KR20110094751A - An improved process for preparing telmisartan - Google Patents
An improved process for preparing telmisartan Download PDFInfo
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- KR20110094751A KR20110094751A KR1020100014346A KR20100014346A KR20110094751A KR 20110094751 A KR20110094751 A KR 20110094751A KR 1020100014346 A KR1020100014346 A KR 1020100014346A KR 20100014346 A KR20100014346 A KR 20100014346A KR 20110094751 A KR20110094751 A KR 20110094751A
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- ICIOUGBIRSVINR-UHFFFAOYSA-N CC(C)CCc1nc(c(C)cc(-c2nc3ccccc3[n]2C)c2)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(O)=O Chemical compound CC(C)CCc1nc(c(C)cc(-c2nc3ccccc3[n]2C)c2)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(O)=O ICIOUGBIRSVINR-UHFFFAOYSA-N 0.000 description 1
- RMXGTMRDXKUUDJ-UHFFFAOYSA-N COC(c(cccc1)c1-c1ccc(CBr)cc1)=O Chemical compound COC(c(cccc1)c1-c1ccc(CBr)cc1)=O RMXGTMRDXKUUDJ-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Description
본 발명은 고혈압 치료제(angiotensin Ⅱ receptor antagonist)로 사용되고 있는 텔미사탄의 개선된 제조방법에 관한 것이다.
The present invention relates to an improved method for preparing telmisartan, which is used as an angiotensin II receptor antagonist.
텔미사탄(Telmisartan)은 하기 화학식 1로 표시된다.Telmisartan is represented by the following formula (1).
<화학식 1><Formula 1>
텔미사탄은 하기 반응식 1에 기재된 방법 또는 하기 반응식 2에 기재된 방법에 의한 제조방법으로 제조되어 오고 있다.
Telmisartan has been produced by the method described in Scheme 1 or by the method described in Scheme 2 below.
하기 반응식 1로 나타낼 수 있는 제조방법은 미국특허공보 제5,591,762호 및 유럽특허공보 제1,912,975호에 공지되어 있다. 하기 반응식 1은 하기 화학식 2 화합물과 하기 화학식 5 화합물을 축합반응시켜 하기 화학식 6 화합물인 t-부틸 에스테르화합물을 제조하고, 하기 화학식 6 화합물을 가수분해시켜 목적화합물인 텔미사탄을 제조하는 것이다.Preparation methods that can be represented by the following scheme 1 are known from U.S. Patent No. 5,591,762 and European Patent No. 1,912,975. The following Reaction Scheme 1 is a condensation reaction of the following Chemical Formula 2 compound with the following Chemical Formula 5 compound to prepare a t -butyl ester compound of the formula (6), and to hydrolyze the compound of the formula (6) to produce the desired compound telmisartan.
<반응식 1><Scheme 1>
미국특허공보 제5,591,762호는 상기 반응식 1에 있어서, 중간체 화합물인 화학식 6 화합물로부터 화학식 1 화합물인 텔미사탄의 제조 단계에서, 화학식 6 화합물인 t-부틸 에스테르화합물을 N,N-디메틸포름아미드 반응용매중에서 트리플루오로아세트산을 사용하여 가수분해시킴으로써 화학식 1 화합물을 제조하는 것을 특징으로 한다.
U.S. Patent No. 5,591,762 discloses a t -butyl ester compound of Formula 6 as a N, N -dimethylformamide reaction solvent in the step of preparing telmisartan, which is a compound of Formula 1, from the compound of Formula 6, which is an intermediate compound. The compound of formula 1 is prepared by hydrolysis using trifluoroacetic acid.
그런데, 상기 종래기술은 유독한 강산인 트리플루오로아세트산을 과량 사용하여 가수분해시킴으로써, 이를 중화시키기 위해 과량의 염기를 사용하여야 하기 때문에 부산물로 생성된 무기염인 소디움트리플루오로아세테이트를 제거하기 위해 work-up 과정(감압증류 후 정제수와 유기용매를 넣고 pH 조절 후 층 분리하고 유기층을 정제수로 세척하고 추출된 유기층을 증류)을 필요로 하며, 반응 완결 후 실리카겔칼럼크로마토그래피를 사용하여 텔미사탄을 분리하는 것이므로 제조공정이 복잡할 뿐만 아니라, 수율이 매우 낮은 큰 단점을 가지고 있다.
By the way, the prior art hydrolyzed trifluoroacetic acid, which is a toxic strong acid, to remove sodium trifluoroacetate, which is an inorganic salt produced as a by-product, because an excess base must be used to neutralize it. After work-up process (reduced distillation under reduced pressure, purified water and organic solvent, adjust pH, separate the layers, wash the organic layer with purified water, and distill the extracted organic layer), and after completion of the reaction, telmisartan was purified using silica gel column chromatography. Because of the separation, not only is the manufacturing process complicated, but also has a large disadvantage of low yield.
유럽특허공보 제1,912,975는 상기 반응식 1에 있어서, 중간체 화합물인 화학식 6 화합물, 즉 t-부틸 에스테르화합물을 이용하여 화학식 1 화합물인 텔미사탄을 제조하는데 있어서, 중간체 화합물인 t-부틸 에스테르화합물을 염산으로 처리하여 t-부틸 에스테르히드로클로라이드 화합물을 얻고, 염산으로 가수분해하여 텔미사탄 디히드로클로라이드 화합물을 얻은 다음 암모니아수용액으로 pH를 조절하여 목적화합물인 텔미사탄을 제조하는 것을 특징으로 한다.
In the above scheme 1, the European Patent Publication No. 1912975, an intermediate compound of formula (VI) compound, i.e., t - in using butyl ester for the production of a telmisartan compound of formula I, an intermediate compound is t - butyl ester compound with hydrochloric acid Treatment to obtain a t -butyl ester hydrochloride compound, hydrolyzed with hydrochloric acid to obtain a telmisartan dihydrochloride compound and then adjusting the pH with an aqueous ammonia solution to prepare the target compound telmisartan.
그런데, 상기 종래기술은 중간체 화합물인 화학식 6 화합물로부터 목적 화합물인 텔미사탄을 제조하기 위한 제조공정이 복잡하고, 중간체 화합물로부터 목적화합물인 텔미사탄을 제조하는 세 공정의 전수율이 54.5%로 매우 낮아 대량생산에 적합하지 않다.
However, the prior art has a complicated manufacturing process for preparing telmisartan as the target compound from the compound of formula (6), which is an intermediate compound, and the total yield of the three processes for producing telmisartan as the target compound from the intermediate compound is very low as 54.5%. Not suitable for mass production
또한, 하기 반응식 2로 나타낼 수 있는 텔미사탄의 제조방법은 미국특허공보 제7,501,448호, 유럽특허공보 제1,748,990호, 유럽특허공보 제1,805,146호, 국제특허공개공보 WO 2009/006860호, 미국특허출원공개공보 제2006/276525호, 중국특허공보 제1,344,712호 및 미국특허출원공개공보 제2006/211866호 등에 공지되어 있다. 즉, 하기 화학식 2 화합물과 하기 화학식 3 화합물을 축합반응시켜 하기 화학식 4 화합물을 제조하고, 화학식 4 화합물을 가수분해시켜 목적화합물인 텔미사탄을 제조하는 것이다.In addition, the method for producing telmisartan which can be represented by the following scheme 2 is US Patent No. 7,501,448, European Patent Publication No. 1,748,990, European Patent Publication No. 1,805,146, International Patent Publication WO 2009/006860, US Patent Application Publication No. 2006/276525, Chinese Patent No. 1,344,712, and US Patent Application Publication No. 2006/211866. That is, the compound of formula 2 and the compound of formula 3 are condensed to prepare a compound of formula 4, and the compound of formula 4 is hydrolyzed to prepare telmisartan.
