WO2004069817A1

WO2004069817A1 - An improved process for preparing nizatidine intermediate

Info

Publication number: WO2004069817A1
Application number: PCT/IN2003/000173
Authority: WO
Inventors: Dinesh R. Kumar
Original assignee: Individual
Current assignee: Individual
Priority date: 2003-02-10
Filing date: 2003-05-02
Publication date: 2004-08-19
Anticipated expiration: 2005-08-10
Also published as: AU2003245032A1

Abstract

The present invention comprises: preparation of dimethylaminothioacetamide by a novel process and its conversion to pure 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline by an improved process. The 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline obtained by the present invention is substantially of good purity, capable of being used to product commercial quantities of Nizatidine pharmaceutical grade. Dimethylaminothioacetamide is prepared by reacting dimethylaminoacetonitrile with phosphorus pentasulfide, which is then reacted with 1,3-dichloroacetone in dialkylethers, to get substantially pure 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline.

Description

TITLE OF INVENTION

AN IMPROVED PROCESS FOR PREPARING NIZATIDINE

INTERMEDIATE.

FIELD OF THE INVENTION

The present invention relates to an improved process for the manufacture of Nizatidine intermediate, 4-chloromethyl-4-hydroxy-2- dimethylaminomet-hyl-2-tMazoline. It is a further object of this invention to provide such a process and quality of the intermediate, which is capable of being used to produce commercial quantities of Nizatidine pharmaceutical grade. BACKGROUND OF THE INVENTION

Nizatidine, the systematic chemical name of which is N-[2-[[[2-[ imemylammo)memyl]-4-tl iazolyl]memyl]mio]e yl]--N'- methyl-2-nitro-l,l-ethenecliamine, which has the formula (I).This compound is a histamine H₂-receptor antagonist which is useful as anti- ulcer agents capable of inmbiting gastric acid secretion in mammals.

United States Patent No. 4,375,547; 4587344, 4777260; 4,904,792 and 5334725 discloses Nizatidine and other related products. The synthesis of nizatidine disclosed in US patent No. 4,904,792 involves a multi-step process. The first step of the process comprises reacting dimethylaminotmoacetamide hydrochloride with ethyl bromopyruvate to obtain 2-(dinιethylaminon ethyl)-4-thiazolecarboxylate. Reduction of this 4- tbiazolecarboxylate derivative with lithium triethylborohydride gives 2-

(<-Umethylaminoπιethyl)-4-tI-ύazolenιethanol, which is then converted into 4- (2-ammoetϊhyl)ti omethyl-2-d by reacting with

2-aminoethanethiol hydrochloride (cysteamine hydrochloride). This 2- ό-imetihylan-ιinoπιethylthiazol derivative is then converted into Nizatidine by reacting _.with N-met-hyl-l-methyltHo-2-mt-coet-hyleneamine in the presence of an acid United States Patent No. 4,382,090 describes a method to prepare 4-

(2-aminoethyl)tMome1_hyl-2-din ethylaminon etihyltl iazol by fusing 4- cmoronιe yl-2-d- nethylaminonιet-hylthiazole with cysteamine hydrochloride at above 100 °C.

United States Patent No. 4,468,517 described a method to prepare 4- cldoronιethyl-2-<-ιimethylaminon et-hylt-lιiazole. The method described in this patent involved reaction of dimet-hylaminotmoacetamide hydrochloride with 1,3-dichloroacetone in haloalkane (1,2-dichloroethane) as a solvent to obta 4-cHoromethyl^-hydroxy-2-dimet^ This 2-thiazoline derivative is then dehydrated with a dehydrating agent like PC1₃, PBr₃, SOCl₂, POCl₃ etc., to get 4-chloromethyl-2- din etihyl-in monietihylthiazole.

European Patent Application EP 0,515,121 and EP 0,960,880 describe the process for the preparation of 2-(dim.et-hylarninomethyl)-4- thiazolemethanol. The process consists of reacting (-Umethylaminothioacetamide hydrochloride with 1,3-dichloroacetone in toluene to get 4-chlorometiιyl-4-hyαioxy-2-d-methylaminomethyl-2- thiazoline, which is then reacted with alkali metal base in an inert solvent such as toluene to get 2-(dimethylam-m.omethyl)-4-thiazolemethanol.

