JPH0210152B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing prostaglandin E ₁ . More specifically, the present invention relates to a method for producing prostaglandin E ₁ by denitrating 6-nitroprostaglandin E ₁ by radical reduction reaction. Natural prostaglandins are known as local hormones with high biological and pharmacological activity, and therefore many studies have been conducted on effective methods of synthesizing them. Among natural prostaglandins, prostaglandin E ₁ has strong platelet aggregation inhibitory and vasodilatory effects, etc.
Reactions as a drug have been reported one after another. Up until now, many reports have been made regarding the production method of prostaglandin E type ₁ , such as Keiro Terashima et al., Prostaglandin and Related Physiologically Active Products, Kodansha Scientific (1981),
JBBindra et al., Prostaglandin Synthesis,
Although detailed in Academic Press (1977) and other publications, even today there are still effective methods for producing prostaglandin E type ₁ , namely (i) the fact that the starting material can be easily obtained as an optically active substance, and (ii) There is a desire to establish a manufacturing method that takes into account (iii) a short manufacturing process and (iii) a high overall yield. The present invention was developed as a result of intensive research from these viewpoints.
We have discovered that prostaglandin E type ₁ can be easily obtained by denitrating 6-nitroprostaglandin E type ₁ , which is easily available as an optically active form, by a radical reduction reaction, and have arrived at the present invention. It is something. That is, the method of the present invention is based on the following formula [] [In the formula, R ¹ is a hydrogen atom, a C ₁ to C ₁₀ alkyl group,
A 5- to 6-membered alicyclic group or phenyl group,
R ² and R ³ are the same or different and are a hydrogen atom, a tri(C ₁ to _{C 6} ) hydrocarbon-silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R ⁴ is a C ₄ to _{C 6} A linear or branched alkyl group that may contain an oxygen atom, a 5- to 6-membered alicyclic group, or a 5- to 6-membered alicyclic group substituted
Represents a _C1 - _C2 alkyl group. ] 6-nitroprostaglandin E class ₁ , which is a compound represented by the formula, its stereoisomer, or a mixture of any proportion thereof, is reacted with tributyltin hydride in the presence of a radical generator, and if necessary, a deprotection reaction and a reaction are carried out. / or subjected to a hydrolysis reaction. The following formula [] [In the formula, R″ is a hydrogen atom, a C ₁ to C ₁₀ alkyl group,
A 5- to 6-membered alicyclic group or phenyl group,
R ²¹ and R ³¹ are the same or different and are a hydrogen atom, a tri(C ₁ to _{C 6} ) hydrocarbon-silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R ⁴ is a C ₄ to _{C 8} a straight-chain or branched alkyl group that may contain an oxygen atom, 5 to 6
represents a _C1 - _C2 alkyl group substituted with a 5- to 6-membered alicyclic group or a 5- to 6-membered alicyclic group. ] This is a new method for producing prostaglandin E ₁ , which is a compound represented by the following, its stereoisomer, or a mixture of any proportion thereof. The 6-nitroprostaglandin E type ₁ represented by the above formula [] used in the method of the present invention is obtained by conjugately adding an organocopper lithium compound to 4-substituted-eucyclopentenones, which were separately proposed by the present inventors. It can then be easily obtained by a method of reacting a nitroolefin derivative. The manufacturing process is illustrated as follows. In the above formula [], R ¹ is a hydrogen atom, C ₁ to _{C 10}
an alkyl group, a 5- to 6-membered alicyclic group, or a phenyl group. Examples of C ₁ to _{C 10} alkyl groups include methyl group, ethyl group, propyl group, butyl group, t-butyl group, decyl group, etc., but methyl group,
Ethyl group is preferred. Examples of the 5- to 6-membered alicyclic group include a cyclopentyl group and a cyclohexyl group. As R ¹ , a methyl group and an ethyl group are particularly preferred. R ² and R ³ are the same or different, a hydrogen atom,
Represents a tri(C ₁ -C ₆ ) hydrocarbon-silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. Examples of the tri(C ₁ -C ₆ ) hydrocarbon-silyl group include a trimethyl group, a t-butyldimethylsilyl group, a t-butylphenylsilyl group, and a t-butyldimethylsilyl group is particularly preferred. Examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include methoxymethyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group or 6,6-
