CS215681B1 - Process for the preparation of 5-halo-7-hydroxymethyl-bicyclo (2,2,1) -heptan-2-one - Google Patents

Abstract

The invention relates to a compound of the general formula where X denotes chlorine, bromine or iodine, suitable for further preparation of prostaglandin. The essence of the invention lies in the fact that 3-oxo-tricyclo-(2,2,1,0 ’ 7 heptane-7-carboxylic acid is treated with alcohol in the presence of a catalyst and solvents, the reaction mixture is neutralized to a ketal, which is reduced to a hydroxymethyl ketal. Subsequent deketalization with a ketone leads to the formation of 7-hydroxymethyl-tricyclo(2,2,1,0 2’6)heptan-2-one, which is cleaved by the action of hydrohalic acid to form 5-halogeno-7-hydroxymethyl-bicyclo (2,2,1)heptan-2-one. The invention is useful in agriculture, especially for controlled oestrus in cattle.

Description

The present invention relates to a process for the preparation of 5-halo-7-hydroxymethyl-bicyclo (2,2,1) heptan-2-one in general.

(I) wherein X represents chlorine, bromine or iodine.

The compounds of formula (I) are important intermediates in the synthesis of prostadienoic acid derivatives, known as prostaglandins, from which derivatives (3a cf., 4 β>, 5,6aα) (hexahydro-5-hydroxy-4- The hydroxy-methyl-2H-cyclopenta (b) furan-2-one, which is the basic starting material in the synthesis of primary and derived types of prostaglandins, is very complex in the literature and is quite complex in the literature. low yields (see for example J.Amer.Chem.Soc. 95, 7522 (1973); U.S. Pat. No. 3,943,115).

The present invention provides an improved process for the preparation of compounds of formula (I) which is based on 3-oxo-tricyclo (2,2,1,0 ') heptane-7-carboxylic acid II

A (II) is treated with an alcohol or a diol containing 1 to 3 carbon atoms to catalyze acidic reagents in the presence of an organic solvent such as benzene, toluene and lower chlorinated alkanes, and the resulting reaction water is separated by azeotropic distillation or by an inorganic desiccant. After completion of the reaction, the reaction solution is neutralized preferably with sodium bicarbonate and, after evaporation of the solvents, the ketal of the acid, optionally partially esterified with the alcohol used, of formula III, is isolated,

(III) wherein R represents an alkyl of 1 to 3 carbon atoms or together R + R represents a - (OH ₂ ) _{n -} group wherein n = 2 to 3.

In the next step, reduction of the ketal III with a complex hydride (molar ratio 1: 0.75 to 2) at 0 to 60 ° C yields the corresponding hydroxymethyl ketal IV,

MSW ^OR 2 wherein R is as defined above, then under acid catalysis deprotected R.

This decetalization is carried out with a lower ketone having 3 to 6 carbon atoms in the presence of a strong organic acid (e.g. t-toluenesulfonic acid) or an ion exchanger in an H ⁺ -cycle at 2 [deg.] C elevated temperature. From the 7-hydroxymethyl-tricyclo [2.2.1.0 '] heptan-3-one thus prepared

Subsequent treatment with the hydrohalic acid cleaves the C-C bond of the cyclopropane moiety to give the desired crystalline halogen derivative of the Formula I in high yield, which is readily purified by crystallization from a suitable solvent.

The process according to the invention brings a technological simplification of the production of the compounds of the general formula I. The advantage of the process according to the invention is that all the reaction steps can be carried out on a technological scale without difficulty using cheap and readily available reagents.

Both reactions (IV -> V -> 1) can be carried out in one step by treatment with hydrohalic acid at a temperature of 20 to 120 ° C, in which in one step the C-C bond of the cyclopropane group is split and decetalized. In terms of technical solution and yields and purity of the product, the two-step process is preferable.

The invention is not limited to the specific conditions set forth in the following examples, which are illustrative only and not limiting.

Example 1

3-Oxo-tricyclo [2.2.1.0] (heptane-7-carboxylic acid) ethylene ketal compound of formula III wherein R + R = (CH3) g)

Reaction water was separated from a mixture of 23.65 g (155 millimoles) of the keto acid (compound of formula II), 21.24 g (19.8 ml) of ethylene glycol, 150 mg of p-toluenesulfonic acid and 200 ml of benzene using azeotropic adapter. After heating for 12 hours at a bath temperature of 115-120 ° C, a total of 5.7 ml of water was separated. After cooling, the benzene solution was washed with 10 ml of saturated sodium bicarbonate solution, 10 ml of saturated sodium chloride solution and dried over magnesium sulfate, and the solvents were removed by rotary evaporation. 34.15 g of an oily product are obtained, the structure of which is in accordance with the interpretation of the mass, infrared and proton NMR spectra.

Example 2 p Z ·

7-Hydroxymethyl-trioylcloyl (2,2,1,0 ') heptan-3-one (IV), wherein R + R = (CH2 _{) 2}

To a suspension of 7 g of lithium aluminum hydride in 400 ml of ether was added 34.15 g of ethylene ketal of formula III (see Example 1) dissolved in 100 ml of ether over 0.5 hour. After heating to boiling for 2 hours, the reaction mixture was cooled and quenched with 28 ml of 4% sodium hydroxide solution, the precipitated inorganic salts were aspirated, decanted with 100 ml of hot ether and distilled from the combined ether extracts after drying with magnesium sulfate. an oily product which was uniform according to gas chromatography and whose structure was in accordance with the interpretation of spectral data.