<반응식 2><Scheme 2>
미국특허공보 제7,501,448호는 상기 반응식 2에 있어서, 화학식 2 화합물과 화학식 3 화합물을 한 공정내에서 축합반응과 가수분해반응을 동시에 진행하여 목적화합물인 텔미사탄을 제조하는 것으로서, 축합반응과 가수분해반응을 동시에 진행하기 위하여 염기를 과량(6.5~8 당량) 사용하며, 반응 완결 후 층분리한 다음 유기층을 나누어 처리하였고, 아세트산으로 pH를 조절하는 것을 특징으로 한다.
U.S. Patent No. 7,501,448 in the above Reaction Scheme 2, wherein the compound of formula 2 and the compound of formula 3 in the same process to perform the condensation reaction and hydrolysis reaction to produce the desired compound telmisartan, condensation reaction and hydrolysis In order to proceed with the reaction at the same time, an excess of base (6.5 ~ 8 equivalents) is used, and after completion of the reaction, the layers are separated and the organic layer is treated separately, characterized by adjusting the pH with acetic acid.
상기 제조방법은 한 공정 내에서 축합반응과 가수분해반응을 진행하기 위해서 염기성화합물을 과량 사용한 이유로 인하여 부산물로 생성된 무기염을 제거하기 위해서 work-up 과정을 거쳐야 하기 때문에 목적화합물을 얻기 위한 많은 시간이 소요되며, 목적화합물을 얻기 위하여 유기층을 나누어 처리하는 등 제조공정이 복잡하고 수율이 낮은 단점을 가지고 있다.
Since the preparation method requires a work-up process to remove inorganic salts formed as by-products due to excessive use of basic compounds in order to proceed with condensation and hydrolysis reactions in one process, a lot of time is required to obtain a target compound. This takes a disadvantage in that the manufacturing process is complicated and the yield is low, such as dividing the organic layer in order to obtain the target compound.
유럽특허공보 제1,748,990호도 화학식 2 화합물과 화학식 3 화합물을 한 공정 내에서 축합반응과 가수분해반응을 진행하여 목적화합물인 텔미사탄을 제조하는 것으로서, 염기를 과량(5.4~7.6 당량)으로 사용하는 것과 반응 완결 후 디클로로메탄으로 추출, 감압 후 아세톤을 가하고 여과하여 목적화합물인 텔미사탄을 수득하는 것을 특징으로 한다.
European Patent Publication No. 1,748,990 also condenses and hydrolyzes a compound of Formula 2 and a compound of Formula 3 in one process to produce telmisartan as a target compound, using an excess of base (5.4 to 7.6 equivalents). After completion of the reaction, the mixture was extracted with dichloromethane, reduced pressure, acetone was added and filtered to obtain the desired compound telmisartan.
그러나, 상기 제조방법 역시 한 공정 내에서 축합반응과 가수분해반응을 진행하기 위해서 염기성화합물을 과량 사용한 이유로 인하여 work-up 과정을 거쳐야 하기 때문에 목적화합물을 얻기 위한 많은 시간이 소요되며, 디클로로메탄이 목적화합물인 텔미사탄에 잔류용매로 남게 되는 큰 단점이 있어 대량생산에 적합하지 않다.
However, the preparation method also takes a lot of time to obtain the target compound because the work-up process has to go through due to the excessive use of the basic compound in order to proceed the condensation reaction and hydrolysis reaction in one process, dichloromethane There is a big disadvantage that the compound telmisartan remains as a residual solvent, which is not suitable for mass production.
유럽특허공보 제1,805,146호에서는 축합반응과 가수분해반응을 두 단계로 진행하여 텔미사탄을 제조하는 것으로서, 상기 반응단계 중 축합반응 단계에서는 화학식 3 화합물인 메틸 2-[4-(브로모메틸)페닐]벤조에이트 화합물을 과량(1.6 당량)으로 사용하여 중간체 화합물인 화학식 4 화합물을 제조하며, 반응 완결 후 메탄올에 녹아 있는 염산을 사용하여 텔미사탄 메틸에스테르 히드로클로라이드 화합물을 제조한 후에 가수분해반응을 한다. 가수분해반응 단계에서 아세토니트릴 용매에서 수산화칼륨을 과량(5.3 당량)으로 사용하여 텔미사탄칼륨염을 얻고 이것을 아세토니트릴과 물의 혼합용매에서 아세트산으로 pH를 조절하여 텔미사탄을 제조하는 것이다.
In European Patent Publication No. 1,805,146, telmisartan is prepared by performing a condensation reaction and a hydrolysis reaction in two steps, and in the condensation reaction step, methyl 2- [4- (bromomethyl) phenyl ] By benzoate compound is used in excess (1.6 equivalents) to prepare compound (4), which is an intermediate compound. After completion of the reaction, telmisartan methyl ester hydrochloride compound is prepared using hydrochloric acid dissolved in methanol. . In the hydrolysis step, telmisartan salt is obtained by using potassium hydroxide in an acetonitrile solvent in an excess (5.3 equivalents) to obtain telmisartan potassium salt, and adjusting the pH with acetic acid in a mixed solvent of acetonitrile and water to prepare telmisartan.
그런데, 상기 제조방법은 축합반응시 화학식 3 화합물의 과량 사용은 반응 후 남은 화학식 3 화합물 자체가 중간체 화합물의 불순물로 존재할 가능성이 있고, 가수분해반응을 진행하기 위해 염기성화합물을 과량 사용함으로써 work-up 과정을 거쳐야 하기 때문에 목적화합물을 얻기 위한 많은 시간이 소요되며, 중간체 화합물인 화학식 4 화합물로부터 목적 화합물인 텔미사탄을 제조하기 위한 제조공정이 복잡하고 수율이 낮은 단점을 가지고 있다.
By the way, in the above production method, the excessive use of the compound of formula (3) during the condensation reaction may exist as an impurity of the intermediate compound itself after the reaction of the compound of formula (3), work-up by using an excess of the basic compound to proceed the hydrolysis reaction It takes a long time to obtain the target compound because it has to go through the process, the manufacturing process for producing the target compound telmisartan from the compound of formula 4 intermediate compound has a disadvantage of low yield.
국제특허공개공보 WO 2009/006860호에서는 상기 반응식 2에 있어서, 목적 화합물인 텔미사탄을 제조하기 위한 가수분해 반응시 물의 양을 1% 이하로 유지하며 중간체 화합물인 화학식 3 화합물에 수산화칼륨을 과량(3.5 당량) 첨가하고 메탄올 용매에서 24시간 환류교반하며 반응완결 후에 아세트산이나 포름산으로 pH를 조절하여 텔미사탄을 제조하는 것이다.
In International Patent Publication No. WO 2009/006860, in the reaction scheme 2, the amount of water is maintained at 1% or less during the hydrolysis reaction to prepare telmisartan, the target compound, and potassium hydroxide is excessively added to the compound of formula 3 which is an intermediate compound. 3.5 equivalents) was added, and the mixture was stirred under reflux for 24 hours in methanol solvent. After completion of the reaction, pH was adjusted with acetic acid or formic acid to prepare telmisartan.
