JPS6043350B2 - 2-Azaerythrinane derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an 8-oxo-2-azaerythrinane derivative and an acid addition salt represented by the following general formula [1].

However, Y represents O or 1.

), b represents 1 or 2, R1 and R2 are the same or different and represent hydrogen, lower alkoxy, halogen or a hydrogen group, R3 represents hydrogen, lower alkyl, lower alkoxy, halogen, nitro group, or hydroxyl group. represent. However, R2 and R3 may collectively represent tetramethylene.
R4 is hydrogen, lower alkyl, lower alkoxy
/R5 carbonyl, -CH2CH=C5
R6 (here, R5 and R6 are the same or different and represent hydrogen, lower alkyl or phenyl).

), (where m represents 1, 2 or 3.

), (CH2)m--CO-<'C)) m represents 1, 2 or 3, and R7 represents hydrogen, halogen, lower alkyl or lower alkoxy.

), 1(CH2)In1 shopH-(7S\ (here m represents L2 or 3), ゞH2'' 2K8 (here R8 represents hydrogen or lower alkyl), - general formula [■] (In the formula, R9 = benzyl, phenethyl, methyl,
or ethoxycarbonyl group, RlO=ethyl group, n=1
, 2) and the general formula [■]
(wherein R1, R2, R3, Y and = are the same as above) are heated and condensed in an inert organic solvent,
It can be obtained by isolating the condensate or without isolating it by heating under acidic conditions to cause ring closure.
As the inert organic solvent used in the thermal condensation, it is preferable to use a high boiling point solvent such as benzene, toluene, xylene, DMFl dioxane, cellosolve, diglyme, etc., and heat it to reflux with a water remover attached. Next, the ring-closing reaction under acidic conditions is carried out using mineral acids such as sulfuric acid, hydrobromic acid, hydrochloric acid, phosphoric acid, or formic acid, p-toluenesulfonic acid, trichloroacetic acid, triple or 1℃H2 monoconvex-N<7--゛ represents.

Moreover, the second part represents an unsaturated bond or a saturated bond. The present inventors have synthesized a number of azaerythrinane derivatives, and while intensively researching their pharmacological effects, fortunately discovered the remarkable analgesic effect of these compounds and completed the present invention.

The compound of the present invention is a novel compound that has not been described in any literature, has a central nervous system depressing effect, and is useful as a pharmaceutical. The compound of the present invention can be produced by various methods, but organic acids such as oroacetic acid, polyphosphoric acid (PPA), polyphosphoric acid ester (PPE), phosphorus pentoxide, acidic ion exchange resin, etc. can be used alone or in an aqueous solution. It is carried out by heating in an organic solvent.

The reaction temperature is within the range of 30 to 250°C, preferably 80°C.
It is best to carry out the reaction at a temperature of -160°C, and the reaction time ranges from 3 to several hours to achieve the ring-closing reaction. R of general formula [■]
When 9=CO2C2ll5 is used as a raw material, it may undergo partial hydrolysis during the reaction under acidic conditions, and is produced as a mixture of R4=CO2C2H5 and R4=H in general formula [1], so it is neutral. Substances and basic substances must be separated and isolated. However, if either one is desired, it is possible by selecting acidic conditions. General formula [1
] The compound [■] used in the synthesis of ethyl 4-piperidone-3-carboxylate shown below was used as a raw material, and after introducing a mono(CH2)NCO2RlO group at the 3-position, it was hydrolyzed and decarboxylated to form a ketocarboxylic acid. , can be obtained by esterification.

The R9=ethoxycarbonyl compound can be easily obtained by debenzylating the R9=benzyl compound of the formula [■] by reacting it with ethyl chloroformate. R4 in general formula [1]
For substituents other than R9, R4=ethoxycarbonyl and R in the general formula [1] synthesized by the ring-closing reaction
Using 4=benzyl, the former is hydrolyzed under acidic or alkaline conditions to form [1] R4=H form, and the latter benzyl group is reductively eliminated by hydrolysis to form [1') R4=
The above-mentioned [
1') R4 = ethoxycarbonyl body, hydrolyzed in the same manner to obtain [1] R4 = H body, and then this [1') R4
Desired substituents may be introduced using the =H form. Deethoxycarbonylation is preferably carried out under acidic conditions, particularly when heated under reflux in a mineral acid [1,1R4=H form can be easily obtained] . [Alkylation of 1'1R4=H can be easily carried out by general alkylation.

For example, a method is used in which alkyl halides or reactive esters are reacted in the presence of a deoxidizing agent, or aldehydes are reductively alkylated. Aralkylation and allylation can be carried out in the same manner. [1') R4 = 2-benzoylethyl form is obtained by Mannich reaction using acetophenone and formalin, [1) R4 = 3-oxy-3-phenylpropyl form is obtained by reducing the 2-benzoylethyl form obtained by Mannich reaction. can get. [1] R
4=Butyrophenones are produced by ketalizing 3-benzoylpropyl halides to protect the carbonyl group [1]R
It is obtained by reacting with 4=H form and then deketalizing by hydrolysis. [1] R1, R2=H. ．． The R3=nitro compound can be obtained in good yield by nitrating the R1, R2, R3, R4=H form under general nitration conditions. [1] In the formula 2 [one and
It can be easily obtained by acylating and arylating the compound.

