Browse Prior Art Database

A PROCESS FOR THE PREPARATION OF METHOHEXITAL

IP.com Disclosure Number: IPCOM000236749D
Publication Date: 2014-May-14
Document File: 4 page(s) / 120K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present invention relates to a process for the preparation of Methohexital of Formula (I) and its intermediate 3-hexyn-2-ol (II).

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 40% of the total text.

Page 01 of 4

A PROCESS FOR THE PREPARATION OF METHOHEXITAL


[0001] Methohexital (I) is chemically known as (±)-1-methyl-5-(1-methyl-2-pentyl)-5- (2-propenyl)-2,4,6-(1H,3H,5H)-pyrimidinetrione.

NH

    CH3 O

CHCH2

CCH

O

CH2

N

O

CH3CH2C

Formula (I)

CH3


[0002] The present document discloses a process for the preparation of Methohexital (I) from 3-hexyn-2-ol (II). The route of synthesis is summarized in Scheme-1:

Conc. HCl 2-propanol / water

OH

CH3 CH3

Formula (II)

SOCl2, CH2Cl2,

Triethylamine

Cl

Ethyl cyano acetate, Sodium ethoxide, Ethanol, MTBE

CH3

CN

Step-(i)

CH3 CH3

Step-(ii)

Formula (III)

          COOC2H5 H3C Formula (IV)

Allyl bromide, Sodium ethoxide, Ethanol

    CH3 O

CHCH2

CCH

N

O

     CH3 HN

CHCH2

CCH

O

O

CH2

CH2

NH

N

O

NH

N-Methylurea, NaNH2, THF

Toluene

Step-(iii)

CHCH2

CCH

CN

COOC2H5

CH3CH2C

CH3CH2C

CH2

CH3CH2C

CH3

Formula (V)

Step-(v)

CH3

CH3OH/ water

CH3

Step-(iv)

Methohexital (I)

Formula (VI)

                          Scheme-1
[0003] Additionally, the present document discloses a process for the preparation of 3- hexyn-2-ol (II), which is a key intermediate of Methohexital (I), such process comprising at least the following steps:

(i) 3-butyn-2-ol in tert-butyl methyl ether is treated with ethyl vinyl ether in presence of concentrated hydrochloric acid to produce 3-(1-ethoxyethoxy)-1-butyne; this step is reported in Bulletin of the Academy of Science of the USSR, Division of Chemical Science 1965, 14(12), 2167-69;

(ii) 3-(1-ethoxyethoxy)-1-butyne is treated with diethylsulphate in presence of sodamide in THF to produce 2-(1-ethoxyethoxy)-3-hexyne;

1


Page 02 of 4

(iii) 2-(1-ethoxyethoxy)-3-hexyne in tert-butyl methyl ether is treated with concentrated hydrochloric acid to produce 3-hexyn-2-ol (II).

Example 1: Process for the preparation of Methohexital (I):

Step-(i): Process for the preparation of 2-chloro-3-hexyne (III).

Triethylamine (154.5 g) was added to the 3-hexyn-2-ol (150 g) in dichloromethane (1500
ml) at -10±2°C. Thionyl chloride (218.4 g) was slowly added to the above solution at -12±2°C. After completion of reaction the reaction mixture was quenched with DM water (750 ml) and the organic layer was separated from the aqueous layer. The organic layer was washed with 10%w/w aqueous sodium bicarbonate solution and the organic layer was concentrated under reduced pressure to produce the above title compound as a residue.

Step-(ii): 2-Cyano-3-methyl-4-heptynoic acid ethyl ester (IV).

Ethyl cyanoacetate (432.3 g) was slowly added to the 20% w/w sodium ethoxide in ethanol solution (795.9 g) at 27±2°C. 2-Chloro-3-hexyne residue (170 g) in ethanol (540 ml) was added to the reaction mixture at 25-30°C and the reaction mixture was stirred for 30 min. The temperature of the reaction mixture was increased to 60-65°C and continued the reaction till the completion. The reaction mixture was concentrated under reduced pressure at 50°C till no more solvent distils and the reaction mixture was cooled to 18±2°C. Tert- butyl methyl ether (600 ml) was added to the residue follow...