JPH025749B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel method for producing prostaglandin E ₁ class useful as a pharmaceutical. More specifically, the present invention relates to a method for producing prostaglandin E ₁ , which is useful as a pharmaceutical, by selectively reducing the double bonds at positions 7 and 8 of Δ ⁷ -prostaglandin E ₁ . Conventional technology △ ⁷ - A reaction system using Raney nickel or zinc-acetic acid is known as a method for reducing the double bonds at the 7 and 8 positions of prostaglandin E class ₁ (Japanese Patent Application Laid-open No.
58-83670). This reaction is an excellent method for producing prostaglandin E ₁ class, which is useful as a pharmaceutical. A particular difficulty with this reaction is that a side reaction in which the carbonyl group at position 9 is reduced tends to occur. Purpose of _the Invention The present inventors have conducted intensive research to find a more advantageous chemical synthesis method for prostaglandin E ₁ class ^. The present invention was achieved by discovering that prostaglandin E ₁ can be easily obtained in high yield by selectively reducing heavy bonds. However, the purpose of the present invention is ^to
The object of this invention is to selectively reduce the double bonds at positions 7 and 8 of prostaglandin E ₁ class to efficiently obtain prostaglandin E ₁ class useful as a pharmaceutical. Structure and Effects of the Invention The manufacturing method of the present invention has the following formula [] [In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and R ² and R ³ are the same or different and represent a hydrogen atom, a tri(C ₁ to C ₇ ) hydrocarbon-silyl group, or a hydroxyl group. It represents a group that forms an acetal bond with an oxygen atom or an acyl group having 2 to 7 carbon atoms, and R ₄ is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted alkyl group having 5 to 7 carbon atoms.
7 represents a cycloalkyl group. Display〓〓 is 7,
Indicates that the double bond at position 8 is in E-configuration, Z-configuration, or both coexist in any proportion. X is an ethylene group (-CH ₂ CH ₂ -) or a trans-vinylene group

Represents [formula]. ] Using an organotin compound to replace the double bond at position 7 of △ ⁷ - prostaglandin E class ₁ , which is a compound represented by, its 15-epi form, its enantiomer, or a mixture thereof in any proportion. The following formula [], which is selectively reduced by [In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ and X are the same as above. ] This is a method for producing prostaglandin E ₁ , which is a compound represented by the following, its 15-epi form, its enantiomer, or a mixture thereof in any proportion. The production method of the present invention is to selectively reduce the double bond to produce prostaglandin E type ₁ using a compound of the above formula [] having a double bond at the 7 and 8 positions as described above. It is. In the above formula [], R ¹ is a hydrogen atom or has 1 carbon number
~10 alkyl groups. Preferred examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, and octyl groups. Particularly preferred as R ¹ are a hydrogen atom and a methyl group. R ² and R ³ are the same or different, and tri (C ₁
~ _C7 ) Hydrocarbon - a silyl group, a group that forms an acetal bond with the oxygen atom of a hydroxyl group, or a group with 2 carbon atoms
~7 acyl groups. As a tri(C ₁ - C ₇ ) hydrocarbon-silyl group,
For example, trimethylsilyl, triethylsilyl, t
-tri(C ₁ -C ₄ ) such as butyldimethylsilyl group
Alkylsilyl; diphenyl(C ₁ -C ₄ )alkylsilyl such as t-butyldiphenylsilyl or tribenzylsilyl is preferred. Groups that form an acetal bond with the oxygen atom of a hydroxyl group include, for example, methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2
-Ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxo-bicyclo [3.1.0 ]hex-4-yl group and the like. Examples of the acyl group having 2 to 7 carbon atoms include acetyl, propionyl, n-butyryl, n-valeryl, caproyl, and benzzoyl groups. Of these,
R ²¹ and R ³¹ are 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-
Methoxy-2-propyl, (2-methoxyethoxy)methyl or 6,6-dimethyl-3-oxa-
