HU188890B - New process for preparing bicyclic lactones - Google Patents

Abstract

Cpds. of formula (I) are prepd. by oxidising bicyclic alcohols of formula (III) in an aprotic solvent with an oxidising agent contg. +6-valent chromium or a carbo-diimide. In the formula, R1 is benzoyl, p-phenyl-benzoyl or p-phenyl-carbamoyl gp.; Y is a trans-vinylene, trans-bromo-vinylene (-CH=CBr-) or ethynylene gp.; R2 is opt. branched alkyl, alkenyl or alkynyl with 5-11C or cyclo-alkyl with 3-7C; Z is carbonyl.

Description

The present invention relates to a novel process for the preparation of bicyclic lactones of the formula I wherein

R 'is benzoyl, p-phenyl-benzoyl, p-phenyl-phenylcarbamoyl,

Y is trans-vinylene, trans-bromo-vinyleneC1 (-CH = Br-), or ethynylene

R ² 5-11 carbon linear or branched alkyl, alkenyl or alkynyl or C3-7 cycloalkyl preparation.

Known bicyclic lactones of formula I are intermediates for the production of natural prostaglandins and other prostanoids, as well as prostacyclin and analogs thereof. (Chemical and Engineering News 1982, August 16, 30; Chemistry, Biochemistry and Pharmacological Activity of Prostanoids, Pergamon Press, 1979. Eds. SM Roberts and F. Scheinmann, pp. 338-345 and 346-361; Prostaglandins 4). 143-145 (1973); European Patent 11591; German Patent Publication No. 2845770.

The bicyclic lactones of formula 1 were first prepared by reacting a bicyclic aldehyde of formula II (wherein R ^{1 is} benzoyl or p-phenylbenzoyl) with dimethyl-2.

with an anion formed from oxo - heptylphosphonate. The Wittig-Horner reaction gave a good yield of the bicyclic lactone of formula I (R ¹ is benzoyl or p-phenylbenzoyl, R ² is pentyl, Y is vinylene. [JACS, 92, 397-9 (1970) and 1495- (1971)].

A new, more industrially feasible process for the preparation of compounds of formula I is described in U.S. Patent No. 173,171. Unlike the above, aldehyde II is reacted with triphenyl 2 - oxo - heptyl phosphorane instead of an anion formed from a phosphonate.

For the remainder of the prostaglandin total synthesis, the carbonyl groups of the bicyclic lactones of formula I are reduced. The resulting epimeric configuration of the bicyclic alcohols of formula III according to the natural prostaglandin nomenclature is further used for the total synthesis of prostanoids and prostacyclines, while the 15P-epimers remain as a by-product (Bindra and Bindra, 1977, Pres. side).

When separating the alpha 15 alpha and 15 alpha epimeric alcohols of formula III, the meaning of the group is determined by the strategy of the particular synthesis. If prostaglandin E ₂ is synthesized after separation of the epimeric alcohols, it is convenient to carry out the separation in the form of a lithium, where Z is C = O in the compound of formula ΠΙ. If our goal is the synthesis of prostaglandin - F ₂ , then in the lactol form - where Z in the compound of formula III is CH-OH

epimer separation is preferred.

It is an object of the present invention to provide a process for converting an unusable βepimer into a bicyclic lactone of formula I for use in the total synthesis of prostaglandin. The use of such a process would improve the overall cost-effectiveness of the synthesis.

The above object can be achieved by the process of the present invention as follows. Bicyclic alcohols of formula III, which are a valuable by-product of the synthesis of prostaglandins, are oxidized with compounds containing the chlorine + 6 oxidation degree or carbodiimides to produce the bicyclic lactones of formula I as a valuable by-product.

It is known [JACS, 93, 1491-1493 (1971)] that the use of special oxidizing agents, such as active inanganic (IV) -dioxide or dichlorodicyanobenzoquinone, in the 15-position -CHOH- of the bicyclic alcohols of formula III - can be oxidized to a group. These reagents are indeed useful under laboratory conditions for performing oxidation, but are not suitable for industrial production, due in part to the poor handling and poor availability of reagents. A disadvantage is also the selectivity of these oxidants. Because these oxidants do not oxidize the -CHOH- group at Z to a -CO- group, a second oxidant must be used to oxidize this group. Oxidation of secondary and primary hydroxy groups to the oxo group is described as the preferred oxidizing agent of the known chromium (VI) trioxide and sulfoxide containing oxidants, for example, the "sulfonine chloride" J.

