KR100302348B1 - A process for preparing nizatidine - Google Patents
A process for preparing nizatidine Download PDFInfo
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- KR100302348B1 KR100302348B1 KR1019990014715A KR19990014715A KR100302348B1 KR 100302348 B1 KR100302348 B1 KR 100302348B1 KR 1019990014715 A KR1019990014715 A KR 1019990014715A KR 19990014715 A KR19990014715 A KR 19990014715A KR 100302348 B1 KR100302348 B1 KR 100302348B1
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- formula
- nizatidine
- compound
- methyl
- chloromethyl
- Prior art date
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- SGXXNSQHWDMGGP-IZZDOVSWSA-N nizatidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CSC(CN(C)C)=N1 SGXXNSQHWDMGGP-IZZDOVSWSA-N 0.000 title claims abstract description 15
- 229960004872 nizatidine Drugs 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- BUDMJAMXOTXJAA-UHFFFAOYSA-N 1-[4-(chloromethyl)-1,3-thiazol-2-yl]-n,n-dimethylmethanamine Chemical compound CN(C)CC1=NC(CCl)=CS1 BUDMJAMXOTXJAA-UHFFFAOYSA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- -1 lithium triethylborohydride Chemical compound 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 4
- VJJZXQCIDAQYNQ-UHFFFAOYSA-N 1-[4-(chloromethyl)-1,3-thiazol-2-yl]-n,n-dimethylmethanamine;hydrochloride Chemical compound Cl.CN(C)CC1=NC(CCl)=CS1 VJJZXQCIDAQYNQ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 3
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- QNEVCTUHZWPHJE-UHFFFAOYSA-N 4-(chloromethyl)-2-[(dimethylamino)methyl]-5h-1,3-thiazol-4-ol Chemical compound CN(C)CC1=NC(O)(CCl)CS1 QNEVCTUHZWPHJE-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- YQFHPXZGXNYYLD-UHFFFAOYSA-N n-methyl-1-methylsulfanyl-2-nitroethenamine Chemical compound CNC(SC)=C[N+]([O-])=O YQFHPXZGXNYYLD-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- PVPMWECHNTUXJE-UHFFFAOYSA-N 1-n'-methyl-2-nitrobut-1-ene-1,1-diamine Chemical compound CCC([N+]([O-])=O)=C(N)NC PVPMWECHNTUXJE-UHFFFAOYSA-N 0.000 description 1
- GQGHFSJGSKEKJZ-UHFFFAOYSA-N 2-(dimethylamino)ethanethioamide Chemical compound CN(C)CC(N)=S GQGHFSJGSKEKJZ-UHFFFAOYSA-N 0.000 description 1
- OQANDCSWKZVVQI-UHFFFAOYSA-N 2-(dimethylamino)ethanethioamide;hydrochloride Chemical compound [Cl-].C[NH+](C)CC(N)=S OQANDCSWKZVVQI-UHFFFAOYSA-N 0.000 description 1
- FDMDNIIUCZHKFE-UHFFFAOYSA-N 2-[[2-[(dimethylamino)methyl]-1,3-thiazol-4-yl]methylsulfanyl]ethanamine Chemical compound CN(C)CC1=NC(CSCCN)=CS1 FDMDNIIUCZHKFE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
Abstract
본 발명은 4-클로로메틸-2-디메틸아미노메틸티아졸 또는 그의 산부가염과N-메틸-1-(2-머캅토)에틸아미노-2-니트로에틸렌아민을 염기 존재하에서 반응시키는 공정을 포함하는 니자티딘의 제조방법에 관한 것이다.The present invention includes a step of reacting 4-chloromethyl-2-dimethylaminomethylthiazole or an acid addition salt thereof with N -methyl-1- (2-mercapto) ethylamino-2-nitroethyleneamine in the presence of a base. It relates to a method for producing nizatidine.
Description
본 발명은 니자티딘(Nizatidine)의 제조방법에 관한 것이다.The present invention relates to a method for preparing nizatidine.
하기 화학식 1로 표시되는 니자티딘은 히스타민 H2수용체의 길항제로 작용하며 소화성 궤양 치료에 유용한 약물로서, 그 화학명은N-2-[(2-디메틸아미노메틸Nizatidine represented by the following formula (1) acts as an antagonist of histamine H 2 receptor and is useful for treating peptic ulcer, and its chemical name is N- 2-[(2-dimethylaminomethyl
-4-티아졸릴)메틸티오]에틸-N'-메틸-2-니트로-1,1-에텐디아민이다.-4-thiazolyl) methylthio] ethyl- N' -methyl-2-nitro-1,1-ethenediamine.
