HU213385B - Process for the preparation of ethyl-4-(trichloro-acetamido)-5-hexenoate - Google Patents

Abstract

The present invention relates to a novel process for the preparation of ethyl 4- (trichloroacetamino) -5-hexenoate. According to the present invention, (i) dehydrated and formylated in the presence of erythritol formic acid during a thermal reaction; (ii) reacting the resulting 4- (formyloxy) -3-hydroxy-1-butene with triethyl orthoacetate under thermal reaction conditions to give ethyl 6- (formyloxy) -4-hexenoate in the presence of ethanol and hydrochloric acid. Converted to 6-hydroxy-4-hexanoate; (iii) converting the thus obtained ethyl 6-hydroxy-4-hexenoate by reaction with trichloroacetonitrile to ethyl 6- (trichloroacetimidyloxy) -4-hexenoate and then rearranging this compound thermally. EN 213 385 B Scope of the description: 5 pages (including 2 sheets)

Description

The present invention relates to a process for the preparation of a compound of formula (6) by thermal rearrangement reactions. The compound in question is an intermediate of the process for the preparation of 4-amino-5-hexenoic acid according to Scheme B.

4-Amino-5-hexenoic acid, also known as vigabatrin or vinyl-GAB A, is a GABA-T inhibitor marketed under the trademark SABRIL for the treatment of epilepsy (see SM Grant et al., Drugs, 41 (6)). : 889-926,1991).

The present invention relates to a process for the preparation of ethyl 4- (trichloroacetamido) 5-hexenoate which comprises (i) dehydrating and formylating erythritol in the presence of formic acid in a thermal reaction;

(ii) reacting the resulting 4- (formyloxy) -3-hydroxy-1-butene with triethyl orthoacetate under thermal reaction conditions to form the ethyl 6-formyloxy-4-hexenoate in the presence of ethanol and hydrochloric acid. converting it to hydroxy-4-hexenoate;

(iii) converting the resulting ethyl 6-hydroxy-4-hexenoate to ethyl 6- (trichloroacetimidoyloxy) -4-hexenoate by reaction with trichloroacetonitrile, followed by thermal rearrangement.

The process of the invention is based essentially on known thermal reactions using an erythritol starting compound. Thermal reactions include the elimination reaction (1) resulting in the double bond, the Claisen rearrangement (2), and the Overman rearrangement (3). The process of the present invention is illustrated in Scheme A.

Step (a) of the process is a known thermal rearrangement reaction to produce 4- (formyloxy) -3-hydroxy-1-butene (2) from erythritol (1) (see Prevost, C., Ann. Chem.). [10], 10, 398, 1928). Although it is not necessary to process the reaction mixture, it is possible to obtain a better yield of the pure compound by purifying the product again by distillation. In step (b), a second thermal rearrangement reaction followed by hydrolysis is carried out by heating 4- (formyloxy) -3-hydroxybutbutene to 140-150 ° C in the presence of excess orthoacetate (4-1) under reaction conditions. between which the alcohol formed is removed in situ (see Johnson W. and Coll. J. Am. Chem. Soc. 92, 741, 1970). After removal of the excess orthoacetate or after hydrolysis, the resulting ethyl 6- (formyloxy) -4-hexenoate can be used in this form in the next reaction step or, if desired, purified by distillation or purified by flash chromatography on silica gel. Alternatively, the above thermal rearrangement may be carried out using an equivalent amount of orthoacetate in an inert solvent, the solvent having a boiling point of ca. Between 140 ° C and 150 ° C (eg xylene). The reaction time of the above reactions can be monitored by measuring the amount of alcohol (methanol or ethanol), since this alcohol is distilled from the reaction mixture.

In step (c), the formate is converted to the corresponding alcohol compound so that the formate is ca. The mixture was allowed to stir at 15-25 ° C in dry ethanol to which a catalytic amount of alcoholic hydrogen chloride gas solution was added. In step (d), trichloroacetonitrile is reacted with ethyl 6-hydroxy-4-hexenoate in the presence of a catalytic amount of sodium hydride (about 0.1 equivalents) in an aprotic dry solvent (preferably dry ether) under a gas atmosphere, preferably nitrogen. At 0 ° C. Thus, the imidate (5) intermediate is formed in situ, which is then converted, by thermal rearrangement, to the ethyl 4-trichloroacetamido-5-hexeonate (6). The thermal rearrangement reaction is carried out according to the procedure described in Overman L.J., Am. Chem. Soc. 98, 2901, 1976.

The advantages of the process according to the invention are as follows:

(1) no carcinogenic material is used or hazardous reactants or solvents are used, (2) the starting material can be obtained from a cheap raw material (potato starch), (3) the reaction sequence can be carried out in only one purification step. until the final hydrolysis step, (4) only a small number of organic solvents are used, (5) excess reactants (e.g. trichloro-orthoacetate) and solvents (e.g. xylene) can be recovered or recycled, (6) no undesirable by-products are formed, (7) the reactions are easy to perform, no special temperature control is required and the products can be purified without chromatography.

The process of the invention is illustrated in detail by the following example.

Example 1

Step a) Preparation of 4- (formyloxy) -3-hydroxy-1-butene:

A solution of erythritol (g, 0.5 mol) in aqueous formic acid (150 g, 75%) was heated above 100 ° C for 12 hours, then the water and formic acid were distilled off from the reaction mixture and the reaction mixture was heated above 200 ° C. burner. The product is swallowed by distillation (m.p. 230 ° C, 30 g) and purified by distillation.

(M.p .: 90 ° C / 15 mmHg, 1995 Pa).

1 H NMR Spectrum (90 MHz) (CDCl 3, TMS) δ ppm.

3.23 (s, IH, OH), 3.6 (m, IH, CH), 4.23 (t, 2H, _CH2), 5.33 (m, 2H, _CH2 =), 5.83 (m, IH, CH =); 8.16 (s, 1H, HCO ₂ ).

Step b) Preparation of Ethyl 6- (Formyloxy) -4-Hexenoate:

A mixture of 1.06 g (10 mmol) of 4- (formyloxy) -3-hydroxy-1-butene and 1 drop of propionic acid in 6 g (40 mmol) of triethyl orthoacetate was heated to 140 ° C while distilling the ethanol. is removed. After 2 hours, excess ethyl orthoacetate was removed by vacuum distillation. The residue was hydrolysed with water and the aqueous mixture was extracted with ethyl acetate. The product was purified by flash chromatography

Purification on silica gel (2: 8) using ethyl acetate: hexane as eluant gave 1 g of product, 60% yield. Preferably, a distillation purification step may also be used if a larger amount of product is produced.

1 H NMR (90 MHz) (CDCl ₃ , TMS) δ ppm. 1.26 (t, 3H, CH ₃ , J = 6Hz), 2.4 (s, 4H, (CH ₂ ) ₂ ), 4.1 (q, 2H, CH ₂ , J = 6Hz), 4.6 (d, 2H, CH ₂ -C =, J = 6 Hz), 5.73 (m, 2H, CH = CH), 8:06 (s, 1 H, HCO _2).

Step c) Preparation of ethyl 6-hydroxy-4-hexeonate:

To a solution of ethyl 6- (formyloxy) -4-hexenoate (0.9 g, 5 mmol) in dry ethanol (10 mL) was added a few drops of a saturated alcoholic hydrogen chloride solution and the mixture was heated at 20 ° C for 2 hours. The solvent was evaporated in vacuo and the residue used in the next step without purification (0.7 g quantitative). The compound is partially decomposed by flash chromatography on silica gel.

1 H NMR (90 MHz) (CDCl ₃ , TMS) δ ppm. 1.26 (t, 3H, CH ₃ , J = 6Hz), 2.4 (s, 4H, (CH ₂ ) ₂ ), 2.83 (s, 1H, OH), 4.1 (s, 2H, CH 2 -C =), 4.16 (q, 2H, CH ₃ CH ₂ , J = 6Hz), 5.7 (s, 2H, CH = CH).

Steps d) and e) Preparation of ethyl 4- (trichloroacetamido) -5-hexenoate:

To a solution of 0.7 g (5 mmol) of ethyl 6-hydroxy-4-hexenoate and 0.6 g (5 mmol) of trichloroacetonitrile in 50 mL of dry ether at 0 ° C was added 0.03 g (50% by weight) sodium hydride (0.5 mmol) was added. After stirring for 1 hour, ethanol (0.5 mmol) was added and the solvent was evaporated in vacuo. Imidate formation is monitored by NMR analysis (NH ca.

8.5 ppm). A solution of the crude imidate in xylene (30 mL) was heated to reflux for 1 hour. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (2: 8) ethyl acetate: hexane as eluent.

1.1 g of the title compound are obtained (about 70% yield). 1 H NMR (90 MHz) (CDCl ₃ , TMS) δ ppm.

1.23 (t, 3H, CH ₃ , J = 6Hz), 2.0 (t, 2H, (CH ₂ -CH ₂ -CO ₂ , J = 5Hz), 2.36 (s, 2H, CH ₂ CO ₂ ), 4.1 ( q, 2H, _{CH3 CH2,} J = 6 Hz), 4.4 (t, 1H, CH-CH _2j, J = 5 Hz), 5.1 (m, 2H, _CH2), 5.76 (m, 1H, CH = CH ₂ ) 7.2 (s, 1H, NH).

An aliquot of the sample was purified by distillation for analysis (F.p. 150 ° C, 0.5 mm Hg, 67 Pa).

Analysis calculated for C 10 H ₁₄ NO ₃ Cl ₃ : C 39.69; H4.66; Found: C, 39.87; H4.62; N4.49

Claims (1)

A process for the preparation of ethyl 4- (trichloroacetamido) -5-hexenoate comprising (i) dehydrating and formylating erythritol in the presence of formic acid in a thermal reaction; (ii) reacting the resulting 4- (formyloxy) -3-hydroxy-3-butene with triethyl orthoacetate under thermal reaction conditions to form the ethyl 6-formyloxy-4-hexenoate in the presence of ethanol and hydrochloric acid. converting it to hydroxy-4-hexanoate; (iii) converting the resulting ethyl 6-hydroxy-4-hexenoate to ethyl 6- (trichloroacetimidoyloxy) -4-hexenoate by reaction with trichloroacetonitrile, followed by thermal rearrangement. HU 213 385 B Int Cl ⁶ : C 07 C233 / 04 The ReaUcioviztat HU213 385 B Int Cl ⁶ : C 07 C233 / 04