-absorbing properties retained within this processed film unit. protected by substances or optical filter agents. In a preferred embodiment, the optical filter agent is an anti-sensitive dye, i.e. a dye with spectral absorption properties that can be changed reversibly in response to changes in the surrounding pH, especially at a given alkaline pH or above. It is a pH-sensitive dye that has a light-absorbing form and a colorless or non-light-absorbing form below the mottling. PH-sensitive dyes are usually included in the processing composition, but can also be present initially within the film unit, for example when the colorless dye is present in a layer above the light-sensitive layer if the photographic exposure has to be carried through this layer. It can exist in the form of This matrix-sensitive dye transforms into its colored form upon application of an alkaline processing composition and, after the desired processing time, reduces the surrounding matrix, for example by incorporating an acid-reactive layer as part of the film unit. By subtracting , it returns to its colorless form. Examples of lake-sensitive dyes that have been found to be particularly useful as optical filter agents include Stanley Em.
Snenley M. Bloom, Alan
L. Paula (Nan L. Nor), Paul
S. Haihua (Pasan S. Hu〆fer) and Paul Tei. MacGregor (PauIT.MacOr
US Pat. No. 3,702,244 issued to
Myron S. No. and King November 7, 1972. Myron S. Simon and David P. There are phthalein and naphthalein dyes described in U.S. Pat. No. 3,702,245 issued to David P. Waller, and 19
7 Rod King April 10th Alan P. There are 9-pyridylfluorene dyes described in U.S. Pat. No. 3,726,675 issued to Polar. Stan Raym., filed September 23, 1977. Bloom, Alan L. Paula and James W. Hawley (
JamesW. U.S. Patent Application No. 836,006 under examination by Foley et al.
For use in a negative-positive film unit, the optical filter agent is produced from a substantially colorless filter agent precursor compound and is capable of dissipation regardless of changes in feed.

A colorless optical filter agent precursor is first deposited in a layer of a film unit, such as a layer coated over a photosensitive element, and then, after imagewise exposure of the photosensitive element, this colorless precursor is A colored optical filter agent is produced by contacting the material with a base, such as an aqueous alkaline processing composition. After being in contact with the base for a certain period of time,
The colored optical filter agent disappears by forming a new compound that is substantially colorless and unlike either the optical filter agent or its precursors, neither of which can be reversed by a pH change. A compound useful for producing a colored optical filter agent above a given alkaline pH, while producing a colorless product above a given pH, i.e., an optical filter agent precursor, includes (i) a color-forming compound; ionizable protons released into the base to yield a chromophore, and (ii) undergo an irretrograde decomposition reaction with the base that involves decomposition of this chromophore, producing a substantially colorless product. It has the following groups. Dutt is Jay. Chemi. Soshi (J
．． Chem. Soc. ), 121, 2389 pages (192
reported the condensation of saccharin with aromatic amines and phenol in the presence of concentrated sulfuric acid and also in the presence of molten zinc chloride.

The resulting condensation product with saccharin was named ``sulfamphthalene'' by analogy with ``phthalein'' and ``sulfone phthalein.''

3,3-di(4'-hydroxyphenyl)-2,3-dihydrobenz[d]isothiazole-1,1-dioxide structure (i.e. "phenolsulfamphthalein J
was given to the condensation product obtained from saccharin and phenol, but the compound corresponding to the proposed structure has properties different from those reported, such as being colorless rather than pink in alkali. It was discovered that

It was also found that a compound corresponding to this given structure could not be synthesized by repeating the method reported by Dutt. The present invention finds use in the aforementioned photographic products and provides a colored optical filter agent for protecting imagewise exposed photosensitive elements from undesired additional exposure during processing under ambient light. This invention relates to novel sulfur phthaleins that act as colorless precursors.

According to the present invention, novel 3,3-disubstituted sulfamphthaleins are provided having a substituent on the nitrogen atom, ie at the 2-position of the sulfamphthalein ring.

The 313 monosubstituents may be the same or different, and at least one of the 3 and 3 substituents has a color-generating group, i.e. an ionizable proton that is released in the base to form a chromophore. It is the basis. These compounds are defined more specifically below. As noted above, the compounds of this invention are useful as optical filter agents and filter agent precursors in photography.

Due to the 2-substituent on the sulfamphthalein ring, some of the compounds of the present invention act as traditional pH-sensitive dyes, i.e., these compounds
Below this alkaline pH it has a colorless form and in the presence of a base above this alkaline pH it produces a light-absorbing form or a colored optical filter agent, which is produced by reducing the pH below this alkaline pH. It is decolorized by retrogradation to the original colorless precursor. The remaining compounds according to the invention also yield light-absorbing forms or colored optical filter agents above a certain alkaline pH, but without regressing to the original colorless precursors and p
Becomes colorless without reducing H. The colored optical filter agent produced by the latter compound is decolored by undergoing an irreversible total reaction with a base at a pH above the above-mentioned alkaline pH to form a colorless product. Because of their ability to be apparently independent of pH reduction, these compounds can be used in photographic methods where the pH of the system remains virtually unchanged after processing, and in methods that lower the pH at the final stage of processing. It can also be used to quickly visualize the final image.
Furthermore, since the optical filter agents of the present invention are irreversibly bleached to a colorless product that is inert to changes in pH, there is a possibility of color reproduction over time due to accidental increases in pH. can be removed. Figures 1 and 2 show the spectral absorption characteristics of colored optical filter agents formed in basic solution with colorless precursor compounds having the formulas {2) and (15) below. It is a graph.

These graphs cover the wavelength range of 35 to 70 meters and show the optical transmission density of each filter agent measured with a logarithmic slide rule.
ensi○), that is, it shows absorption characteristics. Compounds of the invention useful in providing the colored optical filter agents described above can be represented by the following formula: In the above formula, RI is a hydrogen atom, lower alkyl or lower alkoxy group, and R2 is a hydrogen atom, lower alkyl or It is a lower alkoxy group, R3 is a hydrogen atom, R4 is a hydrogen atom or a lower alkoxy group, and R5 is hydroxy, lower alkoxy, N(CH2CH20H)2, N(CQC day 2
-Halo)2 (where Halo is a halogen atom), N(lower alkyl)2, NHCOCH8, or, R6 is a hydrogen atom, lower alkoxy or a lower alkyl group, and R7 is a hydrogen atom, lower alkyl , a lower alkoxy or hydroxy group, or R6 and R7 together represent the carbon atoms necessary to complete the fused benzene ring, and Z
is or, Y is one CN, one S02C, or, Halo is a halogen atom, R9 is a lower alkyl group, phenyl group or a nitro-substituted phenyl group, RII is a lower alkyl group, a halogen-substituted lower It is an alkyl group or a nitro-substituted or dimethylamino-substituted phenyl group.

As used herein, the name "sulfamphthalein" refers to 2,3-dihydrobenzo[d]isothiazole-1,1-dioxide represented by the formula.

A first group of compounds contemplated by the present invention includes a substituent (
where Y is as defined in Formula 1).

A particular example of the first group of compounds is the following compound: The first group of compounds is 'a-3-(4'-OP-1'-phenyl)
-3-(phenyl or naphthyl)-2,3-dihydrobenz[d]isothiazole-1,1-dioxide (where P is a protecting group compatible with the organometallic reagent) and {b-acylating agent, ( where W is chloro or bromo and Y is as defined in formula 1) is reacted in pyridine to form the corresponding 3,3-disubstituted-21
It can be produced by producing 3-dihydrobenz[d]isothiazole-1,1-dioxide.

This N-acylated compound is then treated with a weak acid to remove the protecting group or groups, and the 3,3-di-substituted 2,3-
A dihydrobenz[d]isothiazole-1,1-dioxide product is obtained. Optionally, this N-acylation step is performed by reacting with an alkali metal hydride to form the corresponding N
- formation of the alkali metal salt and subsequent reaction with the acylating agent can be carried out. 3-(4'-OP-1'-phenyl)-3 used as intermediate in the above method {a'
-(phenyl or naphthyl)-2,3-dihydrobenz[d]isothiazole-111-dioxide is 3-(
It can be synthesized by reacting 4'-OP-1'-phenyl)penz[d]isothiazole-1,1-dioxide with a phenyllithium or naphthyllithium reactant.

3-(410P-r-phenyl)penz(d)isothiazole-1,1-dioxide converts the blocked 4-halophenol to the corresponding Grignard or lithium compound and then converts this compound into saccharin or saccharin. Produced by reaction with pseudochloride.

The protecting groups chosen for the production of blocked phenols, and optionally for the protection of other substituents, should be compatible with the lithium and Grignard reagents, and should also protect hydroxyl and other groups from the starting material. and must be protected against reaction under conditions encountered in the synthesis of intermediates and subsequent steps in the synthesis of the desired product. Furthermore, the protecting group or groups selected should be such that they can be easily removed under neutral or mildly acidic conditions to regenerate hydroxy and other groups to yield the desired product. The following examples illustrate the preparation of a first group of new compounds.

Example 1 Preparation of a compound having the following formula: (a-N-(p-furomophenyl)morpholine (0.
4 ml) was added to 20 ml of tetrahydrofuran (THF) and the solution was cooled to -65q0.

Add 0.69% of 2.4M butyllithium in hexane to the solution with stirring and continue stirring for 1 hour. (After 15 minutes the solution becomes cloudy and a white precipitate forms). Add 3-(3',5-dimethyl-4') in THF product Z to this solution.
-Methoxymethoxy1'-phenyl)penz[d]isothiazole-1,1-dioxide 0.5 mL at -65°C
Add under nitrogen atmosphere. The resulting reaction mixture is a clear orange-yellow solution. The reaction mixture was kept at sea for 1 hour, poured into 100 ml of water, and acidified with concentrated hydrochloric acid (p
H6), then extracted with ether. ether to Na2S
Dry on 04 and evaporate leaving an oil. This oil is taken up in ligroin (boiling range 30-60q0) and refluxed for 1 hour. The white solid formed was collected and 3-(3',5-dimethyl-4'-methoxymethoxy-1'-phenyl)-3-(4''-1N-morpholinyl-1''-phenyl)-2. 0.7 ml of 3-dihydrobenz[d]isothiazole-1,1-dioxide is obtained.

'b) The compound produced in step [a} (0.7 hours) was placed in pyridine 20 under nitrogen atmosphere, and 8-cyanoethyl chloroformate** (CIC
02CQC day 2CN) Add 0.15'.

The resulting reaction solution was allowed to warm up gently for 1 hour, then poured into a 100% solution of water and extracted with chloroform. The chloroform solution was dried over Na2SO4 and evaporated to remove the solid formed. Ligroin (boiling range 30~
60oo). The resulting compound has the formula N
-acylated compound, 3-(3,5'-dimethyl-4'-methoxymethoxy1'-phenyl)-3-(4''-N
-morpholinyl-1'-phenyl)-2-(8-cyanocarboethoxy)-12,3-dihydrobenz[d]isothiazole-1,1-dioxide.