종래 니자티딘의 제조방법으로서 한국특허 제21059호에 기술된 방법에 따르면, 하기 반응식 1과 같이, 화학식 2의 2-[(2-디메틸아미노메틸-4-티아졸릴)메틸티오]에틸아민과 화학식 3의N-메틸-1-메틸티오-2-니트로에틸렌아민을 반응시켜 니자티딘을 제조한다.According to the method described in Korean Patent No. 21059 as a conventional method for preparing nizatidine, as shown in Scheme 1 below, 2-[(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamine Nizatidine is prepared by reacting N -methyl-1-methylthio-2-nitroethyleneamine of formula (3).
그러나, 상기 공지의 방법에 따라 니자티딘을 제조할 경우, 중간체인 화학식 2의 화합물을 제조하기 위해서는 하기 반응식 2와 같이, 1)출발물질로서 고가인 에틸브로모피루베이트를 반응시키는 공정, 2)고가이고 취급하기 어려운 리튬 트리에틸보로하이드라이드(LiBEt3H)를 사용하여 환원시키는 공정 및 3)강산인 브롬화 수소산을 사용하는 공정 등으로 화학식 2의 화합물을 제조하여야 하므로 경제적인 어려움과 위험성이 수반되는 단점이 있다.However, in the case of preparing nizatidine according to the above known method, in order to prepare a compound of formula (2), which is an intermediate, as shown in Scheme 2, 1) a step of reacting expensive ethyl bromopyruvate as starting material, 2 Economic difficulties and risks as the compound of formula 2 should be prepared by reducing with expensive and difficult to handle lithium triethylborohydride (LiBEt 3 H) and 3) using hydrobromic acid as a strong acid. There is a disadvantage associated with this.
또한, 한국특허 제29806호에 기술된 제조방법에 따르면, 하기 반응식 3과 같이, 화학식 2의 화합물과 화학식 4의N-메틸-1-알콕시-2-니트로에틸렌아민을 수용액 중에서 반응시켜 니자티딘을 제조한다.In addition, according to the preparation method described in Korean Patent No. 29806, Nizatidine is reacted by reacting the compound of Formula 2 with N -methyl-1-alkoxy-2-nitroethyleneamine of Formula 4 in an aqueous solution as in Scheme 3 below. To prepare.
(상기 반응식 3에서 R은 메틸 또는 에틸기이다.)(In Scheme 3, R is a methyl or ethyl group.)
그러나, 상기 공지의 방법에 따를 경우, 화학식 2의 화합물을 사용하므로 상기(한국특허 제21059호)에서 지적한 문제점을 그대로 가지고 있을 뿐 아니라, 수율이 40% 내지 54%로 저조하고, 또한 하기 반응식 4에서와 같이 중간체로 사용되는 화학식 4의 화합물 합성시의 수율도 35%로 극히 낮아 경제성이 적은 단점이 있다.However, according to the known method, since the compound of Formula 2 is used, not only has the problems indicated in the above (Korean Patent No. 21059), but the yield is low at 40% to 54%, and the following Reaction Scheme 4 As shown in the synthesis of the compound of formula 4 used as an intermediate, the yield is extremely low as 35% has the disadvantage of less economical.
또한, 한국특허 제21753호에 기술된 방법에 따르면, 반응식 5에 나타낸 바와 같이, 화학식 2의 화합물과 화학식 5의 메틸 카르본 이미도 디티오산 디메틸에스테르를 반응시켜 합성한 화학식 6의 화합물을 니트로메탄과 반응시켜 니자티딘을 제조한다.In addition, according to the method described in Korean Patent No. 21753, as shown in Scheme 5, a compound of Formula 6 synthesized by reacting a compound of Formula 2 with methyl carboxy imido dithioic acid dimethyl ester of Formula 5 is nitromethane. React with to prepare nizatidine.
상기 공지방법에 따를 경우에도 화학식 2의 화합물을 출발물질로 사용하므로 상기(한국특허 제21059호)에서 지적한 문제점을 그대로 가지고 있을 뿐만 아니라, 니자티딘의 순도가 낮아 여러 번의 정제가 필요하며 과량 사용하는 니트로메탄의 처리가 어려운 단점이 있다.In the case of following the well-known method, the compound of formula 2 is used as a starting material, and thus has the problems described above (Korean Patent No. 21059) as it is, and the purity of nizatidine is low, requiring several purifications and excessive use. There is a disadvantage that the treatment of nitromethane is difficult.
