JPH0140813B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel prostaglandin intermediate and a method for producing the same. Prostaglandin compounds are said to be widely present in living organisms, and because of their unique biological activity, attempts are being made to synthesize prostaglandin derivatives and discover new drugs. Under these circumstances, it is necessary to search for new prostaglandin derivatives when searching for drugs, but developing new synthetic intermediates is important in order to obtain previously unknown prostaglandin derivatives. is very important. According to the present invention, the following formula [] [In the formula, R ¹ is an alkyl group or a cycloalkyl group having 1 to 10 carbon atoms, R ² is a hydrogen atom or a methyl group, R ³ and R ⁴ are the same or different and represent a hydrogen atom or a protective group, and Y is

[Formula] or

Represents [formula]. ] A novel prostaglandin intermediate is provided. By using this new prostaglandin intermediate, a new 4-thiaprostaglandin E ₁ which has excellent pharmacological effects as shown in the figure below is produced.
or 4-thiaprostaglandin _I. Therefore, the novel prostaglandin intermediate of the present invention is an extremely useful compound. [In the above general formula, R represents a lower alkyl group and X represents a chlorine atom. ] In the novel prostaglandin intermediate of the present invention represented by the above formula [], R ¹ has 1 to 1 carbon atoms.
10 alkyl or cycloalkyl groups, particularly preferred are pentyl, hexyl, 2-methylhexyl, and cyclohexyl. R ² is a hydrogen atom or a methyl group, and R ³ and R ⁴ are the same or different and are a hydrogen atom or a protective group. Particularly preferred as the protecting group are t-butyldimethylsilyl group, tetrahydropyran-2
-yl group, (1S,5R)-6,6-dimethyl-3-
Oxa-4-oxobicyclo[3.1.0]hexan-2-yl group, (1R,5S)-6,6-dimethyl-
A 3-oxa-4-oxobicyclo[3.1.0]hexane-2-yl group is mentioned. Y is

[Formula] or

Represents [formula]. The novel prostaglandin intermediate of the above formula [] has an asymmetric carbon atom of 11 < It includes mixtures in proportions of. Preferred specific examples of the novel prostaglandin intermediate of the present invention are as follows. 2-allyl-3-(3'(S)-t-butylmedithylsiloxy-1'-octenyl)-4-t-butyldimethylsiloxycyclopentanone, 2-allyl-3-(3'(S)- t-Butyldimethylsiloxy-1'-nonenyl)-4-t-butyldimethylsiloxycyclopentanone, 2-allyl-3-(3'(S)-t-butyldimethylsiloxy-5'(S)-methyl- 1′-nonenyl)
-4-t-butyldimethylsiloxycyclopentanone, 2-allyl-3-(3'-t-butyldimethylsiloxy-3'-methyl-1'-octenyl)-4-t
-Butyldimethylsiloxycyclopentanone, 2-allyl-3-(3'(S)-t-butyldimethylsiloxy-3'-cyclohexyl-1'-propenyl)-4-t-butyldimethylsiloxycyclopentanone, 2 -Allyl-3-(3'(S)-t-butyldimethylsiloxy-1'-octenyl)-4-t-butyldimethylsiloxycyclopentanol, 2-allyl-3-(3'(S)-t- Butyldimethylsiloxy-1'-nonenyl)-4-t-butyldimethylsiloxycyclopentanol, 2-allyl-3-(3'(S)-t-butyldimethylsiloxy-5'(S)-methyl-1' -nonenyl)
-4-t-butyldimethylsiloxycyclopentanol, 2-allyl-3(3'-t-butyldimethylsiloxy-3'-methyl-1'-octenyl)-4-t-
Butyldimethylsiloxycyclopentanol, 2-allyl-3-(3'(S)-t-butyldimethylsiloxy-3'-cyclohexyl-1'-propenyl)-4-t-butyldimethylsiloxycyclopentanol, 2- Allyl-3-(3'(S)-t-butyldimethylsiloxy-1'-octenyl)-4-((1'R,
5′R)-6′,6′-dimethyl-3′-oxa-4′-oxobicyclo[3.1.0]hexane-2-yl)cyclopent-2-enone, 2-allyl-3-(3′( S)-t-butyldimethylsiloxy-1'-octenyl)-4-((1'R,
5′S)-6′,6′-dimethyl-3′-oxa-4′-oxobicyclo[3.1.0]hexan-2-yl)cyclopentanol, etc. However, among the novel prostaglandin intermediates of the present invention, Y is