The compound obtained in step 'c}[b} is dissolved in methanol, acidified with concentrated hydrochloric acid, and then refluxed for 1 hour. TLC from ether on silica gel showed 4 spots.
Evaporation of this methanol solution leaves 0.6 cm of solid. Put 200 ml of this solid in ether and 1 ml of silica gel.
000 plate, allow the plate to dry and remove the color bands. N from silica gel using acetone
- Removing the acylated product. Remove the acetone, add ether and reflux the solution. The white solid formed is collected by filtration to yield the title compound. The 3-(3',6-dimethyl-4'-methoxymethoxy-1'-phenyl)penz[d]isothiazole-1,1-dioxide having the formula used in step {a} above is prepared as follows. Manufacture: (
i) 700 ml of dry chloroform in a two- and three-frame flask equipped with a mechanical lamp, nitrogen inlet tube and dropping funnel.
Insert '.

Immerse the flask in an ice water bath. Powdered phosphorus pentoxide (300.0%) is added to the cold chloroform that is heated vigorously. To this mixture was added 400% of 4-bromo-2,6-dimethylphenol (201.0%) and 400% of dry dimethoxymethane.
Add the solution over 1 hour. During this time, the phosphorus pentoxide powder coalesces into an amorphous mass, making it difficult to disassemble. T.L.C.
Analysis (on silica gel, 9:1 petroleum ether-ethyl acetate) showed that much unreacted raw phenol was still present. Increase the temperature of the reaction mixture to about 25 oo.
Additional 50 increments of phosphorus pentoxide are added to the concentrated reaction mixture every 30-48 minutes until TLC analysis shows the absence of starting phenol. The organic phase is removed by decantation, washed twice with 250 parts each of aqueous 10% sodium hydroxide, and then dried over calcium sulfate. The solvent is removed under reduced pressure leaving a pale yellow oil. This oil was distilled from 25 ml of anhydrous potassium carbonate to give a colorless oil of 4-bromo-
220.0 g of 2,6-dimethyl-methylene methoxy phenyl ether was obtained (boiling point 11.0 at 0.5 Hg).
(ii) 4-bromo-2,6-dimethyl-methylene methoxy phenyl ether (85.04 m; 0.347 mol) is dissolved over about 800 m of tetrahydrofuran. The solution was cooled to -790 under nitrogen plunkett and 2.4M n-butyllithium in hexane (144.8 K;
0.346 mol) is added dropwise. The addition is completed within 2 hours, yielding a white slurry. (iii) Dissolve saccharin (61.2 mm; 0.334 mol) in 600 ml of dry tetrahydrofuran and allow the solution to cool to about 17,500 ml.

2.4 M n-butyllithium (130.4'; 0.311 mol) in hexane is slowly added dropwise to the cooled solution under a nitrogen plunket. The temperature is -70qo
Avoid going above and beyond. Addition is completed with about 9 powders,
A clear, very pale yellow solution is obtained. (The yellow solution obtained in the IJ side step is slowly added to the white slurry obtained in step (ii) while keeping the temperature at -70°C.
(over 3 hours).

During this time, the solids disappear, yielding a clear, caramel-colored reaction mixture that first becomes a gray color and then becomes progressively lighter over time. The reaction mixture is allowed to come to room temperature overnight and then treated with 36.0 g of ammonium chloride in 250 g of water while cooling in an ice-water bath. The organic part is collected by decantation and dried over anhydrous calcium sulfate. The solvent is removed under reduced pressure to obtain a pink oil, which becomes solid upon standing in the open air. This solid was recrystallized twice from 1-propanol, washed with a 60:40% petroleum ether-tetrahydrofuran mixture, and then dried in vacuo to yield the title compound 6 as a white crystalline solid.
Get 8.0 evenings. 3-(3',5-dimethyl-4'-methoxymethoxy1'-phenyl)penz[d]isothiazole-1,1-dioxide is prepared as follows: dry tetrahydrofuran (10-15 I) is mixed with magnesium Turnings (0.20 pm) are added under nitrogen atmosphere. Magnesium turnings, 4-fromo-2, 6
-dimethyl-methylene methoxy phenyl ether (2.
Gradually add a solution of 0.0% in tetrahydrofuran (30%) while heating. A self-sustaining reaction is seen after approximately 20 minutes of external heating to reflux. The remaining phenyl ether solution is then added at a rate that maintains a full reaction. After the addition is complete, continue refluxing by external heating,
After 1 hour the solution is allowed to cool to room temperature and kept under nitrogen atmosphere. A solution of saccharine pseudochloride (1.89 pm) in tetrahydrofuran (40 ml) is cooled to -78 pm, and a previously prepared solution of magnesium bromide reagent is added dropwise to the pseudochloride solution under a nitrogen atmosphere. . The resulting reaction mixture was cooled and stirred for about 2 hours,
Next, let it stand overnight at room temperature. The reaction mixture is then cooled in an ice-water bath and treated with saturated aqueous ammonium chloride solution. The aqueous solution is extracted several times with chloroform and the combined chloroform extracts are collected, washed with water, dried over anhydrous sodium sulfate and then over anhydrous calcium sulfate. Remove the chloroform to obtain a colorless oil. This oil is extracted several times with small portions of light petroleum ether, leaving behind a pale yellow sticky tar. The yellow tar is treated with ether leaving behind an off-white solid. The off-white solid is dissolved in a small amount of chloroform, treated with carbon black and then filtered through Celite. The solvent is removed to give the title compound as an off-white solid, which is converted to P2Q.
Dry in vacuum in the presence of. Yield 0.520 evening. 3-
Chlorbenz[d]isothiazole-1,1-dioxide (saccharin pseudochloride) is prepared as follows: Saccharin 35 and PC 1543.7 are heated to 170 qo for 1.5 hours.

During this time complete dissolution occurs and POC13 begins to reflux. POC13 is removed under reduced pressure, leaving a crystalline residue. Add diethyl ether to the crystalline residue and shake well. The title compound 12.5 is obtained as white crystals (melting point range: 146-14700). ) Morpholine is prepared as follows: Dissolve 25 parts of N-phenylmorpholine in 200 parts of carbon tetrachloride and stir well.

To this, add 27.2 grams of N-bromosuccinimide all at once. It generates a fever of 4500℃.

The reaction solution is stirred until the temperature starts to drop and then heated to reflux for 3 hours. TLC using 3/2 petroleum ether on silica gel showed the reaction was complete. The reaction solution is then allowed to cool, the succinimide is removed by filtration, and the solution is evaporated to produce a yellow solid. The solid is dissolved in 250 ml of ethanol and allowed to cool to give the title compound 22 as white crystals. The 8-cyanoethyl chloroformate having the formula (CNCH2CH2COOCI) used in step 'b} is prepared as follows: 34.0 ml of phosgene gas is collected in 100 ml of dry benzene cooled in an ice bath. Add until combined.

Hydroxyacrylonitrile (
20.2 evening) is added. (Temperature rises slightly to about 8°C). The resulting heterogeneous mixture is cooled to 3° C. with stirring, and pyridine in 25 g of benzene (22.6 g) is added dropwise. Although it generates heat, the temperature does not rise above 1000°C. The damage continues to be very severe until a solid begins to form. After about 1 hour, the reaction mixture was heated to about 5°C.
Wait for 18 minutes, then raise the temperature to 15q0-2000, and hold the lamp for another 15 minutes. The reaction mixture is then cooled to 5°C and made up by adding 26' of ice water. The solid melts with the release of heat and evolution of gas. The temperature is the following 15
- Do not raise the level above 15 qo for 2 minutes. The reaction mixture is then heated at room temperature for 2 hours and the benzene layer is decanted off and dried over anhydrous Na2S04 and then over anhydrous CaSOL. The solvent is removed under reduced pressure to yield a colorless oil. This oil has a boiling point range of 68. -70. yo (pot temperature 98-103oo
) to give the title compound 1 as a colorless oil.
8.2 Generate evening. Examples 2 and 3 Compounds having the formula: Example 2 Example 3 were prepared in step 'b-3-(3,5-dimethyl-4'-methoxymethoxy-1'-phenyl)-3-
(4″-N-morpholinyl-1″-phenyl)-2.3
-dihydrobenz[d]isothiazole-1,1-dioxide is reacted with a suitable acylating agent, i.e., to form the corresponding N-acylated compound, which is treated as in step 'c} above. It is prepared in the same manner as described in Example 1, except that the protecting group is removed.

Example 4 Preparation of a compound having the following formula: (a) 55 ml of 4-furomo-2,6-dimethoxymethylene methoxyphenyl ether is dissolved in 300 ml of anhydrous tetrahydrofuran under nitrogen flow.

The solution is allowed to cool to -65o0 over time for some of the phenyl ether to precipitate. Set the temperature to -5000
Butyrulithium (2 in hexane) at a rate kept below
．． 4M) Add 79 ships. The temperature of the resulting solution is -40
Add 19 parts of saccharin pseudochloride in 2 parts to keep it below 0.00 m. The reaction solution was heated to -65°C.
Cool and stir for 40 minutes. TLC showed one major spot on silica gel using 2 drops of Enal 10/methanol. Pour the reaction solution into 2,000 ml of water and add acid to pH 6. At this pH the color of the mixture changes from orange to yellow. Dilute the mixture with ether (2)
Extract twice and wash the ether solution with water. The ethereal solution is dried over sodium sulfate and then evaporated leaving a bright yellow solid. This solid was recrystallized from n-propanol at 450 °C to give off-white crystals (melting point range 151 °C).
．． 5o -152.5q0) as 3.3-di (3.5
-dimethoxy4'-methoxymethoxy1'-phenyl)-2,3-dihydrobenz[d]isothiazole-
42 ml of 1,1-dioxide is obtained. 'b) The compound prepared in the boiling step (27.0 min) is dissolved in dioxane 125' at room temperature under a nitrogen atmosphere. Add NaH (5
Add 2.50 g of 7% dispersion in oil and stir the resulting dispersion for 45 minutes. (Hydrogen generation can be seen). next"
When ' of CICOOCH2CH2CN8.0 is added, heat generation occurs.

The resulting reaction mixture was heated for 3 hours. The initial yellow color disappears and a white dispersion forms. The dispersion is poured into 2 portions of water, made neutral with dilute HCl, and then extracted with chloroform. The chloroform phase is washed with water, separated, dried over sodium sulfate and then evaporated to yield a white solid. The solid is taken up with ethyl ether, isolated by filtration, dried in vacuo and crystallized from methanol. The formed white needle-like crystals were collected in a furnace and 3,3-di(3,5-dimethoxy-4-methoxymethoxy-1'-phenyl)-2
．． A >N-COOCH2CQCN derivative of 3-dihydrobenz[d]isothiazole-1,1-dioxide is obtained. {c- {3・3- manufactured as in the W process
Di(3,5-dimethoxy4'-methoxymethoxy1
'-phenyl)-2-6-cyanocarboethoxy 2.
3.7 ml of 3-dihydrobenz[d]isothiazole-1,1-dioxide was poured into 200 methanol and HC
1 Add 2 drops.

The resulting solution is refluxed and the reaction is followed by TLC on silica gel with ether. When TLC shows that no more blocked compound remains, the reaction is stopped and the methanol is removed under reduced pressure to give an egg white solid (3.2 evenings). Melt this while heating over 80% of 1,2-dichloroethane, and add 80% of petroleum ether while stirring in a spiral. The solution is allowed to cool and the light beige crystals formed are collected and dissolved in 175 ml of ethanol under reflux. The ethanol solution is allowed to cool in the refrigerator overnight and the title compound 2.7 is collected as white needles (melting point range 191o-19oO). Methoxymethylation of 4-furomo2,6-dimethoxy-phenol is carried out as follows: To a 3-tough flask add 300 g of P2Q under a nitrogen atmosphere, then add 800 g of chloroform (pre-dried over P205). .