Dimethyl-3-oxa-2-oxo-bicyclo[3.1.0]hex-4-yl group may be mentioned, but 2-tetrahydropyranyl group is particularly preferred. These silyl groups and groups forming acetal bonds are to be understood as protecting groups for hydroxyl groups. These protecting groups can be easily removed under mildly acidic to neutral conditions after the reaction of the present invention is completed, resulting in a free hydroxyl group, which is the final product useful as a drug. R ⁴ is a linear or branched alkyl group that may contain a C ₄ to C ₈ oxygen atom, a 5- to 6-membered alicyclic group, or a 5- to 6-membered alicyclic group substituted ( _C1 - _C2 ) represents an alkyl group. Examples of the straight chain or branched alkyl group which may contain a C ₄ to C ₈ oxygen atom include a 2-ethoxyethyl group, a pentyl group, a hexyl group, a 2-hexyl group,
Examples include 2-methylhexyl group, heptyl group, octyl group, etc., preferably pentyl group, hexyl group, 2-hexyl group, 2-methylhexyl group, etc. Examples of the 5- to 6-membered alicyclic group include a cyclopentyl group and a cyclohexyl group; examples of the (C ₁ to C ₂ ) alkyl group substituted with a 5- to 6-membered alicyclic group include a cyclopentylmethyl group, a cyclohexylmethyl group, a 2- Cyclopentylethyl group, 2-cyclohexylethyl group, 1-cyclopentylethyl group,
Examples include 1-cyclohexylethyl group. Particularly preferred R ⁴ is a 2-ethoxyethyl group, a pentyl group, a hexyl group, a 2-hexyl group, a 2-methylhexyl group, a cyclopentyl group, a cyclohexyl group, a cyclopentylethyl group, or a cyclohexylmethyl group. In the above formula [], R ¹ is a C ₁ -C ₁₀ alkyl group in which a carboxylic acid is protected as an ester, a 5- to 6-membered alicyclic group, or a phenyl group, and R ² and R ³ is preferably a tri(C ₁ -C ₆ ) hydrocarbon-silyl group in which the hydroxyl group is protected, or a derivative which is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, After the completion of the reaction, the prostaglandin represented by the above formula [] can be obtained by performing a hydrolysis reaction and/or a deprotection reaction.
It may be advantageous to use derivatives of E ₁ class in which R ¹ , R ² , and/or R ² are hydrogen atoms. Also, the above formula []. The prostaglandin derivative represented by [] has non-carbon atoms at the 6th, 8th, 11th, 12th, and 15th positions of the prostaglandin nomenclature, so various stereoisomers exist, but the present invention The method is to convert the natural stereoisomers of these isomers into the formula []. Although illustrated and representative as [ ], the production method of the present invention can be carried out without any problem for all of these stereoisomers and mixtures thereof in arbitrary proportions, and thus includes all cases. Specific examples of the compounds represented by the above formula [] are 01) 6-nitroprostaglandin E ₁ 02) 6-nitro-18-oxaprostaglandin E ₁ 03) 20-methyl-6-nitrostaglandin E ₁ 04) 17,20-dimethyl-6-nitroprostaglandin E ₁ 05) 16,17,18,19,20-pental-15-cyclohexyl-6-nitroprostaglandin
E ₁ 06) 16,17,18,19,20-pental-15-cyclopentyl-6-nitrostaglandin E ₁ 07) 17,18,19,20-tetranol-16-cyclohexyl-6-nitroprostaglandin E ₁ 08) 15-epimers of compounds 01) to 07) Enantiomers of compounds 01) to 08) 10) Methyl esters of compounds 01) to 09) 11) Compounds 01) to 09) Ethyl esters 12) Hydroxyl groups (1 and 15) of compounds 01) to 11)
Examples thereof include ethers in which the t-butyldimethylsilyl group and/or the 2-tetrahydropyranyl group are protected. The manufacturing method of the present invention is represented by the above formula [] 6
-Prostaglandin E ₁ type represented by the above formula [] is produced by reacting nitro prostaglandin E ₁ type with tributyltin hydride in the presence of a radical generator, and subjecting it to deprotection reaction and/or hydrolysis if necessary. be done. Conventionally, techniques for denitration of aliphatic nitro compounds by radical reduction have been reported. for example
N. Kornblum et al., Journal of the American
Chemical Society, 100 , 289 (1978) reported a method using the sodium salt of methyl mercaptan, and Yutsune Kaji et al., Tetrahedron Letters,
22, 1705 (1981), J.Cham.Sos, Chemical
Communication, 33 (1982), and Chemistry
