HU206695B - Process for producing epoxy-carbamae derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of compounds of formula (I), which may be used as intermediates, wherein R is C 1-6 alkyl. The process involves reacting 1,3-cyclopentadiene with a carbamate of formula (II) followed by a compound of formula (IV) with a suitable epoxidant. NHCOOR (I) (II) NHCOOR (iv) EN 206 695 B Scope of the description: 4 pages (including 1 sheet)

Description

The present invention relates to a process for the preparation of a carbamate derivative of formula (I) which can be used as an intermediate in the manufacture of a medicament.

European Patent 0127143 discloses certain cycloalkanolaminoalkylaryl ketone derivatives useful as antihypertensive agents. One class of these compounds can be prepared by using the compound of formula (A) as an intermediate, wherein

Ph is a phenyl ring optionally substituted with up to 3 substituents selected from C 1-6 alkyl or C 1-6 alkoxy, halogen, nitro, trifluoromethyl or trifluoromethoxy.

The carbamate derivatives of formula (I) are cis-hydroxytransphenoxycyclopentylamine compounds of the formula (A) which are incorporated herein by reference. Intermediates of the production process described in our application, incorporated herein by reference.

The process of the present invention provides compounds of formula I wherein R is C 1-6 alkyl.

The term "C 1-6 alkyl" as used herein, means a straight or branched chain or cyclic alkyl group having up to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, η-butyl, t-butyl, pentyl. , hexyl, cyclopropyl or cyclopentyl.

In the process of the present invention, the cyclopentadiene (II) is reacted with a carbamate compound (ΙΠ) where R is a C 1-6 alkyl group to give the corresponding compound (IV) which is treated with a suitable epoxidant.

Reaction of the compounds of the formulas II and III gives the N-cyclopentenylcarbamate derivative of the formula IV wherein R is a C 1-6 alkyl group.

This reaction is carried out in the presence of an acidic catalyst such as boron trifluoride, aluminum chloride or methanesulfonic acid, preferably methanesulfonic acid. Approximately one mole of the acid catalyst per mole of the compound of formula (III). 0.05 to approx. An amount of 0.3 mol is used.

The molar ratio of compound of formula (III) to cyclopentadiene can vary widely, but is generally about 1 to about 1 mol of compound of formula (III). 1 - approx. 4 mol of cyclopentadiene were used.

The reaction is usually carried out in an organic solvent such as acetonitrile, toluene, dichloromethane or methylene chloride. The reaction temperature is preferably 10 to 80 ° C, more preferably 50 to 70 ° C, and the reaction time is suitably 0.5 to 6 hours.

Preferably, the compound of formula (IV) is recovered from the reaction zone prior to the next step of the synthesis. This can be accomplished by a variety of methods known in the art, such as vacuum distillation or extraction with a two-phase solvent system. Suitable biphasic systems for this purpose include methylethyl ketone / water, hexane / water and toluene / ethylene glycol. The desired product appears in the organic phase. In industrial scale production, the preferred method is to dissolve the crude carbamate derivative in a mixture of hexane and methylene chloride, followed by a mixture of methanol, water and sodium chloride 60: 40: 2 40: 60: 2, more preferably 49: 49 : 2.

In the next step of the synthesis, N- (2,3-epoxy-cyclopentyl) -carbamate of formula (I) is prepared, wherein R is as defined in formula (IV). THE

The 2,3-epoxy substituent is preferably in the cis position.

The compound of formula (I) of the desired configuration is prepared by treating the N-cyclopentenylcarbamate of formula (IV) with a suitable epoxidizing agent such as an alkyl peracid, an aryl peroxyacid or vanadium (V) oxide and t-butyl. -hyperoxide mixture. Usually peracetic acid is used as alkyl peracid. Generally, about 1 mol of a compound of formula (IV) will have a concentration of about 1 mol. 1 - approx. 1.5 M epoxidizing reagent was used.

The reaction is usually carried out in an organic solvent such as methylene chloride, toluene, hexane or dichloroethane for about 10 minutes. 10 and approx. 20 ° C. The reaction time is approx. 1 hour approx. It can take up to 17 hours.

After completion of the reaction, the reaction mixture is usually treated with an inorganic or organic base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide or triethylamine. N- (2,3-epoxy-cyclopentyl) -carbamate is present in the organic phase and can be used as an intermediate without further purification. The compound of formula (I) obtained by the process of the present invention can be converted to the oxazolone of formula (VI) wherein Ph is a phenyl ring and then hydrolyzed to form cis-hydroxy-trans-phenoxy-cyclopentylamine.

The following examples are intended to illustrate the invention but are not intended to limit its scope.

/. example

Procedure for the preparation of N-cloplopentylmethyl carbamate Methylsulfonic acid (1 mole) and methanesulfonic acid (19.6 g, 0.1 mol) were dissolved in toluene (150 g) and freshly distilled (132 g, 2 moles) at 75 'C over 1 hour cyclopentadiene. After the addition was complete, the solution was heated for an additional 1 hour, cooled to room temperature, and washed with 100 g of 10% sodium hydroxide solution and 100 g of water. The organic layer was evaporated under reduced pressure and the product was obtained by fractional distillation at 100 ° C and 67 Pa to give 79.0 g of liquid N-cyclopentylmethyl carbamate (yield 56%).

Example 2

Process for the preparation of N- (2,3-epoxy-cyclopentyl) -methyl carbamate

110 g (0.68 mol) of N-cyclopentylmethyl carbamate and

695 Β g of sodium acetate are dissolved in 629 g of methylene chloride and 155 g of 35% peracetic acid are added over 1 hour at 10-15 ° C. The reaction mixture was stirred at 14 ° C for 24 hours and then diluted with 248 g of water, then neutralized by careful addition of 187 g of 50% sodium hydroxide solution and 32 g of 30% 5% sodium bisulfite. The organic layer was separated from the aqueous layer and set aside for further purification. The aqueous layer was extracted with methylene chloride (2 x 120 g). The organic phases were then combined and concentrated under reduced pressure to give crude N- (2,3-epoxycyclopentyl) methylcarbamate as a 110 g thick oil which was used in the next step of the synthesis without further purification. A sample of analytical purity can be prepared by column chromatography using silica gel as the stationary phase and ethyl acetate / hexane as the mobile phase. Melting point 44-45 ° C.

Claims (3)

PATENT CLAIMS A process for the preparation of a compound of formula 0 wherein R is a C 1 -C 6 alkyl group by reacting 1,3-cyclopentadiene in the presence of an acidic catalyst with a substituted carbamate of formula (HE) wherein R is as defined above. The compound of formula (IV) wherein R is as defined above is reacted with a suitable epoxidizing agent. Process for the preparation of a compound of formula (Γ) according to claim 1, wherein R is methyl, characterized in that the appropriate starting materials are used. The process for the preparation of a compound of formula (I) according to claim 1, wherein the 2,3-epoxy group is in the cis position, characterized in that the appropriate starting materials are used.