그런데, 이러한 방법은 가수분해 반응시 염기성 화합물을 과량 사용하고, 반응시간이 오래 걸리며, 여과시에 여과속도가 느려(가수분해반응시 메탄올 용매(1% 이하의 물을 포함)에서 반응함으로 가수분해 후 pH 조절시 생성되는 무기염인 포타슘아세테이트나 포타슘포르메이트가 같이 석출되어 여과속도가 느려지고 여과한 고체에도 무기염이 남아 있을 가능성이 크기 때문에) 목적화합물을 얻기 위한 많은 시간이 소요되는 단점을 가지고 있다.
However, this method uses excessive amounts of basic compounds in the hydrolysis reaction, takes a long reaction time, and slows the filtration rate during the filtration (in the case of the hydrolysis reaction, the reaction is carried out in a methanol solvent (containing less than 1% of water). After the pH adjustment, the inorganic salts, potassium acetate or potassium formate, are precipitated together, so the filtration rate is slowed down and inorganic salts remain in the filtered solid.) have.
미국특허출원공개공보 제2006/276525호의 제조방법은 중간체 화합물인 화학식 4 화합물을 이용하여 목적 화합물인 텔미사탄을 제조하는 상기 반응식 2에 있어서, 메탄올 6배와 소량의 물에서 수산화나트륨수용액 과량(3.3 당량)을 사용하여 반응하고 반응완결 후 용매부분을 감압농축한 다음 85℃에서 물 10배를 첨가하여 녹지 않은 물질을 여과하고 아세트산으로 중화하여 여과하여 텔미사탄을 제조하는 것이다.
The preparation method of U.S. Patent Application Publication No. 2006/276525 uses the compound of formula 4, which is an intermediate compound, to prepare telmisartan as the target compound, wherein the aqueous solution of sodium hydroxide in methanol 6 times and a small amount of water (3.3) is used. After the reaction was completed, and the reaction part was concentrated under reduced pressure, and then, 10 parts of water was added at 85 ° C. to filter the undissolved material, and neutralized with acetic acid to filter to produce telmisartan.
그런데, 상기 종래기술은 가수분해 반응시 염기성 화합물을 과량 사용함으로써 work-up 과정을 거쳐야 하며, 물에서만 결정을 석출시키기 때문에 실제 여과속도가 매우 느리고, 목적물의 순도가 낮아 수회 정제를 필요하여 전체 수율이 62.3%로 매우 낮으며, 제조단계가 많아 대량생산방법으로 적합하지 않다.
However, the prior art requires a work-up process by using an excessive amount of a basic compound during the hydrolysis reaction, and because crystals are precipitated only in water, the actual filtration rate is very slow, and the purity of the target product is low, requiring several times of purification. This is very low as 62.3%, and there are many manufacturing steps, which is not suitable for mass production.
중국특허공보 제1,344,712호의 제조방법에서는 상기 반응식 2에 있어서, 화학식 2 화합물과 화학식 3 화합물로부터 탄산칼륨을 과량(3 당량) 사용하여 중간체 화합물인 텔미사탄 메틸에스테르 화합물을 제조하며, 목적 화합물인 텔미사탄은 에탄올 3.8배와 4M 수산화나트륨수용액을 사용하여 제조하고, 반응완결 후 잔류물이 2.3배가 될 때까지 증류한 다음 염산으로 pH를 조절하고 결정을 여과, N,N-디메틸포름아미드로 정제하여 제조하는 것이다.
In the preparation method of Chinese Patent Publication No. 1,344,712, in the above Scheme 2, an intermediate compound telmisartan methyl ester compound is prepared by using an excess amount (3 equivalents) of potassium carbonate from a compound of Formula 2 and a compound of Formula 3, and a target compound telmisartan Was prepared using 3.8 times of ethanol and 4M aqueous sodium hydroxide solution, and after completion of the reaction, the residue was distilled until the residue became 2.3 times, and then the pH was adjusted with hydrochloric acid, and the crystals were filtered and purified with N, N-dimethylformamide. It is.
그런데, 이러한 방법은 축합반응시 염기성 화합물을 과량 사용함으로써 work-up 과정을 거쳐야 하며, 소량의 물을 사용하기 때문에 무기염이 결정에 존재할 수 있고, 75.1%의 낮은 수율로 얻는 단점을 가지고 있다.
However, this method requires a work-up process by using an excessive amount of a basic compound in the condensation reaction, and since a small amount of water may be used, inorganic salts may be present in the crystal and have a low yield of 75.1%.
미국특허출원공개공보 제2006/211866호의 제조방법에서는 상기 반응식 2에 있어서, 중간체인 텔미사탄 메틸에스테르 제조시 수산화칼륨 과량(4 당량)과 상전이촉매인 t-부틸암모늄브로마이드 소량을 넣고 메틸이소부틸케톤/정제수=4/5에서 반응하여 제조하며, 목적 화합물인 텔미사탄은 가수분해반응시 수산화칼륨 과량(4 당량)을 사용하여 메탄올수용액에서 반응시켜 제조한다.
In the preparation method of U.S. Patent Application Publication No. 2006/211866, in the reaction scheme 2, methylisobutyl ketone is added in the production of intermediate telmisartan methyl ester by adding an excess of potassium hydroxide (4 equivalents) and a small amount of t-butylammonium bromide as a phase transfer catalyst. / Purified water = 4/5, the target compound telmisartan is prepared by reaction in aqueous methanol solution using an excess of potassium hydroxide (4 equivalents) during the hydrolysis reaction.
그런데, 상기 제조방법은 가수분해 반응 후 pH를 조절하여 얻은 텔미사탄 고체에 포함된 부산물인 무기염을 제거하기 위하여 무기염이 포함되어 있는 텔미사탄을 디클로로메탄/메탄올=8/2에서 녹인 후 여과, 농축하여 메탄올 용매에서 텔미사탄을 분리하는 공정을 필요로 하며, 그 결과 73.0%의 낮은 수율로 얻는 단점을 가지고 있다.
By the way, in the above method, in order to remove the inorganic salt which is a by-product included in the telmisartan solid obtained by adjusting the pH after the hydrolysis reaction, telmisartan containing the inorganic salt was dissolved in dichloromethane / methanol = 8/2 and then filtered. , It is necessary to separate the telmisartan from the methanol solvent by concentration, and as a result has a disadvantage of obtaining a low yield of 73.0%.
따라서, 본 발명자들은 상기 반응식 2에 의한 텔미사탄의 제조방법에 있어서, 축합반응 및 가수분해반응시 첨가되는 염기에 의해 생성되는 부산물인 무기염을 쉽게 제거하기 위한 공정을 연구하던 중에 축합반응시 4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸의 사용량을 기준으로 반응용매로서 디메틸설폭시드와 이소프로판올의 혼합용매를 디메틸설폭시드 0.5~1.5배, 이소프로판올 1.5~4.5배를 사용하여 중간체 화합물을 제조하고 가수분해반응은 중간체 화합물을 기준으로 메탄올 7~9배와 정제수 5~7배의 혼합용매에서 반응시켜 텔미사탄을 제조함으로써 부산물인 무기염을 제거하기 위한 공정을 별도로 필요치 않으며, 대량생산에 적합하고 고순도 및 고수율로 제조될 수 있는 텔미사탄의 개선된 제조방법을 완성하였다.
Therefore, the present inventors in the method for producing telmisartan according to Scheme 2, while studying the process for easily removing inorganic salts by-products generated by the base added during the condensation reaction and hydrolysis reaction 4 A mixed solvent of dimethyl sulfoxide and isopropanol was used as a reaction solvent based on the amount of -methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole. The intermediate compound was prepared using sulfoxide 0.5-1.5 times and isopropanol 1.5-4.5 times, and the hydrolysis reaction was carried out in a mixed solvent of methanol 7-9 times and purified water 5-7 times based on the intermediate compound to produce telmisartan. By doing so, there is no need for a separate process for removing inorganic salts, which are by-products, and have completed an improved method for producing telmisartan, which is suitable for mass production and can be manufactured with high purity and high yield.
