CS214514B1 - Method of making the /3a alpha,4beta,6a alpha/hexahydro-5-acyloxy-4-carboxy-2h-cyclopenta/b/ furran-2-on - Google Patents

Description

The invention relates to a process for the preparation of (3aaC, 4 (2 ', 5a, 6a)) hexahydro-5-acyloxy-4-carboxy-2H-cyclopenta-QbJ-pyran-2-one of formula I,

wherein R 1 represents alkyl and 1 to 3 carbon atoms, which is an important intermediate in the synthesis of prostadienoic acid derivatives referred to as prostaglandins. High biological

234 514 The efficacy of this class of substances in both human and veterinary medicine has prompted their very intensive research to prepare them synthetically.

The most important of these is a synthesis called horbornadien, which means that the starting material is norbornadien. Some modifications are described in J.Amer. Chem. Soc. 22, 7522 (1973), J. Chem. Soo. Chem. Commun. 1974, 151, J. Org. Chem. 2, 786 (1977) and U.S. Patent Nos. 3,992,438 and 3,943,151. this group also includes AO 202 478, which describes a process for the preparation of the haloeeters of formula II

wherein X is Cl, Br or I and R is alkyl of 1 to 6 carbon atoms.

The invention solves a process for converting type II substances into products I in such a way that the individual intermediates of the whole process need not be isolated and the conversion is in fact carried out as a single operation. The advantage is that type I substances are very easy to purify by due to crystallization from water. The type I acids can then be easily converted to prostaglanines using MS. Certificate No. (PV 2556-79).

X

The process according to the invention solves a process for the preparation of (3a, 4a, 5a, 6aa) - hexahydro-5-aoyloxy-4-carboxy-2H-cyclopenta [b] furan-2-one of the formula I

wherein R ¹ is alkyl and 1 to 3 carbon atoms, characterized in that the 5-halo-2-catabicyclo [2.2.1] heptane-7-carboxylic acid alkyl ester of the formula

(II), p

where R is C 1 -C 6 alkyl and X is chlorine, bromine or iodine, converted by treatment with peroxyacid or hydrogen peroxide, preferably a solution of peracetic acid in dichloromethane or di-chloroethane, to? -lactone (5 "halo-3-hydroxy-2- alkyloxycarbonyl-cyclopent-1-yl) acetic acid of the general formula ΪΧΙ,

(III), p

where R and X are as defined above This lactone in an alkaline medium will succumb to hydrolysis of the ester function, the nuclophilic halogen substitution and the opening of the <F-lactone ring to form a salt (lt <1,2 / 1,3,5, 5o <). - (3,5-dihydroxy-2-kerbeta-y-cyclopent'-1-yl) acetic acid of formula IV,

OH

OH (IV), where Me is an alkali metal which is converted without isolation by acidification with an inorganic or organic acid, preferably acetic acid, to (3aO6, 4 → 5, 5 *, 6β <30) hexahydro-5-hydroxy-4- carboxy-2H-cyclopenta [f] furan-2-one of formula V,

The OH is converted to an acid of formula I by treatment with an acylating agent, preferably an excess of acetyl chloride. This is isolated after removal of the excess acylating agent by addition of water and suction. The analytical preparation is obtained by crystallization from water.

The invention is illustrated by the following non-limiting examples.

Example 1 (3ao <4 ^> 5 t <., 6AC <) hexahydro-5-acetoxy-4-carboxy-2-cyklopanta [b2 ~ ^{furan 2_on} (Ϊ ^»= CH-j)

10.1 g of ester II (X = O ¹ , R ² = CH 2) was dissolved in 100 ml of dichloroethene and 75 ml of a 1M solution of peracetic acid in dichloroethane was added over 2 hours at 0 ° C. The mixture was then left at room temperature for 72 hours and finally heated until loss of reaction to the presence of peroxides. The mixture was evaporated to dryness in vacuo and dissolved in a solution of 6 g of Nadi in 80 ml of water. After 24 hours, the pH of the mixture was adjusted to 5-6 by addition of acid.