The mixture was cooled to -15°C in a dry ice acetone bath, then maintaining the temperature at -1500 or below,
Add 5M of 4-furomo-2,6-dimethoxyphenol in 800ml of dimethoxymethane over 2 powders.
1 part' of concentrated sulfuric acid is added to the resulting reaction mixture, and the temperature is then raised to room temperature. During this time, a sticky mass of P205 appears. The reaction mixture was heated for 3 hours. T.L.C.
indicated that the reaction was complete. 10 chloroform layer
Add 400% aqueous sodium hydroxide to the ground by decantation, stir well, and separate the chloroform layer.
Washed with water, dried over Na2S04 and then evaporated leaving light tan crystals. Add n-propanol to the crystalline residue, simmer and filter to give white crystals (melting point range 9 -
100oC) to obtain the title compound 32.7 times. Examples 5 and 6 Compounds having the formula: Example 5 Example 6 are prepared according to the method described in Example 1.

Provided that 3-(3',5-dimethoxyemethoxymethoxy1'-phenyl)penz[d]isothiazole-1,1-dioxide is used in step a}, and a suitable acylating agent, i.e. and using.

3-(3',6-dimethoxy4'-methoxymethoxy-1'-phenyl)penz used in step 'a} above [
d] Isothiazole-1,1-dioxide is prepared as follows: (i' Using a 18 gauge needle, add saccharin (previously dried overnight under vacuum at 80:00)9
．． 16 days of dry tetrahydrofuran and a solution of 250 n
- Add 20.0 kg of phthyllithium (2.4 M in hexane) dropwise over 1 hour under nitrogen atmosphere at 175°C to 173°C with rapid heating.

A reaction solution containing the N-lithium salt of saccharin in tetrahydrofuran was prepared without isolating this lithium salt (iii
) Straight bales are used in the process. {ii) 13.86 g of 4-promo 2,6-dimethoxy-methylene methoxy phenyl ether was dissolved in 300 g of dry tetrahydrofuran under a nitrogen atmosphere in a dry 1-well flask, and n-butyllithium (hexane Medium 2.4M) 20. Total secretion -7y
Drip and add while stirring with C.

After the addition is complete, the reaction solution is heated at -75°C for about 30 minutes. (ii) The solution of saccharin lithium salt produced in step (l) was transferred to the addition funnel using a double tip needle under nitrogen pressure, and the solution of saccharin lithium salt produced in step (ii)
Add to the solution of 1-2,6-dimethoxymethylene methoxy phenyl ether in about 1 stroke at a temperature of -70°C to -70°C with stirring. 75% of the reaction mixture
Boil for about 2 hours at qo, then warm to 0℃ for 1 hour. (i
A solution of 5.2 parts ammonium chloride and 175 parts water is added dropwise to the reaction mixture in the side step, and the reaction mixture is transferred to a 1-k separating funnel.

Once the two phases have separated, separate the aqueous phase and determine its pH.
from about 11 to about 6- by dropwise addition of 5% aqueous hydrochloric acid solution.
Lower it to 7.

(You can see a color change from yellow to colorless). The aqueous phase is returned to the separating funnel, separated, and the aqueous phase is separated off again and then extracted with fresh ether (100 g). The ether and tetrahydrofuranohexane extracts are combined, dried over magnesium sulfate overnight, filtered, and then the solvent removed to give a yellow oil that crystallizes. Add ether (100') to the crystalline material, grind the crystalline material with a motor under the ether, take the furnace, and wash with ether.
Then wash with petroleum ether and air dry. A second product from the furnace liquor is collected to give the title compound in a total amount of 13.0 minutes. Examples 7-11 Compounds of the following formulas are prepared according to the method shown in Example 1: Example 7 Example 8 Example 9 Example 1O Example 11 However, in the 'a} step 3-(3,5-dimethyl-4'-methoxymethoxy -1'-phenyl)penz[d]isothiazole-1,1-dioxide is reacted with a suitable thiium reagent, namely and, respectively, and in step {c} the protected N·N-di(3-hydroxy 2 from ethyl)anilino group
The '-tetrahydropyranyl group is removed simultaneously with the 4'-methoxymethyl protecting group.

N-(p-Li-phenyl)tetrahydro 2 days/Rainbow H
-1,3,6-dioxazosine can be produced by reacting the corresponding p-halophenyl compound with n-butyllithium.

N-(p-halophenyl)tetrahydro 2 days/4H-
1,3,6-dioxazosine is p-ha. It is prepared by reacting 1N.N'-di(8-hydroxyethyl)aniline with a dihalomethane in the presence of a solid alkali metal hydroxide or a concentrated aqueous solution thereof and a quaternary ammonium salt. Examples 12-14 The compounds having the following formulas are prepared in the same manner as described in Example 4: Example 12 Example 13 Example 14 The acylating agents used are and respectively.

Example 15 Preparation of a compound having the following formula: [a} 2'-tetrahydropyranyl-4-bromophenyl ether (9.0%) in 20% tetrahydrofuran is mixed with 0.0% magnesium in 20% tetrahydrofuran.
85 is added dropwise under a nitrogen atmosphere.

After the addition is complete, the dispersion is refluxed for 2 hours, then saccharin pseudochloride (3.5 hours) is added in portions. An exotherm is seen and the green solution formed then turns yellow-brown. The reaction solution was incubated overnight and then slowly added to 500 ml of water. The precipitate formed is slowly filtered off and the resulting solid is dissolved in ether, dried and then evaporated to yield a bright yellow solid with the following formula:
Compound A as prepared in step 'b'{a) was placed in 100 [of dioxane] and sodium hydride (57
% (as a dispersion in oil) is added at room temperature under a nitrogen atmosphere (hydrogen evolution is observed).

The reaction mixture containing the N-sodium salt of the compound is incubated for 1 hour and then CICOOCH2CQCN2.4' is added. A white precipitate forms immediately. The reaction mixture was incubated overnight and then poured into 200 ml of water. The aqueous mixture is extracted three times with 250 skin parts each time and the ether extracts are collected and dried over sodium sulfate. The ether is removed in vacuo and the resulting solid is washed with petroleum ether. Dry to give crude N-acylated derivative 10.5
Get the evening. This N-acylated compound has the formula:

Compound B as prepared in step 'c}'b} (5.
0 ml) is dissolved in 50 ml of warm methanol containing 2 drops of concentrated HCl.

The solution was allowed to stand at room temperature for 30 minutes, at which point analysis showed that both tetrahydropyranyl protecting groups had been removed. methanol and HCI are removed in vacuo;
A light yellow solid of 5.0% was obtained. This is fractionated by column chromatography (silica gel; ether) to obtain a pure sample of the title compound. p used in the production of compound A
-Tetrahydropyranylation of fromophenol is carried out as follows: 1 dihydropyran containing 2 drops of concentrated HC1.
Add 10.0 ml of P-furomophenol to 0.5 ml.

(This reaction is exothermic; temperature rises to 35q C). After the addition is complete, the resulting colorless solution is stirred for 50 minutes.
Heat to C, then let cool for 1 hour with candlelight. The solution is extracted with 20% ether (and 10% NaOHIO) on the table. The ether phase is dried over anhydrous NaSO and
Evaporation under reduced pressure leaves an oil behind. 80 parts of ethanol is added to this oil and the resulting ethanol solution is allowed to stand.
The white crystals formed are filtered and dried under vacuum to yield blocked phenol 7.39. The mother liquor is concentrated to half its original volume and allowed to cool. The additional crystals that formed were isolated and the flocculated phenol was further removed.
Get 1 ta. 3 as described in step (a) of Example 1 above.
-(3,5'dimethyl-4-methoxymethoxy-1'
-Phenyl)penz[d]isothiazole-1,1-dioxide is reacted with any selected IJ thium reactant to produce an intermediate having each of the following formulas: and 31(
3'-5'-dimethoxy4'-methoxymethoxy1
'-Phenyl)penz[d]isothiazole-1,1-dioxide is prepared by reacting with the appropriate lithium reagent, namely and, respectively, using the methods described in the previous examples, Each of the above intermediates can be reacted with an acylating agent of the formula (wherein W and Y have the same meanings as above) to produce the corresponding compound, which can be treated with a weak acid to remove the protecting group. , it will be clear that the respective products can be obtained.

Also, in the method described in the above examples, 1-
It will also be apparent that naphthol can be used to generate the corresponding 4-hydroxy-1 naphthyl compounds.

For example, the toxymethyl ether and 2-tetrahydropyranyl ether of 4-furomo-1-naphthol are prepared according to the methoxymethylation and tetrahydropyranylations described above, and then with N-butyllithium as also described above. It is converted into the corresponding 4-lithium derivative by the reaction. This lithium derivative can be reacted with the N-lithium salt of saccharin to produce the corresponding 3-(4'-OP-1'-naphthyl)penz[d]isothiazole-111-dioxide, which can then be used as the selected The corresponding 3-(4'-OP-1'-naphthyl)-3-(phenyl)-2,3-dihydrobenz[d
] Isothiazole-1,1-dioxide can be produced.
If it is desired to produce sulfamnaphthalein, 2,3-dihydro-3-oxonaphtho[1181de]-1.
2-thiazine-1,1-dioxide or its pseudochloride can be used to obtain the corresponding sulfamnaphthalein intermediates and products.

This pseudochloride can be prepared from 3-oxothiazine by reaction with PC15 as described above for the preparation of saccharin pseudochloride. A second group of compounds contemplated by the present invention is a compound in which Z is of the formula:
o is chloro or bromo).

Particular examples of this group of compounds within the scope of the invention are as follows: Compounds of the second group are {a'3-(4'-OP-1'
-phenyl)-3-(phenyl or naphthyl)-2.
3-dihydrobenz[d]isothiazole-1,1-dioxide, where P is a protecting group compatible with the organometallic reagent, and a 'b-acylating agent, where W is chloro or bromo, and HElo is chloro or bromo) in pyridine to produce the corresponding 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxide.

This N-acylated compound is then treated with a weak acid to give a protecting group (
(single or multiple) removal, 3,3-di substitution-2,3
-dihydrobenz[d]isothiazole-1,1-dioxide product. Optionally, the N-acylation step can also be carried out in the order of [a} reacting with an alkali metal hydride to form the corresponding N-alkali metal salt and then reacting with an acylating agent. The following examples further illustrate the invention and are not intended to limit its scope.

Example 1 Preparation of a compound having the following formula: 'a} 2'-tetrahydropyranyl 4-bromophenyl ether (9.0%) in tetrahydrofuran 20%
0.8' of magnesium in 20' of tetrahydrofuran
5. Add dropwise under nitrogen atmosphere.

After the addition is complete, the dispersion is refluxed for 2 hours, and then 1 part* of saccharinpsoid chloride (3.5 hours) is added. An exotherm is seen and the green solution formed turns yellow-brown. The reaction solution was incubated overnight and then slowly added to 500ml of water. The precipitate formed is slowly filtered off and the resulting solid is dissolved in ether, dried and then evaporated to yield a light yellow solid with the formula: {b}'a
} 1.0 μm of the compound prepared in step 1 is placed in 15 μm of dioxane and 0.08 μm of sodium hydride (as a 67% dispersion in oil) is added at room temperature under nitrogen atmosphere.

(Evolution of hydrogen is observed. The resulting mixture containing the N-sodium salt of the above compound is allowed to stand for 1 hour, then 0.342 hours is added.