본 발명은 4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸 화합물과 메틸 2-[4-(브로모메틸)페닐]벤조에이트 화합물로부터 축합반응에 의해 중간체 화합물인 메틸 2-(4-{[4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸-1-일]메틸}페닐)벤조에이트 화합물을 제조하고, 이를 가수분해반응에 의해 텔미사탄을 제조하는 방법에 있어서,The present invention relates to 4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole compound and methyl 2- [4- (bromomethyl) phenyl ] Methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -as an intermediate compound by condensation reaction from a benzoate compound In the method for producing a benzimidazol-1-yl] methyl} phenyl) benzoate compound, and producing it by the hydrolysis reaction,
축합반응 및 가수분해반응시 생성되는 부산물인 무기염을 쉽게 제거할 수 있으며 높은 수율과 높은 순도로 목적 화합물인 텔미사탄을 제조하는 방법을 제공하는 것을 목적으로 한다.
It is an object of the present invention to provide a method for preparing telmisartan, a desired compound, which can easily remove inorganic salts, which are by-products generated during condensation and hydrolysis reactions, in high yield and high purity.
본 발명은 하기 화학식 1 화합물인 텔미사탄의 제조방법에 관한 것이다.The present invention relates to a method for preparing telmisartan, which is a compound of Formula 1.
<화학식 1><Formula 1>
본 발명에 따른 텔미사탄은 종래기술에서 언급한 하기 반응식 2에 의한 방법에 따라 제조된다.Telmisartan according to the present invention is prepared according to the method according to Scheme 2 below mentioned in the prior art.
<반응식 2><Scheme 2>
반응식 2는 화학식 2 화합물인 4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸 화합물과 화학식 3 화합물인 메틸 2-[4-(브로모메틸)페닐]벤조에이트 화합물을 축합반응시켜 화학식 4 화합물인 메틸 2-(4-{[4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸-1-일]메틸}페닐)벤조에이트 화합물을 제조하며, 이는 목적화합물인 텔미사탄의 중간체 화합물로서 가수분해반응에 의해 화학식 1 화합물인 텔미사탄을 제조한다.
Scheme 2 is 4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole compound, which is a compound of Formula 2, and methyl 2- [ Condensation reaction of 4- (bromomethyl) phenyl] benzoate compound to yield methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl- 1H -benzimidazol-1-yl] methyl} phenyl) benzoate compound was prepared, which was prepared as a compound of formula 1 by the hydrolysis reaction as an intermediate compound of telmisartan as the target compound. do.
본 발명은 상기 반응식 2에 의해 제조되는 텔미사탄의 제조방법, 즉 화학식 2 화합물과 화학식 3 화합물을 축합반응시켜 중간체 화합물을 제조하고, 이를 가수분해반응에 의해 화학식 1 화합물인 텔미사탄을 제조하는 방법에 있어서,The present invention is a method for preparing telmisartan prepared by the above Scheme 2, that is, a method of preparing an intermediate compound by condensation of a compound of Formula 2 with a compound of Formula 3, and producing Telmisartan as a compound of Formula 1 by hydrolysis. To
중간체 화합물인 화학식 4 화합물의 제조단계에서, 반응용매로서 디메틸설폭시드와 이소프로판올의 혼합용매를 화학식 2 화합물의 사용량을 기준으로 디메틸설폭시드 0.5~1.5배, 이소프로판올 1.5~4.5배를 사용한 축합반응과 목적 화합물인 텔미사탄의 제조단계에서, 화학식 4 화합물의 사용량을 기준으로 메탄올 7~9배와 정제수 5~7배의 혼합용매에서 가수분해반응 하는 것을 제공한다.
Condensation reaction and purpose using a mixed solvent of dimethyl sulfoxide and isopropanol as a reaction solvent using dimethyl sulfoxide 0.5 to 1.5 times and isopropanol 1.5 to 4.5 times based on the amount of the compound In the preparation step of the compound telmisartan, it provides a hydrolysis reaction in a mixed solvent of methanol 7-9 times and purified water 5-7 times based on the amount of the compound of formula (4).
상기 반응식 2에 의한 텔미사탄의 종래 제조방법에서는 화학식 4 화합물인 중간체 텔미사탄 메틸에스테르 화합물 제조시 대부분의 염기를 과량으로 사용하고 있고 부산물로 생성된 무기염을 제거하기 위한 공정이 필요한 단점을 가지고 있다.
In the conventional method for preparing telmisartan according to Scheme 2, most of the bases are used in the preparation of the intermediate telmisartan methyl ester compound, which is a compound of Formula 4, and a process for removing the inorganic salts generated as a by-product has a disadvantage. .
이에 대하여, 본 발명에 따른 중간체 화합물인 화학식 4 화합물을 제조하기 위한 축합반응은 질소기류 하에서 진행하며, 반응 용매로서 디메틸설폭시드와 이소프로판올의 혼합용매를 화학식 2 화합물의 사용량을 기준으로 디메틸설폭시드 0.5~1.5배, 이소프로판올 1.5~4.5배를 사용하고, 염기로서 포타슘 t-부톡시드를 1~1.2 당량을 사용하여 반응시킨다. 반응 완결 후에 정제수 4~7배를 주입하여 교반한 다음 생성된 결정을 여과하고 정제수와 아세톤으로 차례로 세척, 건조하여 중간체인 화학식 4 화합물을 얻을 수 있다. 반응 온도는 10℃ 내지 80℃ 범위를 유지하며, 바람직하게는 25℃ 내지 50℃ 범위를 유지하는 것이 좋다.
In contrast, the condensation reaction for preparing the compound of formula 4, which is an intermediate compound according to the present invention, is carried out under a nitrogen stream, and a mixed solvent of dimethyl sulfoxide and isopropanol as a reaction solvent is based on the amount of the compound of formula 2 dimethyl sulfoxide 0.5. 1.5-4.5 times isopropanol is used, and potassium t-butoxide is reacted using 1-1.2 equivalents as a base. After completion of the reaction, 4-7 times purified water was injected and stirred, and the resulting crystals were filtered, washed successively with purified water and acetone, and dried to obtain the compound of formula 4 as an intermediate. The reaction temperature is maintained in the range of 10 ° C to 80 ° C, preferably 25 ° C to 50 ° C.
중간체 화합물인 화학식 4 화합물을 제조하기 위한 축합반응에서 반응용매 및 석출용매의 비율을 정한 실험결과는 다음과 같다.
Experimental results of determining the ratio of the reaction solvent and the precipitation solvent in the condensation reaction to prepare the compound of formula 4 as an intermediate compound are as follows.
첫 번째로, 디메틸설폭시드의 양을 정하기 위해서 이소프로판올과 정제수를 3 : 5로 고정하고 디메틸설폭시드의 양을 0.1, 0.5, 1.5, 2.5배로 변화시켜 하기 실시예 1과 동일한 방법으로 제조하여 얻어진 화학식 4 화합물에 대한 수율 및 순도는 하기 표 1과 같다.
First, in order to determine the amount of dimethyl sulfoxide, isopropanol and purified water were fixed at 3: 5, and the amount of dimethyl sulfoxide was changed to 0.1, 0.5, 1.5, and 2.5 times to obtain the chemical formula obtained by the same method as in Example 1 below. Yield and purity for the 4 compound are shown in Table 1 below.