Letters, 1079 (1982) reports a method using tributyltin hydride. However, according to these reports, such denitration reactions proceed only with tertiary nitro compounds or secondary nitro compounds activated by electron-withdrawing groups, and the denitration reaction proceeds only with tertiary nitro compounds or secondary nitro compounds activated by electron-withdrawing groups. It is stated that a secondary nitro compound that is not activated by an electron-withdrawing group as represented by the formula [] is inactive under the conditions of the above cited document, and that the denitration reaction does not proceed. As a result of intensive research aimed at overcoming this difficulty, the inventors of the present invention have found that the denitration reaction of the inert secondary nitro compound of the above formula [] has become possible by using tributyltin hydride under appropriate conditions. be. The reaction conditions will be described below. The amount of tributyltin hydride used in the method of the present invention is expressed by the above formula []6
-0.5 to nitroprostaglandin E class ₁
It is used in an amount of 50 equivalents, preferably 0.8 to 10 equivalents, and more preferably 1.0 to 5 equivalents. In the method of the present invention, a suitable radical generator is used as a reaction aid to initiate the reaction. Radical generators that are normally used as reaction aids in radical reduction reactions using tributyltin hydride are preferably used, such as α,α ¹ -azobisisobutyronitrile, bis-t-butyl peroxide, potassium graphite, etc. Examples include methods using Aito, sodium amalgam, and light irradiation. It is effective to use the radical reaction aid in an amount of 0.05 to 20% by weight, preferably 0.1 to 5% by weight based on tributyltin hydride. The reaction is usually carried out under an inert atmosphere such as nitrogen or argon. The method of the present invention may be carried out using tributyltin hydride itself as a solvent, or a solvent commonly used for reducing tributyltin hydride may be used. As such solvents, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as hexane and heptane, ethers, and ethers such as tetrahydrofuran are preferably used. When using a solvent, for tributyltin hydride
It is sufficient to use 0.5 to 50 times the volume. The reaction temperature varies depending on the reaction aid used and reaction conditions, but is usually 0 to 150°C, preferably 80 to 120°C.
It is carried out in the range of °C. The reaction time varies depending on the reaction conditions such as the amount of reaction aid, tributyltin hydride, and reaction temperature, and the reaction end point is determined by tracking the reaction using thin layer chromatography, etc., but it can take from 0.5 hours at a reaction temperature of 100°C. It will end in 12 hours. After completion of the reaction, prostaglandin E type ₁ represented by the above formula [] can be isolated by extracting the reaction mixture by conventional methods, washing, drying, chromatography, etc., and removing the solvent under reduced pressure. The reaction mixture obtained by removing the reaction mixture can be isolated by directly subjecting it to chromatography. If the thus isolated prostaglandin E type ₁ represented by the above formula [] is a derivative with a protected hydroxyl group and/or an ester derivative, the protecting group for the hydroxyl group can be removed by a conventional method if necessary. Prostaglandin E ₁ of the above formula [], which is a carboxylic acid form, can be produced by converting it into a free hydroxyl group and/or subjecting its ester derivative to a hydrolysis reaction by a commonly used method. Further, R ¹¹ , R ²¹ , and R ³¹ in the above formula [] are exemplified as RM, R ² , and R ³ in the above formula []. Further, specific examples of the prostaglandin E ₁ type represented by the above formula [] include those corresponding to the compounds exemplified by the above formula []. The thus obtained prostaglandin E ₁ represented by the above formula [] can be converted into natural prostaglandin E ₁ and its derivatives by finally removing the protecting group. As mentioned above, the feature of the production method of the present invention is that the starting material can be easily obtained as an optically active substance, and it is a novel method that can efficiently provide prostaglandin E type ₁ , which is extremely useful as a pharmaceutical, in a short production process. It is a manufacturing method. Hereinafter, the method of the present invention will be explained in more detail with reference to Examples. Example 1 dl-15(RS)-11,15-bis(t-butyldimedylsilyl)-6-nitroprostaglandin
Dissolve E ₁ methyl ester (57 mg, 0.089 mmol) in 3 ml of toluene and add tributyltin hydride.