또 다른 한국특허 제82910호에 기술된 방법에 따르면, 하기 반응식 6과 같이, 화학식 2의 화합물을 화학식 7의 1,1-이치환-2-니트로에텐(1,1-DisubstitutedAccording to the method described in another Korean Patent No. 82910, as shown in Scheme 6, the compound of formula 2 is 1,1-disubstituted-2-nitroethene (1,1-Disubstituted)
-2-nitroethene) 또는 화학식 8의 1,1,1-삼치환-2-니트로에탄(1,1,1-Tri-substituted-2-nitroethane)과 반응시켜 중간체인 화학식 9의 화합물을 얻고, 다시 이것을 메틸아민과 반응시켜 니자티딘을 제조한다.-2-nitroethene) or 1,1,1-trisubstituted-2-nitroethane of formula 8 to obtain an intermediate compound 9 This is reacted with methylamine to prepare nizatidine.
(상기 반응식 6에서 X는 할로겐 또는 페녹시기이다.)(X in Scheme 6 is a halogen or phenoxy group.)
상기 제조방법에 따를 경우에도 화학식 2의 화합물을 출발물질로 사용함으로써 상기에서 지적한 문제점을 그대로 가지고 있을 뿐만 아니라, 고가의 할로겐화 니트로 화합물인 화학식 7 및 화학식 8의 화합물을 사용해야 하므로 경제성이 낮다는 단점이 있다.According to the preparation method, the use of the compound of Formula 2 as a starting material not only has the above-mentioned problems, but also requires the use of the compounds of Formula 7 and Formula 8, which are expensive halogenated nitro compounds. have.
이에, 본 발명자들은 상기 문제점들을 해결하기 위하여 연구를 거듭한 결과, 보다 간편하고 제조가 용이한 새로운 방법을 발견하게 되어 본 발명을 완성하게 되었다.Accordingly, the present inventors have conducted research to solve the above problems, and as a result, have found a new method that is simpler and easier to manufacture, thus completing the present invention.
따라서, 본 발명의 목적은 니자티딘의 제조방법을 제공하는 것을 목적으로 한다.Accordingly, it is an object of the present invention to provide a method for preparing nizatidine.
본 발명은 화학식 10의 4-클로로메틸-2-디메틸아미노메틸티아졸 또는 그의 산부가염과 화학식 11의N-메틸-1-(2-머캅토)에틸아미노-2-니트로에틸렌아민을 염기 존재하에서 반응시키는 공정을 포함하는 니자티딘의 제조방법에 관한 것이다.The present invention provides 4-chloromethyl-2-dimethylaminomethylthiazole of formula 10 or an acid addition salt thereof and N -methyl-1- (2-mercapto) ethylamino-2-nitroethyleneamine of formula 11 in the presence of a base. It relates to a method for producing nizatidine, including the step of reacting.
본 발명에 따른 제조방법을 반응식으로 나타내면 하기 반응식 7과 같다.Representation of the production method according to the invention is shown in Scheme 7 below.
본 발명에 따른 제조방법에서 사용 가능한 염기로는 수산화칼륨, 수산화나트륨, 탄산칼륨 및 탄산나트륨 등이 바람직하다.As a base which can be used in the manufacturing method which concerns on this invention, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, etc. are preferable.
본 발명에 따른 제조방법에서 사용가능한 반응용매로는 메탄올, 에탄올, 이소프로판올 또는 이들의 수용액이 바람직하며, 반응온도는 -20 내지 50℃가 바람직하다.As a reaction solvent usable in the production method according to the present invention, methanol, ethanol, isopropanol or an aqueous solution thereof is preferable, and the reaction temperature is preferably -20 to 50 ° C.
본 발명에서 출발물질로 사용되는 화학식 11의 화합물은 하기 반응식 8에서와 같이 1-메틸아미노-1-메틸티오-2-니트로에텐(1-Methylamino-1-methylthio-2-nitroethene)을 시스테아민 히드로클로라이드(Cysteamine hydrochloride)와 반응시켜 제조할 수 있으며 추가의 정제 공정없이 본 발명의 제조방법에 사용될 수 있다.The compound of formula 11 used as a starting material in the present invention is 1-methylamino-1-methylthio-2-nitroethene (1-Methylamino-1-methylthio-2-nitroethene) as shown in Scheme 8 It can be prepared by reacting with Cysteamine hydrochloride and can be used in the process of the present invention without further purification process.