상기 표 1에서와 같이 디메틸설폭시드를 0.1배를 사용한 경우 중간체 화합물인 화학식 4 화합물의 순도가 93.0%로 낮았고, 2.5배를 사용한 경우는 중간체 화합물인 화학식 4 화합물의 수율이 87.5%로 낮아서 본 발명에서 목적하는 화학식 4 화합물을 고수율 및 고순도로 제조하기 위해서는 화학식 2 화합물의 사용량을 기준으로 디메틸설폭시드의 양을 0.5~1.5배로 하여야 한다.
When the dimethyl sulfoxide was used 0.1 times as shown in Table 1, the purity of the compound of formula 4, which is an intermediate compound, was low as 93.0%, and when 2.5 times was used, the yield of the compound of formula 4, which is an intermediate compound, was low as 87.5%. In order to prepare the desired compound of Formula 4 in high yield and high purity, the amount of dimethyl sulfoxide should be 0.5 to 1.5 times based on the amount of the compound of Formula 2 used.
두 번째로, 이소프로판올의 양을 정하기 위해서 디메틸설폭시드와 정제수를 1 : 5로 고정하고 이소프로판올의 양을 0.5, 1.5, 4.5, 6배로 변화시켜 하기 실시예 1과 동일한 방법으로 제조하여 얻어진 화학식 4 화합물에 대한 수율 및 순도는 하기 표 2와 같다.
Secondly, in order to determine the amount of isopropanol, dimethyl sulfoxide and purified water were fixed at 1: 5, and the amount of isopropanol was changed to 0.5, 1.5, 4.5, and 6 times to prepare the compound according to the same method as in Example 1 below. Yield and purity for Table 2 are as follows.
상기 표 2에서와 같이 이소프로판올 0.5배를 사용한 경우 중간체 화합물인 화학식 4 화합물의 제조에 따른 교반상태와 순도(90.8%)가 불량하였고, 6배를 사용한 경우는 중간체 화합물인 화학식 4 화합물의 수율이 80.2%로 낮아 본 발명에서 목적하는 화학식 4 화합물을 고수율 및 고순도로 제조하기 위해서는 화학식 2 화합물의 사용량을 기준으로 이소프로판올의 양을 1.5~4.5배로 하여야 한다.
When 0.5 times isopropanol was used as shown in Table 2, the stirring state and purity (90.8%) were poor according to the preparation of the compound of formula 4, which is an intermediate compound, and the yield of the compound of formula 4, which is an intermediate compound, was 80.2 when 6 times was used. In order to prepare the compound of formula 4 desired in the present invention in high yield and high purity, the amount of isopropanol should be 1.5 to 4.5 times based on the amount of the compound of formula 2 used.
세 번째로, 정제수의 양을 정하기 위해서 디메틸설폭시드와 이소프로판올을 1 : 3으로 고정하고 석출시 정제수의 양을 2, 4, 7, 9배로 변화하여 하기 실시예 1과 동일한 방법으로 제조하여 얻어진 화학식 4 화합물에 대한 수율 및 순도는 하기 표 3과 같다.
Third, in order to determine the amount of purified water, dimethylsulfoxide and isopropanol were fixed to 1: 3, and the amount of purified water was changed to 2, 4, 7, 9 times when precipitated, and was prepared in the same manner as in Example 1 below. Yield and purity for the compound 4 are shown in Table 3.
상기 표 3에서와 같이 정제수 2배를 사용한 경우 중간체 화합물인 화학식 4 화합물의 수율이 85.4%로 낮았고, 9배를 사용한 경우는 중간체 화합물인 화학식 4 화합물의 순도가 92.1%로 낮아 본 발명에서 목적하는 화학식 4 화합물을 고수율 및 고순도로 제조하기 위해서는 화학식 2 화합물의 사용량을 기준으로 정제수의 양을 4~7배로 하여야 한다.
As shown in Table 3, when the purified water was used twice, the yield of the compound of formula 4, which is an intermediate compound, was low as 85.4%, and when 9 times was used, the purity of the compound of formula 4, which is an intermediate compound, was lowered to 92.1%. In order to prepare the compound of Formula 4 in high yield and high purity, the amount of purified water should be 4 to 7 times based on the amount of the compound of Formula 2 used.
그러므로 본 발명에 따른 축합반응은 염기성화합물인 포타슘 t-부톡시드를 1~1.2 당량을 사용하여 화학식 2 화합물의 사용량을 기준으로 디메틸설폭시드 : 이소프로판올을 0.5~1.5 : 1.5~4.5배로 하는 반응용매 내에서 반응시키고 반응 완결 후 정제수를 4~7배 첨가하여 결정을 석출시켜 여과하기 때문에 매우 간단한 공정으로 95.1%의 높은 수율로 중간체 텔미사탄 메틸에스테르 화합물인 화학식 4 화합물을 얻을 수 있어 대량생산방법으로서 특히 유용하다.
Therefore, the condensation reaction according to the present invention uses 1 to 1.2 equivalents of potassium t-butoxide, which is a basic compound, in the reaction solvent of dimethyl sulfoxide: isopropanol 0.5 to 1.5: 1.5 to 4.5 times based on the amount of the compound of formula (2). After the reaction was completed and the reaction was completed, 4-7 times of purified water was added to precipitate crystals and filtered. Thus, the compound of formula 4, which is an intermediate telmisartan methyl ester compound, can be obtained with a high yield of 95.1% by a very simple process. useful.
한편, 본 발명에 따른 목적 화합물인 화학식 1 화합물을 제조하기 위한 가수분해반응은 수산화나트륨 2 당량 정도를 사용하고, 화학식 4 화합물의 사용량을 기준으로 반응용매로 정제수 5~7배와 메탄올 7~9배 정도의 적절한 비율로 사용하여 반응시킨다. 반응 완결 후 염산을 첨가하여 결정이 석출되는 동안 충분한 양의 정제수와 메탄올을 사용하고 여과, 세척시 충분한 량의 정제수로 세척하여 목적 화합물인 화학식 1 화합물을 제조한다.
On the other hand, the hydrolysis reaction for preparing the compound of Formula 1, which is the target compound according to the present invention, uses about 2 equivalents of sodium hydroxide, and based on the amount of the compound of Formula 4, the reaction solvent 5-7 times purified water and methanol 7-9 The reaction is carried out using an appropriate ratio of about 2 times. After completion of the reaction, hydrochloric acid was added to the reaction mixture, while sufficient amount of purified water and methanol were used, followed by filtration and washing with sufficient amount of purified water to prepare a compound of formula 1 as a target compound.
반응식 2를 이용한 종래기술에서는 가수분해반응을 하여 텔미사탄을 제조하는 단계에서 과량의 염기나 산을 사용하기 때문에 부산물로 생성된 무기염을 제거해주기 위한 공정이 필요하고 사용된 용매에서 석출된 고체를 여과시 여과속도가 느리다. 또한, 반응식 1을 이용한 종래기술에서는 강산인 트리플루오로아세트산을 사용함으로써 부산물로 생성된 무기염을 제거하기 위해서 반응 완결 후 work-up 과정을 거쳐 실리카겔칼럼크로마토그래피로 분리하여 텔미사탄을 제조하는 등 제조공정이 매우 복잡하다.
In the prior art using Scheme 2, since an excess base or acid is used in the step of producing telmisartan by hydrolysis, a process for removing inorganic salts generated as a by-product is required, and the solid precipitated in the solvent used is Slow filtration speed during filtration In addition, in the prior art using the reaction formula 1 by using a strong acid trifluoroacetic acid in order to remove the inorganic salts generated as by-products through the work-up after completion of the separation by silica gel column chromatography to produce telmisartan, etc. The manufacturing process is very complicated.