7586-7587. (1972) and J. Org. Chem., 38, 1233 (1973)]. However, if the compounds containing a -CH-CH-CHOHO moiety are to be oxidized therewith, the side reactions are predominant and halogenated or an unwanted second double bond is substituted for the desired product. The formation of a methylthio - methyl ether derivative is also described in the article.

Notwithstanding the foregoing, it has surprisingly been found that the bicyclic alcohols of formula 111 can be oxidized in good yields to the bicyclic lactones of general formula I using chromium compounds or carbodiimides containing 6 chromium atoms of oxidation.

Examples of such oxidizing agents are pyridinium chloro chromate (Tetrahedron Letters, 1975, 2647-), the so-called Collins reagent (Tetrahedron Letters, 1968, 3363- and J. Org. Chem., 35, 4000- (1970)), the so-called Jones reagent (Fieser and Fieser I. 142, John Wiley and Sons Inc., 1967), pyridinium dichromate (Tetrahedron Letters, 1979, 399-) or some disubstituted carbodiimide (JACS, 87, 5661- (1965)). may.

The amount of oxidizing agent to be used will depend on whether the compound of formula III to be oxidized is Z-CO- or -CHOH

-2188,890 mean. In the case where Z is -CO-, 2 to 12 equivalents of the pyridinium chlorochromate, the Collins reagent, 1 to 3 equivalents of the Jones reagent, 1 to 4 equivalents of the pyridinium dichromate, and 2 to the equivalent of the carbodiimide reagent. 4 equivalents should be used. If Z in the compound of Formula III to be oxidised is Z-CHOH, then double the amounts of reagent given above must be used.

The solvent of the present invention may be any one of the solvents described in the description of the oxidizing agent. For example, in the case of Jonesreagent, acetone, in the case of Coilins, pyridine, a halogenated solvent such as dichloromethane, dichloroethane, pyridine chlorochromate or pyridinium dichromate oxidizing agent, a halogenated hydrocarbon, acetone, acetonitrile or ethyl acetate can be used in the oxidation reaction.

In the case of carbodiimide oxidation, dimethylsulfoxide is used as both a medium and a reagent.

The oxidation process of the present invention may be carried out at a temperature in the range of -20 ° C to + 30 ° C.

Isolation of the compounds of Formula I from the oxidation reaction mixture after extraction can be accomplished by crystallization and, if necessary, purification by chromatography or separation.

Further details of the present invention will be illustrated by the following non-limiting examples.

Example 2

3,3aP, 4,5,6,6aP-Hexahydro-2-oxo-4β - (3-oxo-1-trans-6-cis-octadien-1-yl) -5a-benzoyloxy-2H-cyclopenta [b] furan

Example 1 was repeated except that 8.7 g of 23.5 mM of 3,3ap.4,5,6,6ap-hexahydro-2-hydroxy-4β- [3 (R) -hydroxy-1] was used. Trans-6-cis-octadien-1-yl] -5a-benzoyloxy-2H-cyclopenta [b] furan was added and acetone was used as solvent instead of dichloromethane.

Weight of product: 7.9 g (91.5%)

R _f = 0.6 (2: 1 benzene-ethyl acetate)

Example 3

3,3aP, 4,5,6,6aP - Hexahydro - 2 - oxo - 4β - (3

- oxo - 4 - methyl - 6,7 - didehydro - 1 - trans

- octenyl) - 5a - (4 - phenylbenzoyloxy) - 2H

- cyclopenta [b] furan

Example 1 was performed with the difference that 10.8 g of 23.5 mM of 3,3ap, 4,5,6,6aP-hexahydro-2-hydroxy-4β - [3 (R) -hydroxy-4 - methyl

- 6,7 - didehydro - 1 - trans - octenyl] - 5a - (4 - phenyl

benzoyloxy) - 2H - cyclopenta [b] furan was added and ethyl acetate was used as solvent instead of dichloromethane.

Weight of product: 9.81 g (91.6%)

(: 1 mixture of benzene and ethyl acetate 2) _Rf = 0.65

Example 1

Example 4

3,3ap, 4,5,6,6aP-Hexahydro-2-oxo-4β- (3-oxo-1-trans-octenyl) -5a- (4-phenylbenzoyloxy) -2H-cyclopentafbjfuran

60.7 g of 282 mM pyridinium chlorochromate and 46.2 g of 564 mM sodium acetate are suspended in 200 ml of distilled dichloromethane, followed by 10.6 g.

