DESC:Detailed Description of the Invention

Those skilled in the art will be aware that invention described herein is subject to variations and modifications other than those specifically described. As used herein the following definitions apply unless clearly indicated otherwise. It should be understood that unless expressly stated to the contrary, “a compound of general
Formula I” refers to and includes any and all compounds described by Formula I, its embodiments, inclusive of all salts thereof. It should also be noted that the singular forms “a” “an” and “the” include plural reference unless the context clearly dictates otherwise.

The term “aryl” as used herein refers to mono, bi, or tricyclic aromatic radicals having usually from 6 to 14, preferably 6, 10 or 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl and anthracenyl; preferably phenyl is the aryl group.
The aryl group is further substituted with one or more halo, alkyl or alkoxy; wherein the term “halo” as used herein refers to fluoro, chloro or bromo; the term “alkyl” as used herein refers to straight or branched aliphatic chain containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl or isobutyl; the term
“alkoxy” as used herein refers to straight or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 6 carbon atoms, such as methoxy, ethoxy, propyloxy,, butyloxy, isopropyloxy or isobutyloxy.

The term “one-pot” as used herein refers to a set-up in which the product of a first reaction is used as adduct in a subsequent second reaction without intermediate workup. Accordingly, the term “one-pot process” refers to a situation wherein no efforts for product isolation or purification are being made in between the reactions that are carried out in the one-pot process.

The term “intermediate workup” as used herein in the context of the term “one-pot” refers to a situation, wherein no isolation of reaction products is being
carried out between the reaction steps, while exchange of solvents, or the addition of acids or bases between the reaction steps may be optionally be carried out.

The term “base” as used herein refers to tertiary amines such as trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, N- methylpiperidine, imidazole, pyridine, substituted pyridines, such as collidine, lutidine or 4-dimethylaminopyridine, and also polycyclic amides and amidines, such as 1,8- diazabicyclo[5.4.0]undec -7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO).

The term “solvent” as used herein refers to water, aliphatic hydrocarbon, such as pentane, hexane or cyclohexane; aromatic hydrocarbon, such as benzene, toluene, o-, m-, and p-xylene; halogenated aromatic or aliphatic hydrocarbon, such as dichloromethane, chloroform, carbon tetrachloride or chlorobenzene; alcohols, such as methanol, ethanol, propanol, isopropanol or n-butanol; ethers, such as dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, dioxane or tetrahydrofuran; nitriles, such as acetonitrile; ketones, such as acetone or methyl isobutyl ketone; acetates, such as ethyl acetate; amides and urea derivatives, such as dimethylformamide, N-methyl-2-pyrrolidone or dimethyl acetamide; dimethyl sulfoxide, and mixture thereof.

The term “about” as used herein refers to the given value ± A, wherein A ranges from 1 to 10. The term “ambient temperature” as used herein refers to a temperature ranges from about 20 to 30 0C.

The compound of Formula I has basic group; hence a “pharmaceutically acceptable salt thereof” can be formed by reacting the compound with an acid following the process known to an ordinary person skilled in the art. The term “pharmaceutically acceptable” as used herein refers to a compound of Formula I suitable for administration to animals as approved by a regulatory agency. Preferred examples of a salt of the present invention includes, but not limited to, hydrochloride, hydrobromide, nitrate, perchlorate, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluensulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate. In a particular embodiment, the salt of a compound of Formula I is hydrochloride.

According to a first aspect of the present invention, there is provided a process for the preparation of a compound of Formula I

R

comprising:
(a) reacting arylamine of formula R-NH2 with carbon disulphide to produce a compound of formula II;
R'
R-NHC(=S)S-
R' R'
(b) reacting a compound of Formula II with 3-amino-1-propanol to produce a compound of Formula III;

and

R-NHC(=S)NH(CH ) OH
2 3

(c) reacting a compound of Formula III with hydrochloric acid followed by neutralization with sodium hydroxide; wherein R is selected from aryl substituted with halo, alkyl or alkoxy.

In one embodiment, the method is one-pot synthesis, which does not require isolation and purification of the intermediate compound of Formula II. In yet another embodiment, the intermediate compound of Formula III is used in situ to produce compound of Formula I, such as xylazine or analogs thereof. In a particular embodiment, the yield of xylazine base ranges from about 65 to 80%. In yet another particular embodiment, the yield of xylazine base is about 65 to 70%, which is higher than reported in the prior arts discussed hereinbefore.