Also, 111Y = - fortune telling? The body can also be obtained by a linear ring closure reaction, but it is also easy to methylate the body.

After the ring-closing reaction, [1] A method for converting R4 = benzyl group into another substituent is to react the desired substituent with a halide or its active ester to form a quaternary salt, and then reductive debenzylation. Alternatively, there is a method of debenzylation using thiophenol in an alkaline solution. [1]
A compound in which R1, R2, and R3 are hydroxyl groups can be obtained by demethylating the corresponding -methoxy compound.

Demethylation of the methoxy group can be carried out in a good yield by a conventional method, for example, by heating with hydrobromic acid. If the substituent of R4 undergoes a change under demethylation conditions,
General formula [■] shown below (in the formula, Y...n is the same as above)
The methoxy group of is demethylated to give [■], and then [■
] was substituted with R4 at the N-position under the above alkylation conditions to produce [■
].

However, in order to prevent simultaneous O-alkylation, when using a deoxidizing agent, it is preferable to use a carbonate. A similar method can be used for substituents that do not undergo changes under demethylation conditions.
■] can be obtained. The compound represented by the general formula [1] has two asymmetric carbons (C-5 and C-6 positions), but in the case of the erythrinane skeleton, the ring bond between A and B is a Cis bond during the ring-closing reaction. A. M.O.
ndOn et al. [Ber. ,? , 46 (1965)] demonstrated this in its skeleton synthesis.

Therefore, the compound [1] produced by the same reaction is A/
It is a racemic form of Bcis. Morphine, a typical analgesic, is levorotatory, and morphine-like synthetic analgesics are generally more active when they are levorotatory. In any case, if a racemic compound is optically resolved to obtain an optically active compound, one of the compounds will generally be more active and stronger than the racemic compound. Optically active derivatives of the compound represented by the general formula [1] can also be obtained.

Optical resolution can be easily carried out using optically active organic acids and their salts and fractional crystallization as usual. Optical resolution is possible for each of the formulas [1], but it can also be obtained by a method in which a desired substituent is introduced into the R4 position after resolution of the compound where R4=H in the formula [1] . The compound represented by the general formula [1] obtained as described above can be converted into a crystalline acid addition salt with hydrochloric acid or a physiologically acceptable acid.

The analgesic effect of the compounds of the present invention will be described below.

The method of KOstar et al. [Fed. PrOc. , Tan, 41
2 (1959)], Dd strain male mice (body weight 25-32 years) were used in groups of 6, and 0.6% acetic acid was administered intraperitoneally to 10mtIk9.
The number of ng was measured, and inhibition relative to the control group was used as an index.

In addition, the LD5O value was calculated by Weil's method from the mortality rate 24 hours after administration of each test drug (1.p.) using male Dd mice weighing 23 to 30 da, with 4 mice per group. . These results are shown in Table 1. With these,
The excellent pharmacological effects of the compounds of the present invention are obvious.

Table 2 shows some of the compounds of the present invention.

In addition, the compounds in Table 2 are expressed with the symbols in general formula [1], : means an unsaturated bond unless otherwise specified, and n is the compound number 35 to 42. It is 2 for 8 compounds and 1 for all others.

Further, all of compound numbers 167 to 170 are optically active compounds. Examples related to the production of the compounds of the present invention are listed below.

Example 1 2-benzy-8-oxo-2-azaerythrinane (compound number 1) ethyl 1-benzy-4-piperidone-3
- 2.75y of acetate is dissolved in 20ml of dry benzene, 1.6g of ethyl chloroformate is added thereto, and the mixture is heated under reflux for 2 hours.

After cooling, the reaction solution was washed with water and dried to remove benzene, and the residue was distilled under reduced pressure to obtain ethyl 1-ethoxycarbonyl-4-
Piperidone-3-acetate is obtained. B. p. l4
4 to 80.2 tons Hg gain = 1.70y (75.6%) + TCm-1: 2980, 1700 (shoulder to 1720), 1475, 143゜1380, 134F3s130
&1276, 1237, 118011145.111\
102α760 Ethyl 1-benzyl-4-piperidone-3-acetate 19.3y and 8.5V of β-phenethylamine are placed in an eggplant-shaped flask equipped with a Dean & Stark separator, and 150 mL of toluene is added to the flask.
Add and heat to reflux for an hour.

During this time, H2O distilled out is removed using a separator.
The reaction solution is concentrated and the residue is further heated on an oil bath at 150-60°C for 3 hours. After cooling, polyphosphoric acid (
Add 200y of PPA) and heat and stir on an oil bath at 150'C for 3 hours.