2-oxo-bicyclo[3.1.0]hex-4-yl group is preferred. It is to be understood that these silyl groups, groups forming an acetal bond, etc. are hydroxyl group-protecting groups. These silyl groups, groups forming acetal bonds, and acyl groups are easily removed under acidic to neutral conditions. A 2-tetrahydropyranyl group or a t-butyldimethylsilyl group is particularly preferred as R ² and R ³ . R ⁴ is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted alkyl group having 5 to 7 carbon atoms
represents a cycloalkyl group. Unsubstituted carbon number 1
~10 alkyl groups may be linear or branched, such as methyl, ethyl,
Propyl, butyl, n-pentyl, n-hexyl, 2-methyl-1-hexyl, 2-methyl-2
-hexyl, n-heptyl, n-octyl and the like, preferably n-pentyl, n-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl and the like. Substituents for the alkyl group having 1 to 10 carbon atoms include halogen atoms such as fluorine, chlorine, and bromine; methoxy, ethoxy, n-propoxy,
Alkoxy groups such as iso-propoxy, n-butoxy, chloromethoxy, dichloromethoxy, and trifluoromethoxy groups; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and hexyloxycarbonyl groups; cycloalkyl groups such as cyclopentyl and cyclohexyl groups etc. Examples of the unsubstituted cycloalkyl group having 5 to 7 carbon atoms include cyclopentyl and cyclohexyl groups. As a substituent of a C5-7 cycloalkyl group having a substituent,
The same substituents as mentioned above can be mentioned.
R ⁴ is n-pentyl, 2-methyl-1-
Hexyl, 2-methyl-2-hexyl, cyclopentyl, cyclohexyl and the like are preferred. The present invention includes the 15-epi form of the above formula [], their mirror images, and mixtures of these isomers in arbitrary proportions. △ ⁷ -Prostaglandin E ₁ represented by the above formula [] is prepared by, for example, the method described in JP-A-58-83670, and the protected 4- It can be easily obtained from hydroxy-2-cyclopentenone via 7-hydroxyprostaglandin E ₁ class. The Δ ⁷ -prostaglandin E ₁ of the above formula [] has isomers with respect to the double bond (Δ ⁷ ) at the 7th and 8th positions. In other words, they are 7Z body and 7E body,
The present invention includes 7Z form, 7E form and mixtures thereof. The method of the present invention selectively reduces the double bonds at positions 7 and 8 of the above formula [], and prostaglandin E ₁
The purpose is to lead to the same kind. That is, by reacting the compound of the above formula [] with an organic tin hydrogen compound, the corresponding compound of the formula [] can be easily obtained. As the organic tin hydrogen compound, for example, tributyltin hydride, triphenyltin hydride, triethyltin hydride, tripropyltin hydride, etc. are used, and the amount used is usually 1 equivalent to 10,000 equivalents based on the raw material compound []. , preferably from 1 equivalent to 1000 equivalents. The reaction solvent may be an alcoholic solvent or the like if necessary, but a solventless reaction is generally preferred. A free radical initiator may be used to make the reaction proceed smoothly, and α,α'-azobisisobutyronitrile and bis-t-butyl peroxide are mainly used, and the amount depends on the starting materials [ ] It is usually 0.01 equivalent to 10 equivalents, preferably 0.1 equivalent to 1 equivalent.
The reaction temperature is 0°C to 200°C, preferably 30°C to 140°C. After the reaction is complete,
Prostaglandin represented by the above formula []
E ₁ type is separated and purified, for example, by directly subjecting the reaction solution to chromatography. The obtained product may be protected by a known method (EJCorly5, J.Amen, Chem,
Soc, 94 , 6190 (1972) and RFNewton5,
Tetrahedron Lett, 41 , 3981 (1979)). Furthermore, if necessary, the ester group at the 1st position may be hydrolyzed. Such hydrolysis can be carried out, for example, using an enzyme such as pituger vera esterase. Thus, the targeted prostaglandin
E class ₁ is manufactured. The feature of the present invention is that selectively compounds 7, 8
It is a useful method for synthesizing prostaglandin E ₁ , as it involves reducing the double bond in position. Preferred specific examples of such prostaglandin E ₁ (PGE ₁ ) are as follows. (1) PGE ₁ , (2) (17s)-17,20-dimethyl PGE ₁ , (3) (17R)-17,20-dimethyl PGE ₁ , (4) 16,17,18,19,20-pentanol -15-cyclopentyl PGE ₁ , (5) 16,17,18,19,20-bentanol-15-cyclohexyl PGE ₁ , (6) 2,3-dehydro form of the compounds of (1) to (5) (7) Methyl ester of the compounds (1) to (6). The method of the present invention will be explained below with reference to Examples. Reference example dl-7-hydroxy in a 10ml eggplant flask.