The mixture was evaporated to dryness, which was repeated three more times with 100 ml of acetic acid each time and once with 100 ml of toluene. To the residue was added 80 mL of acetyl chloride and left at room temperature for 12 hours. The mixture was then evaporated to dryness in vacuo and acid was precipitated by addition of 20 ml of water, filtered off with suction and recrystallized from 35 ml of water. 5.7 g (50%) were obtained.

Example 2

Acid I (R ^CH CH)

Starting from 11.3 g of ester II (X = Br, R = CH 3), the procedure of Example 1 was followed. Crystallization finally gave 5.2 g (46%) of the acid.

Example 3

Acid I (R ^ = CH3)

Starting from 16.1 g of ester II (X = 1, R ² = η-Ο Ο Η Η), the procedure of Example 1 was followed. Crystallization gave 3.6 g (32 $) of acid I.

Example 4

Acid 1 (R CHCH CH).

¹

Starting from 13.5 g of ester II (X = Cl, ^RnC 6 ^H ii), the procedure of Example 1 was followed. Crystallization yielded 5.1 g (45%) of acid X.

Example 5

Acid I (R ^ CH3)

However, the portion of Example 1, peroxo compound oxidation and alkaline hydrolysis were combined in a single operation such that the starting ester was dissolved in an excess of alkaline hydrogen peroxide at 0 ° C. After 72 hours the peroxides were removed and the mixture was further processed as described in Example 1. 19 9 of acid I were obtained.

Example 6

Acid I (R ^CH CH)

The procedure was carried out entirely according to Example 1, except that the acetylation was carried out with acetic anhydride in pyridine. After processing, 27% of acid I was obtained.

Example 7

Acid I (R ^ = n-C -H ^). The reaction was carried out according to Example I, but only 130 ml of butyric acid chloride were added in the last step. The reaction mixture was then worked up in the same manner as described in Example 1 and 359 of acid I were obtained.

Example 8

Acid I (R ^ and CH ^) g of the mother liquor residue after crystallization of lactonester XII (R ”CH ^, X = Cl) was dissolved in a solution of 55 g of KOH in 750 ml of cold water. After 24 hours, the mixture was neutralized at room temperature by the addition of an ion exchanger in a Η ⁴ * cycle to pH 5-6. After filtration, the mixture was then evaporated to dryness. The residue was evaporated three times under vacuum with 200 ml of acetic acid and once with 200 ml of toluene. Acetyl chloride (500 ml) was added to the residue with cooling and left at room temperature for 12 hours with occasional stirring. The mixture was evaporated in vacuo and 100 mL of cold water was added. The resulting acid was recrystallized from 200 mL of water to give 30 g of product 1 (36%).

Claims (2)

SUBJECT OF THE INVENTION 1 * A process for the preparation of (3a, xL, 4R, 5is (6a, 6) hexahydro-5-acyloxy-4-kBrboxy-2H-cyclopentine) 3-furan-2-one of the general formula I B-Lcoo wherein B is C 1 -C 3 alkyl, characterized in that the 5-halo-2-keto-bicyclo-2,2,11-heptane-7-carboxylic acid alkyl ester of formula II wherein B is alkyl β 1 to C 6 carbon atoms and X denotes chlorine, bromine or iodine by treatment with a peracid, preferably a solution of peracetic acid in dichloromethane or dichloroethane, or hydrogen peroxide, to give 5-lactone (5-halo-3-hydroxy-2-alkoxycarbonyl-cyclopent-1) -yl) acetic acids of formula III (III), wherein Hal is as defined above, which, by treatment with alkaline reagents, provides the salt of (lot, 2 / 1,3 (1,5) -) - (3,5-dihydroxy) -2-carboxy-cyclopent-1-yl) -acetic acid of formula IV OH (IV), where the label is an alkali metal which is converted without isolation by acidifying the reaction mixture with an organic or inorganic acid, preferably acetic acid, to (3a4.4 / 1.5%, 6a). carboxy-2H-cyclopentafb2-furan-2-one of formula V, which is converted to the product of formula I by treatment with an chelating agent, preferably an excess of acetyl chloride. 2. The method according to claim 1, wherein the product is a single operation. the whole process is carried out without isolating the intermediate3. 2. The process of claim 1 wherein the oxidation of the peroxy compound and the alkaline hydrolysis are combined and both operations are performed with an alkaline solution of hydrogen peroxide.