A white precipitate forms immediately. The reaction mixture was incubated overnight and then poured into 100 ml of water. The white precipitate formed was filtered and extracted with diethyl ether to produce a yellow glass, which was mixed with ligroin (90o -100q
reflux in the brood range). The ligroin is removed by decantation to obtain a solid consisting of an N-acylated derivative of the above compound in which the acyl group is .

{c} Add 10% HCI solution 2' to this solid,
The 1-tetrahydropyranyl protecting group is removed and the resulting orange solid is filtered and dried to yield the product.

The second precipitated product was collected from the water precipitate, filtered and 10%
Treatment with HCI yields an additional 0.5 liters of solid. The mass is collected and fractionated by pre-TLC (silica gel noether) to obtain a pure sample of the title compound. Example 17 Preparation of a compound having the formula: {The title compound is prepared according to the method of Example 16, except that in step b', is used as the acylating agent.

The 2'-tetrahydropyranyl 4-furomophenyl ether used in step 'a} is prepared as follows: Concentrated H
10.5 ml of dihydropyran containing 2 drops of C1 p-
Add Bromophenol 10.0%.

(The reaction is exothermic and the temperature rises to 35 qo).
After the addition is complete, the resulting colorless solution is heated to 50 °C and then allowed to cool for 1 hour under lighting. This solution is extracted with 20% ether and 10% NaOHIO. The ether phase is dried over anhydrous N04 and evaporated under reduced pressure to give an oil. Add 80 units of ethanol to this oil and allow the resulting ethanol solution to stand. The white crystals formed are filtered off and dried in vacuo to yield the blocked phenol 7.3. Concentrate the mother liquor to half its original volume and allow to cool. Further formed crystals are isolated, producing additional blocked phenol 2.1. An intermediate having the formula is prepared as follows: N-(
p-Bromophenyl)morpholine (0.4 pm) is added to 20 ml of tetrahydrofuran (THF) and the solution is allowed to cool to -65 pm. Add 0.69' of 2.4M butyl-lithium in hexane to this solution with stirring and continue stirring for 1 hour. (After 15 minutes the solution becomes cloudy and forms a white precipitate). Add this solution to 3-(
0.5 ml of 3,6-dimethyl-4'-methoxymethoxy1'-phenyl)penz[d]isothiazole-1,1-dioxide is added at -6 ml under nitrogen atmosphere. The resulting reaction mixture is a clear orange-yellow solution. The reaction mixture is incubated for 1 hour, poured into 100 ml of water, made acidic (pH 6) with concentrated hydrochloric acid, and then extracted with ether.
When the ether phase is dried over NSO4 and evaporated,
Oil remains. Add this oil to ligroin (boiling range 30-60
00) and reflux for 1 hour. The white solid formed was collected and the title compound 31(3',5-dimethyl-4'-methoxymethoxy1'-phenyl)-31(
4″-N-morpholinyl-1″-phenyl)-12,3-
0.7 ml of dihydrobenz[d]isothiazole-1,1-dioxide is obtained. 31 (3', 5-dimethyl-4'
-Methoxymethoxy-1'-phenyl)penz[d]isothiazole-1,1-dioxide is reacted with any selected lithium reactant as described in the above method to prepare each intermediate having the following formula: The reactants used are the following compounds: N
-(p-Li-phenyl)tetrahydro-2day・4H-
1,3,6-dioxazosine can be produced by reacting the corresponding p-halophenyl compound with n-butyllithium.

N-(p-halophenyl)tetrahydro-2day・4H-
1,3,6-dioxazosine is produced by reacting p-halo N,N'-di(8-hydroxyethyl)aniline with a certain dihalomethane in the presence of a solid alkali metal hydroxide or its concentrated aqueous solution and a quaternary ammonium salt. Manufactured by The formula used in step {a-a-step above: do.

(i) Dried cloves in a three-frame flask equipped with a mechanical blower, nitrogen inlet tube, and dropping funnel.

Insert Holm 700 top. Immerse the flask in an ice-water bath. Powdered phosphorus pentoxide (300.0mg) is added to the cold chloroform that has been vigorously poured. To this mixture is added a solution of 4-bromo-2,6-dimethylphenol (201.0 μl) in dry dimethoxymethane over 1 hour. During this time, the phosphorus pentoxide powder coalesces into an amorphous mass, making it difficult to disassemble. TLC analysis (on silica gel using 9:1 petroleum ether-ethyl acetate) showed that much unreacted raw phenol was still present.
The temperature of the reaction mixture is increased to about 25 qo. additional 5
Adding 0.0 liters of phosphorus pentoxide to the reaction mixture,
Add every 30-45 minutes until TLC analysis shows no raw phenol present. The organic layer is collected by decantation, washed twice with 250 parts each of 10% aqueous sodium hydroxide, and dried over calcium sulfate.
The solvent is removed under reduced pressure leaving a pale yellow oil. This oil was distilled from 25% of anhydrous potassium carbonate to give 220.0% of 4-furomo-2,6-dimethyl-methylene methoxy phenyl ether as a colorless oil (boiling point 11:0 at 0.5 feet of Hg). obtain. (il) 4-promo-2,6-dimethyl-methylenemethoxyphenyl ether (85.04 min; 0.
347 mol) is dissolved in approximately 800 ml of tetrahydrofuran.

The solution is cooled to -75 oo under nitrogen plunkett and 2.4M n-butyllithium (144.8'; 0.346 mol) in hexane is added dropwise. The addition is completed within 2 hours to obtain a white slurry. (iii) Dissolve saccharin (61.2 mm; 0.334 mol) in dry tetrahydrofuran and allow the solution to cool to about 176 mm.

2.4M n-butyllithium (130.4
[; 0.311 mol) is slowly added dropwise to this cold solution under a nitrogen planket. Prevent the temperature from rising above -70C. The addition is complete in about 9 minutes, resulting in a clear, very pale yellow solution. G's
Add the yellow solution obtained in step (ii) slowly (over 3 hours) to the white slurry obtained in step (ii) while maintaining the temperature at -7000.

During this time the solid disappears giving a clear caramel colored reaction mixture. The solution first becomes gradated in color over time and then becomes progressively lighter. The reaction mixture is allowed to come to room temperature overnight and then treated with 36.0 g of ammonium chloride in 250 g. of water while cooling in an ice-water bath. The organic portion is decanted off and dried over anhydrous calcium sulfate. The solvent is removed under reduced pressure to obtain a pink oil. The oil becomes solid upon exposure to open air. The solid is recrystallized twice from 1-propanol and washed with a 60:40% mixture of petroleum ether-tetrahydrofuran. , followed by drying in vacuo to yield the title compound 68.0 as a white crystalline solid.
3-(3',5-dimethyl-4'-methoxymethoxy1'-phenyl)penz[d]isothiazole-111
-dioxide is also prepared as follows: Magnesium turnings (0.20 evening)
Dry tetrahydrofuran (10-15M) is added to the solution under nitrogen atmosphere.

In this magnesium turnings, 4-bromo-2,6-
Dimethyl-methylene methoxy phenyl ether (2.0
Gradually add the tetrahydrofuran (30ml) solution prepared in the evening above to the mixture while heating. A self-sustaining reaction is observed after approximately 20 minutes of reflux with external heating. Add the remaining phenyl ether solution at a rate that maintains full reaction. Reflux with external heating is continued after the addition is complete, and after about 1 hour the solution is allowed to cool to room temperature and kept under a nitrogen atmosphere. A solution of saccharine pseudochloride (1.89 °C) in tetrahydrofuran (40 °C) is cooled to -7800 °C and the previously made magnesium bromide reagent solution is added dropwise to this pseudochloride solution under a nitrogen atmosphere. . The resulting reaction mixture is allowed to cool for approximately 2 hours and then allowed to stand overnight at room temperature. The reaction mixture is then cooled in an ice-water bath and treated with saturated aqueous ammonium chloride solution. The aqueous solution is extracted several times with chloroform and the combined chloroform extracts are washed with water and dried over anhydrous sodium sulfate and then over anhydrous calcium sulfate. After evaporating the chloroform, a colorless oil is obtained. This is extracted several times with small portions of light petroleum ether, leaving behind a pale yellow sticky tar. Treatment of yellow tar with ether leaves an off-white solid behind. The off-white solid is dissolved in a small amount of chloroform, then treated with carbon black and filtered through Celite. Removal of the solvent gives the title compound as an off-white solid. The product is dried in vacuo in the presence of P2Q. Yield 0.5
20th evening. 3-Chlorbenz[d]isothiazole-1.
1-dioxide (saccharin pseudochloride) is prepared as follows; saccharin 35 and PC1
Heat 543.7 at 170°C for 1.5 hours, during which time complete melting occurs and POC13 begins to reflux.

POC13 is removed under reduced pressure to obtain a crystalline residue. Add diethyl ether to the crystalline residue and stir well. The title compound is collected as white crystals at 12.5 pm (melting point range 1460-14700). 3-(3,5-dimethoxy-4'-methoxymethoxy-1'-phenyl)penz[d]isothiazole-1,1-dioxide is reacted with the appropriate tium reagent, namely and, respectively, according to the procedure described above. Prepare each intermediate having the following formula: 3-(3'.5-
Dimethoxy-4'-methoxymethoxy-1'-phenyl)penz[d]isothiazole-1,1-dioxide is prepared as follows: Using a syringe with an 18 gauge needle, add saccharin (pre-dried overnight at 80 oo in vacuum). 250 ml of dry tetrahydrofuran on the evening of September 16th
n-butyllithium (2.4M in hexane) in solution 20
．． Add 0 and 0 and dropwise at -750 to -17300 under nitrogen atmosphere over 1 hour with rapid stirring.

The reaction solution containing the N-lithium salt of saccharin in tetrahydrofuran is used directly in step (iii) without isolating this lithium salt. (i!) In a dry 1-tuff flask, 4-bromo-216- 13.86 g of dimethoxy methylene methoxy phenyl ether was dissolved in 300 g of dry tetrahydrofuran under a nitrogen atmosphere,
Then n-butyllithium (2.4M in hexane) 20.
83 and add it dropwise at -75o0 while stirring.
After the addition is complete, the reaction solution is heated at -75qC for about 30 minutes. The solution of saccharin lithium salt produced in the Sengawa process was transferred to the addition funnel under nitrogen pressure using a double-tipped needle, and the solution of 4-Li-2 produced in step (ii) was transferred to the addition funnel under nitrogen pressure.
Add to the solution of 6-dimethoxymethylene-methoxyphenyl ether at a temperature of -7500 to -70 oo over a period of about 15 minutes with stirring. -75q of reaction mixture
Warm at 0°C for about 2 hours and then warm to 0°C for 1 hour. GW
Add 5.2 parts of ammonium chloride to the reaction mixture in the side step and 1 part of water.
75 solution was added dropwise and the reaction mixture was transferred to a separatory funnel.

After the two phases have separated, the aqueous phase is collected and the mottling is reduced from about 11 to about 6-7 by dropwise addition of 5% aqueous hydrochloric acid.