1104 mg, 0.356 mmol, 4 eq) and α,α ¹ -azobisisobutyronitrile (7.3 mg, 0.045) were added and heated under reflux for 2 hours. After cooling, the mixture was subjected to silica gel column chromatography and eluted with benzene. The eluted benzene solution was concentrated to obtain 32 mg of crude product,
dl, which is a denitrated form, was subjected to preparative thin layer chromatography (hexane: ethyl acetate = 6:1).
-15(RS)-11.15-bis(t-butyldimethylsilyl) prostaglandin E ₁ methyl ester (20 mg, 0.034 mmol, 38%) was obtained. Thin layer chromatography (3-solvent system), NMR, IR, and mass of this product completely matched with the standard specimen obtained separately. NMR (CDcl ₃ , δ (ppm)); 0.07 (12H, S), 0.89 (18HS), 0.90 (3H,
m), 1.1-3.0 (24H, m), 3.70 (3H, S) 3.7
~4.4 (2H, m), 5.4 ~ 5.7 (2H, m) IR (solution film, cm ^-1 ); 2960, 2950, 2870, 1740, 1460, 1430,
1360, 1250, 1160, 1115, 1100, 1000, 965,
870, 835, 770. Mass (20eV; m/e, %); 581 (M-μe, 0.3), 565 (M-oμe, 0.4), 539
(M-tβu, 24) 536(10), 504(4), 464(4), 408
(23), 407 (73), 393 (26), 376 (20), 375
(62), 301 (27), 215 (10), 75 (100). Example 2 11,15bis(t-butyldimethylsilyl)-6
- Tributyltin hydride (290 mg, 1 mmol, 5 eq) was added to nitroprostaglandin E ₁ methyl ester (127 mg, 0.198 mmol), and α, α ¹ -
While gradually adding azobisisobutyronitrile
The reaction was carried out at 110°C for 1.5 hours. After cooling, it was subjected to silica gel column chromatography to obtain 86 mg of a crude product, which was then subjected to preparative thin layer chromatography (hexane: ethyl acetate = 6 ± 1) in the same manner as in Example 1.
11,15-bis-(t-butyldimethylsilyl) prostaglandin E ¹ methyl ester (30 mg,
0.050 mmol, 25%) was obtained. The various spectral data of this product completely matched those of a separately prepared standard. Prostaglandin E ₁ (14 mg,
0.039 mmol, 78%) was obtained. This item completely matched the standard. Examples 3 to 7 Denitrated products were obtained by heating and refluxing 3 to 5 equivalents of tributyltin hydride in toluene in substantially the same manner as in Example 1. (Yield 39-58%). The 6-nitro compound used was 11,15-bis(t-butyldimethylsilyl)-16,17,18,19,20-pentanol-15-cyclohexyl-6-nitroprostaglandin E ₁ methyl ester (Example 3) ), 11, 15―
Bis(t-butyldimethylsilyl)-16, 17,
18,19,20-pentanol-15-cyclopentyl-
6-nitroprostaglandin E ₁ methyl ester (reaction aid 4), 11,15-bis(t-butyldimethylsilyl)-17,(S), 20-dimethyl-6-
Nitroprostaglandin E ₁ methyl ester (Example 5), 11,15-bis(t-butyldimethylsilyl)-17(R), 20-dimethyl-6-nitroprostaglandin E ₁ methyl ester (Example 6) ), and 11,15-bis(t-butyldimethylsilyl)-17,18,19,20-tetranol-16-cyclohexyl-6-nitroprostaglandin
Prostaglandin E ₁ , which is the E ₁ methyl ester (Example 7) and the corresponding denitrated form, was obtained. These various spectral data were consistent with the standard specimen. Various spectra of the products obtained in each example are shown below. [Product of Example ₃ ] NMR [CDCl3, δ (ppm)] 0.06 (12H, S), 0.87 (18H, S), 1.1-3.0