PGE ₁ methyl ester (di-THP) 167mg
(0.302 mmol) and 2.5 ml of dry dichloromethane
and 220mg of 4-dimethylaminopyridine
(1.80 mmol) was added. This was cooled in an ice bath, and 70μ (0.90 mmol) of methanesulfonyl chloride was added dropwise. The ice bath was removed and the mixture was stirred at room temperature (24°C) for 11 hours. The reaction mixture was added to 15 ml of saturated aqueous sodium bicarbonate solution, shaken, and extracted with dichloromethane (10 ml x 3). The organic layer is 10% hydrochloric acid,
After washing with a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. Concentrate and disperse with silica gel column chromatography (7 g, hexane: ethyl acetate = 4:1), dl-7,
8 dehydro PGE ₁ methyl ester (di-THP form)
67.4 mg (42%) of methyl ester was obtained. Spectre data Hnmr (CDCl ₃ ) δ: 6.72 (dt.J=7.8, 2.0Hz,
1H), 5.8-5.1 (m, 2H), 4.8-4.5 (m,
2H), 4.3-3.2 (m, 10H), 2.6-2.0 (m,
6H), 0.88 (t, 3H) IR:neat): 1743,
1734, 1653cm ^-1 Mass (75eV, m/e): 534
(M ⁺ ) Example 1 7,8-dehydro PGE ₁ methyl ester 11,15
-Bistetrahydropyranyl ether 19mg
(0.036 mmol), add 0.25 ml of tributyltin hydride and 5 mg of bis-t-butyl peroxide,
Stirred at 100-110°C for 10 minutes. Cool and directly chromatograph on silica gel (3 g, hexane:
Ethyl acetate=5:1→3:1) to obtain 15.2 mg (80%) of PGE ₁ methyl ester 11,15-bistetrahydropyranyl ether. TLC: Rf = 0.41 (hexane: ethyl acetate = 2:
1) IR = (neat): 1743, 905, 860 cm ^-1 NMR (δppm in CDCl ₃ ): 0.89 (t, 3H), 1.04
~1.98 (m, 30H), 1.98 ~ 2.58 (m, 5H),
2.76 (dd, 1H), 3.68 (S, 3H), 3.30~4.35
(m, 6H), 4.70 (m, 2H), 5.42~5.76 (m,
2H) Example 2 7,8-dehydro PGE ₁ methyl ester 11,15
-bis-t-butyldimethylsilyl ether 47mg
After adding 0.75 ml of tributyltin hydride to (0.062 mmol) and adding 10 mg of bis-t-butyl peroxide, the mixture was stirred at 100°C for 10 minutes. The mixture was cooled to room temperature and directly subjected to column chromatography (8 g, hexane:ethyl acetate = 30:1) to obtain 26.4 mg (71%) of PGE ₁ methyl ester 11,15-bis-t-butyldimethylsilyl ether. IR: (neat): 1743, 1253, 835, 774 cm ^-1 NMR (δppm in CDCl ₃ ): 0 ~ 0.2 (m, 12H), 0.89 (S, 18H), 0.7 ~
1.1 (m, 3H), 1.1~3.0 (m, 24H), 3.70 (S,
3H), 3.7-4.4 (m, 2H), 5.4-5.7 (m, 2H) Example 3 (17S)-17,20-dimethyl-2,3,7,8
-DehydroPGE ₁ methyl ester 11,15-bis-
After adding 1 ml of tributyltin hydride to 80 mg of t-butyldimethylsilyl ether and adding 15 mg of bis-t-butyl peroxide, the mixture was stirred at 100°C for 10 minutes. Cool to room temperature and perform direct column chromatography (10 g, hexane: ethyl acetate = 30:
1) and (17S)-17,20-dimethyl-2,3
-DehydroDGE ₁ methyl ester 11,15-bis-
t-butyldimethylsilyl ether 8 mg (10%)
I got it. In this case, a product in which the ketone at position 9 was reduced could not be obtained. NMR; (δppm in CDCl ₃ ) 0 to 0.2 (m, 12H), 0.7 to 1.0 (m, 24H), 0.9
~3.4 (m, 21H), 3.74 (S, 3H), 3.8~4.5
(m, 2H), 5.4-5.8 (m, 2H), 5.84 (brd,
1H, J=16.0Hz), 7.02(dt, 1H, J=16.0,