According to another embodiment, step (a) is carried out in the presence of a base selected from tertiary amines, such as trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, N-methylpiperidine, imidazole, pyridine, substituted pyridines, such as collidine, lutidine or 4-dimethylaminopyridine, and also polycyclic amides and amidines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO). In a preferred embodiment, the base is selected from triethyl amine, diisopropylethyl amine, pyridine or 1,8-

Diazabicyclo[5.4.0]undec-7-ene. In another preferred embodiment, the base is trimethylamine.

According to another embodiment, step (a) is carried out in a solvent selected from water, pentane, hexane, cyclohexane, benzene, toluene, o-xylene, m-xylene, p- xylene, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, methanol, ethanol, propanol, isopropanol, n-butanol, dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, methyl isobutyl ketone, ethyl acetate, dimethylformamide, N-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide or mixture thereof. In a preferred embodiment, the solvent is selected from water, methanol, ethanol, isopropanol, n- butanol, hexanes, toluene, ethyl acetate, methyl tert-butyl ether, dimethylformamide, methyl isobutyl ketone or acetone. In yet another preferred embodiment, the solvent is water, methanol, ethanol, isopropanol or n-butanol.

According to another embodiment, step (a) is carried out at a temperature ranges from about 0 to 30 0C, preferably about 10 to 15 0C. In another embodiment, step (b) is carried out at a temperature ranges from about 75 to 100 0C, preferably about 80 to 90 0C. In yet another embodiment, step (c) is carried out at a temperature ranges from about 80 to 100 0C, preferably about 95 to 100 0C.

According to another preferred embodiment, R in Formula I is an aromatic radical having 6, 10 or 14 carbon atoms, such as phenyl, naphthyl and anthracenyl, more preferably phenyl, wherein phenyl is substituted with one or more halo, alkyl or alkoxy, preferably alkyl such as methyl. In a preferred embodiment, R is 2,6- dimethylphenyl.

According another embodiment of the present invention, there is provided one- pot process for the preparation of xylazine or a pharmaceutically acceptable salt thereof, comprises reacting 2,6-xylidene (i) with carbon disulphide in the presence of triethylamine, in a solvent to form carbamodithionate (ii), followed by sequentially treating with 3-amino-1-propanol to form thiourea (iii), and with concentrated hydrochloric acid to form (N-2,6-dimethylphenyl)-5,6-dihydro- 4H-1,3-

thiazin-2-amine hydrochoride salt, which is finally neutralized with sodium hydroxide to form xylazine free base.
(i) (ii) (iii) Xylazine free base

In a preferred embodiment, the solvent is selected from water, pentane, hexane, cyclohexane, carbon tetrachloride, dioxane, toluene, diisopropyl ether, diethyl ether, t-butyl methyl ether, chloroform, ethyl acetate, tetrahydrofuran, acetone, methyl isobutyl ketone, dimethylformamide, acetonitrile, dimethyl sulfoxide, dichloromethane, methanol, isopropanol or n-butanol. In yet another preferred embodiment, the solvent is selected from water, methanol, ethanol, isopropanol, n- butanol, hexanes, toluene, ethyl acetate, methyl tert-butyl ether, dimethylformamide, methyl isobutyl ketone or acetone, more preferably water, methanol, ethanol, isopropanol or n-butanol.

According to another aspect, xylazine or pharmaceutically acceptable salt thereof obtained by the process of the present invention is substantially pure. For the purpose of the present invention, the term “substantially pure” as used herein includes reference to purity of, or more than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.8% purity as determined, for example, by HPLC as evident by HPLC chromatogram shown in Figure 1.

