WO2004069817A1 - Procede ameliore destine a la preparation d'un produit intermediaire de la nizatidine - Google Patents

Procede ameliore destine a la preparation d'un produit intermediaire de la nizatidine Download PDF

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Publication number
WO2004069817A1
WO2004069817A1 PCT/IN2003/000173 IN0300173W WO2004069817A1 WO 2004069817 A1 WO2004069817 A1 WO 2004069817A1 IN 0300173 W IN0300173 W IN 0300173W WO 2004069817 A1 WO2004069817 A1 WO 2004069817A1
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WO
WIPO (PCT)
Prior art keywords
improved process
temperature
reaction
chloromethyl
thiazoline
Prior art date
Application number
PCT/IN2003/000173
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English (en)
Inventor
Dinesh R. Kumar
Original Assignee
Kumar Dinesh R
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kumar Dinesh R filed Critical Kumar Dinesh R
Priority to AU2003245032A priority Critical patent/AU2003245032A1/en
Publication of WO2004069817A1 publication Critical patent/WO2004069817A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms

Definitions

  • 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.
  • 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 H 2 -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-(din ⁇ ethylaminon ethyl)-4-thiazolecarboxylate.
  • Reduction of this 4- tbiazolecarboxylate derivative with lithium triethylborohydride gives 2-
  • United States Patent No. 4,468,517 described a method to prepare 4- cldoron ⁇ ethyl-2- ⁇ - ⁇ imethylaminon et-hylt-l ⁇ iazole.
  • 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 PC1 3 , PBr 3 , SOCl 2 , POCl 3 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-chlorometi ⁇ yl-4-hy ⁇ ioxy-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 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.
  • 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.
  • an inert solvent such as toluene.
  • 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-din ⁇ ethylan- ⁇ inon 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- ⁇ _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.
  • 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 netihylan ⁇ inotmoacetan ⁇ ide by a novel process and its conversion to pure 4-chlorometi ⁇ yl-4-hydroxy-2-d- ⁇ meth ⁇ by an improved process.
  • dimethylan-i oacetomtrile is reacted with phosphorus pentasulfide in aqueous medium to obtain di-methylan ⁇ inothioacetamide.
  • This process avoids the conventional use of hydrogen sulfide for the preparation of di-methylan ⁇ mot-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- ⁇ inot_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--tl ⁇ iazoline.
  • 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- ⁇ !in ⁇ ethylammomethyl-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.
  • 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.
  • 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.
  • 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 following example illustrates the process to convert this pure 4- cHoromethyl-4-hy ⁇ -roxy-2- ⁇ -imet ⁇ Nizatidine.
  • Example No 3 Preparation of N- [2- [ [ [2- [(Dimethyla ⁇ -nino)methyl] -4- thiazolyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l,l-ethenediamine.
  • A. Preparation of 4-chloromethyl-2- ⁇ methylam on ⁇ ethylthiazole Hydrochloride.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne la préparation de diméthylaminothioacétamide selon un nouveau procédé et sa conversion en 4-chlorométhyl-4-hydroxy-2-diméthylaminométhyl-2-thiazoline pure selon un procédé amélioré. Cette 4-chlorométhyl-4-hydroxy-2-diméthylaminométhyl-2-thiazoline est sensiblement pure et peut être utilisée pour produire des quantités commerciales de Nizatidine de qualité pharmaceutique. Le diméthylaminothioacétamide est préparé selon un procédé consistant à faire réagir du diméthylaminoacétonitrile avec du pentasulfure de phosphore, puis à faire réagir le produit obtenu avec du 1,3-dichloroacétone en présence de dialkyléthers, pour obtenir de la 4-chlorométhyl-4-hydroxy-2-diméthylaminométhyl-2-thiazoline sensiblement pure.
PCT/IN2003/000173 2003-02-10 2003-05-02 Procede ameliore destine a la preparation d'un produit intermediaire de la nizatidine WO2004069817A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003245032A AU2003245032A1 (en) 2003-02-10 2003-05-02 An improved process for preparing nizatidine intermediate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN115/MAS/2003 2003-02-10
IN115MA2003 2003-02-10

Publications (1)

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WO2004069817A1 true WO2004069817A1 (fr) 2004-08-19

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015002150A1 (fr) 2013-07-03 2015-01-08 株式会社新日本科学 Nouveau composé, agent de détection du transporteur de cations organiques 3 et inhibiteur de l'activité du transporteur de cations organiques 3
CN106279060A (zh) * 2016-08-10 2017-01-04 四川摩尔生物制药有限公司 尼扎替丁原料药的制备方法
CN108484462A (zh) * 2018-04-28 2018-09-04 江苏宝盛龙城药业有限公司 N,n-二甲氨基硫代乙酰胺的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4468517A (en) * 1983-05-12 1984-08-28 Eli Lilly And Company Synthesis of thiazoles
US5457206A (en) * 1991-05-21 1995-10-10 Eli Lilly And Company Process for preparing intermediates to nizatidine and related compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4468517A (en) * 1983-05-12 1984-08-28 Eli Lilly And Company Synthesis of thiazoles
US5457206A (en) * 1991-05-21 1995-10-10 Eli Lilly And Company Process for preparing intermediates to nizatidine and related compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015002150A1 (fr) 2013-07-03 2015-01-08 株式会社新日本科学 Nouveau composé, agent de détection du transporteur de cations organiques 3 et inhibiteur de l'activité du transporteur de cations organiques 3
CN106279060A (zh) * 2016-08-10 2017-01-04 四川摩尔生物制药有限公司 尼扎替丁原料药的制备方法
CN108484462A (zh) * 2018-04-28 2018-09-04 江苏宝盛龙城药业有限公司 N,n-二甲氨基硫代乙酰胺的合成方法

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