After cooling, the reaction solution was poured into 1.51 g of ice water, neutralized by adding potassium carbonate, and the liberated oil was extracted with CHCl3, washed with water, dried, and CHCl3 was distilled off, and the residue was mixed with Et2O.
Add and heat to dissolve, remove impurities, concentrate the Et2O solution of Oki liquid, and crystallize the residue as HCl salt. Recrystallize from ethanol. HCl salt yield = 19.0q. ．． mp268
゜C (Dec.) IRvl: Rope c! n-1:1700(
5-membered ring lactam) Example 28-Oxo-2-phenethyl-2-azaerythrinane (Compound No. 13) Equimolar amount of 5.8y of ethyl 1-phenethyl-4-piperidone-3-acetate was placed in a two-diameter eggplant-shaped flask equipped with a water remover. 2.49 of β-phenethylamine was added, 50 ml of toluene was added, and the mixture was heated under reflux for an hour.

During this time, distilled water is removed using a separator. The reaction solution was concentrated, and the residue was further heated on an oil bath at 150-60°C for 3
Heat for an hour. After cooling, 70y of polyphosphoric acid was added to the reaction mixture, and the mixture was heated and stirred on a 140°C oil bath for 6 hours. After cooling, the reaction solution was poured into 300n1 of ice water, neutralized with K2CO3, and the liberated oil was extracted with CHCl3, washed with water, dried, and concentrated with C.
HCl3 is distilled off. Et2O is added to the residue to remove insoluble matter, and the Et2O solution is concentrated. 4.5y of residue was obtained, crystallized as hydrochloride, collected, recrystallized from EtOH, yield = 2.6fmp, diluted at 290°C (Dec.).
-1:1680 (5-membered ring lactam) Example 32-methyl? -Oxo 2-Ather B-Homoerythrinane (Compound No. 35) Ethyl β-(1-methyl-4-piperidone-31) propionate 5.0y and 8.9V of β-phenethylamine in an equal molar amount were placed in an eggplant-shaped flask equipped with a Dean & Stark separator. Put it inside and add 1 toluene to it.
Add 50 ml of the mixture and heat under reflux for 1 hour.

During this time, distilled H2O is removed using a separator. The reaction solution is concentrated and the residue is further heated on an oil bath at 150-60°C for 3 hours. After cooling, polyphosphoric acid (PP) was added to the reaction mixture.
A) Add 200y and heat and stir on an oil bath at 140 to 50°C for 5 hours. After cooling, the reaction solution was poured into 1.5e ice water.
Neutralize by adding potassium carbonate and convert the liberated oil to CHC.
After extraction with 13 liters of water, washing with water and drying, CHCl3 was distilled off, Et2O was added to the residue and dissolved by heating to remove insoluble matter. crystal. Sulfate yield = 16.0ymp276eC (De
c. )IRp! :■d-1:1640 (6-membered ring lactam) Example 48-oxo-2-azaerythrinane (compound number 43) (a) 33.5y of 1-benzy-8-oxo2-azaerythrinane hydrochloride was dissolved in 300ml of 30% aqueous ethanol solution. Dissolve 10% Pd-C5. Catalytic reduction is carried out in a normal pressure catalytic reduction apparatus using Oy as a catalyst.

After reduction, the catalyst was removed and the Oki liquid was concentrated under reduced pressure. The remaining hydrochloride salt (Mp24O~2°C) was dissolved in water, neutralized with potassium carbonate, and salted out with common salt to remove the liberated base. Extract with CHCl3, wash with water, dry, and then distill off CHCl3. The residue is crystallized from Et2O and filtered off. Gain = 22.0f,
．． CIRv for mp119-21? ■CM-1:3300
(>NH), 1670 (5-membered ring lactam) (b) On the other hand, 18.0y of ethyl 8-oxo-2-azaerythrinane-2-carboxylate was added to 100ml of concentrated hydrochloric acid.
After heating under reflux for an hour, concentrating under reduced pressure, and recrystallizing the residue from EtOH, the hydrochloride salt was 13.0y (Mp24O~2℃).
can be obtained.

Example 58-Oxo-2-azaerythrinane-2-carboxylate (Compound No. 117) (a) 8.8y of 1-benzy-8-oxo-2-azaerythrinane was dissolved in 50ml of dry benzene and placed in an eggplant-shaped flask.
Add to this 1.2 times the mole of ethyl chloroformate 3.5y
was added dropwise and heated under reflux for 5 hours.

After cooling, the reaction mixture is washed with 10% hydrochloric acid and then with water, and the benzene layer is dried and distilled off. Add 20m of n-hexane to the residue.
Crystallize by adding 1? It is taken and recrystallized from ethyl acetate.
Amount obtained = 7.3mp141~2 or CIRv 翫 ■C7x-1
:1680-1690 (5-membered ring lactam and urethane) (b) 1.28 f of ethyl 3-ethoxycarbonylmethyl-4-piperidone-3-carboxylate and 0.61 da of β-phenethylamine were dissolved in 20 ml of toluene, Heat under reflux for 1 hour in a flask equipped with a water remover.