[Formula] is the following formula [-1] [In the formula, R ¹ , R ² , R ³ , and R ⁴ are the same as defined above. ] The new prostaglandin intermediate represented by the following formula [] [In the formula, R ^4-1 represents a protecting group. ] Cyclopentenones represented by the following formula [-
1] [In the formula, R ¹ and R ² are the same as defined above,
R ^3-1 is a protecting group, X is a group

[Formula] represents a phenylthio group or a 1-pentynyl group. ] Or the following formula [-2] [In the formula, R ¹ , R ² , and R ^3-1 are the same as defined above. ] It can be obtained by reacting with an organocopper compound represented by the following and then deprotecting as necessary. Novel prostaglandin intermediate of the present invention [-
The cyclopentenones represented by the above formula [] used in the production of [1] can be produced from furan derivatives as separately filed by the present inventors. (See figure below) The cyclopentenones represented by the above formula [] include 4(R)-cyclopentenones or their enantiomers, that is, 4(S)-cyclopentenones, or mixtures thereof in arbitrary proportions. By reacting cyclopentenones with organocopper compounds, a 1,4-addition reaction occurs, [-1]
The prostaglandin intermediate of the present invention represented by: As the organic copper compound, an organic copper compound represented by the above formula [-1] or an organic copper compound represented by the above formula [-2] is suitably used. The usage amount is 1.0 for cyclopentenones.
~1.5 times the mole is used, and the reaction temperature is -80° ~ -10
°C, particularly preferably in the range of -78 °C to -20 °C. The reaction is usually achieved by adding a solution of cyclopentenones dissolved in an organic solvent to an organic copper compound dissolved in an organic solvent and stirring the solution. Suitable examples of the organic solvent used here include ethyl ether, tetrahydrofuran, hexamethylphosphorustriamide, n-butylphosphine, and hexamethylphosphorictriamide, either alone or as a mixed solvent. The reaction usually ends with the disappearance of the starting material cyclopentenone by thin layer chromatography, but it is sufficient to carry it out for 0.5 to 3 hours. Column chromatography, liquid chromatography, or thin layer chromatography may be used to further purify the product obtained by post-treatment using conventional methods. The protecting group can then be removed if necessary. Protecting group is t-butyldimethylsilyl group, 2
In the case of -tetrahydropyranyl group, for example, a known acetic acid-water-tetrahydrofuran system can be used. The t-butyldimethylsilyl group can also be suitably formed using a tetra-n-butylammonium fluoride-triethylamine system. The protecting group is (1S,5R)-6,6-dimethyl-3-oxa-4-oxobicyclo[3.1.0]hexane-
2-yl group or (1R,5S)-6,6-dimethyl-3-oxa-4-oxobicyclo [3.1.0]
In the case of a hexane-2-yl group, it can be easily deprotected by heating in a mixture of water and a water-miscible organic solvent such as dioxane or tetrahydrofuran. In this way, a novel prostaglandin intermediate represented by the above formula [-1] is obtained. Also, in the above formula [], Y is

