JPS6022706B2 - Method for producing prostaglandin-like compound intermediate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a prostaglandin-like compound intermediate.

More specifically, the present invention describes the general formula [wherein X is an ethylene group (i.e., 1 CQC day 2 -) or a cis-vinylene group (i.e., RI represents a hydrogen atom, or a straight mirror or branched alkyl group having 1 to 12 carbon atoms, and R2 and R3 may be the same or different, but a hydrogen atom or a hydroxyl group) Represents a protecting group, R4 and R5 may be the same or different, and represent a hydrogen atom, a halogen atom, a trifluoromethyl group, or a straight or branched alkyl or alkoxy group having 1 to 4 carbon atoms, and C2 -C3
and the double bond between C, 3 and C, 4 represents a trans (ie, E) double bond].

The object compound of the present invention is a prostaglandin-like compound, especially a compound with a modified side chain and a transnitrocar bond introduced between C2 and C3 of prostanoic acid represented by the formula. It is extremely important as an intermediate.

The general formula of the conventional method [see Samurai Seki No. 52-25745 specification] [wherein R6 represents a straight chain or branched alkyl group having 1 to 4 carbon atoms, and R4 and R5 have the same meaning as above] ] When the target compound represented by the general formula (1) is produced on an industrial scale using the dialkyl phosphonate represented by There is the complexity of having to perform two types of operations in one process.

The present inventors conducted research to eliminate these complications and increase the yield through industrially easy operations, and found that by using the method of the present invention, the objective could be achieved in a single step with a quantitative yield. The present invention was completed by discovering that a compound can be obtained. The present invention relates to - all compounds represented by the general formula (1),
That is, it relates to an optically active "natural type", its mirror image, or a mixture thereof (particularly a racemate consisting of a mixture of equal amounts of the "natural type" and its mirror image).

Preferred RIs in the general formula (1) include a hydrogen atom, or a straight or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. R4 is preferably a hydrogen atom, and R5 is preferably a hydrogen atom, a chlorine atom, or a trifluoromethyl group.

As the protecting group for the hydroxyl group represented by R2 and R3, any group may be used as long as it does not affect other parts of the compound upon removal and can be easily removed under mild conditions.

Examples of such protecting groups include '1) Tetrahydride.

Double ring groups such as pyran-2-yl group, tetrahydrofuran-2-yl group, tetrahydrothiopyran-2-yl group, '2) acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, Acyl group such as fluoroacetyl group, propionyl group, benzoyl group, p-phenylbenzoyl group, naphthyloyl group, '3'
Ether groups such as 1-ethoxyethyl group, 1-methoxy-1-methylethyl group, 1-ethoxycyclohexyl group, 1-methoxy-1-phenylethyl group, (1) trimethylsilyl group, triethylsilyl group, tri-n-butylsilyl group, and rt-butyl group. Examples include Mitaka silyl groups such as dimethylsilyl group, tribenzylsilyl group, and triphenylsilyl group, [5' trityl group, etc.].