The reaction solution was concentrated, polyphosphoric acid 15y was added to the residue, and 1
Heat and stir on a 20°C oil bath for 5 hours. After cooling, the reaction solution is poured into 100 cc of ice water, chloroform is added to extract neutral substances, washed with water and dried, chloroform is distilled off, and the residue is crystallized from ethyl acetate and collected overnight. Yield = 1.10q.
．． mp140.5-1.5. The CIR was the same as that obtained in (a) above.

Example 6 2-Methyl-8-oxo-2-azaerythrinane (Compound No. 54) 4.85y of 8-oxo2-azaerythrinane was placed in an eggplant-shaped flask, 2.44y of 37% formalin and 5ml of formic acid were added, and the mixture was heated on a 90°C water bath for 3 hours. After heating for a period of time and cooling, 20 ml of ice water was added to the reaction solution, neutralized with potassium carbonate, the liberated oil was extracted with CHCl3, washed with water and dried, CHCl3 was distilled off, and the residue was converted into hydrochloride and crystallized. Recrystallize from ethanol taken off the coast.

Amount of hydrochloride obtained = 3.3y,. mp216-8C (Dec
．． ) IRvH■o-1: 1700 (5-membered ring lactam) Example 7 2-aryl-8-oxo-2-azaerythrinane (compound number 55) 6.6y of 8-oxo-2-azaerythrinane was dissolved in 50 ml of acetone to form a two-diameter triangle. The mixture is placed in a flask, 4.2 g of potassium carbonate is added thereto, suspended, and 3.6 y of allyl bromide is added dropwise while stirring at room temperature.

After the dropwise addition, the mixture was stirred at room temperature for 1 hour and then reacted at 50°C for 1 hour. The reaction solution was concentrated, Et2O was added to the residue, and the residue was washed with water to remove insoluble materials. The Et2O solution is concentrated and the residue is crystallized as the hydrochloride salt, filtered off and recrystallized from ethanol and ether. Hydrochloride yield = 3.5ymp201~5℃IR
pH d-1: 2500 (>N+H), 1700 (5-membered ring lactam) Example 8 2-cyclopropylmethyl-8-oxo-2-azaerythrinane (compound number 57) 8-oxo-2- in a two-bore flask Add 3.6y of azaerythrinane and 2.2g of cyclopropylmethylbromide, add 30mL of DMF and dissolve, add potassium carbonate and iodopotassium to 60~70g.
Stir for 6 hours on an oil bath at °C.

The reaction solution was concentrated under reduced pressure, water was added to the residue, the insoluble oil was extracted with CHCl3, washed with water, dried, the QHCL3 was distilled off, Et2O was added to the residue, the insoluble matter was removed, and the Oki liquid was removed. The residue (4.05y) was purified by column chromatography (silica gel 100y1 ethyl acetate) to give the base 3.1y, which was crystallized as a hydrochloride, collected and recrystallized from ethanol and ether. Yield = 2.4ymp226.5~8
°C (Dec.) IRvK cell-1:1720 (5-membered ring lactam) Example 9 2-(N●N-dimethylcarbamoylmethyl)-8-oxo-2-azaerythrinane (compound number 58) 8 in a two-diameter Erlenmeyer flask - Add 2.4y of oxo-2-azaerythrinane, dissolve in 30ml of acetone, add 3.0 da of potassium carbonate, and stir at room temperature with N.N.
- Add 1.5y of dimethylchloroacetamide dropwise and stir for an additional hour.

The reaction solution was concentrated, the residue was dissolved in ethyl acetate and washed with water.
Next, extract with 10% hydrochloric acid, neutralize the acidic liquid with potassium carbonate,
The free base was extracted with CHCl3, washed with water, and dried with CHCl3.
3 is distilled off. The residue 3.5y was converted into hydrochloride and crystallized.
Strain and recrystallize from ethanol and ether. Gain = 3
．． 0ymp257C (Dec.)■νK. Sea o-1:2
600 (>N+H), 1682 (5-membered ring lactam), 1
670 (amide) Example 10 8-oxo-2-(3-phenylpropyl)-2-azaerythrinane (compound number 59) In a two-diameter Erlenmeyer flask, add 3.6y of 8-oxo-2-azaerythrinane and equimolar amount of 3-phenylpropyl. Add chloride 2.3y and DM
Dissolve in 30ml of F, add 2.1y of potassium carbonate and 1.0f of potassium iodo, and heat and stir at 100°C for 8 hours.

After cooling, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. Then, 10% hydrochloric acid was added to extract the acid-soluble materials, and the acidic solution was neutralized with potassium carbonate to remove the free materials. CHCl
3, washed with water, dried, and CHCl3 was distilled off. The residue is dissolved in ethyl acetate and passed through a column containing silica gel 25y to remove raw materials. The purified base is crystallized as a hydrochloride salt, collected and recrystallized from T2O over EtOH. Amount obtained = 1.7y,. mp97.5-10 (generation) IRv 翫 α
-1:1692 (5-membered ring lactam) Example 112-cinnamyl-8-oxo-2-azaerythrinane (compound number 60) 1.5y of 8-oxo-2-azaerythrinane was placed in a two-diameter Erlenmeyer flask, and dissolved in 30ml of acetone. Carbonic power l month. After adding 7y of cinnamyl chloride and stirring at room temperature, 0.95y of cinnamyl chloride was added dropwise and the mixture was stirred for 1 hour.