(You can see a color change from yellow to colorless). The aqueous phase is returned to the separating funnel and allowed to separate, then the aqueous phase is separated off again and extracted with fresh ether (100M). The ether and tetrahydrofuran/hexane extracts are combined, dried over magnesium sulfate overnight, and filtered to remove the solvent, producing a yellow oil that crystallizes. Ether (
100% of the solution is added, the crystals are ground in a motor with ether, filtered, washed with ether, then petroleum ether and air dried. A second product is collected from the furnace liquor to give a total amount of 13.0 ml of the title compound. 4
- Methoxymethylation of 2,6-dimethoxyphenol is carried out as follows:
into a Z flask under a nitrogen atmosphere, then chloroform (
Add 800 ridges (pre-dried on P205).

The mixture was heated to -15o0 using dry ice-acetone.
Allow to cool to 50° C. and then add 50° C. of 4-furomo-2,6-dimethoxyphenol in 800° C. of dimethoxymethane in 2 portions, maintaining the temperature at -1500° C. or less. 1 part' of concentrated sulfuric acid is added to the resulting reaction mixture and the temperature is then raised to room temperature. During this time, P
2Q sticky tar appears. Heat the reaction mixture for 3 hours. TLC showed the reaction was complete. Decant the chloroform into 10% aqueous sodium hydroxide 400M, mix well, separate the chloroform layer,
Washed with water, dried over Na2S04 and then evaporated to give light tan crystals. Crystallization from n-propanol gives the title compound 32.7 as white crystals (melting point range -10000). An intermediate having the formula: is prepared as follows: 4-bromo 2,6-dimethoxymethylene methoxyphenyl ether is dissolved in 300 g of anhydrous tetrahydrofuran under nitrogen flow.

The solution is allowed to cool to -65 qo during this time some phenyl ether reprecipitates. Add the temperature to -50q
Butyl lithium (2
．． 4M) Add 79'. The resulting solution is -6500
Cool to a temperature and stand for 30 minutes. This solution is heated to -
Add 19 parts of saccharin chloride in two parts so as to maintain the concentration below 40 parts. -6y of reaction solution
Cool to 20°C and stir for 40 minutes. TLC showed one major spot on silica gel using 2 drops of ether 10M/methanol. The reaction solution is poured into 2000 ml of water and acidified to pH 6. These spots change the color of the mixture from orange to yellow. The mixture was extracted twice with ether (2 nights) and the ether solution was washed with water. Dry the ether over sodium sulfate and evaporate to give a light yellow solid. The solid was recrystallized from n-propanol 450
Off-white crystals (melting point range 151.5o -152
．． 5°C) as 3,3-di(3,5-dimethoxy-4'-methoxymethoxy-1'-phenyl)-2,3-dihydrobenz[d]isothiazole-1,1-dioxide 4
Get 2 evenings. Using the method described above, the above intermediate can be reacted with an acylating agent of the formula (wherein W and lo have the meanings given above) to produce the corresponding compound, which can be protected by treatment with a weak acid. It will be clear that the group(s) can be removed to produce the respective product.

The third group of compounds contemplated by the present invention are those in which Z is (However, R9 is defined in formula 1. It is a compound that is as follows.

Particular examples of compounds of the third group are: {a}3-(4'-OP-r-phenyl)-3-(phenyl or naphthyl)-2,3-dihydro Besoz[d]isothiazole-1,1-dioxide (where P represents a protecting group compatible with the organometallic reactant) and [b-acylating agent, ○WGOOR9 (in the formula, W.

chlor or bromo and R9 has the same meaning as above) in pyridine to give 3,3-disubstituted 12,3-dihydrobenz[d]isothiazole-1.
It can be produced by producing 1-dioxide.

This N-acylated compound is then treated with a weak acid to remove its protecting group(s) and 3,3-disubstituted-2,3
-dihydrobenz[d]isothiazole-1,1-dioxide product. Optionally, the N-acylation step can also be carried out in the sequence of 'a) reaction with an alkali metal hydride to form the corresponding N-alkali metal salt and then reaction with an acylating agent. 2,3-dihydronaphtho[1,8-de]-*1,2- as a ring-closing group
Compounds containing thiazine-1,1-dioxide can be prepared using the method described above to prepare 3-(4'-OP-1'-phenyl or 4'
10P-11'naphthyl)-3-(phenyl or naphthyl)-12,3-dihydronaphtho[1.81de]-1
- Manufactured using 2-thiazine-1,1-dioxide. The following examples further illustrate the preparation of this group of compounds. Example 18 Preparation of a compound having the following formula: (a) 2'-tetrahydropyranyl-4-bromophenyl ether (9.0%) in 20% tetrahydrofuran was added to 0% magnesium in 20% tetrahydrofuran.
Add dropwise under nitrogen atmosphere at 85 pm.

After the addition is complete, the dispersion is refluxed for 2 hours and then saccharin butoidochloride (3.5 hours) is added in portions.

An exotherm is seen and the green solution formed turns yellow-brown. The reaction solution was allowed to stand overnight, and then slowly added to 500 ml of water. The precipitate formed is slowly filtered off and the resulting solid is dissolved in ether, dried and evaporated to yield a light yellow solid with the formula:

{b} {Pour the compound produced in step a (1.0 m) into 10 dioxane and add sodium hydride (57 m).
% (as a dispersion in oil) is added at room temperature under a nitrogen atmosphere (hydrogen evolution is slow).

The solution turns from light yellow to greenish and then yellow.
The reaction is accelerated by heating to about 50° C. and then the solution is allowed to cool to room temperature for about 1 hour. Ethyl chloroformate 0 was added to the product solution containing the N-sodium salt of Compound A.
．． Add 18 ml and stir the reaction mixture over the weekend.
{c} To remove the protecting group, the solution was diluted with concentrated HC120
pour it into the '.

After stirring for 15 minutes, the solution turns from pink-red to brown.

The precipitate formed is filtered and dried under vacuum. Crystallization from 1:1 methanol-water gives the title compound as a white solid. Tetrahydropyranylation of P-furomophenol is carried out as follows: concentrated HCl
Add 10.5 drops of P-furomophenol to 10.5 drops of dihydropyran containing 2 drops.

(The reaction is exothermic; temperature rises to 35q0).
After the addition is complete, the resulting colorless solution is heated to 5000 ℃ and then allowed to cool with stirring for 1 hour. Dissolve the solution with 20% ether and 10% NaOHIO*
Ru. The ether phase is dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain an oil. To this oil is added 80% ethanol and the resulting ethanol solution is allowed to stand. The white crystals formed are collected by heating and Dry in vacuo to yield 7.3% of the blocked phenol. Concentrate the mother liquor to 0.5 of its original volume and cool. Isolate the additional crystals that form and further release the blocked phenol. 2
．． Generate 1 data. Examples 19 and 21 Preparation of compounds having the following formulas: Example 19 Example 20 The title compounds were prepared according to the method described in Example 18 above, except that the acylating agents used in step 'b} were and, respectively. do.

An intermediate having the formula: is prepared as follows: (alN-(p-bromophenyl)morpholine (0.4 m) is added to 20' of tetrahydrofuran (THF) and the solution is diluted to -6
Cool to 5qC.

Add 0.6' of 2.4 M butyl lithium in hexane to the solution with stirring and continue to incubate for 1 hour. (After 18 minutes, the solution becomes cloudy and a white lump forms).

Add to this solution 3-(3',5-dimethyl-
4'-Methoxymethoxy1'-phenyl) Penz [d
] Isothiazole-1,1-dioxide 0.5-6
Add under nitrogen atmosphere at 5pm. The resulting reaction mixture is a clear orange-yellow solution. The reaction mixture is incubated for 1 hour, poured into 100 ml of water, acidified (pH 6) with concentrated hydrochloric acid, and then extracted with ether. Etel Phase N
Dry over a2S04 and evaporate to obtain an oil. This oil is taken up in ligroin (boiling range 30-60°C) and refluxed for 1 hour. Collect the white solid that forms to yield 0.7 g of the title compound. 3-(3,5-dimethyl-4
'-Methoxymethoxy1'-phenyl) Penz [d]
By reacting isothiazole-1,1-dioxide with any selected lithium reactant as described above, intermediates having the following formulas are prepared, respectively:
Use each of the following lithium reactants: N-(P-L
i-phevenyl)tetrahydro-nagi-1,3,6-dioxazosine can be prepared by reacting the corresponding P-halofenyl compound with n-butyllithium.

N-(P-halophenyl)tetrahydro 2 days/4H-
1,3,6-dioxazosine is produced by reacting P-haloN,N'-di(8-hydroxyethyl)aniline with certain dihalomethanes, solid alkali metal hydroxides or concentrated aqueous solutions thereof, and quaternary ammonium salts. Manufactured by reacting with 3-(3',5-dimethyl-emethoxymethoxy-1'-phenyl)penz[d]isothiazole-1,1-dioxide having the formula used above is prepared as follows: (i)
2 with mechanical hawking machine, nitrogen inlet pipe and dropping funnel
Pour 700M of dry chloroform into a three-frame flask.

Immerse the flask in ice water. Powdered phosphorus pentoxide (
300.0 minutes) was added to the cold chloroform that had been stirred vigorously. To this mixture was added a solution of 400 g of dry dimethoxymethoxyphenol (201.0 g) over 1 hour. During this time, the phosphorus pentoxide powder coalesces into an amorphous mass, making it difficult to pour. T.L.C.
Analysis (using 9:1 petroleum ether-ethyl acetate on silica gel) showed that much unreacted raw phenol was still present. The temperature of the reaction mixture is increased to about 25 qo. Add an additional 50 increments of phosphorus pentoxide to the reacted reaction mixture every 30-45 minutes until TLC analysis indicates the absence of starting phenol. The organic layer is collected by decantation and washed twice with 250' parts each of 10% aqueous sodium hydroxide, then dried over calcium sulfate. The solvent is removed under reduced pressure to obtain a pale yellow oil. This oil is distilled from anhydrous potassium carbonate to a colorless oil (boiling point 1
4-bromo 2,6-dimethyl-methylene methoxy phenyl ether 220.0 as 1 year old C/0.5 willow Hg)
Get the evening. {ii) 4-bromo 2,6-dimethyl-methylene methoxy phenyl ether (85.04 m; o
．． 347 mol) is dissolved in approximately 800 ml of tetrahydrofuran.

The solution was cooled to -7500 under nitrogen Plunkett and 2.4M n-butyllithium (144.8
0.346 mol) is added dropwise. The addition is completed within 2 hours to obtain a white slurry. Saccharin (61.2 kg; 0.334 mol) is dissolved over 600 ml of dry tetrahydrofuran and the solution is cooled to about 175 qo.

2.4M n-butyllithium in hexane is slowly added dropwise to the cooled solution under a nitrogen blanket. Do not raise the temperature above -700m. Add about 9
Completes in 0 minutes, producing a clear, very pale yellow solution. The yellow solution obtained in the (llll} step of Q is (ii
Add slowly (over 3 hours) to the white slurry obtained in step ) while maintaining the temperature at -7000.

During this time the solids disappear and a clear caramel colored reaction mixture forms. It first becomes clearer over time, and then gradually becomes brighter. The reaction mixture is allowed to rise to room temperature overnight and then treated with 36.0 g of ammonium chloride in 250 g of water while cooling in an ice-water bath. The organic part is collected by decantation and dried over anhydrous calcium sulfate. The solvent is removed under reduced pressure to obtain a pink oil. Oil becomes solid when left in the open air. The solid is recrystallized twice from 1-propanol, washed with a 60:40% mixture of petroleum ether-tetrahydrofuran and dried under reduced pressure to yield the title compound 68.0 as a white crystalline solid. 3-(3,6-dimethyl-4'-methoxymethoxy-1'-phenyl)penz[d]isothiazole-1
1-Dioxide is also prepared as follows: Add dry tetrahydrofuran (10-15 min.) to magnesium turnings (0.20 min.) under a nitrogen atmosphere.

In this magnesium turnings 4-fromo2・6-
Dimethyl-methylene methoxy phenyl ether (2.0
In the evening, gradually add the tetrahydrofuran (30ml) while heating the mixture. A self-sustaining reaction is seen after approximately 20 minutes of external heating to reflux. The remaining solution of phenyl ether is then added at a rate that maintains sufficient reaction. Reflux with external heating is continued after the addition is complete and after 1 hour the solution is allowed to cool to room temperature and kept under nitrogen atmosphere. A solution of saccharine pseudochloride (1.899) in tetrahydrofuran (40 °C) is cooled to -7800, and a previously prepared solution of magnesium bromide reagent is added dropwise to this pseudochloride solution under a nitrogen atmosphere. . The resulting reaction mixture is kept cold for about 2 hours and then kept overnight at room temperature. The reaction mixture is then cooled in an ice-water bath and treated with saturated aqueous ammonium chloride solution. The aqueous solution is extracted several times with chloroform and the combined chloroform extracts are washed with water and dried over anhydrous sodium sulfate and then over anhydrous calcium sulfate. After removing chloroform,
A colorless oil is obtained. Extraction of this oil with a small portion of light petroleum ether leaves behind a pale yellow sticky tar. The yellow tar is treated with ether to give an off-white solid. Dissolve the off-white solid in a small amount of chloroform,
Treated with carbon black and then furnaced through Celite. Evaporation of the solvent gives the title compound as an off-white solid. The product is dried in vacuo in the presence of P2Q. Yield 0.520 evening. 3-Chlorbenz[d]isothiazole-1,1-dioxide (saccharin psoid chloride) is prepared as follows: saccharin 35 and PC1543.7 are mixed in 1. Morning time 1
Heat to 70°C.

During this time complete dissolution occurs and POC13 begins to reflux. POC13 is removed under reduced pressure to obtain a crystalline residue.
Add diethyl ether to the crystalline residue and stir well. Collect the title compound as white crystals. 12.5 nights (melting point range 1460-147°C).

N-(P-bromophenyl)morpholino having the formula is prepared as follows: 25 parts of N-phenylmorpholino is dissolved in 200 parts of carbon tetrachloride and stirred well.

To this, add 27.2 ml of N-bromosuccinimide all at once. Generates a fever of 45 qo.

The reaction solution is heated until the temperature begins to decrease and then heated to reflux for 3 hours. TLC using 3/2 petroleum ether on silica gel showed the reaction was complete. The reaction solution is then allowed to cool, the succinimide is removed from the furnace liquor, and the solution is evaporated to produce a yellow solid. The solid is dissolved in 250M ethanol and then allowed to cool to give the title compound 22 as white crystals. 3-(3',5-dimethoxy-4'-methoxymethoxy1'-phenyl)
Intermediates having the following formula are prepared as described above except that penz[d]isothiazole-1,1-dioxide is reacted with the appropriate tium reactant, namely and, respectively: 3-(3,5-dimethoxy- 4-Methoxymethoxy1'-phenyl)penz[d]isothiazole-1,1-dioxide is prepared as follows: (i) Using a syringe with an 18 gauge needle, add saccharin (pre-dried overnight at 80°C under vacuum). 9.16) Add dropwise to a solution of 250' of dry tetrahydrofuran under a nitrogen atmosphere at -7500 and -7300 with rapid stirring over 1 hour.

A reaction solution containing the N-lithium salt of saccharin in tetrahydrofuran was prepared without isolating this lithium salt (
iii} process. (ii) In a dry flask, dissolve 13.86 g of 4-bromo 2,6-dimethoxymethylene methoxyphenyl ether in 300 g of dry tetrahydrofuran under a nitrogen atmosphere, then -
Add 20.83' of n-butyllithium (2.4 M in hexane) dropwise while stirring at 7520 ml.

After the addition is complete, heat the reaction solution at -7500 for about 30 minutes. The solution of saccharin lithium salt produced in the Sengawa process was transferred to the addition funnel under nitrogen pressure using a double-tipped needle, and the 4-Li-2.6 solution produced in the (ii) process
-dimethoxymethylene methoxy phenyl ether at a temperature of -75oo to -70qo over a period of about 18 minutes with stirring. -75q of reaction mixture
Let it stand at 0°C for about 2 hours, then warm it up to 0°C for 1 hour. M ammonium chloride5.

Add 175 ml of water at 2 ml dropwise to the reaction mixture of step (ili) and transfer the reaction mixture to a 1 ml separatory funnel.

After the two phases have separated, the aqueous phase is separated and the pH is lowered from about 11 to about 6-7 by dropwise addition of 5% aqueous hydrochloric acid.

(You can see a color change from yellow to colorless). The aqueous phase is returned to the separating funnel and the phases are separated, then the aqueous phase is separated again and extracted with fresh ether (100'). The ether and tetrahydrofuran/hexane extracts are combined, dried over magnesium sulfate overnight, filtered, and then the solvent is removed, leaving a yellow oil that crystallizes. Ether (1
00M) and the crystalline material is ground in a motor under ether, filtered, washed with additional ether, **then washed with petroleum ether and air dried. A second crop of product is collected from the filtrate to give the title compound in a total yield of 13.0 ml. Methoxymethylation of 4-furomo-216-dimethoxyphenol is carried out as follows: 300 g of P205 is added to a flask under a nitrogen atmosphere, then 800 g of chloroform (pre-dried over P205) is added to the flask.
Add.

The mixture was cooled to −1500°C in a dry ice acetone bath and then diluted with 4-furomo-1 in dimethoxymethane 800°C.
Add 50 ml of 2Q6-dimethoxyphenol over 25 minutes while maintaining the temperature at -15 qo or less. One drop of concentrated sulfuric acid is added to the resulting reaction mixture, and the temperature is then raised to room temperature. During this time, a sticky mass of P24 appears. The reaction mixture was incubated for 3 hours. TLC showed the reaction was complete. 10% chloroform solution
Decant into 400 ml of aqueous sodium hydroxide, evaporate well, and separate the chloroform layer, wash with water, dry over Na2SO4, and then evaporate to produce light tan crystals. Addition of n-propanol to the crystalline residue, sieving and filtration affords the title compound 32.7% as white crystals (melting point range 98°-100°). An intermediate having the formula is prepared as follows: 4
-Furomo-2,6-dimethoxy-methylenemethoxyphenyl ether 55% is dissolved in 300ml of anhydrous tetrahydrofuran under nitrogen flow.

The solution is allowed to cool to -65 qo, during which time some of the phenyl ether reprecipitates. Set the temperature to -50
butyl lithium (2
．． 4M) Add 79'. The resulting solution is cooled to -65°C and allowed to incubate for 3 minutes. The temperature of this solution is -40
Add 190% of saccharine chloride in two parts to maintain the concentration below 0.000 m. The reaction solution is cooled to -65°C and stirred for 40 minutes. TLC using 10 drops of ether/2 drops of methanol on silica gel showed one major spot. The reaction solution is poured into 2000 ml of water and then acidified to pH 6. At this pH the color of the mixture changes from orange to yellow. The mixture was diluted with ether (2
Extract twice in the evening) and wash the ether with water. Dry the ether over sodium sulfate and evaporate to yield a bright yellow solid. The solid was recrystallized from 450 cores of n-propanol to give off-white crystals (melting point range 151.5
The title compound 42 is obtained as (o-152.500). Using the above examples, the above intermediate can be reacted with an acylating agent of the formula (wherein W and R9 have the same meanings as above) to produce the corresponding compound, which can be treated with a weak acid to It will be clear that the protecting group(s) can be removed to give the respective product.

The fourth group of compounds contemplated by the present invention includes Z (wherein RII is as defined in Formula 1)
It is a compound that is

Particular examples of compounds of the fourth group according to the invention include the following compounds: compounds of the fourth group are 'a)3-(4'-OP-1
'-phenyl)-3-(phenyl or naphthyl)-2
-3-dihydrobenz[d]isothiazole-1,1-dioxide (where P is a protecting group compatible with the organometallic reagent) and {b}acylating agent, (wherein W is chlor or prom) , and RII has the same meaning as above) in pyridine to produce the corresponding -3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxide. .

The N-acylated compound is then treated with a weak acid to remove its protecting group or groups to produce a 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxide product. Optionally, this N-acylation is achieved by reacting with an alkali metal hydride to form the corresponding N-acylation.
-The sequence of forming the alkali metal salt and then reacting with the acylating agent can also be carried out. The following examples further illustrate the preparation of this group of compounds.

Example 21 Preparation of a compound having the formula: (a} N-(P-fromophenyl)morpholine (0.
Add 20% of tetrahydrofuran (THF) to 20% of tetrahydrofuran (THF) and allow the solution to cool to -6yo.

Add 0.69' of 2.4 M Ptyrrhizum in hexane to the solution while stirring and continue the rope worship for 1 hour. (15
After a few minutes, the solution becomes cloudy and a white precipitate forms).
This solution was added with 3-(3,5-dimethyl-4'-methoxymethoxy-1'-phenyl)penz[d
] Isothiazole-1,1-dioxide 0.5-6
Add under nitrogen atmosphere at 500 ml. The resulting reaction mixture is a clear orange-yellow solution. The reaction mixture is heated for 1 hour, poured into 100 ml of water, acidified (pH 6) with concentrated hydrochloric acid, and then extracted with ether. The ether extract is dried over Na2S04 and evaporated to give an oil. This oil is placed in ligroin (boiling range 30-60 pm) and refluxed for 1 hour. Collect the white solid that forms,
3-(315-dimethyl-4'-methoxymethoxy-1'-phenyl)-3-(4''-N-morpholinyl-1''-phenyl)-2,3-dihydrobenz [d] having the formula:
0.7 kg of isothiazole-1,1-dioxide is obtained.

{b} {Dissolve the compound (0.W) produced in step a' in one ounce of pyridine in a nitrogen atmosphere, and add 0.11 ounces of ``to this pyridine solution.

A white lees is formed.

The resulting reaction solution is gently heated (total heating time 1 hour), then poured into 100ml of water and extracted with chloroform. The chloroform phase is dried over anhydrous Na2S04 and evaporated to obtain a solid. The resulting solid has the formula:
N-acylated compound having 3-(3,6-dimethyl-4'-methoxymethoxy1'-phenyl)-3-(
4″-N-morpholinyl-1″-phenyl)-2-(acetyl)-2,3-dihydropenz[d]isothiazole-1,1-dioxide.

[c'' The compound obtained in step b- is dissolved in 25 ml of methanol, acidified with concentrated hydrochloric acid, and then refluxed for 2 hours.

Evaporation of the solution leaves a tan solid. When this sample is dried on silica gel 1000 to TLQ using ether, it exhibits colored bands. The color band is removed, washed with acetone, filtered, and the acetone removed to produce gum. Add table to the gum and reflux the resulting solution to obtain a white solid. This is isolated to give the title compound. 'a' above
} 3-(315-dimethyl-4'-methoxymethoxy-1'-phenyl) penz having the formula used in step;
d] Isothiazole-1,1-dioxide is prepared as follows: (i) In a 2-3 flask equipped with a mechanical lamp, nitrogen inlet tube and dropping funnel, add 700 ml of dry chloroform. put in.