Particularly preferred R2 is an acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, or tetrahydropyran-2-yl group, and particularly preferred R3 is a tetrahydropyran-2-yl group. As a preferable compound represented by the killing formula (1) produced by the method of the present invention, '1}(ban・peel・1ban)-(9o・11Q)-9
-(tetrahydropyran-2-yloxy)-111-(
Tetrahydropyran-2-yloxy)-115-oxo-16-phenyl-17,18,19,20-tetranorproster-2,5,13-threnoic acid methyl ester'2) (spot 1 group) -(9Q 11o) -9- Acetoxy (or chloroacetoxy or dichloroacetoxy or trichloroacetoxy or tetrahydropyran-2-yloxy)-111-(tetrahydropyran-2-yloxy)-115-oxo-16-phenylene-17118.
19,20-tetranorprosta-2,13-genic acid methyl ester '3' (square, skin, 1 fine) - (9Q, 11
o)-9-(tetrahydropyran-2-yloxy)-11-(tetrahydropyran-2-yloxy)-15
-Oxo-16-(3-chlorophenoxy)-17.1
8, 19, 20-tetranorprosta-1 2, 5, 13-
Thorenoic acid methyl ester '4} (wave/group 1) - (9o
・11Q)-9-acetoxy (or chloroacetoxy or dichloroacetoxy or trichloroacetoxy or tetrahydropyran-2-yloxy)-11-(tetrahydropyran-2-yloxy)-15-oxo-16
-(3-chlorophenoxy)-17, 18, 19, 20
-Tetranorprosta-2,13-didionic acid methyl ester [5- (bait/skin/1 spot)-(9o/11o)-9
-(tetrahydropyraz-2-yloxy)-11-(
Tetrahydropyran-2-yloxy)-15-oxo-16-(3-trifluoromethylphenoxy)-17
・18, 19, 20-tetranorproster-2, 5, 1
Methyl ester 3-threnoate (6'(spot/1 spot)-(
9Q・11Q)-9-acetoxy (or chloroacetoxy or dichloroacetoxy or trichloroacetoxy or tetrahydropyran-2-yloxy)-11-(tetrahydropyran-2-yloxy)-115-oxo16-(3-trifluoromethylphenylene/oxy) )-17・
18, 19, 20 - Tetranorprosta-2, 13-genic acid methyl ester '7 - (Group, string, 1 paper) - (9
o・11o)-9-(tetrahydropyran-2-yloxy)-11-(tetrahydropyran-2-yloxy)-15-oxo-16-(4-chlorophenoxy)-17.18.19.20-tetranorb Roster-2/5
・13-Thrienoic acid methyl ester '8' (bait, 1 set)
-(9Q・11Q)-9-acetoxy (or chloroacetoxy or dichloroacetoxy or trichloroacetoxy or tetrahydropyran-2-yloxy)-111-(tetrahydropyran-2-yloxy)-115-oxo16-(4-chlorophenoxy) ) 117.18.1
Examples include methylester 9.20-tetranorprosta-2,13-dienoate.

According to the present invention, the compound represented by the general formula (1) is a compound represented by the general formula [wherein all symbols have the same meanings as above] and the compound represented by the general formula [wherein R7 is unsubstituted] R4 and R5 represent a phenyl group (preferably phenyl group) or a lower alkyl group having 1 to 4 carbon atoms (preferably n-butyl group) substituted with a lower alkyl group having 1 to 4 carbon atoms; The transenone compound (1) can be stereospecifically obtained by subjecting the phosphorane compound represented by the following formula to the Wittig reaction.

The reaction is carried out in an inert organic solvent, such as ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxychetane, hydrocarbons such as benzene, toluene, xylene, n-hexane, dialkyl sulfoxides such as dimethyl sulfoxide, N. The reaction is carried out in dialkylformamides such as N-dimethylformamide, halogenated hydrocarbons such as methylene chloride and chloroform, or lower alkanols such as methanol and ethanol at a temperature ranging from 0 to reflux temperature of the solvent. Since the reaction proceeds quantitatively, there is no need for special separation and purification.
If desired, separation and purification may be carried out by conventional separation and purification means, such as force column chromatography, thin layer chromatography, or high performance liquid chromatography. General formula (V
) can be obtained by a series of reactions shown in the following scheme.

In the formula, all symbols have the same meanings as above. figure
The compound represented by the general formula (skin) is prepared by the method of O. Stephenson (OS) [Journal of the Chemical Society (Journal of the Chemical Society)] from the phenols represented by the general formula (W) and epichlorohydrin. Joumal
of the Chemical Society), 15
71 Page (1954)].

The compound represented by the general formula (W) can be obtained by a known method of converting a hydroxyl group into an oxo group in the compound represented by the general formula (W), such as a method using Jones reagent.
The reaction from the compound represented by the general formula (W) to the compound represented by the general formula (V) is described by N. Fimh.
) et al.'s method [The Journal of Organic Chemistry
emist), total volume, 4421 pages (1973)
[Reference] or the method of M. MiyaM et al. [
the Joumal of○r scales IC Chemis
y, vol. 37, p. 1818 (1972) and Chemical Communication (ChemicalComm)
425 (1971)].

Furthermore, according to the present invention, at least one of R2 and R3 represents a hydroxyl group-protecting group, the other represents a hydrogen atom or a hydroxyl group-protecting group, and the other symbols are represented by the general formula (1) having the same meanings as above. The hydroxyl group of a compound represented by the following formula: [wherein at least one of R8 and R9 represents a hydroxyl group-protecting group, the other represents a hydrogen atom or a hydroxyl group-protecting group, and the other symbols have the same meanings as above] A compound represented by the general formula (1) in which R2 and R3 represent hydrogen atoms and other symbols have the same meanings as above, by showing mild hydrolysis to remove the protecting group and convert it into a hydroxyl group, That is, a prostaglandin-like compound intermediate represented by the general formula (in which all symbols have the same meanings as above) is obtained.

Hydrolysis is carried out under alkaline conditions if the protecting group is a protecting group that can be removed under alkaline conditions, or under acidic conditions if the protecting group is a protecting group that can be removed under acidic conditions, or In the case of different protecting groups, they can be carried out in any order.

Hydrolysis under alkaline conditions is carried out using a hydroxide of an alkali metal such as sodium or potassium in the presence of a water-miscible solvent, such as an ether such as tetrahydrofuran, or an alkanol having 1 to 4 carbon atoms such as methanol.
The process is carried out in an aqueous solution of carbonate or hydrogen carbonate at a temperature below room temperature, preferably 0°C, or in an aqueous solution containing 1 to 1 carbon atoms such as methanol.
The process is carried out using an anhydrous carbonate or bicarbonate of an alkali metal, such as anhydrous potassium carbonate or anhydrous potassium hydrogen carbonate, in an anhydrous alkanol under No. 4 at a temperature of 600 DEG to 0 DEG C.

Hydrolysis under acidic conditions can be carried out in an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid or an inorganic acid such as hydrochloric acid or sulfuric acid, preferably miscible with water. watery organic solvent,
For example, the reaction is carried out in the presence of a lower alkaline alcohol such as methanol or ethanol (preferably methanol) or an ether such as 1,2-dimethoxychetane, dioxane or tetrahydrofuran (preferably tetrahydrofuran) at a temperature from room temperature to 75q0, or 1 in the presence of an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid in an anhydrous alkanol such as 2' methanol or ethanol.
It is carried out at a temperature of oo to 45 qo.

Mild hydrolysis is preferably carried out using a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture of dilute hydrochloric acid and methanol, a mixture of acetic acid, water and tetrahydrofuran, or a mixture of p-toluenesulfonic acid and anhydrous methanol. The compound represented by the general formula (W) is
No. 5745, No. 52-36M6, No. 52-85151
No. and specification of No. 52-111547 or Jikai Sho 5
It is obtained by the method described in Japanese Patent No. 3-149955.

The compound represented by general formula (1) obtained by the method of the present invention can be transformed by using the method described in Hakama Seki No. 52-25745, Hakama Seki No. 52-111 I No. -Δ2-Prostaglandin-like compounds can be produced.

Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

In addition, "TLC", "IR" and "
The symbols ``NMR'' represent ``thin layer chromatography'', ``infrared absorption spectrum'', and ``nuclear magnetic resonance spectrum'', respectively, and the proportion of solvent described in the section of separation by chromatography indicates the volume ratio. Reference Example 1 1-chloro-2-hydroxy-3-(3-chlorophenoxy).

A mixed solution of 140 M of pan-chlorophenol, 260 M of epichlorohydrin, and 2.2 M of piveridine was heated at 100°C.
Stir for 3 hours.

Concentrate the reaction solution under reduced pressure. To the residue dissolved in 600 g of chloroform, 200 g of concentrated hydrochloric acid was added dropwise while cooling with water, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by vacuum distillation afforded the title compound 195 with the following physical properties: Boiling point: 14〆 ~ 14
60/5 kite Hg.

TLC (developing solvent, ethyl acetate: cyclohexane = 1:
2): Rf = 0.5 m (liquid film method): Rf = milk 00, 1600, 1480, 12
50 arc-10NMR (CC14 solution): 6=7.35-
655 (wide, m), 4.30-3.54 (thin, m).

Reference Example 2 1-chloro-2-oxo-3-(3-chlorophenoxy)propane. Alcohol dissolved in acetone 11 minutes [
Manufactured according to Reference Example 1] 1165 Jones reagent under ice cooling
Ice 2.1k9, concentrated sulfuric acid 475' and chromium trioxide 52
5. Adjust the temperature to below 5°C] and stir vigorously for 1 hour at 3.0°C.

Add the same amount of Jones reagent to the reaction solution and heat at 30oC.
Stir at night. The reaction mixture is diluted with 30 sleeves of water and extracted with diethyl ether. The extract is washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by vacuum distillation afforded the title compound 750 with the following physical properties. Boiling point: 137 to 14000/2 wind Hg.

TLC (developing solvent, chromatography.

Hexane: ethyl acetate = 2:1): Rf = 0.5 degrees IR (liquid film method): H = 1742, 160 stops, 148 ratios or -1.