또한, 본 발명에서 출발물질로 사용되는 화학식 10의 화합물의 산부가염은 통상적으로 사용되는 산부가염, 예를 들어 HCl등의 산부가염을 사용할 수 있다.In addition, the acid addition salt of the compound of formula 10 used as a starting material in the present invention may be used acid addition salts, such as acid addition salts commonly used.
상기 화학식 10의 화합물 또는 그의 산부가염은 공지의 화합물로서, 하기의 반응식 9와 같이, 디메틸아미노티오아세트아미드(Dimethylaminothioacetamide)를 1,3-디클로로프로판온과 반응시켜 수득한 4-클로로메틸-4-히드록시-2-디메틸아미노메틸-2-티아졸린(4-Chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline)을 티오닐클로라이드(Thionylchloride)로 0℃ 내지 50℃의 온도에서 반응시켜 수득할 수 있다.(미국특허 제493,883호)The compound of Formula 10 or an acid addition salt thereof is a known compound, 4-chloromethyl-4- obtained by reacting dimethylaminothioacetamide with 1,3-dichloropropanone as shown in Scheme 9 below. It can be obtained by reacting hydroxy-2-dimethylaminomethyl-2-thiazoline (4-Chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline) with thionylchloride at a temperature of 0 ° C to 50 ° C. (US Pat. No. 493,883).
본 발명에 따른 제조방법은 종래기술과 달리 출발물질로서 화학식 2의 화합물을 사용하는 대신 화학식 11의N-메틸-1-(2-머캅토)에틸아미노-2-니트로에틸렌아민을 사용함으로써 화학식 2의 화합물을 사용하는데 따른 문제점을 효과적으로 해결할 수 있다.Unlike the prior art, the preparation method according to the present invention uses N -methyl-1- (2-mercapto) ethylamino-2-nitroethyleneamine of formula 11 instead of using the compound of formula 2 as a starting material. The problem of using the compound can be effectively solved.
본 발명에 따른 제조방법은 반응온도가 높지않은 보다 온화한 조건에서 반응을 수행할 수 있으며, 하기 실시예에서 확인 할 수 있는 바와 같이, 값 비싼 정제 및 처리공정을 거치지 않고도 높은 수율 및 순도로 니자티딘을 제조할 수 있다.The production method according to the present invention can be carried out under milder conditions where the reaction temperature is not high, and as can be seen in the following examples, Niizati with high yield and purity without undergoing expensive purification and treatment processes Dean can be prepared.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 이것이 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the invention.
실시예 1: 4-클로로메틸-2-디메틸아미노메틸티아졸 히드로클로라이드의 제조Example 1: Preparation of 4-chloromethyl-2-dimethylaminomethylthiazole hydrochloride
디메틸아미노티오아세트아미드 히드로클로라이드 10g 및 1,3-디클로로프로판온 9g을 40ml의 클로로포름에 가하였다. 혼합물에 15g의 중탄산나트륨을 천천히 가하여 주위온도에서 24시간 동안 교반한 후 여과하였다. 여액을 진공하에서 증발건조 시킨후, 에틸 아세테이트로 세척하였다. 세척한 고체를 증발건조하여 12.3g의4-클로로메틸-4-히드록시-2-디메틸아미노메틸-2-티아졸린을 수득하였다. 수득한 12.3g의 4-클로로메틸-4-히드록시-2-디메틸아미노메틸-2-티아졸린을 60ml의 클로로포름에 녹인후 빙욕중에서 냉각시켰다. 여기에 10.8ml의 클로로포름에 용해시킨 10.8ml의 티오닐클로라이드를 적가하였다. 50℃로 가온하여 30분동안 교반후 냉각하여 여과하였다. 여과한 고체를 진공하에서 증발건조한 후, 메탄올 20ml와 에틸아세테이트 50ml중에서 슬러리화하였다. 생긴 결정을 여과하여 건조시켜 6.7g의 4-클로로메틸-2-디메틸아미노메틸티아졸 히드로클로라이드를 수득하였다.10 g of dimethylaminothioacetamide hydrochloride and 9 g of 1,3-dichloropropanone were added to 40 ml of chloroform. 15 g of sodium bicarbonate was slowly added to the mixture, stirred at ambient temperature for 24 hours, and filtered. The filtrate was evaporated to dryness in vacuo and then washed with ethyl acetate. The washed solid was evaporated to dryness to afford 12.3 g of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline. The obtained 12.3 g of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline was dissolved in 60 ml of chloroform and cooled in an ice bath. To this was added dropwise 10.8 ml of thionylchloride dissolved in 10.8 ml of chloroform. Warmed to 50 ° C., stirred for 30 minutes, cooled and filtered. The filtered solid was evaporated to dryness in vacuo and then slurried in 20 ml of methanol and 50 ml of ethyl acetate. The resulting crystals were filtered off and dried to yield 6.7 g of 4-chloromethyl-2-dimethylaminomethylthiazole hydrochloride.
융점: 137 내지 140℃(실측 : 135℃)Melting Point: 137-140 ° C (Measured: 135 ° C)
1H NMR (D2O) : δ2.95(6H, s), 4.69(2H,s),4.78(2H,s),7.78(1H,s) 1 H NMR (D 2 O): δ 2.95 (6H, s), 4.69 (2H, s), 4.78 (2H, s), 7.78 (1H, s)
실시예 2:N-2-[(2-디메틸아미노메틸-4-티아졸릴)메틸티오]에틸-N'-메틸-2-니트로-1,1-에텐디아민의 제조Example 2: Preparation of N- 2-[(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethyl- N' -methyl-2-nitro-1,1-ethenediamine
10g의 1-메틸아미노-1-메틸티오-2-니트로에텐을 150ml의 메탄올에 가한후, -20℃로 냉각하였다. 질소를 불어주면서, 8.4g의 시스테아민 히드로클로라이드를 가하였다. 2.2g의 수산화칼륨을 8.5ml의 메탄올에 녹여 30분 동안 천천히 가한후 전반부 3시간 동안 -10℃를 유지 시켰다. 2.2g의 수산화칼륨을 8.5ml의 메탄올에 녹여 30분 동안 천천히 넣은후, 19g의 탄산칼륨을 가하였다. 10.7g의 4-클로로메틸-2-디메틸아미노메틸티아졸 히드로클로라이드를 서서히 가하여 후반부 5시간 동안 교반하였다. 진공 건조하여 메탄올을 제거하고, 잔사를 포화 염화나트륨 수용액에녹였다. 이 용액을 클로로포름으로 추출하여 수분을 제거한 후, 진공 건조시켰다. 고체를 에탄올과 에틸 아세테이트로 결정화하여 13g(83%)의N-2-[(2-디메틸아미노메틸-4-티아졸릴)메틸티오]에틸-N'-메틸-2-니트로-1,1-에텐디아민을 수득하였다.10 g of 1-methylamino-1-methylthio-2-nitroethene was added to 150 ml of methanol and then cooled to -20 ° C. Blowing nitrogen, 8.4 g of cysteamine hydrochloride was added. 2.2 g of potassium hydroxide was dissolved in 8.5 ml of methanol and slowly added for 30 minutes, and then maintained at -10 ° C. for 3 hours. 2.2 g of potassium hydroxide was dissolved in 8.5 ml of methanol and slowly added for 30 minutes, and then 19 g of potassium carbonate was added thereto. 10.7 g of 4-chloromethyl-2-dimethylaminomethylthiazole hydrochloride was slowly added and stirred for the second half hour. Vacuum drying was carried out to remove methanol, and the residue was dissolved in saturated aqueous sodium chloride solution. The solution was extracted with chloroform to remove moisture and then dried in vacuo. The solid was crystallized from ethanol and ethyl acetate to give 13 g (83%) of N- 2-[(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethyl- N' -methyl-2-nitro-1,1- Ethenediamine was obtained.
융점: 130 내지 132℃(실측 : 122℃)Melting Point: 130 to 132 ° C (Actual Measurement: 122 ° C)
1H NMR (CDCl3):δ2.24(6H,s),2.68(2H,t),2.74(3H,s),3.34(2H,m), 1 H NMR (CDCl 3 ): δ 2.24 (6H, s), 2.68 (2H, t), 2.74 (3H, s), 3.34 (2H, m),
3.70(2H,s),3.85(2H,s),6.46(1H,s),7.16(1H,br),7.40(1H,s),9.96(1H,br)3.70 (2H, s), 3.85 (2H, s), 6.46 (1H, s), 7.16 (1H, br), 7.40 (1H, s), 9.96 (1H, br)
실시예 3:N-2-[(2-디메틸아미노메틸-4-티아졸릴)메틸티오]에틸-N'-메틸-2-니트로-1,1-에텐디아민의 제조Example 3: Preparation of N- 2-[(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethyl- N' -methyl-2-nitro-1,1-ethenediamine
5g의 1-메틸아미노-1-메틸티오-2-니트로에텐을 75㎖의 메탄올에 가한후, -5℃로 냉각했다. 질소를 불어주면서, 4.2g의 시스테아민 히드로클로라이드를 가했다. 1.1g의 수산화칼륨을 4.25㎖의 메탄올에 녹여 30분 동안 천천히 가한후, 3시간동안 -5℃를 유지했다. 1.1g의 수산화칼륨을 4.25㎖의 메탄올에 녹여 30동안 천천히 넣은후, 9.5g의 탄산칼륨을 가했다. 5.35g의 4-클로로메틸-2-디메틸아미노메틸 티아졸 히드로클로라이드를 서서히 가하고, 25℃로 온도를 서서히 올려 3시간 동안 교반했다. 진공 건조하여 메탄올을 제거하고, 잔사를 포화 염화나트륨 수용액에 녹인다. 이 용액을 클로로포름으로 추출하여 수분을 제거후 진공 건조시킨다. 고체를 에탄올과 에틸 아세테이트로 결정화하여 6.2g(79%)의N-2-[(2-디메틸아미노메틸-4-티아졸릴)메틸티오]에틸-N'-메틸-2-니트로-1,1-에텐디아민을 수득한다.5 g of 1-methylamino-1-methylthio-2-nitroethene was added to 75 ml of methanol, and then cooled to -5 ° C. While blowing nitrogen, 4.2 g of cysteamine hydrochloride was added. 1.1 g of potassium hydroxide was dissolved in 4.25 ml of methanol, added slowly for 30 minutes, and maintained at −5 ° C. for 3 hours. 1.1 g of potassium hydroxide was dissolved in 4.25 ml of methanol, and slowly added for 30 minutes, and then 9.5 g of potassium carbonate was added thereto. 5.35 g of 4-chloromethyl-2-dimethylaminomethyl thiazole hydrochloride was slowly added, and the temperature was gradually raised to 25 ° C. and stirred for 3 hours. Vacuum drying removes methanol and the residue is taken up in saturated aqueous sodium chloride solution. The solution is extracted with chloroform to remove moisture and then dried in vacuo. The solid was crystallized from ethanol and ethyl acetate to give 6.2 g (79%) of N- 2-[(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethyl- N' -methyl-2-nitro-1,1 Obtain ethenediamine.
융점: 130 내지 132℃(실측 : 122℃)Melting Point: 130 to 132 ° C (Actual Measurement: 122 ° C)
1H NMR (CDCl3):δ2.24(6H,s),2.68(2H,t),2.74(3H,s),3.34(2H,m), 1 H NMR (CDCl 3 ): δ 2.24 (6H, s), 2.68 (2H, t), 2.74 (3H, s), 3.34 (2H, m),
3.70(2H,s),3.85(2H,s),6.46(1H,s),7.16(1H,br),7.40(1H,s),9.96(1H,br)3.70 (2H, s), 3.85 (2H, s), 6.46 (1H, s), 7.16 (1H, br), 7.40 (1H, s), 9.96 (1H, br)
본 발명의 제조방법은 온화한 조건에서 정제 및 처리공정없이 니자티딘을 고수율, 고순도로 경제적으로 제조할 수 있다는 잇점이 있다.The production method of the present invention has the advantage that it is possible to economically produce nizatidine in high yield, high purity without mild purification and processing in mild conditions.
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| US4317829A (en) * | 1973-05-17 | 1982-03-02 | Smith Kline & French Laboratories Limited | Triazole-substituted ethylene derivatives |
| WO1996017839A1 (en) * | 1994-12-08 | 1996-06-13 | Hoechst Marion Roussel, Inc. | Novel processes for preparing ranitidine |
| WO1998011081A1 (en) * | 1996-09-11 | 1998-03-19 | Knoll Aktiengesellschaft | Process for the preparation of nizatidine |
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| US4317829A (en) * | 1973-05-17 | 1982-03-02 | Smith Kline & French Laboratories Limited | Triazole-substituted ethylene derivatives |
| WO1996017839A1 (en) * | 1994-12-08 | 1996-06-13 | Hoechst Marion Roussel, Inc. | Novel processes for preparing ranitidine |
| WO1998011081A1 (en) * | 1996-09-11 | 1998-03-19 | Knoll Aktiengesellschaft | Process for the preparation of nizatidine |
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