Immerse the flask in an ice water bath. Powdered phosphorus pentoxide (3
Stir vigorously and add to the cooled chloroform. To this mixture was added 4-furomo-2,6-dimethylphenol (201.0 ml) of dry dimethoxymethane.
00 solution over 1 hour. During this time,
The phosphorus pentoxide powder will coalesce into an amorphous mass, making it difficult to assemble. TLC analysis (9:1 petroleum ether-ethyl acetate on silica gel) showed that much unreacted raw phenol was still present. Increase the temperature of the reaction mixture to about 25 oo. Add an additional 5 increments of phosphorus pentoxide to the reacted reaction mixture every 30-45 minutes until TLC analysis shows the absence of starting phenol. The organic layer is collected by decantation, washed twice with 250 parts each of aqueous 10% sodium hydroxide, and then dried over calcium sulfate.
The solvent is removed under reduced pressure to obtain a pale yellow oil. This oil was distilled from 25 ml of anhydrous potassium carbonate to produce a colorless oil (boiling point 0.5
220.0 of 4-bromo 2,6-dimethyl-methylene methoxyphenyl ether was obtained as 11 was ○) at side Hg. (ii) 4-bromo 2,6-dimethyl-methylene methoxy phenyl ether (8504; 0.34
7 mol) is dissolved in about 800 ml of tetrahydrofuran.

The solution was cooled to −75° C. under nitrogen Plunkett and diluted with 2.4 M n-butyllithium (144.8
;0.346 mol) is added dropwise. The addition is complete within 2 hours and a white slurry is obtained. Saccharin (61.2 mm; 0.334 mol) is dissolved in 600 ml of dry tetrahydrofuran and the solution is cooled to about -75°C.

2.4M n-butyllithium (130.4; 0.311 mol) in hexane is slowly added dropwise to the cooled solution under a nitrogen plunket. Do not allow temperature to rise above -70oo. The addition is complete in about 90 minutes, yielding a clear, very pale yellow solution. The yellow solution obtained in step (iii) is slowly added (over 3 hours) to the white slurry obtained in step (ii) while maintaining the temperature at -70 qo.

During this time the solid disappears and a clear caramel colored reaction mixture is obtained. This first becomes darker as time passes, and then gradually becomes brighter. The reaction mixture is allowed to rise to room temperature overnight and then treated with ammonium chloride in 250 ml of water while cooling in an ice-water bath. The organic part is separated by decantation and dried over anhydrous calcium sulfate. The solvent is removed under reduced pressure to obtain a pink oil. This oil becomes solid when left in the open air. The solid is recrystallized twice from 1-propanol, washed with a 60:40% mixture of petroleum-tetrahydrofuran, and dried in vacuo to give the title compound 68.0% as a white crystalline mass. 3-(3,5-dimethyl-4'-methoxymethoxy-
1'-phenyl)-benz[d]isothiazole-1.
1-dioxide is also prepared as follows.

Dry tetrahydrofuran (10-15 kg) is added to magnesium turnings (0.20 kg) under nitrogen atmosphere.

While worshiping this magnesium turnings, 4
- Bromo 2,6-dimethyl-methylene methoxy phenyl ether (2.0%) in tetrahydrofuran (30 ml) is added gently. After approximately 20 minutes of reflux with external heating, a self-sustaining reaction is observed.7 The remaining solution of phenyl ether is then added at a rate that maintains a full reaction.

After the addition is complete, reflux with external heating is continued and after 1 hour the solution is allowed to cool to room temperature and kept under nitrogen atmosphere. A solution of saccharin pseudochloride (1.89 m) in tetrahydrofuran (40 Kite) was cooled to -78°C, and a solution of the magnesium bromide reactant prepared in advance was added dropwise to the pseudochloride solution under a nitrogen atmosphere. Add. The resulting reaction mixture is allowed to cool for about 2 hours and then allowed to stand overnight at room temperature. The reaction mixture is cooled in an ice-water bath and then treated with saturated aqueous ammonium chloride solution. The aqueous solution is extracted several times with chloroform and the combined chloroform extracts are washed with water and dried over anhydrous sodium sulfate and then over anhydrous calcium sulfate. Removal of chloroform yields a colorless oil. This oil is extracted several times with small portions of mauve petroleum ether, leaving behind a pale yellow sticky tar.
The yellow tar is treated with ether to give an off-white solid residue. The off-white solid is dissolved in a small amount of chloroform, treated with carbon black, and then filtered through Celite. Removal of the solvent gives the title compound as an off-white solid. The product is dried in vacuo in the presence of P205. Yield: 0.520 yen. 31 (chlorbenz[d]isothiazole-1,1-dioxide (saccharin psoid chloride) is prepared as follows: saccharin 35 and PC1543.7 are mixed in 1
Heat at 70°C for 1.5 hours.

During this time complete dissolution occurs and POC13 begins to reflux. POC13 is removed under reduced pressure to obtain a crystalline residue. Add diethyl ether to the crystalline residue and stir well. The title compound is obtained as white crystals at 12.5 pm (
melting point range 146°C to 147°C). N-(P-furomophenyl)morpholine having the formula used in step a' above is prepared as follows: 250 mg of N-phenylmorpholine is dissolved in 200 mmol of carbon tetrachloride and stirred well.

To this, add 27.2 grams of N-bromosuccinimide all at once. It generates a fever of 4500℃.

The reaction solution is stirred until the temperature starts to drop and then heated to reflux for 3 hours. 3/2 petroleum ether/on silica gel
TLC with ether showed the reaction was complete. The reaction solution is then allowed to cool, the succinimide is removed by filtration, and the solution is evaporated to produce a yellow solid. The solid product is dissolved over ethanol 250 and allowed to cool to give the title compound 222 as white crystals. Example 22-2
In step 4'a) 3-(3,5-dimethyl-4'-methoxymethoxy-1'-phenyl)penz[d]isothiazole-1,1-dioxide is reacted with a suitable thiium reagent, namely and, respectively, and then { c} process -N・Nji(
A compound having the following formula is prepared according to the method described in Example 21, except that the 2'-tetrahydropyranyl group from the 8-hydroxyethyl)anilino group is simultaneously removed with the methoxymethyl protecting group: Example 22 Example 23 Example 24 Examples 25 and 26 3-(3',6-dimethoxy4'-methoxymethoxy1'-phenyl)-benz[d]isothiazole-1
Formula: Example 2 according to the procedure described in Example 21 except that the 1-dioxide is reacted with the appropriate lithium reagent, namely and
Example 5 Compounds with 26 are prepared.

The 3-(3',5-dimethoxy-4'-methoxymethoxy1'-phenyl)penz[d]isothiazole-1,1-dioxide used is prepared as follows: (i
) Using an 18-gauge needle syringe, inject saccharin (80°C
9. Add 20.0 liters of n-butyllithium (2.0 M in hexane) to 175 qo to 173 qo of a solution of 250 ml of dry tetrahydrofuran (pre-dried overnight under vacuum).
Add dropwise over 1 hour under a nitrogen atmosphere with rapid stirring.

The reaction solution containing the N-lithium salt of saccharin in tetrahydrofuran was prepared without isolation of the lithium salt (ii
i) Used directly in the process. (ii) In a dry 1-glass flask, add 30% of 4-furomo-2,6-dimethoxymethylenemethoxyphenyl ether to dry tetrahydrofuran.
20.83 m of n-butyllithium (2.4 M in hexane) are then added dropwise with stirring at -75 ml.

After the addition is complete, the reaction solution is stirred at -75°C for about 30 minutes. (iii) Transfer the solution of the saccharin lithium salt produced in step (i) to the addition funnel under nitrogen pressure using a double-tip needle, and transfer the solution of the saccharin lithium salt produced in step (ii) to the addition funnel, Add to the solution of methylene methoxy phenyl ether at a temperature of -75o to -170qo over a period of about 15 minutes with stirring. The reaction mixture is heated at -7500 for about 2 hours and then flooded to 0°C for 1 hour. A super solution of ammonium chloride of 5.2 parts and 175 parts of water is added dropwise to the reaction mixture of step q), and the reaction mixture is transferred to a separating funnel.

After the two phases have separated, separate the aqueous phase and reduce its pH to 5%.
It is lowered from about 11 to about 6-7 by dropwise addition of aqueous hydrochloric acid.

(You can see a color change from yellow to colorless). The aqueous phase is returned to the separating funnel, the phases are separated, the aqueous phase is separated again and then extracted with fresh ether (100 ml). The ether and tetrahydrofuran/hexane extracts are combined, dried over magnesium sulfate overnight, oven-heated, and the solvent removed to give a yellow oil that crystallizes. Add ether (100') to the crystalline material, grind the crystalline material with a motor under ether, oven, wash with additional ether, then with petroleum ether, and air dry. A secondary product is collected from the filtrate to give the title compound in a total yield of 13.0 minutes. Methoxymethylation of 4-furomo-2,6-dimethoxyphenol is carried out as follows: 300 g of P205 is added to a flask under a nitrogen atmosphere, followed by 800 g of chloroform (pre-dried over P205). Add.

The mixture was cooled to -150°C in a dry ice-acetone bath and then 50°C of 4-furomo-2,6-dimethoxyphenol in 800°C of dimethoxymethane was added to 250°C, maintaining the temperature at -15Qo or below. Add over a period of minutes. A portion of concentrated sulfuric acid is added to the resulting reaction mixture and the temperature is then raised to room temperature. During this time a sticky mass of P2Q appears. The reaction mixture was incubated for 3 hours. TLC showed the reaction was complete. The chloroform phase was collected by decantation, placed in 400' of 10% aqueous sodium hydroxide, vortexed well, and the chloroform phase was collected separately, washed with water, dried over Na2SO4, and then evaporated to give a light yellow-brown color. Obtain crystals. N-propanol is added to the crystalline residue, stirred and then filtered to give the title compound 32.7 kg as white crystals (melting point range 98° to 100 qo). Example 27 Preparation of a compound having the following formula: 9.5 parts of P-fluoroanisole in 20 parts of dry tetrahydrofuran are added dropwise to 1.2 parts of magnesium turnings in 20 parts of tetrahydrofuran.

12 crystals are added and the mixture is heated to reflux.

After refluxing for 1 hour, the mixture is allowed to cool and 5.0 parts of saccharine chloride is added in portions.

Fever is observed. The reaction mixture is refluxed for 1 hour. water 10
Add 0pan', then add dilute HCI to bring the pH to 5. The mixture is then extracted with ether. The ether extract is dried and evaporated to give a yellow residue. Dissolve the residue in 200ml of methanol and add 2.0ml of carbon black. The methanol solution is filtered and evaporated to give a bright yellow solid. This was dried in vacuum, and 3,3-di(4'-methoxy-1'-phenyl)-2,3-dihydrobenz [
d] 8.5 g of isothiazole-1,1-dioxide are obtained. b) Dissolve 1.0 ml of the compound prepared in step a} in 20 ml of dry dioxane.