The details of HPLC system are as follows:
• Column: Waters bondpac C18 , 10µ, 3.9 x 300mm with guard column C18 ,
2.0 mm x 2 cm. (Make - Waters)

• Wavelength: 254 nm

• Flow rate: 2.5 mL/ minutes

• Inject volume: 20 µL

• Run time: 30 minutes

Experimental Procedures

Hereinafter, the present invention is described in details with reference to example(s) such as Example 1 or Example 2 below. It should be noted that the starting materials for the synthetic methods are commercially available and/or have been reported widely in scientific documents or can be formed from commercially available products by appropriately using synthetic methods reported in scientific documents. As a general guide to reaction conditions or reagents, see Advanced Organic Chemistry, Vol. 4 (Jerry March, ed., published by John Willey and Sons, 1992)

(Example 1) 2, 6-Xylidine (50.0g, 0.41mol) was taken in a reaction flask and water (500mL) was added to it at ambient temperature. Triethyl amine (45.5g, 0.45mol) was then added to it, followed by addition of carbon disulphide (32.5g, 0.43mol) at about 15 0C. The temperature was maintained for 6 hours. 3-Amino-1- propanol (30.8g, 0.41mol) was then added over a period of 20 minutes to the reaction mixture at ambient temperature. The reaction mixture was then heated at about 80 0C for about 6 hours. The reaction mixture was then cooled to ambient temperature and concentrated hydrochloric acid (100mL) was added. The temperature was slowly raised to about 95 0C and was maintained for additional 3 hours. The reaction mixture was then cooled to about 20 0C and pH was adjusted to
9.5 to 10.5 by careful addition of sodium hydroxide solution (20%) over a period of about 35 minutes at about 20 0C. The resulting mixture was stirred at the same temperature for 1 hour. The mixture was then filtered and solid so obtained was washed with water and sucked well. It was again washed with acetone (100mL) to obtain the desired pure compound xylazine with purity of more than 99.5% by High Performance Liquid Chromatography (HPLC).

(Example 2) 2, 6-Xylidine (50.0g, 0.41mol) was taken in a reaction flask and n-butanol (300mL) was added to it at ambient temperature. Triethyl amine (45.5g, 0.45mol) was then added to it, followed by addition of carbon disulphide (32.5g, 0.43mol) at about 15 0C. The temperature was maintained at about 15 0C for 6 hours. 3-Amino-1-propanol (30.8g, 0.41mol) was then added over a period of 20 minutes to the reaction mixture at ambient temperature. The reaction mixture was then heated at about 80 0C for about 6 hours. The reaction mixture was then cooled

to ambient temperature and concentrated hydrochloric acid (100mL) was added. The temperature was slowly raised to about 95 0C and was maintained for additional 3 hours. The reaction mixture was then cooled to about 20 0C, water (300mL) was added to it and pH was then adjusted to 9.5 to 10.5 by careful addition of sodium hydroxide solution (20%) over a period of about 35 minutes at about 20 0C The resulting mixture was stirred at the same temperature for about 1 hour. The mixture was then filtered and the solid so obtained was washed with water (300mL) and sucked well. It was again washed with acetone (50mL) to obtain the desired compound xylazine with purity more than 99.5% by HPLC.
,CLAIMS:We Claim
(1) A method for preparing a compound of Formula I

R

Formula I
wherein R is aryl substituted with halo, alkyl or alkoxy, and the said process comprises of:
(d) reacting arylamine of formula R-NH2 with carbon disulphide in presence of a base to produce a compound of formula II;
R'
R-NHC(=S)S-
R' R'
Formula II
(e) reacting a compound of Formula II with 3-amino-1-propanol to produce a compound of Formula III;
R-NHC(=S)NH(CH ) OH
2 3
Formula III
and

(f) reacting a compound of Formula III with hydrochloric acid followed by neutralization with a base selected from sodium hydroxide to form a compound of formula I.

(2) The method according to claim (1) is one-pot.

(3) The method according to claim (1), wherein step (a) is carried out in the presence of a base selected from trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, N-methylpiperidine, imidazole, pyridine, substituted pyridines, such as collidine, lutidine or 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-- 7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO).

(4) The method according to claim (1), wherein step (a) is carried out in a solvent selected from water, pentane, hexane, cyclohexane, benzene, toluene, o-xylene, m- xylene, p-xylene, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene,

methanol, ethanol, propanol, isopropanol, n-butanol, dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, methyl isobutyl ketone, ethyl acetate, dimethylformamide, N-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide or mixture thereof.

(5) The method according to claim (1), wherein R is 2,6-dimethylphenyl.

(6) The method according to claims (1), wherein the compound of Formula I is xylazine or pharmaceutically acceptable salts thereof.

(7) Xylazine obtained according to any of the preceding claims has the purity of more than 99.5% by HPLC.