HU185518B - Process for preparing 2-/e/-phenyl-methylene-cycloheptan-1-one-/e/-oxime - Google Patents

Abstract

The invention relates to a method for producing 2- (E) -phenyl-methylene-cyclophosphatan-1-one (E) -oxime of the formula (I) in other free state by reaction of 2- (E) -phytyl-methylcycloheptane -I-ON THE FORMULA (II) WITH A HYDROXYLAMINE SALT IN THE PRESENCE OF A BASE "IN SITU" HYDROXYLAMINE DESIGNATED THAT MANUFACTURING AND IMMEDIATELY IMPLEMENTING IN A WAESSED AND / OR WATER UNMISTAKED MIXABLE LOW ALIPHATIC ALCOHOLIC MEDIUM PROCEDURE OF THE RESPONSE SET THE ALCOHOLIC STRENGTH OF THE MEDIUM AT 40 TO 60% AND ISOLATING THE 2- (E) -PHENYLMETHYLENE CYCLOHEPTAN-I-ON- (E) -OXIN IN A KNOWN WAY. THE ADVANTAGE OF THE PROCEDURE IS THAT THE DESIRED CONNECTION OF FORMULA I IS MANUFACTURABLE IN ISOMER-FREE CONDITION AND WITH VERY GOOD PROFIT. THE CONNECTION OF FORMULA I IS A KNOWN AND VALUABLE PHARMACEUTICAL INTERMEDIATE PRODUCT.

Description

The present invention relates to a process for the preparation of the 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime of formula (I) in the free form from other isomers. The compound of formula (I) is an intermediate of valuable pharmaceutically active derivatives, which may be used, inter alia, in U.S. Pat. for the synthesis of compounds known from the Hungarian patent.

No process for the preparation of the compound of formula (I) has been reported in the literature.

It is known that a ketone reacts with hydroxylamine "in situ" formed from a hydroxylamine salt in the presence of a base to produce an oxime. Depending on the structural properties of the starting ketone, two isomers may be formed during the reaction. In their simplest case, the compounds of color and anti-complex structures are designated by the designation Z or E, respectively.

The biological activity of the various isomers is known to differ from each other and it is therefore necessary to prepare them purely, which can only be solved from intermediates without isomers.

It has been the object of our research to develop a process for the preparation of 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime in a form free from other isomers.

It has been found that by reacting 2- (E) -phenylmethylene-cycloheptan-1-one of the formula (II) and / or a water-miscible lower aliphatic alcoholic medium with hydroxylamine formed in situ from a hydroxylamine salt in the presence of a base, the alcohol content of the reaction medium is adjusted to 40-60%, preferably 50%, practically the desired (E, E) isomer can be isolated from the reaction mixture. The product contains up to 5% of other isomers which may be purified by methods known per se, if desired.

The starting compound of formula (II) is known and can be prepared by methods described in the literature (e.g., Gazz. Chim. Ital., 91, 326-48 (1961).) Hydroxylamine salts (sulfate, hydrochloride) are commercially available.

The reaction of 2- (E) -phenylmethylene-cycloheptan-1-one with hydroxylamine "in situ" from the hydroxylamine salt (preferably sulphate or hydrochloride) is carried out in aqueous and / or aqueous alcoholic media. For this purpose, straight or branched aliphatic alcohols which are miscible with water can be used. For example, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol. Preferably, the reaction is carried out in a mixture of alcohol and water, preferably a mixture of (50-98): (2-50). After completion of the reaction, the alcohol concentration is adjusted to 40-60%, preferably ca. To 50%.

The reaction is carried out in the presence of a base. Organic bases (pyridine or a mixture of pyridine bases, i.e. 2,3- and 4-picolines, and lutidine) or inorganic bases (alkali metal hydroxides, carbonates or bicarbonates) can be used for this purpose.

The reaction temperature can be varied over a wide range without significantly affecting production. Generally, temperatures of from 20 to 90 ° C, preferably from 75 to 85 ° C, are employed.

The stereochemical purity of the prepared 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime depends on the stereochemical purity of the 2- (E) -phenylmethylene-cycloheptan-1-one used. In fact, if the latter compound is contaminated with a greater amount of its 2- (Z) -isomer, the number of possible isomeric impurities is doubled, and the impurity of the resulting product may exceed the limit given by us.

If a particularly pure product is required, the crude product of the reaction can be purified by methods known per se (e.g., column chromatography, distillation, zone melting, crystallization from petroleum ether or ethanol).

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

Example 1 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one and

7.65 g (0.11 mol) of hydroxylamine hydrochloride are dissolved in 100 cm ^{3 of} 96% ethyl alcohol and 5.94 g (0.056 mol) of sodium carbonate are added to the reaction mixture. It is then heated to reflux and maintained at this temperature until the evolution of carbon dioxide gas has ceased. 98 g of crushed ice are then added to the reaction mixture, and the crystalline 2- (E) -phenylmethylene-cycloheptanone-1- (E) -oxime is isolated by filtration.

Yield: 19.8 g (92%) white, crystals. Mp: 67 ° C

Calculated for C ₄ H ₁₇ NO (215.29) Analysis:

Calculated: C, 78.1; H, 7.96; N, 6.5%.