The methods described in United States Patent No. 4,468,517 for the synthesis of 4-chloromethyl-4-hy( oxy-2-dimethyl-ui-momethyl-2- thiazoline, requires complete evaporation of the solvent 1,2-dichloroethane to get the crude product; it is then washed with ethyl acetate to obtain a pure product. Evaporation of the solvent to complete dryness is an inconvenient and inappropriate operation in large-scale manufacturing. Such evapprations in large-scale operations would produce the solids as lumps; further washing such lumps with solvents would be ineffective due to improper -mixing of -the solid -with solvent. The method described in EP 0,515,121 and EP 0,960,880 for the synthesis of 4-cHorometlιyl-4-hyc oxy*-2-α_im requires isolation of the product from the reaction mixture by precipitation of the product from the mother liquor by the addition of petroleum ether. The crude product obtained by the precipitation is then subjected to an additional purification step by crystallisation from toluene.

A number of procedures are described for the preparation of dimethylammotmoacetamide. Examples are Japanese Patent No. JP 62,273,948, JP 62,273,949, JP 02,264,755 and Org. Prep. Proced. Int., 1992, 24, P.66-7. All the procedures described in the literature- or the preparation of dirnethylaminotitioacetamide from dimethylam oacetomtrile involve the use of hydrogen sulfide under pressure in the presence of promoters or catalysts. The disadvantage with the use of hydrogen sulfide is the difficulty it poses in handling commercial quantities, as it is a very toxic gas. The object of the present invention is to provide an improved manufactxiring process for 4-chloromethyl-4-hydr xy-2- di--netihylam omethyl-2-tibiazoline..

It is a further object of the instant invention to obtain 4- chloron ethyl-4-hydroxy-2-d]imethylaminomethyl-2-tMazoline of substantially good purity, capable of being used to product commercial quantities of Nizatidine pharmaceutical grade. It is yet a further object of this invention to provide a novel process for the preparation of din et-hylaminotmoacetamide, avoiding the use of hydrogen sulfide. SUMMARY OF THE INVENTION

To achieve the afore-mentioned objects, the present invention provides a novel process for preparing dimet-hylammot oacetamide comprising reacting din ethylam oacetomtrile with phosphorus pentasulfide to obtain di-methylaminothioacetaniide. This reaction is carried out in an aqueous medium at a temperature of about 10°C to about 80°C, preferably about 70 °C. It is desirable to add an alkali metal hydroxide selected from potassium hydroxide, sodium hydroxide or lithium hydroxide to the reaction mixture to recover dimed yiam otmoacetamide. The alkali metal hydroxide is sodium hydroxide.

Di-tnethylaminothioacetan ide is extracted with an inert solvent such as toluene. To precipitate αli-methylamj-notmoacetamide as its hydrochloride salt an alcoholic hydrochloric acid is added to the extract. The alcoholic hydrochloric acid is isopropanolic hydrochloric acid.

This present invention further includes an improved process for the preparing 4-chloromethyl-4 hyckoxy-2-dinιethylan-ιinon et_hyl-2-thiazo]ine comprising reacting di-methylan inothioacetaniide or its mineral acid addition salts with 1,3 dichloroacetone in diisopropyletiier in the presence of a base to obtain 4-chloromethyl-4 hydroxy-2-ά_imetihylaminomethyl-2- tmazoline. The reaction temperature is about 30 to about 70°C. 4- chloromethyl-4-hyc oxy-2-dimethylaminomethyl-2-t_hiazoline is isolated from the reaction mixture by filtration to remove the insoluble salts, said filtration being effected at a temperature of about 60 to about 70 °C and thereafter cooled to a temperature of about 0 to about 20 °C. More preferably filtration is effected at a temperature of about 50 to about 55 °C and thereafter cooled to a temperature of about 0 to about 5 °C.

This pure 2-thiazoline derivative on further conversion into Nizatidine by known methods gives pure Nizatidine meeting the requirements of the pharmaceutical substances. Detailed Description of the Invention