Concentrate the reaction solution and dissolve the residue by adding ethyl acetate.
After washing with water and drying, ethyl acetate is distilled off, the residue is converted into a hydrochloride, crystallized, filtered, and recrystallized from ethanol. Gain = 1
．． 5ymp235~6.5 (Dec.) IRvH?礪
1:1705 (5-membered ring lactam) Example 128-oxo-2-phenacyl-2-azaerythrinane (compound number 61) 4.9 f of 8-oxo-2-azaerythrinane was placed in a two-diameter Erlenmeyer flask, and dissolved in 50 ml of methanol. To this, 2.8 y of potassium carbonate was suspended, 4.0 y of phenacyl bromide was added dropwise under stirring at room temperature, and then 5 y of potassium carbonate was added at room temperature.
After stirring for an hour, the mixture was reacted at 50° C. for 1 hour.

Concentrate the reaction solution, add water to the residue, and remove the insoluble oil with C.
Extract with HCl3, wash with water, dry (MgSO4) and extract with CHC
13 was distilled off, the residue was dissolved in Et2O, 10y of silica gel (for chromatography) was added, filtered, and washed with Et2O. The solution was concentrated, and the residue (5.3y) was converted into a hydrochloride, crystallized, filtered, and recrystallized from ethanol and ether. Gain = 3.3f
．． ．． mp223~3.5℃ (Dec.)■ν2ζo-
1:1696 (5-membered ring lactam, carbonyl) Example 1
3 2-(2-benzoylethyl)-8-oxo-2-azaerythrinane (compound number 62) was placed in an eggplant-shaped flask.
Oxo 2-azaerys 1 linane hydrochloride 7.0g, acetophenone 3.6q and paraformaldehyde 2.7
f, add 100 n1 of ethanol, and heat under reflux for 131 V.

The reaction solution was concentrated, the residue was dissolved in H2O, neutralized with potassium carbonate, extracted with CHCl3, washed with water, dried, and CHCl3 was distilled off. Residue 8.7y was purified by column chromatography (using silica gel 25y1 ethyl acetate solvent), 7.3
The base of y is obtained, crystallized as the hydrochloride salt, filtered off and recrystallized from ethanol and ether. Gain = 5.2f. ．． mp
166.5-7.5℃ 1Rp? ■CM-1:1708(
Carbonyl), 1690 (5-membered ring lactam) Example 14 3-(3-benzoylpropyl)-8-oxo-2-azaerythrinane (Compound No. 63) 8-oxo-2-azaerythrinane 3.6y and 4 were placed in a two-bore Erlenmeyer flask. .4
-ethylenedioxy-4-phenylbutyl chloride 3
．． 4y was added, dissolved in 50ml of DMF', 2.1y of potassium carbonate and 1.0y of potassium iodo were added thereto, and the mixture was heated and stirred on an oil bath at 140°C for 8 hours.

The reaction solution was concentrated under reduced pressure, water was added to the residue, the insoluble oil was extracted with CHCl3, washed with water and dried (MgSO4). HCl3 is distilled off. Next, remove the residue with 50Tn1 of concentrated hydrochloric acid.
The mixture was dissolved in a mixture of 50 ml of ethanol and ethanol, and heated under reflux for 2 hours. The reaction solution was concentrated, the residue was dissolved in ice water, neutralized with potassium carbonate, and the free substances were extracted with CHCl3, washed with water, and dried ( Mg
SO4) Shino? HCl3 is distilled off and the residue is crystallized as a hydrochloride salt, collected and recrystallized from ethanol. Amount obtained = 4.
4 da, Mp232~3℃■ν vibration Nc! n-1:1696
(5-membered ring lactam, carbonyl) Example 15 2-(3-hydroxy 3-phenylpropyl)-8
-Oxo2-azaerythrinane (compound number 67) in an Erlenmeyer flask with 2-(2-benzoyl)-8-oxo2
-Add 2.36y of azaerythrinane and 30y of ethanol
Add NaBH43OOm9 dissolved in m1 and stirring at room temperature.

After stirring at room temperature for 5 hours, the mixture was heated to 50°C and reacted for 1 hour.
The reaction solution was concentrated, the residue was dissolved in CHCl3 and washed with water, and the CHCl3 layer was dried and distilled off. The residue was purified by column chromatography (50 y of silica gel, ethanol) to obtain 1.9 y of an oily base, which crystallized as a hydrochloride. Since it did not crystallize, the solvent was evaporated to dryness to form a powder. Gain =
1.9y (hygroscopicity) Example 16 2-furfuryl-8-oxo-2-azaerythrinane (
Compound No. 69) 8-oxo 2 in a two-diameter Erlenmeyer flask
- Add 2.0g of azaerythrinane and 10ml of acetone.
Dissolved in this and carbonated it for 1 month. After adding 0y and stirring at room temperature, a 1.0v (7) Et2O solution of furfuryl chloride was added dropwise, and the mixture was stirred for one hour at room temperature.