[Formula] is the following formula [-3] [In the formula, R ¹ , R ² , R ³ , and R ⁴ are the same as defined above. ] The novel prostaglandin intermediate represented by
The following formula [-2] obtained after reaction with the above-mentioned organocopper compound [In the formula, R ¹ , R ² , R ^3-1 , and R ^4-1 are the same as defined above. ] It can be obtained by subjecting cyclopentanones represented by the following to a reduction reaction, and then deprotecting as necessary. Reducing agents used here include lithium aluminum hydride, sodium polyhydride, zinc polyhydride, etc. In order to proceed with the reduction of carbonyl as stereoselectively as possible to obtain the α-hydroxy form, especially L-
Selectride (lithium tri-sec-butylporohydride), K-selectride (potassium tri-sec-butylporohydride), KS-
Preferably, reducing agents with bulky groups such as selectride (potassium trisamylporohydride) are used. The reduction reaction is preferably carried out in an organic solvent such as tetrahydrofuran, ethyl ether, dioxane, etc., and the reaction temperature is -80°C to 50°C, particularly -80°C to -20°C to perform the reaction stereoselectively. It is preferable to carry out the reaction at a temperature in the range of 0.degree. C., and the reaction time is about 5 minutes to 3 hours. After such a reduction reaction, if necessary, a deprotection reaction similar to that described above is performed to obtain a novel prostaglandin intermediate represented by the above formula [-1]. The thus obtained novel prostaglandin intermediate represented by the formula It becomes possible to produce the above-mentioned novel prostaglandin derivatives that have not been produced previously, and the present invention can fully contribute to the synthesis of pharmaceuticals with new properties. EXAMPLES The present invention will be explained below with reference to examples, but the present invention is not limited to these examples. Example 1 3(S)-t-butyldimethylsiloxy-1-
A solution of 1.29 g of iodo-1-octene in 20 ml of ether was cooled to -70°, 5.83 ml of t-butyllithium (1.2 M hexane solution) was added, and the mixture was stirred for 2 hours. Then, a solution of 0.60 g of phenylthiosteel and 1.3 ml of hexamethylphosphorus triamide in 5 ml of ether was added dropwise, and the mixture was allowed to react for 1 hour. At the same temperature, add a solution of 0.8 g of 2-allyl-4-t-butyldimethylsiloxycyclopent-2-enone in 5 ml of ether, and -
After stirring at 70° for 1 hour, the mixture was reacted at -40°C for 3 hours. Add 100ml of ether and make NH ₄ OH―NH ₄ Cl―
After washing with N ₂ O, the residue was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to obtain an oil. Purified by column chromatography (cyclohexane/ethyl acetate 97:3) to obtain 775 mg of 2-
Allyl-3-(3'(S)-t-butyldimethylsiloxy-1'-octenyl)-4-t-butyldimethylsiloxycyclopentanone was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.85 (21H, s), 1.0−2.0 (8H, m), 2.0−
3.0 (6H, m), 3.8-4.3 (2H, m) 4.7-5.9
(3H, m), 5.43 (2H, m). Example 2 3(S)-t-butyldimethylsiloxy-1-
1.4 g of iodo-1-nonene was reacted in the same manner as in Example 1 to obtain 2-allyl-3-(3'(S)-t-butyldimethylsiloxy-1'-nonenyl)-4-t-
Butyldimethylsiloxycyclopentanone 900mg
I got it. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.88 (21H), 1.0-2.0 (10H), 2.0-3.0
(6H), 3.8-4.3 (2H), 4.7-5.9 (3H), 5.45
(2H) It was. Example 3 3(S)-t-butyldimethylsiloxy-1-
2-allyl-3-(3'(S)
300 mg of -t-butyldimethylsiloxy-5'(S)-methyl-1'-nonenyl)-4-t-butyldimethylsiloxycyclopentanone was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.90 (24H), 1.1−30 (15H), 3.70−4.25
(2H), 4.7-5.9 (3H), and 5.44. Example 4 Example 1 from 480 mg of 3-t-butyldimethylsiloxy-1-iodo-3-methyl-1-octyne
In the same manner as above, 300 mg of 2-allyl-3-(3'-t-butyldimethylsiloxy-3'-methyl-1'-octenyl)-4-t-butyldimethylsiloxycyclopentanone was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.88 (21H), 1.25 (3H, s), 1.1-3.0
(14H), 3.95-4.1 (1H), 4.7-5.9 (3H),
It was 5.50 (2H). Example 5 3(S)-t-butyldimethylsiloxy-3-
Cyclohexyl-1-iodo-1-propene 1.30
2-allyl-3- from g in the same manner as in Example 1
825 mg of (3'(S)-t-butyldimethylsiloxy-3'-cyclohexyl-1'-propenyl)-4-t-butyldimethylsiloxycyclopentanone was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.88 (18H), 1.1−3.0 (17H), 3.85−4.30
(2H), 4.7-5.9 (3H), and 5.45 (2H). Example 6 2-allyl-3-(3'(S)-) obtained in Example 1
t-butyldimethylsiloxy-1'-octenyl)
A solution of 80 mg of -4-t-butyldimethylsiloxycyclopentanone in 40 ml of tetrahydrofuran was cooled to -65°, and 0.2 L-selectride (1.0 M solution) was added.
ml was gradually added. The reaction was complete after 5 minutes. After 15 minutes, add 14 ml of water and add ethyl acetate (3 x 30
ml), and the organic layer was washed with saturated aqueous ammonium chloride and then with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to obtain an oil.
Purification by thin layer chromatography (cyclohexane/ethyl acetate 9/1) yielded 50 mg of 2-allyl-3.
-(3'(S)-t-butyldimethylsiloxy-
1'-octenyl)-4-t-butyldimethylsiloxycyclopentanol was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.85 (21H), 1.0-2.8 (15H), 3.7-4.3
(3H), 4.7-6.0 (5H). Example 7 450 mg of 2-allyl-3-(3'(S)-t-butyldimethylsiloxy-1'-nonenyl)-4-t-butyldimethylsiloxycyclopentanone was reacted in the same manner as in Example 6 to yield 390 mg. 2-Allyl-3
-(3'(S)-t-butyldimethylsiloxy-
1'-nonenyl)-4-t-butyldimethylsiloxycyclopentanol was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.85 (21H), 1.0-2.0 (10H), 2.0-3.0
(7H), 3.8-4.35 (3H), and 4.7-6.0 (5H). Example 8 2-allyl-3-(3'(S)-t-butyldimethylsiloxy-5'(S)-methyl-1'-nonenyl)
A reaction was carried out in the same manner as in Example 6 using 100 mg of -4-t-butyldimethylsiloxycyclopentanone,
65 mg of the corresponding alcohol was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.9 (24H), 1.1−3.0 (16H), 3.75−4.30
(3H), 4.7-5.9 (3H), and 5.48 (2H). Example 9 2-allyl-3-(3'-t-butyldimethylsiloxy-3'-methyl-1'-octenyl)-4-t
-Butyldimethylsiloxycyclopentanone 280
mg was treated in the same manner as in Example 6 to obtain 230 mg of the corresponding alcohol. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.88 (21H), 1.20 (3H), 1.1−3.0 (15H),
They were 3.8-4.2 (2H), 4.7-5.9 (3H), and 5.50 (2H). Example 10 490 mg of 2-allyl-3-(3'(S)-t-butyldimethylsiloxy-3'-cyclohexyl-1'-propenyl)-4-t-butyldimethylsiloxycyclopentanone was added in the same manner as in Example 6. Processed to
350 mg of the corresponding alcohol was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.88 (18H), 1.1-3.0 (18H), 3.8-4.4 (3H)
They were 4.7-5.9 (3H) and 5.42 (2H). Example 11 3(S)-t-butyldimethylsiloxy-1-
Vinyllithium copper was produced from 1.3 g of iodo-1-octene in the same manner as in Example 1, and 2-allyl-4-((1'R,5'S)-6',6'-dimethyl was produced at -70°. ―
A solution of 0.8 g of 3'-oxa-4'-oxobicyclo[3.]1.0]hexane-2-yloxy)cyclopent-2-enone in 5 ml of ether was added, and the reaction and treatment were carried out in the same manner as in Example 1 to obtain 550 mg of 2 -Allyl-3-
(3'(S)-t-butyldimethylsiloxy1'-octenyl)-4-((1'R,5'S)-6',6'-dimethyl-3'-oxa-4'-oxobicyclo[ 3.1.0] Hexane-2-yloxy)cyclopent-2-enone was obtained. The nmr (CDCl ₃ ) spectrum of this product is δ: 0.85 (21H, s), 1.0−2.0 (8H), 1.18−
(3H, s), 1.20 (3H, s), 2.03 (2H, s)
3.8-4.3 (2H, m), 4.7-5.9 (3H, m),
They were 5.25 (1H, s) and 5.45 (2H, m).