Example 3

P £.

7-Hydroxymethyl-tricyclo [2.2.1.0 '(heptan-3-one) compound of formula V]

A mixture of 6.42 g of 7-hydroxymethyl-tricyclo [2.2.1.0.2 < ² >] heptan-3-one (IV, R < + > of water and 50 ml of acetone was stirred at gentle reflux for 10 hours. Progress of the reaction was monitored by thin layer chromatography on silica gel (eluent of 4% methanol in chloroform). After the decetalization was complete, the ion exchanger was filtered off, washed with acetone, the acetone solution was evaporated to dryness on a rotary evaporator, 50 ml of chloroform were added to the residue, the aqueous phase was separated and after drying the chloroform solution with magnesium sulfate. the chloroform was distilled off in vacuo. 4.5 g (93.3%) of an oily product were obtained. The structure of the product was confirmed by spectral data.

Example 4

7-Hydroxymethyl-5-chloro-bicyclo [2.2.1] heptan-2-one] Compound (I) wherein X = Cl / Procedure A:

To a solution of 19.1 ethylene ketal of formula V (see Example 2) in 530 mL of methanol, hydrogen chloride gas was bubbled through the reaction mixture for 2.5 hours. Then the methanol was distilled off in vacuo, 60 ml of conc. hydrochloric acid and refluxed again for 2 hours. After distilling off the hydrochloric acid, the oily residue was dissolved in 50 ml of chloroform, the aqueous phases separated and the chloroform washed with saturated sodium bicarbonate solution. After drying the chloroform solution with magnesium sulfate, the solvents were distilled off and crystallization from benzene yielded 8.2 g of the product.

up to 82 ° C, whose structure was in accordance with the interpretation of the mass spectrum.

Procedure B:

p £,

To 502 mg of 7-hydroxymethyl-tricyclo [2.2.1.0] heptan-3-one of formula V was added 6 ml of hydrochloric acid and 1 ml of acetic acid and the reaction mixture was heated at 70-80 ° C for 10 hours. Then the reaction mixture was evaporated in a vacuum rotary evaporator and the product extracted with chloroform, the chloroform extracts washed with saturated brine, dried over magnesium sulfate and the solvents evaporated. Crystallization of the residue from benzene isolated 562 mg of product m.p. Mp 81-82 ° C. .

Example 5

5-Bromo-7-hydroxymethyl-bicyclo [2.2.1] heptan-2-one] compound of formula I wherein X = Br)

To 435 mg of the ketoalcohol V was added 4 mL of hydrobromic acid and 1.5 mL of acetic acid. The reaction mixture was left at room temperature for 3 hours and then heated to boiling for 1.5 hours. After concentrating the reaction mixture to a small volume, the organics were extracted into chloroform. The chloroform solution was washed with 2% sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. After evaporation of the chloroform, 557 mg (81%) of white crystals of the product were obtained from the distillation residue by crystallization from benzene. Mp 87 ° C. Spectral characteristics were in accordance with the proposed structure.

Example 6. .

7-Hydroxymethyl-5-iodo-bicyclo [2.2.1] heptan-2-one] a compound of formula I wherein X = 1 / o

A mixture of 599 mg of 7-hydroxymethyl-tricyclo [2.2.1.0] heptan-3-one carboxylic acid in 8 ml of hydroiodic acid was heated to boiling for 1-2 hours after stirring at room temperature. After concentrating the reaction mixture on a rotary evaporator, the reaction mixture was worked up in the usual manner as in Example 5. 785 mg of crystalline product was obtained, mp 116-118 ° C. The mass and ³ H NMR spectra were consistent with the proposed structure.

Claims (5)

A process for the preparation of 5-halo-7-hydroxymethyl-bicyclo [2.2.1] heptan-2-one of the general formula I, (I) wherein X represents chlorine, bromine, iodine, 26, characterized in that the 3-oxo-tricyclo [2.2.1.0 '] heptane-7-carboxylic acid of formula (II), (II) is converted into the ketal of formula (III) in the presence of an organic solvent wherein R is C 1 -C 3 alkyl or together R + R is - (CH ₂ ) _n - wherein n = 2 to 3, after which Be obtained the alcohol of formula IV after reduction with a complex hydride at 0 to 60 ° C (IV) wherein R ⁵ my abovementioned meanings, in an environment deketalized ketone containing 3 to 6 carbon uhlí2 6 to catalysis acid-forming agents and the resulting 7-hydroxymethyl-tricyclo / 2,2, l, 0 '/ heptane-3- one of formula V by treatment with hydrohalic acid at a temperature of 20 to 120 ° C gives the desired product of formula X. 2. The process according to claim 1, wherein the alcohol is methanol and the diol is ethylene glycol. 3. A process according to claim 1, wherein the acidic reagent is p-toluenesulfonic acid or phosphorus oxytrichloride or an ion exchanger in the H < 3 > -cycle. 4. The process of claim 1 wherein the complex hydride is lithium aluminum hydride, sodium aluminum hydride, sodium borohydride or sodium dihydro-bis- (2-methoxyethoxy) aluminate in a molar ratio of ketal of formula III: complex hydride of 1: 0.75 to 2. 5. A process according to claim 1, wherein the hydrohalic acid is hydrochloric, hydrobromic or hydroiodic.