23.5 mM 3.3ap, 4,5,6,6ap-hexahydro-2-hydroxy

- 4β - [3 (R) - Hydroxy - 1 - trans - octenyl] - 5a - (4

Phenylbenzyloxy) -2H - cyclopentafbjfuran in 100 ml of distilled dichloromethane was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through silica gel and the filter cake was washed with dichloromethane. The combined filtrate was washed with water. The residue was chromatographed on a silica gel column with 2: 1 benzene-ethyl acetate. R _f = 0.5 (2: 1 mixture of benzene and ethyl acetate) fractions were collected and evaporated. 10.4 g of the title compound are obtained, which is crystallized from i-propanol-water.

Weight: 9.65 g (92%).

R _f = 0.5 with 2: 1 benzene-ethyl acetate.

3,3aP, 4,5,6,6aP - Hexahydro - 2 - oxo - 4β - (3

- oxo - 4,4 - dimethyl - 1 - trans - nonenyl) - 5a

- (4-Phenylbenzoyloxy) -2H-cyclopenta [b] furan

Example 1 except that 11.2 g (23.5 mM) of 3,3aP, 4,5,6,6aP-hexahydro-2-oxo-4β- [3 (R) -hydroxy- 4,4 - dimethyl

- 1 - Trans - nonenyl] - 5a - (4 - phenylbenzoyloxy) -2H - cyclopenta [b] furan 30.4 g (141 mM) of pyridinium chlorochromate and 23.1 g (282 mM) of sodium acetate are weighed. .

Yield: 10.5 g (94.2%)

R _f = 0.52 (2: 1 benzene-ethyl acetate)

Example 5

3,3aP, 4,5,6,6aP - Hexahydro-2-oxo-4β - (3-oxo-1-trans-octenyl) -5a - (4-phenylbenzoyloxy) -2H-cyclopenta [b] furan

26.5 g (70.5 mM) of pyridinium dichromate are suspended in 70 ml of anhydrous dimethylformamide.

188,890 and 10.6 g (23.5 mM) of 3,3afi, 4,5,6,6afi hexahydro-2-hydroxy-4β - [3 (R) -hydroxy-1 trans-octenyl] -5a - ( 4-Phenylbenzoyloxy) -2H-cyclopenta [b] furan, dissolved in 70 ml of anhydrous dimethylformamide, and stirred at room temperature for 2-3 hours.

The reaction mixture was poured into water (10 times), extracted with ether, and the organic phase was dried and evaporated. The crude product obtained, weighing 10.5 g, was purified according to Example 1. 7.9 g (91%) of the title compound are obtained.

_Rf = 0.5 (2: 1 mixture of benzene and ethyl acetate)

Example 6

3,3ap, 4,5,6,6ap - Hexahydro - 2 - oxo - 4β - (3

oxo - 1 - trans - decenyl) - 5a - benzoyloxy - 2H

cyclopentafbjfuran

10.0 g (25 mM) of 3,3αβ, 4,5,6,6αβ-hexahydro-2

- oxo-4β- [3 (R) -hydroxy-1-trans-decenyl] 5a-benzoyloxy-2H-cyclopenta [b] furan and 15.5 g of dicyclohexylcarbodiimide are dissolved in 50 ml of dry dimethyl sulfoxide and stirred under external water cooling, 2.5 ml (0.01 mol) of 4M dimethyl sulfoxide in phosphoric acid are added dropwise to the reaction mixture. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water (500 mL) and the dicyclohexylurea was filtered through a glass filter. The precipitate was washed with dichloromethane (3 x 30 mL) and the filtrates were combined. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 50 mL). The dichloromethane extracts were combined, dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with benzene-ethyl acetate (2: 1). Fractions corresponding to Rf = 0.53 (2: 1 benzene-ethyl acetate) were collected and evaporated. 9.8 g are obtained which is crystallized from i-propanol / water.