The reaction solution was concentrated, water was added to the residue, and the insoluble oil was extracted with ethyl acetate, washed with water and dried (MgSO,), then the ethyl acetate was distilled off, the residue was converted into a hydrochloride, crystallized, and filtered off. Recrystallize from water + acetone. Amount obtained = 2.5y,. mp215~
20°C (Dec.) IRv resistance d-1: 3500 (crystal water), 1680 (5-shell lactam) Example 17 2-tetrahydrofurfuryru-8-oxo-2-azaerythrinane (compound number 71) Two-diameter triangular Add 8-oxo-2-azae to the flask. Add 2.7 Da of Risurinan,
Dissolve in 15ml of acetone and add 2.0y of potassium carbonate to this.
2.1y of tetrahydrofurfuryl bromide was added dropwise while stirring at room temperature, and the reaction mixture was then heated under reflux for 5 hours.

The reaction solution was concentrated, water was added to the residue, and the insoluble oil was extracted with ethyl acetate. After washing with water and drying (MgSO4), the ethyl acetate was distilled off, and the residue was crystallized as a hydrochloride, collected and recrystallized from ethanol and ether. Yield = 2.0q. ．． m
p230~5 ReC (Dec.) IRv? ? C77l-1
:1690 (5-membered ring lactam) Example 1815-Nitro-8-oxo-2-azaerythrinane (Compound No. 53
) 8.4V of 8-oxo-2-azaerythrinane hydrochloride is placed in a three-bore flask, and 50ml of concentrated sulfuric acid is added to dissolve it.

Cool the reaction solution to 0-5℃ and add 11 nL of concentrated nitric acid while stirring.
Gradually add dropwise. During this time, the reaction temperature is maintained at 5-10°C. After the dropwise addition, stirring was continued at 10℃ for 4 hours, and the reaction solution was poured into ice water for 20 minutes.
Pour into 0ml and neutralize with aqueous ammonia while cooling. The educts are extracted twice with CHCl3, the CHCl3 layer is washed with water and dried, and CHCl3 is distilled off. The residue is crystallized, washed with cold acetone, and recrystallized from acetone. Amount obtained = 8.0y1Mpl6O~2℃, hydrochloride Mp3O8
℃(Dec.)■ν瓢Nc77! -1:3305(>N
H), 1685 (5-membered ring lactam), 1522, 135
0 (-NO2), NMR (CDCl3) δ: 8.41 (
1H1 tablet, J=2.5Hz);Cl4-H1&
11 (1H..d-D,.J=8.5s2.5Hz)C
l6-Hl7.35 (1H1 tablet, J=8.5H
2); Cl7-H Example 19 2-benzyl-8-oxo 11a-propionyl-2
●11a-diaza C-homoerythrinane (Compound No. 138) 2-benzy-8-oxo 2●11a-diaza C-homoerythrinane 60 f is added to 30 da of 11a-diaza C-homoerythrinane and heated on an oil bath at 120°C for 2 hours.

The reaction solution was concentrated under reduced pressure, ice water was added to the residue, the mixture was made alkaline with potassium carbonate, and the free base was extracted with ethyl acetate.
After washing with water and drying, ethyl acetate is distilled off, and the residue is crystallized as a hydrochloride salt, taken overnight, and recrystallized from ethanol. Gain =
27.0y, smp285~94℃(Dec.) [Base Mpl54~5℃) Nail ν2?礪-1: 1700 (5-membered ring lactam), 1650 (amide) Example 20 11a-aryl-2-benzyl-8-oxo 2.11
a-diazer C-homoerythrinane (compound number 139
) 2-benzyru-8-oxo 2.11a diazur C
- 3 m of toluene with 500 m9 of homoerythrinane dried
1 and add 110% sodium amide powder to it.
mg and heated under reflux for 1 hour.

After cooling, 750 m9 of allylpromide was added dropwise, and the mixture was heated and stirred at 60°C for about a minute. After the reaction, the residue is concentrated under reduced pressure, water is added to the residue, and the insoluble oil is extracted with CHCl3, washed with water, dried, and QHCl3 is distilled off. A small amount of the residue is crystallized by adding ethanol, collected, and recrystallized from ethyl acetate. Yield = 250 m9, Mpl46-8°C, hydrochloride (EtOH
Upper T2O) Mp25O~600c (Dec.) ■ν vibration N
c77! -1:1700 (5-membered ring lactam) Example 21
8-oxo 2-phenethyl B-homo 2●11a-
Diazaerythrinane (Compound No. 116) 8-oxo-2-phenethyl-11a-propionyl-B-homo2
・11a-diazaerythrinane hydrochloride 3.0g 45%
Dissolve in 50 ml of sulfuric acid solution and heat under reflux for 50 hours.

After cooling, the reaction solution is neutralized with potassium carbonate, the liberated base is extracted with chloroform, washed with water, dried, and the chloroform is distilled off. The residue is crystallized from ethyl acetate and recrystallized from the same solvent. Amount obtained = 0.501mp177~80°C1 hydrochloride (recrystallized from ethanol-ether) Mp2OO~
5℃ (Dec.) IRv? N-1:3300 (〉NH
), 1670 (lactam ring) Example 22 2-benzyl-15-hydroxy 8-oxo 2-
Azaerythrinane (Compound No. 142) 4.0 g of 2-benzy-15-methoxy-8-oxo-2-azaerythrinane hydrochloride was dissolved in 25 ml of 48% hydrobromic acid and heated under reflux for 2 hours.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding ice water.
The crystals that precipitate as alkaline with aqueous ammonia are taken out and recrystallized from ethanol. Amount obtained = 2.9y1mp2
10~3°CIRv? X↓Cm-1:3180(-0H
), 1650 (5-membered ring lactam) Example 23 17-hydroxy 8-oxo 2-azaerythrinane (compound number 144) 17-methoxy 8-oxo 2-azaerythrinane 3.8y was dissolved in 48% hydrobromic acid 10
mt and heated under reflux for 2 hours.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 15 ml of ice water and made alkaline with aqueous ammonia. Collect the precipitated crystals, wash with water and ethanol, and air dry. Gain = 3.5
y,. mp308°C (Dec.) (recrystallized from ethanol) IRv? Tsunatan -1:340 to 3260 (-0H1
〉NH), 1682 (5-membered ring lactam) Example 24 2-aryl-17-hydroxy-8-oxo-2-azaerythrinane (compound number 147) DM 1.0y of 17-hydroxy-8-oxo-2-azaerythrinane
Suspend in SO3OmL and add 1.0ml of bicarbonate of soda to this.
Add 5y and add allyl bromide dropwise while stirring at room temperature.
Continue stirring at ℃ for 1 hour.

The reaction solution was added to 80 mL of ice water, made acidic with 10% hydrochloric acid, made alkaline with ammonia water, extracted with ethyl acetate, and added 10% NaOH solution to the organic layer to remove alkali-soluble materials.
Extract twice, NaOU? After making the liquid acidic, it was made alkaline with ammonia water, extracted with CHCl3, washed with water and dried with QHCl.
3 is distilled off. The residue (0.95y) was crystallized as a hydrochloride, collected and recrystallized from ethanol and ether. Yield = 0.85y. smp276℃(Dec.)IRpH:
↓C77! -1:3120 (-0H), 1675 (5-membered ring lactam) Example 25 2-aryl 16-(hydroxy 8-oxo 2-
Azaerythrinane (Compound No. 150) 1.0y of 16-hydroxy-8-oxo-2-azaerythrinane was D
Dissolve in MF25mt by heating, let stand to cool, add 1.5V of sodium bicarbonate after cooling, and add 0.50V of allylpromide while stirring at room temperature.
After stirring at room temperature for 1 hour, the mixture was reacted at 40°C for 2 hours.

Concentrate the reaction solution, add water to the residue, extract the insoluble oil with ethyl acetate, add 5% NaOH aqueous solution to the organic layer to extract the alkali-soluble matter, make the alkali solution acidic, and then It is made alkaline with aqueous ammonia, extracted with CHCl3, washed with water and dried, CHCl3 is distilled off, the residue is crystallized with ether, filtered off and recrystallized from ether. Amount of base obtained = 6
70m9, Mp2O3~5 C (hydrochloride Mpl99~2
00℃(Dec.))IRvH? Cm-1: 3400~
2500 (>N+H), 1688 (5-membered ring lagtam) Example 29 Optical resolution of 8-oxo-2-azaerythrinane (compound number 167) L-(+) monotartrate 13.6V and equimolar 8-oxo-2 - 22.0 g of azaerythrinane was heated and dissolved in 350 mt of ethanol and allowed to cool.

After 4 hours, the precipitated crystals are collected and the crude crystals are recrystallized from 700 mt of 90% aqueous ethanol.

Recrystallize a total of three times to obtain 11.7y. Mp223℃
(Dec.) Colorless needle crystals [α] Skin 6 = 85.9D (C =
1.003 kg H2O) Concentrate the first mother liquor and the primary recrystallization mother liquor, dissolve the residue in water, neutralize with potassium carbonate, extract the liberated base with chloroform, wash with water, dry and distill off the chloroform. A residue of 11.29 is obtained. 6.8 y of D-(-) monotartaric acid in an equimolar amount to this crude base was dissolved by heating in 300 ml of 90% aqueous ethanol and allowed to cool. After 4 hours, the precipitated crystals are collected and recrystallized three times from 90% aqueous ethanol in the same manner as above.

Yield: 9.2y. ．． mp2230C (Dec.) Each tartrate salt obtained as above is dissolved in water, neutralized with potassium carbonate, free base is extracted, crystallized and recrystallized from ether.

(10)-8-oxo2-azaerythrinanni yield = 6
．． 1y. ．． mp151~2℃ [α] Bass 3.6=112
．． 80 (C=1.07&ethanol)(-)-8-oxo-2-azaerythnanni yield=5.0y. smp15
1~2EC [α] = Furnace. 6=-112.8. (C=1.
087, ethanol) Example 30 (+)-2-(3-Methyl-2-butenyl)-8-oxo-2-azaerythrinane (Compound No. 168) (+)-8-oxo-2-azaerythrinane (1.50y) in 30mt of acetone Dissolve, suspend 1.70y of potassium carbonate, and add 0.95q of 3-methyl-2-butenyl bromide while stirring at room temperature.
was added dropwise, and then stirred at room temperature for (a) hours.

The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with water, dried, and the solvent was distilled off. The residue is treated with ethanolic hydrochloric acid, crystallized as a hydrochloride salt, collected, and air-dried. Yield = 2.0y1 Recrystallized from ethanol-acetone.
Mp2l9~20°C (Dec.), [α]? =70.
90 (ethanol to C=1.215) (1)-2-(3
-Methyl-2-butenyl)-8-oxo-2-azaerythrinane (1)-8-oxo-2-azaerythrinane is used in the same amount as the above (+) form by reaction and post-treatment in the same manner.

Yield: 2.0y. ．． mp219-20°C (Dec.) Example 31 (+)-2-Cinnamyl-8-oxo-2-azaerythrinane (Compound No. 169) (+)-8-oxo-2-
Dissolve 1.50y of azaerythrinane in 30Tn1 of acetone, suspend 1.70y of potassium carbonate therein,
Add 0.95 g of cinnamyl bromide dropwise while stirring at room temperature,
After that, the mixture was stirred for two hours at room temperature.

The reaction solution was concentrated, the residue was extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off. Add ether to the residue,
Insoluble matter is removed, and ethanolic hydrochloric acid is added to the bottom liquid to crystallize it as a hydrochloride, which is removed. Yield = 2.0y1 Recrystallized from ethanol. Mp24O~2℃(Dec.), [α
]? =51.00 (C=1.03 surface water) The (-) body is also reacted and post-treated in the same manner as above.

Yield = 1.5y. ．． mp240~2 Logic (Dec.),
[α] Bas 3 = -50.8. (C=1.097\H2O)
Example 32 (10)-8-oxo2-phenethyl-2-azaerythrinane (compound number 170) (+)-8-oxo2-
Dissolve 1.5 g of azaerythrinane in 20 mL of DMF,
This includes 1.70y of potassium carbonate and 1.0y of potassium iodide.
y was suspended, 1.20 y of β-phenethylbromide was added dropwise while stirring at room temperature, and stirring was continued for 15 A on an oil bath at 80 to 90°C.

After cooling, pour the reaction solution into ice water, add ethyl acetate and extract.
Wash with water, dry and remove the solvent. The residue is dissolved in ethanol, β-naphthalenesulfonic acid is added thereto and concentrated, and the residue is crystallized, collected, washed with acetone, and recrystallized from acetone. Gain = 2.5f. ．． mp209~12℃,
[α]? = 52.3 7 (ethanol to C = 1.6) (
1) The body is also reacted and post-treated in the same manner as above.

Claims (1)

[Claims] 8-oxo-2- represented by the following general formula [I]
Azaerythrinane derivatives and acid addition salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] However, Y
▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or - (CH
_2) m- (here m represents 0 or 1), m represents 1 or 2, R_1 and R_2
are the same or different and represent hydrogen, lower alkoxy, halogen, or hydroxyl group, and R_3 represents hydrogen, lower alkyl, lower alkoxy, halogen, nitro group, or hydroxyl group. However, R_2 and R_3 may collectively represent tetramethylene. R_4 is hydrogen, lower alkyl, lower alkoxycarbonyl, ▲numerical formula, chemical formula, table, etc.▼(R
_5 and R_6 are the same or different and represent hydrogen, lower alkyl or phenyl. ), ▲Mathematical formulas, chemical formulas, tables, etc.▼(Here m is 1
, 2 or 3. ), ▲Mathematical formulas, chemical formulas, tables, etc.▼(Here m is 1
, 2 or 3, and R_7 represents hydrogen, halogen, lower alkyl or lower alkoxy. ), ▲Mathematical formulas, chemical formulas, tables, etc.▼(Here m is 1
, 2 or 3. ), ▲Mathematical formulas, chemical formulas, tables, etc.▼(R_8 here
represents hydrogen or lower alkyl. ), -CH_2C≡CH, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas,
Represents ▼, which has chemical formulas, tables, etc., or ▲, which has mathematical formulas, chemical formulas, tables, etc. In addition, part (■) represents an unsaturated bond or a saturated bond.