Add to this NaHO. C. 12 was added as a 57% dispersion in oil and the solution was concentrated until hydrogen evolution ceased. Additional NaH dispersion is added in portions until no more hydrogen is evolved (approximately 0.05 minutes). The solution was allowed to stand for 1 hour and 0.20% of acetyl chloride was added. The temperature is 2.0 to 27. zu0
rise to Continue the rope worship for 3 hours at room temperature, then slowly add 200 g of water. The white solid formed is filtered off, washed with water and then dissolved in ether. 0.0% solution. State N
Extracted with aOH, dried and then evaporated to give 2-(acetyl)-3,3-di(4'-methoxy-1'-phenyl)-2,3-dihydrobenz[d]isothiazole-1,1-dioxide 0. Get 6 evenings. 'c
} 0.5 parts of the compound prepared in step b) is dissolved in 20 parts of dichloromethane, cooled to 170 parts, and then a solution of 0.5 parts of boron tribromide in 10 parts of dichloromethane is added dropwise.

A red color appears immediately. After addition* is completed (about 10 minutes)
The solution is allowed to reach room temperature, then refluxed for 3 hours, then incubated overnight at room temperature. Water is added and the dichloromethane layer is isolated, dried over sodium sulfate and evaporated to give a solid residue. The solid was extracted with ether and the ether solution was filtered, dried and evaporated to give a pink solid (0.45
generate. Solid to 0. Resigned to the state potassium hydroxide,
Extract with ether and then reacidify the aqueous solution with acetic acid. The solid formed is extracted with ether, the ethereal solution is dried and evaporated to yield the title compound as an egg-white solid. Examples 28 and 29 Preparation of compounds having the following formulas: Example 28 Example 29 {a} 2'-tetrahydropyranyl 4-bromophenyl ether (9.0 mg) in 20 g of tetrahydrofuran was added to 20 g of tetrahydrofuran. Magnesium 0.
85 is added dropwise under a nitrogen atmosphere.

After the addition is complete, the dispersion is refluxed for 2 hours, then saccharine pseudochloride (3.5 hours) is added in portions.
An exotherm is seen and the green solution formed turns yellow-brown.
The reaction solution is concentrated overnight and then 500 g of water is slowly added. The precipitate formed is slowly filtered off and the resulting solid is dissolved in ether, dried and evaporated to yield a bright yellow solid with the formula:

[The compound prepared in step a- is reacted with NaH and then with a suitable acylating agent, namely and, as described in step 'b' of Example 27, and then the N-acylated compound is
The protecting group is removed by treatment with I solution to yield the title compound.

Tetrahydropyranylation of P-bromophenol used in the production of compound A was carried out as follows.
Add 10.5 drops of P-bromophenol to 10.5 drops of dihydropyran containing 2 drops.

(The reaction is exothermic and the temperature rises to 360°C). After the addition is complete, the colorless solution obtained is heated to 50 qO and allowed to cool with stirring for 1 hour. solution in ether 2
Extract with 0.0 and 10% NaOHIO. The ether layer is dried over anhydrous Na2S04 and evaporated under reduced pressure, leaving an oil. Add 80' of ethanol to the oil,
The resulting ethanol solution is allowed to stand. The white crystals formed are filtered and dried in vacuo to yield the blocked phenol 7.3. Concentrate the mother liquor to half its original volume and allow to cool. The additional crystals that formed were isolated, yielding an additional 2.1 taters of blocked phenol. Example 3
Preparation of a compound having the formula: The title compound is prepared according to the method described in Examples 28 and 29, except that the acylating agent used is.

Examples 31-37 Preparation of compounds having the formula: Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 Example 37 3-(3'
The title compounds are prepared by reacting 5-dimethyl-4'-methoxymethoxy-1'-phenyl)penz[d]isothiazole-111-dioxide with the selected aryllithium reagent.

The lithium reactants used are as follows. and the obtained 3,3-disubstituted-2,3-dihydrobenz[d
] Isothiazole-1,1-dioxide is then reacted with NaH and in sequence as described in Example 27 to give the corresponding intermediate.

This intermediate is then treated with dilute hydrochloric acid to remove the protecting group and yield the title compound.

Example 38 Following the method described in Examples 28 and 29, but using as the acylating agent, a compound having the formula is prepared.

An intermediate having the formula Produced according to the method described in Example 21, except for the respective reactions.

N-(P-Li-phenyl)tetrahydro-2day・'H
-1,3,6-dioxazosine can be produced by reacting the corresponding P-halophenyl compound with n-butyllithium.

N-(P-halophenyl)tetrahydro-plaque・4H-1
・316-dioxazosine is P-halo N・N′-di(
8-Hydroxyethyl)aniline is prepared by reacting certain dihalomethanes with solid alkali metal hydroxides or concentrated aqueous solutions thereof and quaternary ammonium salts. An intermediate having the formula: is prepared as follows: 4-fromo-
2,6-dimethoxymethylene methoxyphenyl ether is melted on a 300 ml tabletop of anhydrous tetrahydrofuran under nitrogen flow.

The solution is allowed to cool to -65°C, during which time some of the phenyl ether reprecipitates. To this was added 79' of butyl lithium (2.0 M in hexane) at a temperature of -50 oo.
Add at a speed that maintains the temperature. The resulting solution is cooled to -6500 and then heated for 3 minutes. The temperature of this solution is -
Add 19 parts of saccharinpsoid chloride in two parts to maintain the pH below 4,000. The reaction solution was heated to -65
Allow to cool to qo, then sauté for 4 minutes. TLC was performed on silica gel using 10 drops of ether/2 drops of methanol.
The main spots are shown. The reaction solution is poured into 2000 Z of water and acidified to pH 6. The color of the mixture is this p
H changes from orange to yellow. Pour the mixture into ether (
2) Extract twice and wash the aqueous solution with water. The ethereal solution is dried over sodium sulfate and evaporated to leave a bright yellow solid. Solid with n-propanol 450'
Recrystallized from
．． 50-152.5qo) to obtain the title compound 42. Using the methods described in the previous examples, the above intermediate can be reacted with an acylating agent of the formula, in which W and RII have the same meanings as above, to produce the corresponding compound, which can be reacted with a weak acid It will be clear that the protecting group can be removed by treatment to generate each product.

The physical property data of the compounds produced in each of Examples 1 to 38 are shown below.

As mentioned above, the compounds according to the invention are useful as photographic optical filter agents and filter agent precursor compounds.

Generally speaking, these compounds have a certain alkaline p
In the presence of H or higher base, the colorless to colored compound is converted by removal of the ionizable proton from the -OH functionality of the 4'-hydroxyphenyl group with ring opening of the sulfur phthalein. Ru.

The colored compound formed in the presence of a base undergoes irreversible oxidation of the 2-substituent of the sulfamphthalein ring after a predetermined period of contact with the above base at a constant alkaline pH, usually pHI 0 or higher. The cleavage turns into a new compound that is virtually colorless. The new compound produced, with a different substituent at the 2-position of the sulfamphthalein ring, is not only different from the previous colored compound, but also changes in pH to either the colored compound or the colorless precursor compound. is also irreversible. Compounds that operate in this manner include all of the first to second groups of compounds.

However, certain groups of the remaining compounds, namely Groups 3-4, fall within the scope of compounds that act as traditional pH-sensitive dyes. That is, these compounds have a colorless form below a certain alkaline pH, and in the presence of a base above this alkaline pH they form a light-absorbing form or a colored optical filter agent, which increases the pH. By reducing the pH below the alkaline pH, the color is decolored back to the active, colorless precursor compound. Specifically, compounds of formula 1 in which R9 is lower alkyl or unsubstituted phenyl and RII is a group other than methyl substituted with one or two halo groups;
In compounds of the formula, the colored compound formed becomes colorless by reducing the pH below the above alkaline pH.

The former group, i.e. compounds of the invention which form colored compounds in the presence of a base which become colorless after being in contact with said base for a predetermined period of time, are those described in the aforementioned U.S. Patent Application No. 836,006. are useful in photographic systems; whereas compounds of the latter group of the present invention, i.e., compounds that become colorless by reducing the pH, are disclosed in U.S. Pat.
It is useful in the photographic system described in No. 7437.

To account for the time factor in the former group of compounds that become colorless after being in contact with a base for a predetermined time:
A colored optical filter agent derived from a precursor compound having a group or groups in the 2-position of the benz[d]isothiazole-1,1-dioxide ring has a concentration of about INNaO
3 sand in H, half-life of 14 s and 7 s (ha
lf-life) (TI'2); pens [d]
A colored optical filter agent produced from a precursor compound having an isothiazole-1,1-dioxide group at the 2-position has a half-life (TI/2) of approximately 8.9 sand and 13 seconds at INNaOH, respectively. ; pens [d]
The colored compound produced from the precursor compound having a group in the 2-position of the isothiazole-1,1-dioxide ring has a concentration of about 2. and a colored optical filter agent produced from a precursor compound having a group in the 2-position has a half-life (TI'2) of about 95 and 120 minutes at INNaOH. ).

The term TI/2 refers to the measured time required for half of the colored form to be bleached. Di(3',5-
(3,5-dimethyl-4'-hydroxy-1'-phenyl) as a 3,3-substituent as exemplified by compounds of formula (15). and (4″-morpholino-1″-phenyl),
The spectral absorption characteristics of the colored forms of the compounds formed in alkalinity above PHIO are shown graphically in the accompanying Figures 1 and 2, respectively.

[Brief explanation of the drawing]

Figures 1 and 2 show the spectral absorption characteristics of colored optical filter agents formed in basic solution from colorless precursor compounds having the formulas shown above as [2} and (15). It is a graph. FIG. lFIG. 2

Claims (1)

[Claims] 1 Formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. or a lower alkoxy group, R^3 is a hydrogen atom, R^4 is a hydrogen atom or a lower alkoxy group, R
^5 is hydroxy, lower alkoxy, N(CH_2CH
_2OH)_2, N(CH_2CH_2-Halo)_
2 (However, Halo is a halogen atom), N (lower alkyl)_2, NHCOCH_3, ▲ mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ where R^6 is a hydrogen atom, lower alkoxy or lower alkyl group, and R^7 is a hydrogen atom, lower alkyl, lower alkoxy or hydroxy is a group or R
^6 and R^7 together represent the carbon atoms necessary to complete the fused benzene ring, and Z is ▲There is a mathematical formula, chemical formula, table, etc.▼ or ▲There is a mathematical formula, chemical formula, table, etc.▼ Yes, Y is -CN, -SO_2CH_3, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , Halo is a halogen atom, and R^9 is a lower alkyl group, phenyl or a nitro-substituted phenyl group, and R^1^1 is a lower alkyl group, a halogen-substituted lower alkyl group, or a nitro-substituted or dimethylamino-substituted phenyl group]. 2. The compound according to claim 1, wherein Z is ▲a mathematical formula, a chemical formula, a table, etc.▼ (provided that Y is as defined in claim 1). 3. The compound according to claim 2, wherein Y is -CN. 4 Claim 2 in which Y is -SO_2CH_3
Compounds described in Section. 5. The compound according to claim 2, wherein Y is ▲a mathematical formula, a chemical formula, a table, etc.▼. 6. The compound according to claim 2, wherein Y is ▲a mathematical formula, a chemical formula, a table, etc.▼. 7. The compound according to claim 1, wherein Z is ▲a mathematical formula, a chemical formula, a table, etc.▼ (however, Halo is as defined in claim 1). 8. The compound according to claim 1, wherein Z is ▲a mathematical formula, a chemical formula, a table, etc.▼ (provided that R^9 is as defined in claim 1). 9. The compound according to claim 1, wherein Z is ▲a mathematical formula, a chemical formula, a table, etc.▼ (provided that R^1^1 is as defined in claim 1).