Yield: 9.1 g (90%)

_Rf = 0.53 (2: 1 mixture of benzene and ethyl acetate)

Example 7

3,3: ιβ, 4,5,6,6αβ - Hexahydro - 2 - oxo - 4β - (3

- oxo - 1 - trans - nonenyl) - 5a - (4 - phenylbenzoyloxy) - 2H - cyclopentafbjfuran

34.5 g (134 mM) of CrO ₃ (C ₅ H _s N) ₂ Chromium (VI) - trioxide - pyridine complex was suspended in 30 ml of dry dichloroethane, and 10 g (22.3 mM) of 20: 80 3 (S) : 3 (R) epimer ratio of 3,3ap, 4,5,6,6afi hexahydro-2-oxo-4β- (3-hydroxy-1-trans-nonenyl) -5α- (4-phenylbenzoyloxy) -2H-cyclopentafbjfuran - solution of epimeric mixture in dichloromethane (10 mL) was added dropwise. After stirring at room temperature for 15 minutes, diethyl ether (50 ml) was added, stirred for 5 minutes, and the precipitated chromium salts were filtered off.

The filtrate was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure.

8.1 g (81.5%) of the title product are obtained.

Product analytical feature:

R, 0.5 (2: 1 benzene-ethyl acetate in a running mixture)

Example 8

3,3afi, 4,5,6,6afi - Hexahydro - 2 - oxo - 4β - (3

- oxo - 1 - trans - nonenyl) - 5a - (4 - phenyl - phenyl!

- carbamoyl) - 2H - cyclopenta [b] furan g (21.05 mM) 3.3afi, 4,5,6,6afi - hexahydro - 2

- Oxo-4β- [3 (R) -hydroxy-1-trans-nonenyl] -5a- (4-phenyl-phenylcarbamoyl) -2H-cyclopenta [b] furan was dissolved in 10 ml of potassium permanganate in distilled acetone. The solution was cooled to 0 ° C and 11.6 mL of 2mM / mL (23.15mM) standard Jones reagent was added dropwise to the reaction mixture over half an hour and stirred for another half hour. The excess oxidant was then quenched with isopropanol (5 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with 50 ml of 10% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure.

7.5 g (75%) of the title compound are obtained.

Product analytical feature:

R _f = 0.5 (2: 1 benzene-ethyl acetate).

Claims (13)

Claims A process for the preparation of a bicyclic lactone of formula I wherein: R ^{1 is} benzoyl, p-phenyl-benzoyl or p-phenyl-phenyl-carbamoyl, Y is trans-vinylene-trans-bromo-vinylene or ethylidene, R ^{2 is} a bicyclic alcohol of formula III wherein R ¹ , R ² and Y are as defined above and Z is carbonyl or CH- to form a linear or branched C 5 -C 11 alkyl, alkenyl or alkynyl group or C 3 -C 7 cycloalkyl group. Represents an OH group - characterized in that it is oxidized by oxidation of an a and β epimer mixture or a β-epimer obtained after separation of the two epimers and a CH-OH group optionally substituted with Z + 6 oxidation chlorine or carbodiimide. solvent. 2. A process according to claim 1 wherein the oxidizing agent containing + 6 oxidation chromium is Jones reagent. 188,890 3. The process of claim 1 wherein the oxidizing agent containing + 6 oxidation chromium is Collinsreagent. The process according to claim 1, wherein the oxidizing agent containing + 6 oxidation chromium is pyridinium chlorochromate. 5. The process according to claim 1, wherein the oxidant containing 1 chromium atom + 6 oxidation is pyridinium dichromate. 6. A process according to claim 1, wherein the carbodiimide is dicyclohexylcarbodiimide. The process according to claim 1 or 4, wherein the oxidation is carried out with pyridinium chlorochromate in dichloromethane. 8. Process according to claim 1 or 4, characterized in that the oxidation is carried out with pyridinium chlorochromate in an acetone medium. 9. A process according to claim 1 or 4, wherein the oxidation is carried out with pyridinium chlorochromate in an ethyl acetate medium in the presence of sodium acetate. 10. A process according to claim 1 or 5, wherein the oxidation is carried out with pyridinium dichromate in dimethylformamide medium. 11. A process according to claim 1 or 6, wherein the oxidation is carried out with dicyclohexylcarbodiimide in dimethyl sulfoxide in the presence of phosphoric acid. 12. Process according to claim 1 or 3, characterized in that the oxidation is carried out with a chromium (VI) -oxide-pyridine complex (Collins reagent) in dichloromethane. 13. A process according to claim 1 or 2, wherein the oxidation is carried out with Jones reagent in acetone medium.