NMR (CC14 solution): 6 = 7.50-676 ('days, m), 4.80 (ga, s), 4.40 (2 days, s).
Reference Example 3 (3-chlorophenoxy)acetylmethylene tri-n-butylphosphorane Tri-n-butylphosphine dissolved in 200% of chloroform 41.2 Oxo form [manufactured in Reference Example 2] 44.5 After dripping the evening,
Heat to reflux for 1 hour.

The reaction solution was concentrated under reduced pressure to obtain a crude product of (3-chlorophetoxy)acetylmethyltri-n-butylphosphonium chloride. After washing the crude product dissolved in 1 liter of water with diethyl ether, the solution was dissolved in 0.0 ml of sodium hydroxide aqueous solution.
．． Add 11 ounces of water and stir at room temperature for 20 minutes.

The reaction solution is extracted with diethyl ether, and the extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized by flashing n-hexane to give the title compound 60 as white plate-like crystals having the following physical properties. Eagle points: 500 to 5chi0.

Melon (KBr tablet method): Li = 3975, 3950, 2 total 0
, 160Q15281480141 129 123 stop 106 base NMR (COC13 solution): 6; 7.55-
6.70 (Misaki, m), 4.28 (Ga, S), 3.14 (
IH, d).

Example 1 (Crab/skin/1 group)-(9Q/11Q)-9/
11-bis(tetrahydropyran-2-yloxy)-15-oxo-16-(3-chlorophenoxy)-17
・18, 19, 20-tetranorproster-2, 5, 1
Methyl 3-trienoate chloroform 750'
IQ・4Q-bis(tetrahydropyran-2) dissolved in
-yloxy)-2Q-(6-methoxycarbonylhex-2-trans-5-dienyl)-38-formylcyclobentane [Compound described in Reference Example 1 of Specification of Tokokukan Sho 52-125745] 50 and (3-chloro phenoxy)acetylmethylene tri-n-butylphosphorane [
[Produced in Reference Example 3] was heated under reflux for 6 hours.

Concentrate the reaction solution under reduced pressure. When the residue was purified by silica gel column chromatography using a mixed solvent of cyclohexane and ethyl acetate (3:1) as the eluent, the retention period was 5.
The title compound 63, which had physical properties identical to those described in Reference Example 2 of Specification No. 2-25745, was obtained. Reference example 4 (spot/skin/1 spot) -(9Q/11o)-9,11-dihydroxy-15-oxo-16-(3-chlorophenoxy)-17,18,19,20-tetranorprosta-
2,5,13-Thrienoic acid methylester/bis(tetrahydropyran-
2-yl) ether form [manufactured in Example 1] 7. Add 50 qo of 65% acetic acid aqueous solution to 465 qo and mix with 400 to 45 qo.
Stir the time.

Pour the reaction solution into ice water and extract with ethyl acetate. The extract is washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was used as an eluent in a mixed solvent of ethyl acetate and benzene (2
Purification by silica gel column chromatography using: 1) yielded the title compound 4. with the following physical properties. I was able to obtain a bright spot. TLC (developing solvent, ethyl acetate:benzene = 2:.): Rf = 0.33m (liquid film method): = milk 50
,3100,3050,295017201690,1
66016301600, 1590, 1480144 Roux-1.

NMR (CDC13 solution): 6=7.23-6.65(
thin m), 6.45 (IH, d), 5.80 (IH di
), 5.595.30 (2 days, m), 4.69 (2 days,
s), 4.26-3. (ga, m), 3.70 (thin, s)
.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X is an ethylene group (i.e. -CH_2CH_2
-) or cis-vinylene group (i.e. ▲ mathematical formula, chemical formula,
There are tables etc. ▼ ), R^1 represents a hydrogen atom or a straight or branched alkyl group having 1 to 12 carbon atoms, and R^2 and R^3 may be the same or different, but hydrogen Represents an atom or a protecting group for a hydroxyl group. ] Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. Represents a linear or branched alkyl or alkoxy group having 1 to 4 carbon atoms, and R^7 is a phenyl group having 1 to 4 carbon atoms, which is unsubstituted or substituted with a lower alkyl group having 1 to 4 carbon atoms. Represents a lower alkyl group. ] The phosphorane compound represented by
ig) General formulas characterized by being subjected to reactions ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, between C_2 and C_3 and C
The double bond between _1_3 and C_1_4 represents a trans (ie, E) double bond, and all other symbols represent the same meanings as above. ] A method for producing a prostaglandin-like compound intermediate.