Found: C: 78.0% H: 8.0% N: 6.5%

NMR (CDCl ₃ ): 6.95 ppm

6.55 ppm

2.5 ppm

U.V. λmax: 258 nm; (258) = 740.23

Example 2:

g (0.1 mol) of 2- (E) -phenylmethylenecycloheptan-l-one in 100 cm ³ of methyl alcohol was added (0.11 mole) of hydroxylamine hydrochloride, 7.64 g and 8.7 g (0.11 mole ) pyridine was weighed. The reaction mixture was stirred for 2 hours at room temperature and then 100 g of crushed ice was added. White crystalline form precipitates

2- (E) -phenylmethylenecycloheptan-l-one- (E) -oxime.

Yield: 16.55 g (76.97%) Mp: 66-67 ° C

The analytical data are the same as in Example 1.

Example 3 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one,

7.64 g (0.11 mol) of hydroxylamine hydrochloride and 5.83 g (0.055 mol) of sodium carbonate are reacted in 200 cm ^{3 of} ethanol-water (1/1) at the boiling point of the reaction mixture and the mixture is then stirred vigorously. Cool to 5-10 ° C. Crystalline 2- (E) phenylmethylene-cycloheptan-1-one (E) -oxime is isolated from the reaction mixture by filtration.

Yield: 17.65 g (82%) Mp: 66-67 ° C

Example 4 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one, 100 cm ^{3 of} water, 8.7 g (0.11 mol) of pyridine and 7.64 g of (O) Hydroxylamine hydrochloride (11 mol) was stirred at 80 ° C for several hours with vigorous stirring, then ethyl alcohol (100 cm ³ ) was added to the reaction mixture and stirred until crystallized under slow cooling.

Yield: 15.7 g (72.92%) of white crystalline 2- (E) phenylmethylene-cycloheptan-1-one (E) -oxime. Mp: 66-67 ° C.

-2185 518

Example 5 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one and

Hydroxylamine sulfate, 21.49 g (0.11 mole) of 95 cm ³ and 5 cm ³ propanol-water mixture, and stirring

10.94 g (0.056 mol) of potassium carbonate are added, g After a few hours of reflux, the reaction is complete. The reaction mixture is cooled to about 50 ° C and 100 g of crushed ice are added, and the crystals are filtered off and dried.

Yield: 18.48 g (87.5%) of a white crystalline solid which has a minimum of 95% 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime. Mp: 67 ° C

Calc'd for C ₁₄ H ₁₇ NO (215.29) Analysis:

Calculated: C, 78.1; H, 7.96; N, 6.5;

Found: C, 77.91; H, 7.8; N, 6.47.

Example 6 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one and 7.65 g (0.11 mol) of hydroxylamine hydrochloride in 100 cm ^{3 of} ethyl alcohol with vigorous stirring to boiling point heat and a solution of 6.17 g (0.11 mol) of potassium hydroxide in 100 cm ^{3 of} water is added dropwise to the reaction mixture. After half an hour of reaction, 2- (E) -phenylmethylene-cycloheptan-1-one (E) -25-oxime is crystallized by slow cooling.

Yield: 20.3 g (94.3%) Mp 67 ° C.

Example 7 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one, m.p.

Of hydroxylamine hydrochloride, 90 cm ³ of ethanol, 10 cm ³ of water and sodium hydrogen carbonate, 9.24 g (0.11 mol) 7.65 g (0.11 mole) are refluxed with stirring for 3 hours, and then 80 g of crushed ice was added to the reaction mixture, and the white crystalline 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime was filtered off and dried.

Yield: 20.2 g (93.8%) Mp 67 ° C.

Calc'd for C ₁₄ H ₁₇ NO (215.29) Analysis:

Calculated: C, 78.1; H, 7.96; N, 6.5;

Found: C, 78.23; H, 7.72; N, 6.53.

Claims (6)

PATENT CLAIMS A process for the preparation of 2- (E) -phenylmethylene-cycloheptane l-one (E) -oxime of formula (I) in free form from other isomers using 2- (E) -phenylmethylene-cycloheptan-1-one of formula (Π) and by reacting hydroxylamine "in situ" formed from a hydroxylamine salt in the presence of a base, characterized in that the reaction is carried out in an aqueous and / or water-miscible lower aliphatic alcoholic medium, and after the reaction is adjusted to 40-60% and isolating the 2- (E) phenylmethylene-cycloheptan-1-one (E) -oxime in a manner known per se. Process for carrying out the process according to claim 1, characterized in that the reaction is carried out in a straight or branched chain alcohol having 1 to 3 carbon atoms, preferably ethanol. 3. The process according to claim 1, wherein the reaction is carried out in a mixture of alcohol and water. 4. A process according to claim 3 wherein the medium is a mixture of alcohol and water (50-98): (2-50). 5. A process according to any one of claims 1 to 6, wherein the alcohol content of the medium is adjusted to 40-60% by addition of water (ice) or infinitely miscible water, preferably about ca. To 50%. 6. Process for carrying out the process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature of from 20 to 90 ° C, preferably from 75 to 85 ° C.