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ is an alkyl group or cycloalkyl group having 1 to 10 carbon atoms, R ² is a hydrogen atom or a methyl group, R ³ and R ⁴ are the same or different hydrogen atoms,
t-butyldimethylsilyl group, tetrahydropyran-2-yl group, (1S,5R)-6,6-dimethyl-3-oxa-4-oxobicyclo[3.1.0]hexan-2-yl group, or (1R, 5S) -6,6-
It represents a dimethyl-3-oxa-4-oxobicyclo[3.1.0]hexane-2-yl group, and Y represents [Formula] or [Formula]. A novel prostaglandin intermediate represented by 2. The novel prostaglandin intermediate according to claim 1, wherein R ¹ is a pentyl group, hexyl group, 2-methylhexyl group, or cyclohexyl group, and R ² is a hydrogen atom. 3. The novel prostaglandin intermediate according to claim ¹ , wherein R 1 is a pentyl group and R ² is a methyl group. 4 The following formula [] [In the formula, R ^4-1 represents a protecting group. ] Cyclopentenones represented by the following formula [-
1] [In the formula, R ¹ and R ² are the same as defined above, and R ^3-1
represents a protecting group, and X represents a group [Formula] phenylthio group or 1-pentynyl group. ] Or the following formula [-2] [In the formula, R ¹ , R ² , and R ^3-1 are the same as defined above. ] The following formula [-1] is characterized by reacting with an organocopper compound represented by and then deprotecting as necessary. [In the formula, R ¹ , R ² , R ³ , and R ⁴ are the same as defined above. ] A method for producing a novel prostaglandin intermediate represented by: 5 The following formula [-2] [In the formula, R ¹ , R ² and R ^3-1 are the same as defined above, and R ^4-1 is a protecting group. ] The following formula [-3], which is characterized by subjecting a cyclopentanone represented by to a reduction reaction and then deprotecting as necessary. [In the formula, R ¹ , R ² , R ³ , and R ⁴ are the same as defined above. ] A method for producing a novel prostaglandin intermediate represented by: