GB2212492A

GB2212492A - Process for the manufacture of a thiazine derivative

Info

Publication number: GB2212492A
Application number: GB8726864A
Authority: GB
Inventors: Michael Hilary Burke; Anthony William Fitzgerald
Original assignee: Individual
Current assignee: Individual
Priority date: 1987-11-17
Filing date: 1987-11-17
Publication date: 1989-07-26
Anticipated expiration: 2007-11-17
Also published as: GB8726864D0; GB2212492B

Abstract

A highly yielding process for the preparation of xylazine base (i) comprises reacting the thiourea (ii) with 3-amino-1-propanol (iii) at a temperature of from 123 DEG to 127 DEG C for a period of from 2.5 to 3.0 hours. <IMAGE>

Description

This invention relates to an improved process for the manufacture of xylazine base.

Xylazine ((N-2,6-dimethylphenyl)-5,6-dihydro 4H-1,3 -thiazin-2-amine) is used in veterinary medicine as an analgesic, muscle relaxant and sedative.

Processes for preparing xylazine base are described, for example, in U.S. Patent Specification No. 3,235,550. Example I of the latter Specification describes the preparation of xylazine base from 2,6-dimethylphenyl isothiocyanate and 3-amino-lpropanol, the 2,6-dimethylphenyl isothiocyanate being formed by the reaction of thiophosgene with 2,6-dimethylaniline. Thiophosgene is a hazardous chemical being highly toxic by ingestion and inhalation.

Examples IV and V of U.S. Patent Specification No.

3,235,550 describe the preparation of xylazine from N- (2, 6-dimethylphenyl) thiourea with l-chloro-3 bromopropane and 3-chloropropylamine- (1), respectively.

No yields of the product are given in Examples IV and V of U.S. Patent Specification No. 3,235,550. However, the processes described in said Examples cannot be performed on a commercially viable scale. Furthermore, when the Examples were repeated by the Applicants, a yield of only 20% was obtained.

It is an object of the present invention to provide an improved process for the manufacture of xylazine base which results in yields of xylazine base which are higher than those obtained in conventional methods for its preparation and which process does not involve the use of any hazardous chemicals.

According to the invention there is provided a process for the preparation of xylazine base ((N-2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2- amine) of the formula:

which comprises reacting N-(2,6-dimethylphenyl) thiourea of the formula:

with 3-amino-l-propanol of the formula: NH2 (CH2) 30H (III) at a temperature of from 1230 to 127 0C for a period of from 2.5 to 3.0 hours.

The Applicants have found it is critical to carry out the reaction in the above temperature range for the time specified. The formation of end product and the progress of the reaction has been monitored by high performance liquid chromatography (HPLC) which has enabled the optimum conditions of the reaction to be determined.

Preferably the reaction is carried out at a temperature of 1250C for 2.75 hours.

Preferably the compound of formula (II) is reacted with a molar excess of the compound of formula (III).

The reaction is preferably carried out in the presence of an inorganic acid, especially in the presence of hydrochloric acid.

The liberation of xylazine base from its acid salt is achieved by reacting the salt with an inorganic base, especially ammonium hydroxide. The use of ammonium hydroxide is found to give a particularly effective precipitation of the xylazine base.

Preferably, the compound of the formula (II) is prepared by reacting 2,6-dimethylaniline of the formula

with benzoyl thiocyanate of the formula

to form benzoyl thiourea of the formula

The benzoyl thiourea of the formula (VI) thus formed is reacted with a base in an aqueous medium so as to form the compound of the formula (II).

Preferably the base used is sodium hydroxide.

The benzoyl thiocyanate of the formula (V) is in turn preferably prepared by reacting benzoyl chloride of the formula

with ammonium thiocyanate of the formula * NH4SCN (VIII) The reaction of the compound of the formula (II) with the compound of the formula (III) involves the production of a thiourea propanol intermediate of the formula

and the presence of which has been identified in the reation mixture by means of HPLC. It is the intermediate of formula (IX) which reacts with the inorganic acid to form the acid salt of xylazine of the formula

which in turn is converted into xylazine base of the formula (I) by reaction with the inorganic base.

The preferred process according to the invention is indicated in the following reaction scheme A.

In the accompanying drawings: Fig. 1 is a HPLC trace of the xylazine base obtained according to the process of the invention; Fig. 2 is a HPLC trace of a reference xylazine base as obtained from Bayer Aktiengesellschaft; and Fig. 3 is a HPLC trace showing the presence of the propanol thiourea intermediate of the formula (IX) indicated at a. This trace also indicates the presence of N-(2,6-dimethylphenyl)thiourea (II) indicated at b and xylazine base (I) indicated at c, since the trace obtained resulted from HPLC performed on the reaction mixture.

The invention will be further illustrated by the following Examples.

EXAMPLE 1 Preparation of N- (2, 6-dimethylphenyl) thiourea Acetone (100 ml) was dried over calcium chloride (CaC12) and filtered. Ammonium thiocyanate (21.0g; 0.267 mole) was dried in a vacuum oven at 8OOC. The ammonium thiocyanate was then dissolved in the acetone in a 500 ml two-necked flask fitted with a reflux condenser and a 100 ml dropping funnel. Benzoyl chloride (32.34g; 0.23 mole) was added at fast drip with stirring. Then 2,6 dimethylaniline (24.24g; 0.20 mole) was added at such a rate that the mixture refluxed gently (exothermic reaction). After the addition was complete, the mixture was refluxed for a further five (5) minutes and then cooled to l00C.

The intermediate benzoyl thiourea was filtered off, removing as much of the acetone present as possible before rinsing out the reaction flask and washing the filter cake well with water to remove the ammonium chloride formed in the reaction.

The intermediate benzoyl thiourea was then heated to boiling for five (5) minutes with a solution of NaOH (30g) in water (270 ml).

The solution was cooled and the product (N(2,6-dimethylphenyl)thiourea) filtered off, washed with water and dried.

Theoretical yield: 36.0g Actual yield : 90% of theoretical Melting point : 191-192 0C (expected: 191-1920C) NMR and IR spectra showed the characteristics of N-(2,6 dimethylphenyl) thiourea confirming the identity of the product.

EXAMPLE 2 Preparation of ((N-2,6-dimethylphenyl)-5,6-dihydro 4H-l, 3-thiazin-2-amine) (xylazine) base N-(2t6-dimethylphenyl) thiourea (4.5g; 0.025 mole) and 3-amino-1-propanol (2.44g; 0.0325 mole) in a 30% excess were heated together for 2.75 hours at 1250C.

After cooling, hydrochloric acid (conc.) (5 ml) (36% w/w) was added and the mixture refluxed for thirty (30) minutes. The reaction mixture was cooled in ice and then demineralized water was added in order that impurities might precipitate out (the reaction mixture turned a milky yellow colour). The solution was then filtered.

Ammonia solution (0.88) (20 ml) was added dropwise and xylazine base obtained. This was filtered off, washed well with water and dried.

Theoretical yield : 5.5g Yield before recrystallization: 62.2% Yield after recrystallization (using ethanol) : 45.5% Melting point : 1360 - 1380C 0 (expected 135-140 ) NMR and IR spectra showed the characteristics of (N-2,6-dimethylphenylamino)-4H-5,6-dihydro-1,3-thiazine base.

A high pressure liquid chromatogram (HPLC) of this product (see Fig. 1) compared well with a reference sample (see Fig. 2). The presence of the propanol thiourea intermediate (IX) is indicated in Fig. 3.

Conditions for HPLC were as follows.

Column : Waters Micro-Bondpak C18 System : ACS Solvent system A - Methanol containing 2% acetic acid and 0.2% PIC B8 (octane sulphonic acid) B - Water containing 2% acetic acid and 0.2% PIC B8.

Gradient: Time %A %B Flow Rate (ml/min) 0 20 80 1.5 10 70 30 1.5 20 70 30 1.5 25 20 80 1.5 30 20 80 1.5 As indicated above, it was possible to obtain a second crop of xylazine base by distilling the ethanol used in recrystallization. The base thus produced requires further recrystallization. In this way the overall yield can be increased by about 5%. It will be appreciated that second crop yields are a bonus.

A sequence of reactions using NT2,6-dimethylphenyl urea and 3-amino-l-propanol in the ratio 1:1; 1:1.2; 1:1.3; and 1:1.5 was set up and samples of the reaction mixtures were run on HPLC at 15 minute intervals. In this way the highest intermediate/impurity ratio was obtained and thereby the optimum conditions for the reaction, as indicated above.

Claims

CLAIMS:

1. A process for the preparation of xylazine base ((N-2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2- amine) of the formula

which comprises reacting N-2,6-dimethylphenyl thiourea of the formula

with 3-amino-l-propanol of the formula NH2 (CH2) 30H (III) at a temperature of from 1230 to 127 0C for a period of from 2.5 to 3.0 hours.

2. A process according to claim 1, wherein the reaction is carried out at a temperature of 1250C for 2.75 hours.

3. A process according to claim 1 or 2, wherein the compound of formula (II) is reacted with a molar excess of the compound of formula (III).

4. A process according to any preceding claim, which is carried out in the presence of an inorganic acid.

5. A process according to claim 4, which is carried out in the presence of hydrochloric acid.

6. A process according to claim 4 or 5, wherein the xylazine base of the formula (I) is released from its acid salt by reaction of the salt with an inorganic base.

7. A process according to claim 6, wherein the inorganic base is ammonium hydroxide.

8. A process according to any preceding claim, wherein the compound of the formula

prepared by reacting 2,6-dimethylaniline of the formula

with benzoyl thiocyanate of the formula

to form benzoyl thiourea of the formula

and reacting the benzoyl thiourea of the formula (VI) thus obtained with a base in an aqueous medium.

9. A process according to claim 8, wherein the base used is sodium hydroxide.

10. A process according to any preceding claim wherein the reaction of the compound of the formula (II) with the compound of the formula (III) results in the formation of an intermediate of the formula

as confirmed by HPLC.

11. A process according to claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples.

12. Xylazine base whenever obtained by a process claimed in a preceding claim.