그러므로 종래기술들은 축합반응 및 가수분해반응시에 과량의 염기를 사용함으로써 생성된 부산물인 무기염을 제거하기 위한 공정이 필요하고 여과속도가 느린 것 등의 문제가 있어 대량생산 방법으로 적합하지 않다.
Therefore, the prior arts require a process for removing inorganic salts, which are by-products generated by using an excess of base in the condensation and hydrolysis reactions, and are not suitable for mass production methods due to problems such as slow filtration rate.
반면에, 본 발명에 따른 목적 화합물인 화학식 1 화합물을 제조하기 위한 가수분해반응은 수산화나트륨 2 당량 정도를 사용하고, 화학식 4 화합물의 사용량을 기준으로 반응용매로 정제수 5~7배와 메탄올 7~9배 정도의 적절한 비율로 사용하여 반응시켜 결정이 석출되는 동안 충분한 양의 정제수와 메탄올을 사용하고 여과, 세척시 충분한 량의 정제수로 세척하기 때문에 무기염이 제거되어 무기염을 제거하기 위한 다른 공정이 필요하지 않아, 간단한 공정으로 94.2%의 높은 수율과 높은 순도(99.9% 이상의 HPLC 순도)로 텔미사탄을 제조할 수 있어 대량생산방법으로서 특히 유용하다.
On the other hand, the hydrolysis reaction for preparing the compound of Formula 1, which is the target compound according to the present invention, uses about 2 equivalents of sodium hydroxide, and based on the amount of the compound of Formula 4, the reaction solvent is 5 to 7 times purified water and 7 to methanol. Another process for removing inorganic salts by removing inorganic salts by using a sufficient amount of purified water and methanol while the crystals are precipitated and reacting with an appropriate ratio of about 9 times and washing with a sufficient amount of purified water during filtration and washing. Since it is not necessary, telmisartan can be produced with a high yield of 94.2% and high purity (HPLC purity of 99.9% or more) by a simple process, which is particularly useful as a mass production method.
본 발명에 따른 목적 화합물인 화학식 1 화합물을 제조하기 위한 가수분해반응에서 반응용매의 비율을 정한 실험결과는 다음과 같다.
Experimental results for determining the proportion of the reaction solvent in the hydrolysis reaction to prepare the compound of formula 1 according to the present invention are as follows.
첫 번째로, 정제수의 양을 정하기 위해서 화학식 4 화합물의 사용량을 기준으로 메탄올을 8배로 고정하고 정제수 양을 3, 5, 7, 9배로 변화하여 하기 실시예 2와 동일한 방법으로 제조하여 얻어진 화학식 1 화합물에 대한 수율 및 순도는 하기 표 4와 같다.
First, in order to determine the amount of purified water, the fixed amount of methanol was fixed 8 times based on the amount of the compound of Formula 4, and the amount of purified water was changed to 3, 5, 7, 9 times to prepare the same method as in Example 2 below. Yields and purity for the compounds are shown in Table 4 below.
상기 표 4에서와 같이 정제수 3배를 사용한 경우 목적 화합물인 화학식 1 화합물의 수율이 87.5%로 낮았고 교반상태가 불량하였으며, 9배를 사용한 경우는 여과상태가 불량하여 메탄올을 8배로 할 때, 정제수의 양을 5~7배로 하여야 한다.
As shown in Table 4, when 3 times purified water was used, the yield of the compound of formula 1, which is the target compound, was low as 87.5%, and the stirring state was poor. When 9 times was used, the filtered state was poor, and when methanol was 8 times, purified water was used. The amount of must be 5-7 times.
두 번째로, 정제수의 양을 정하기 위해서 본 발명에 따른 목적 화합물인 화학식 1 화합물을 제조하기 위한 가수분해반응에서 반응용매의 비율을 화학식 4 화합물의 사용량을 기준으로 정제수를 6배로 고정하고 메탄올의 양을 5, 7, 9, 11배로 변화하여 하기 실시예 2와 동일한 방법으로 제조하여 얻어진 화학식 1 화합물에 대한 수율 및 순도는 하기 표 5와 같다.
Secondly, in order to determine the amount of purified water, the ratio of the reaction solvent in the hydrolysis reaction for preparing the compound of Formula 1, which is the target compound according to the present invention, is fixed 6 times based on the amount of the compound of Formula 4, and the amount of methanol To 5, 7, 9, 11 times the yield and purity for the compound of Formula 1 obtained by the same method as in Example 2 is obtained in Table 5.
상기 표 5에서와 같이 메탄올 5배를 사용한 경우 목적 화합물인 화학식 1 화합물을 제조하기 위한 교반상태와 여과상태가 불량하였고 HPLC에서 unknown impurity도 0.1% 이상(기준 0.1% 이하)으로 검출되었으며, 11배를 사용한 경우는 수율이 84.4%로 낮아 본 발명에서 목적하는 화학식 1 화합물을 고수율 및 고순도로 제조하기 위해서는 화학식 4 화합물의 사용량을 기준으로 정제수를 6배로 할 때, 메탄올의 양을 7~9배로 하여야 한다.
As shown in Table 5, when 5 times methanol was used, the stirring state and the filtration state for preparing the compound of Formula 1, which is the target compound, were poor, and the unknown impurity was also detected by HPLC at 0.1% or more (0.1% or less). In the case of using, the yield is low as 84.4% in order to manufacture the compound of formula 1 desired in high yield and high purity in the present invention, when the purified water is 6 times based on the amount of the compound of formula 4, the amount of methanol is 7 to 9 times. shall.
그러므로 본 발명에 따른 가수분해반응은 화학식 4 화합물의 사용량을 기준으로 메탄올 7~9배와 정제수 5~7배의 혼합용매에서 반응시키고 여과함으로써 다른 불순물도 제거시키는 효과를 얻고 별도의 공정 없이 무기염과 불순물을 동시에 쉽게 제거하여 94.2%의 높은 수율과 높은 순도(99.9% 이상의 HPLC 순도)로 목적 화합물인 화학식 1 화합물을 얻을 수 있다.
Therefore, the hydrolysis reaction according to the present invention is based on the amount of the compound of formula 4 and reacted in a mixed solvent of methanol 7-9 times and purified water 5-7 times and filtered to obtain the effect of removing other impurities and inorganic salts without a separate process And impurities can be easily removed at the same time to obtain the compound of formula 1 as a target compound with a high yield of 94.2% and high purity (at least 99.9% HPLC purity).
또한, 본 발명은 중간체 화합물인 화학식 4 화합물을 건조하지 않고 젖은 상태로 가수분해반응을 진행할 수도 있다. 가수분해 반응시에는 정제수와 알코올의 혼합용매에서 염기성 화합물을 첨가하여 반응을 하며 반응 완결 후에는 산을 사용하여 중화한 다음 석출된 고체를 여과하여 화학식 1 화합물인 텔미사탄을 제조할 수 있다.
In addition, the present invention may proceed with the hydrolysis reaction in a wet state without drying the compound of formula (4) which is an intermediate compound. In the hydrolysis reaction, a basic compound may be added in a mixed solvent of purified water and alcohol to react, and after completion of the reaction, neutralization using an acid may be performed to filter the precipitated solid, thereby preparing telmisartan.