7.0Hz) Example 4 (17S)-17,20-dimethyl-2,3-dehydro PGE ₁ methyl ester Dissolve 35 mg of 11,15-bis-t-butyldimethylsilyl ether in 2 ml of acetonitrile-47% hydrofluoric acid (20:1) solution. After stirring for 25 minutes, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, overconcentrated, and subjected to silica gel column chromatography to obtain (17S)-17,20-dimethyl-2,3-dehydro PGE ₁ methyl ester 17
mg (yield 72%). NMR (δppm in CDCl ₃ ): 0.7 to 1.0 (m, 6H), 1.0 to 3.2 (m, 23H),
3.72 (s, 3H), 3.8~4.5 (m, 2H), 5.3~6.0
(m, 3H), 6, 96 (dt 1H, J=16.0, 6.8
Hz) Example 5 60 mg (10 μmol) of PGE methyl ester bis-t-butyldimethylsilyl ether in 1 ml of a mixture of tetrahydrofuran-water-acetic acid (1:1:3)
and stirred at room temperature for 48 hours. Toluene was added to the reaction solution, and the solvent was distilled off under reduced pressure to obtain 3.0 mg (3.1 μmol) (80% yield) of PGE ₁ methyl ester as a product. Spectrum data Hnmr (CDCl ₃ ) (δ: 5.6−5.4 (m, 2H); 4.2−
3.8 (m, 2H), 3.63 (s, 3H), 2.7−1.0
(27H), 0.9 (t, J = 7Hz, 3H) IR (neat): 1750cm ^-1 Mass (20eV, m/e) 368 (M ⁺ ) This component was determined by HPLC as (-)-PGE ₁ methyl ester It matched the standard. (WATERS6000A,
JASCO UV IDEC 100, UV210nm, flow rate 1.5
ml/min, 900Psi, solvent: hexane:tetrahydrofuran, column Develosil 100-5)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, R ² and R ³ are the same or different,
Hydrogen atom, tri(C ₁ - C ₇ ) hydrocarbon-silyl group,
Represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group or an acyl group having 2 to 7 carbon atoms, and R ⁴ is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted alkyl group having 5 to 7 carbon atoms. represents a cycloalkyl group. The symbol 〓〓 indicates that the double bond at the 7th and 8th positions is in the E-configuration, the Z-configuration, or both coexist in an arbitrary ratio. X represents an ethylene group (-CH ₂ CH ₂ -) or a trans-vinylene group [Formula]. ], its ¹⁵ -epi form, its enantiomer, or a mixture of them in any _proportion . The following formula [], which is selectively reduced by using a compound, and then subjected to deprotection and/or hydrolysis reaction as necessary. [In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ and X are the same as above. ] A method for producing prostaglandin E type ₁ , which is a compound represented by the above, its 15-epi form, its enantiomer, or a mixture thereof in any proportion. 2. The method for producing prostaglandin E ₁ type according to claim 1, wherein in the above formula [], R ¹ is a hydrogen atom or a methyl group. 3 In the above formula [], R ⁴ is n-pentyl group, 2-methyl-1-hexyl group, 2-methyl-
A method for producing prostaglandin E ₁ according to claim 1 or 2, which is a 2-hexyl group, a cyclopentyl group, or a cyclohexyl group. 4 Prostaglandin E ₁ type according to any one of claims 1 to 3, wherein in the above formula [], R ² and R ³ are a 2-tetrahydropyranyl group or a t-butyldimethylsilyl group. manufacturing method.