(27H, m), 3.70 (3H, S), 3,7~4.4
(2H, m), 5.4-5.7 (2H, m). IR (solution film, cm ^-1 ) 1740, 1460, 1360, 1255, 1100, 835, 770. Mass (m/e) 551 (M-57) [Product of Example 4] NMR [CDCl ₃ , δ (ppm)] 0.06 (12H, S), 0.87 (18H, S), 1.1-3.0
(25H, m), 3.70 (3H, S), 3,7~4.4
(2H, m), 5.4-5.7 (2H, m). IR (solution film, cm ^-1 ) 1740, 1460, 1360, 1255, 1100, 835, 770. Mass (m/e) 537 (M-57) [Product of Example 5] NMR [CDCl ₃ , δ (ppm)] 0.06 (12H, S), around 0.9 (24H, m), 1.1 ~
3.0 (25H, m), 3.70 (3H, S) 3,7~4.4
(2H, m), 5.4-5.7 (2H, m). IR (liquid film, cm ^-1 ) 1740, 1460, 1360, 1255, 1100, 835, 770. Mass (m/e) 567 (M-57) [Product of Example 6] NMR [CDCl ₃ , δ (ppm)] 0.06 (12H, S), around 0.9 (24H, m), 1.1 ~
3.0 (25H, m), 3.70 (3H, S), 3,7~4.4
(2H, m) 5.4-5.7 (2H, m). IR (solution film, cm ^-1 ) 1740, 1460, 1360, 1255, 1100, 835, 770. Mass (m/e) 565 (M-57) [Product of Example 7] NMR [CDCl ₃ , δ (ppm)] 0.06 (12H, S), 0.87 (18H, S), 1.1-3.0
(29H, m), 3.70 (3H, S), 3,7~4.4
(2H, m) 5.4-5.7 (2H, m). IR (solution film, cm ^-1 ) 1740, 1460, 1360, 1255, 1100, 835, 770. Mass (m/e) 567 (M-57)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ is a hydrogen atom, a C ₁ to C ₁₀ alkyl group,
A 5- to 6-membered alicyclic group or phenyl group,
R ² and R ³ are the same or different and are a hydrogen atom, a tri(C ₁ to _{C 6} ) hydrocarbon-silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R ⁴ is a C ₄ to _{C 8} A linear or branched alkyl group that may contain an oxygen atom, a 5- to 6-membered alicyclic group, or a 5- to 6-membered alicyclic group substituted
Represents a _C1 - _C2 alkyl group. ] 6-nitroprostaglandin E type ₁ , which is a compound or stereoisomer or a mixture thereof in any proportion, is reacted with tributyltin hydride in the presence of a radical generator,
The following formula [] is characterized by subjecting it to deprotection reaction and/or hydrolysis if necessary. [In the formula, R ¹¹ is a hydrogen atom, a C ₁ to C ₁₀ alkyl group,
A 5- to 6-membered alicyclic group or phenyl group,
R ²¹ and R ³¹ are the same or different and are a hydrogen atom, a tri(C ₁ - _{C 6} ) hydrocarbon-silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R ⁴ is the same as defined above. be. ] A method for producing prostaglandin E type ₁ , which is a compound or stereoisomer or a mixture thereof in any proportion. 2. The manufacturing method according to claim 1, wherein R ¹ in the above formula [] is a C ₁ -C ₁₀ alkyl group, a 5- to 6-membered alicyclic group, or a phenyl group. 3 A tri(C ₁ to C ₆ ) hydrocarbon-silyl group in which R ² and R ₃ are the same or different in the above formula [],
or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, the manufacturing method according to claim 1 or 2. 4 In the above reaction, the radical generator is α, α′-
The manufacturing method according to any one of claims 1 to 3, which comprises azobisisobutyronitrile, bis-t-butyl peroxide, potassium graphite, sodium amalgam, and light irradiation.