이상에서 설명한 본 발명의 제조방법을 수행하게 되면, 상기 화학식 2 화합물과 화학식 3 화합물을 축합반응시켜 중간체인 화학식 4 화합물을 제조한 후 가수분해반응하여 목적하는 상기 화학식 1 화합물인 텔미사탄을 제조하는 전체 반응 수율이 89.6% 정도로 높고 높은 순도(99.9% 이상의 HPLC 순도)로 얻을 수 있으며, 공정이 간단하여 대량생산방법으로서 특히 유용하다.
When the preparation method of the present invention described above is carried out, the compound of formula 2 is prepared by condensation reaction of the compound of formula 2 and compound of formula 3, and then the hydrolysis reaction is performed to produce the desired compound of formula 1, telmisartan. The overall reaction yield is as high as 89.6% and can be obtained with high purity (99.9% or more HPLC purity), and the process is simple and is particularly useful as a mass production method.
본 발명은 화학식 2 화합물과 화학식 3 화합물을 축합반응시켜 중간체인 화학식 4 화합물을 제조한 후 가수분해반응하여 목적하는 상기 화학식 1 화합물인 텔미사탄의 제조방법에 있어서, 축합반응 및 가수분해반응시 생성되는 부산물인 무기염을 쉽게 제거할 수 있어, 무기염을 제거하기 위한 별도의 공정을 필요로 하지 않으며, 높은 수율과 높은 순도로 목적 화합물인 텔미사탄을 제조할 수 있고, 공정이 간단하여 대량생산방법으로서 특히 유용하다.
In the present invention, a compound of formula (2) and compound (3) are condensed to prepare compound (4), which is an intermediate, and then hydrolyzed to produce telmisartan, the compound of formula (1). It is easy to remove inorganic salts, which are by-products, and does not require a separate process to remove inorganic salts, and can produce telmisartan as a target compound with high yield and high purity. It is particularly useful as a method.
상기한 바와 같은 본 발명의 제조방법은 다음의 실시예에 의거하여 더욱 상세히 설명하는 바, 본 발명이 이에 한정되는 것은 아니다.
The manufacturing method of the present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.
<< 실시예Example 1> 1> 메틸methyl 2-(4-{[4- 2- (4-{[4- 메틸methyl -6-(1--6- (1- 메틸methyl -1H--1H- 벤즈이미다졸Benzimidazole -2-일)-2-프로필-1H--2-yl) -2-propyl-1H- 벤즈이미다졸Benzimidazole -1-일]-1 day] 메틸methyl }} 페닐Phenyl )) 벤조에이트Benzoate (화학식 4)의 제조Preparation of (Formula 4)
질소기류 하에서 이소프로판올 150ml에 4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸 50g을 넣고 교반하면서 디메틸설폭시드 50ml와 포타슘 t-부톡시드 20.28g을 넣은 후 서서히 가열하여 40~45℃에서 1시간 동안 교반하였다. 상기 반응액을 30~35℃로 냉각하고 메틸 2-[4-(브로모메틸)페닐]벤조에이트 55.14g을 주입한 후 6시간 동안 교반하고 정제수 250ml를 주입하여 20~25℃에서 1시간 동안 교반하였다. 생성된 결정을 여과하고 정제수 50ml와 아세톤 50ml로 차례로 세척, 건조하여 메틸 2-(4-{[4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸-1-일]메틸}페닐)벤조에이트 82.58g을 얻었다(수율 95.1%).50 ml of 4-dimethyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole was added to 150 ml of isopropanol under nitrogen stream and 50 ml of dimethyl sulfoxide and potassium were stirred. After 20.28 g of t-butoxide was added thereto, the mixture was slowly heated and stirred at 40 to 45 ° C. for 1 hour. The reaction solution was cooled to 30-35 ° C., 55.14 g of methyl 2- [4- (bromomethyl) phenyl] benzoate was injected, stirred for 6 hours, and 250 ml of purified water was injected for 1 hour at 20-25 ° C. Stirred. The resulting crystals were filtered off, washed successively with 50 ml of purified water and 50 ml of acetone, and dried to give methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2- 82.58 g of propyl-1 H -benzimidazol-1-yl] methyl} phenyl) benzoate was obtained (yield 95.1%).
m/e 528.6(parent ion); 1H NMR(DMSO-d6) δ0.99(t, 3H, J=7.24Hz), 1.73~1.88(m, 2H), 2.64(s, 3H), 2.92(t, 2H, J=7.42Hz), 3.50(s, 3H), 3.84(s, 3H), 5.64(s, 2H), 7.12~7.32(m, 6H), 7.33~7.82(m, 8H)
m / e 528.6 (parent ion); 1 H NMR (DMSO-d 6 ) δ 0.99 (t, 3H, J = 7.24 Hz), 1.73-1.88 (m, 2H), 2.64 (s, 3H), 2.92 (t, 2H, J = 7.42 Hz) , 3.50 (s, 3H), 3.84 (s, 3H), 5.64 (s, 2H), 7.12-7.32 (m, 6H), 7.33-7.82 (m, 8H)
<< 실시예Example 2> 2> 텔미사탄(화학식 1)의Of telmisartan (Formula 1) 제조 Produce
정제수 80ml에 수산화나트륨 12.1g을 넣고 교반하면서 메탄올 160ml와 메틸 2-(4-{[4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸-1-일]메틸}페닐)벤조에이트 80g을 넣은 후 70~75℃에서 가열하여 4시간 동안 환류 교반하였다. 상기 반응액을 고온여과하고 여액을 냉각하여 20~25℃에서 메탄올 480ml를 넣고 염산(20%)을 서서히 적가하여 pH 7.0으로 조절한 다음 2시간 동안 교반하였다. 반응 혼합물에 정제수 400ml를 넣고 2시간 동안 교반하여 생성된 결정을 여과하고 정제수 320ml와 메탄올 80ml로 차례로 세척한 다음 건조하여 목적화합물 텔미사탄을 거의 백색의 고체로 73.36g을 얻었다(수율 94.2%).12.1 g of sodium hydroxide was added to 80 ml of purified water, and 160 ml of methanol and methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 were stirred with stirring. 80 g of H -benzimidazol-1-yl] methyl} phenyl) benzoate was added thereto, and the mixture was heated at 70 to 75 ° C. and stirred under reflux for 4 hours. The reaction solution was filtered hot, the filtrate was cooled, 480 ml of methanol was added at 20-25 ° C., hydrochloric acid (20%) was added dropwise to pH 7.0, and then stirred for 2 hours. 400 ml of purified water was added to the reaction mixture, followed by stirring for 2 hours. The resulting crystals were filtered, washed sequentially with 320 ml of purified water and 80 ml of methanol, and dried to give 73.36 g of the target compound telmisartan as an almost white solid (yield 94.2%).
m.p. 269.2℃(DSC) ; m/e 514.6(parent ion); 1H NMR(DMSO-d6) δ1.00(t, 3H, J=7.32Hz), 1.76~1.88(m, 2H), 2.64(s, 3H), 2.93(t, 2H, J=7.48Hz), 3.82(s, 3H), 5.63(s, 2H), 7.15~7.37(m, 7H), 7.41~7.61(m, 4H), 7.67~7.75(m, 3H)
mp 269.2 ° C. (DSC); m / e 514.6 (parent ion); 1 H NMR (DMSO-d 6 ) δ1.00 (t, 3H, J = 7.32 Hz), 1.76-1.88 (m, 2H), 2.64 (s, 3H), 2.93 (t, 2H, J = 7.48 Hz) , 3.82 (s, 3H), 5.63 (s, 2H), 7.15 ~ 7.37 (m, 7H), 7.41 ~ 7.61 (m, 4H), 7.67 ~ 7.75 (m, 3H)
<< 실시예Example 3> 3> 텔미사탄(화학식 1)의Of telmisartan (Formula 1) 제조 Produce
정제수 80ml에 수산화칼륨 17.0g을 넣고 교반하면서 메탄올 160ml와 메틸 2-(4-{[4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸-1-일]메틸}페닐)벤조에이트 80g을 넣은 후 70~75℃에서 가열하여 4시간 동안 환류 교반하였다. 상기 반응액을 고온여과하고 여액을 냉각하여 20~25℃에서 메탄올 480ml를 넣고 염산(20%)을 서서히 적가하여 pH 6.8로 조절한 다음 2시간 동안 교반하였다. 반응 혼합물에 정제수 400ml를 넣고 2시간 동안 교반하여 생성된 결정을 여과하고 정제수 320ml와 메탄올 80ml로 차례로 세척한 다음 건조하여 목적화합물 텔미사탄을 거의 백색의 고체로 73.2g을 얻었다(수율 94.0%).