The present invention provides an improved process for the manufacture of Ni-zatidine intermediate. The present invention for the manufacture of this intermediate comprises of: Preparation of d netihylanιinotmoacetanτide by a novel process and its conversion to pure 4-chlorometiιyl-4-hydroxy-2-d-ιmeth^ by an improved process. In said novel process, dimethylan-i oacetomtrile is reacted with phosphorus pentasulfide in aqueous medium to obtain di-methylanτinothioacetamide. This process avoids the conventional use of hydrogen sulfide for the preparation of di-methylanτmot-hioacetamide from diiuet-hylanriinoacetonitrile as described in the earlier reported methods. The product o-in ethylaminothioacetamide can be recovered from the reaction mixture by basification to pH 10-11 followed by extraction with toluene. Addition of alcoholic hydrochloric acid into the toluene extract precipitates the product as its hydrochloride salt. This di-methyl- τinot_hioacetamide or its mineral acid addition salts is then reacted with 1,3-dichloroacetone to get 4-chloromethyl-4-hydroxy-2- d nethylami-nomethyl-2--tlτiazoline. This reaction is carried out at a temperature between 30-70° C in the presence of base and in diisopropyletiier as a solvent. The use of diisopropyletiier as a solvent in the process for 4-chloromethyl-4 hydroxy-2-dimetihylaminomethyl-2- thiazoline affords the advantage of simplicity in isolation of the product in good yield and substantially good purity. The product 4-chloromethyl-4- hyd-toxy-2-α!inιethylammomethyl-2-tMazolin is isolated from the reaction mixture by filtration at 60-70° C to remove the insoluble salts and directly crystallized from the filtrate by cooling to a temperature between 10-20° C. The product crystallizing out from diisopropylether is in substantially good purity which does not require repurification. The purity of this particular intermediate is very important for the preparation of Nizatidine of desired purity. The impure 4-chloromethyl-4- hy<-koxy-2-di-methylammomethyl-2-tHazoline affords impure N atidine, which is rather difficult to purify and meet the requirements of the pharmaceutical grade material. The following examples further- illustrate the present invention. It is being understood that the current invention is not intended to be limited bj the details disclosed therein. Example No: 1 Preparation of dirnethylaniinothioacetaniide hydrochloride Into water (3000 ml), phosphorus pentasulfi.de (1302 g; 2.93 mol) and dimethylam oacetonitrile (1000 g; 11.88 mol) are added one after another at 10°C. The mixture is then slowly warmed to 70°C and maintained for 3 hrs to complete the reaction. The reaction mixture is then cooled to 20°C and sodiu hydroxide (53% w/w, 2200 g, 29.15 mol) is added into it below 20°C. The reaction mixture is then warmed to 50°C and extracted with toluene (2 x 2000 l). Isopropanolic hydrochloric acid (12% w/w; 3700 ml) is added into the extract at 25 to 30°C to adjust the pH to 2 and the mass stirred for 1 h to precipitate the product. The slurry is filtered, washed with isopropyl alcohol (1000 ml) and dried to get (1360 g) dimethyl ammotMoacetamide hydrochloride. Yield = 74.0%, HPLC purity = 97.6% Example No: 2

Preparation of 4-chloromethyl-4-hydr oxy-2-dimethylaminomethyl-2- thiazoline

Dimethylam othioacetamide hydrochloride (1000 g; 6.472 mol) is suspended in diisopropyletiier (4000 ml). Added into this suspension is sodium bicarbonate (1200 g; 14.28 mol) and sodium sulphate (1000 g). The slurry is heated to 55-60° C and stirred for 1 hr. Into this suspension is added 1,3 dichloroacetone (1000 g; 7.87 mol) dissolved in diisopropylether (1000 ml). The reaction is continued at 50-55° C for 2 h. The progress of the reaction is monitored by a qualitative HPLC analysis. Upon completion of the reaction, the reaction mixture is^* filtered hot at 50-55° C to remove insoluble inorganic salts. The mother liquor is cooled slowly to 0-5° C to crystallize out the product. The product is then filtered and washed with precooled diisopropylether (250 ml). The product is dried at 50° C under reduced pressure to obtain 1120 g. Yield = 83%; HPLC purity = 98.2%. The following example illustrates the process to convert this pure 4- cHoromethyl-4-hyσ-roxy-2-ά-imet^^ Nizatidine. Example No 3: Preparation of N- [2- [ [ [2- [(Dimethylaι-nino)methyl] -4- thiazolyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l,l-ethenediamine. A. Preparation of 4-chloromethyl-2-ααmethylam onιethylthiazole Hydrochloride.

Thionyl chloride (430 ml; 5.9 mol) is added into chloroform (1000 ml) and cooled to 20° C. Into this solution is added 4-chloromethyl-4- hyά^oxy-2-dinιethylam ome yl-2-thiazoline (1000 g; 4.79 mol), dissolved in chloroform (4000 ml). The reaction mixture is further gradually heated to 60-65° C and maintained at this temperature till qualitative HPLC analysis shows the completion of the reaction. The reaction mixture is then cooled slowly to 30° C to get the product crystallized out. The product is filtered, washed and dried under reduced pressure to obtain 900 g of pure product. Yield = 83.3 %. B. Preparation of 4-(2-am oethyl)thiomethyl-2- ά-imethylam omethylthiazole.

2-A-minoethanetl iol hydrochloride (cysteamine hydrochloride, 520 g; 4.5 mol) is suspended in water (500 ml). This suspension is cooled to 5° C and sodium hydroxide solution (45 % w/w, 870 ml; 14.7 mol) is added into it at 5-10° C. Into this suspension, hydroxylamine sulphate (100 g; 0.6 mol) is added and stirred. A solution of 4-chloromethyl-2- di-n ethyl- inomethylthiazole hydrochloride (1000 g; 4.43 mol) dissolved in water (1250 ml) is prepared separately. This solution is added into the said suspension below 10° C and the reaction continued at 10° C for another 1 h. The completion of the reaction is determined by qualitative HPLC. The reaction mixture is then diluted with water (2000 ml), heated to 40-45° C and extracted with toluene (2 x 2000 ml). The toluene extract is treated with activated carbon at 40-45° C for 30 min. Activated carbon is removed by filtration through hyflo bed and evaporated toluene from the filtrate under reduced pressure at 60° C to obtain 910 g of the product. Yield = 88 %. C. Preparation of N-(2-(((2-(Dimethylamino)methyl)-4- tltiazolyl)m.ethyl)tltio)elhyl)-N'-methyl-2-nitro-l ,1 -etheneά-iamine (Nizatidine).

N-methyl-l-methyltHo-2-mtroethyleneamine (NMSM, 610 g; 4.12 mol) is mixed with water (1500 ml), and the mixture is cool to 20-25° C. 4- (2-Am-hoethyl)d omethyl-2-<^ (1000 g; 4.32 mol) dissolved in water (1500 ml) is added into this suspension at 20-25° C. The reaction mixture is warmed to 30-35° C and continued the reaction for 8 h. The progress of the reaction is monitored by qualitative HPLC analysis. The reaction mixture is extracted with toluene (2 x 1000 ml), and the aqueous layer is treated with activated carbon (50 g) at 55-60° C for 30 min. Activated carbon is removed by filtration through hyflo bed and the aqueous filtrate is extracted with chloroform (4 x 1000 ml)rThe cHorόform extract is concentrated under reduced pressure at less than 50° C; ethyl acetate (3000 ml) is added into the concentrate and reconcentrated. Acetone (300 ml), ethyl acetate (300 ml) is added into the concentrate and cooled to 0-5° C to crystallize the product. The product is filtered, washed with precooled ethyl acetate (250 ml), and dried to obtain pure Nizatidine 1160 g. Yield = 81.0%; HPLC purity -= 99.3%.

Claims

I Claim:

1. An improved process for preparing 4-chloromethyl-4 hydroxy-2- dimethylammomethyl-2-thiazoline comprising reacting ciuhiethylam othioacetamide or its mineral acid addition salts with 1,3 dichloroacetone in diisopropylether in the presence of a base to obtain 4- cmoromemyl-4 hyά oxy-2-dimemy thiazoline.

2. An improved process for the preparing (dimethylammothioacetamide of claim 1 comprising reacting αirnethylaminoacetonitrile with phosphorus pentasulfide to obtain ά-iniethylammothioacetamide or its mineral acid salt.

3. An improved process as claimed in claim 2 wherein the reaction is carried out in an aqueous medium.

4. An improved process as claimed in claim 2 or 3 wherein the reaction is carried out at a temperature of about 10°C to about 80°C.

5. An improved process as claimed in claim 4 wherein the reaction temperature is about 70 °C.

6_. An improved process as claimed in claim 2 wherein an alkali metal hydroxide is added to the reaction mixture to recover dJ-methylan-ιinolhioacetamide.

7. An improved process as claimed in 6 wherein said alkali metal hydroxide is selected from potassium hydroxide, sodium hydroxide or lithium hydroxide

8. An improved process as claimed in 7 wherein said alkali metal hydroxide is sodium hydroxide

9. An improved process as claimed in any preceding claim further comprising extracting dimethylammotmoacetamide with an inert solvent.

10. An improved process as claimed in any-prfcceding-daim -said-inert — solvent includes is toluene.

11. An improved process as claimed in claim 9 or 10 wherein alcoholic hydrochloric acid is added to the extract to precipitate dimethylammothioacetamide as its hydrochloride salt.

12. An improved process as claimed in claim 10 wherein said alcoholic hydrochloric acid is isopropanolic hydrochloric acid.

13. An improved process as claimed in claim 1 wherein the reaction temperature is about 30 to about 70°C.

14. An improved process as claimed in claim 1 wherein further comprising isolating 4-chloromethyl-4 hydroxy-2- dJn ethylan-ιmon ethyl-2-thiazoline from the reaction mixture by filtration to remove the insoluble salts.

15. An improved process as claimed in claim 10 wherein filtration is effected at a temperature between 60-70 °C and thereafter cooled to a temperature between 0-20 °C

16. An improved process as claimed in claim 11 wherein filtration is effected at a temperature between 50-55 °C and thereafter cooled to a temperature between 0-5 °C.

17. An improved process as claimed in 1 wherein the base used is sodium bicarbonate.