17.0 g of potassium hydroxide was added to 80 ml of purified water and 160 ml of methanol and methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 were stirred with stirring. 80 g of H -benzimidazol-1-yl] methyl} phenyl) benzoate was added thereto, and the mixture was heated at 70 to 75 ° C. and stirred under reflux for 4 hours. The reaction solution was filtered hot, the filtrate was cooled, 480 ml of methanol was added at 20 to 25 ° C., and hydrochloric acid (20%) was slowly added dropwise to pH 6.8, followed by stirring for 2 hours. 400 ml of purified water was added to the reaction mixture, which was then stirred for 2 hours. The resulting crystals were filtered, washed sequentially with 320 ml of purified water and 80 ml of methanol, and dried to give 73.2 g of the target compound telmisartan as an almost white solid (yield 94.0%).
<< 실시예Example 4> 4> 텔미사탄(화학식 1)의Of telmisartan (Formula 1) 제조 Produce
질소기류 하에서 이소프로판올 150ml에 4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸 50그람을 넣고 교반하면서 디메틸설폭시드 50ml와 포타슘 t-부톡시드 20.28g을 넣은 후 서서히 가열하여 40~45℃에서 1시간 동안 교반하였다. 상기 반응액을 30~35℃로 냉각하고 메틸 2-[4-(브로모메틸)페닐]벤조에이트 55.14g을 주입한 후 6시간 동안 교반하고 정제수 250ml를 주입하여 20~25℃에서 1시간 동안 교반하였다. 생성된 결정을 여과하고 정제수 50ml와 아세톤 50ml로 차례로 세척하여 젖은 상태로 메틸 2-(4-{[4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸-1-일]메틸}페닐)벤조에이트 화합물을 얻었다. 정제수 80ml에 수산화나트륨 12.5g을 넣고 교반하면서 메탄올 160ml와 상기에서 얻은 젖은 상태의 고체를 넣은 후 가열하여 70~75℃에서 4시간 동안 교반하였다. 상기 반응액을 고온여과하고 여액을 냉각하여 20~25℃에서 메탄올 480ml를 넣고 염산(20%)을 서서히 적가하여 pH 7.3으로 조절한 다음 2시간 동안 교반하였다. 반응 혼합물에 정제수 400ml를 넣고 2시간 동안 교반하여 생성된 결정을 여과하고 정제수 320ml와 메탄올 80ml로 차례로 세척한 다음 건조하여 목적화합물 텔미사탄을 거의 백색의 고체로 75.66g을 얻었다(수율 89.5%).
50 ml of 4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole was added to 150 ml of isopropanol under nitrogen stream and 50 ml of dimethyl sulfoxide was stirred. After adding 20.28 g of potassium t-butoxide, the mixture was slowly heated and stirred at 40 to 45 ° C. for 1 hour. The reaction solution was cooled to 30-35 ° C., 55.14 g of methyl 2- [4- (bromomethyl) phenyl] benzoate was injected, stirred for 6 hours, and 250 ml of purified water was injected for 1 hour at 20-25 ° C. Stirred. The resulting crystals were filtered, washed sequentially with 50 ml of purified water and 50 ml of acetone, and then wetted with methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2 -Propyl- 1H -benzimidazol-1-yl] methyl} phenyl) benzoate compound was obtained. 12.5 g of sodium hydroxide was added to 80 ml of purified water, followed by stirring, 160 ml of methanol and the wet solid obtained above were heated and stirred at 70 to 75 ° C. for 4 hours. The reaction solution was filtered hot, the filtrate was cooled, 480 ml of methanol was added at 20-25 ° C., and hydrochloric acid (20%) was slowly added dropwise to pH 7.3, followed by stirring for 2 hours. 400 ml of purified water was added to the reaction mixture, which was then stirred for 2 hours. The resulting crystals were filtered, washed sequentially with 320 ml of purified water and 80 ml of methanol, and dried to obtain 75.66 g of the target compound telmisartan as an almost white solid (yield 89.5%).
<< 실시예Example 5> 5> 텔미사탄(화학식 1)의Of telmisartan (Formula 1) 제조 Produce
질소기류 하에서 이소프로판올 150ml에 4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸 50그람을 넣고 교반하면서 디메틸설폭시드 50ml와 포타슘 t-부톡시드 20.28g을 넣은 후 서서히 가열하여 40~45℃에서 1시간 동안 교반하였다. 상기 반응액을 30~35℃로 냉각하고 메틸 2-[4-(브로모메틸)페닐]벤조에이트 55.14g을 주입한 후 6시간 동안 교반하고 정제수 250ml를 주입하여 20~25℃에서 1시간 동안 교반하였다. 생성된 결정을 여과하고 정제수 50ml와 아세톤 50ml로 차례로 세척하여 젖은 상태로 메틸 2-(4-{[4-메틸-6-(1-메틸-1H-벤즈이미다졸-2-일)-2-프로필-1H-벤즈이미다졸-1-일]메틸}페닐)벤조에이트 화합물을 얻었다. 정제수 80ml에 수산화칼륨 17.5g을 넣고 교반하면서 메탄올 160ml와 상기에서 얻은 젖은 상태의 고체를 넣은 후 가열하여 70~75℃에서 4시간 동안 교반하였다. 상기 반응액을 고온여과하고 여액을 냉각하여 20~25℃에서 메탄올 480ml를 넣고 염산(20%)을 서서히 적가하여 pH 6.8로 조절한 다음 2시간 동안 교반하였다. 반응 혼합물에 정제수 400ml를 넣고 2시간 동안 교반하여 생성된 결정을 여과하고 정제수 320ml와 메탄올 80ml로 차례로 세척한 다음 건조하여 목적화합물 텔미사탄을 거의 백색의 고체로 75.49g을 얻었다(수율 89.3%).50 ml of 4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole was added to 150 ml of isopropanol under nitrogen stream and 50 ml of dimethyl sulfoxide was stirred. After adding 20.28 g of potassium t-butoxide, the mixture was slowly heated and stirred at 40 to 45 ° C. for 1 hour. The reaction solution was cooled to 30-35 ° C., 55.14 g of methyl 2- [4- (bromomethyl) phenyl] benzoate was injected, stirred for 6 hours, and 250 ml of purified water was injected for 1 hour at 20-25 ° C. Stirred. The resulting crystals were filtered, washed sequentially with 50 ml of purified water and 50 ml of acetone, and then wetted with methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2 -Propyl- 1H -benzimidazol-1-yl] methyl} phenyl) benzoate compound was obtained. 17.5 g of potassium hydroxide was added to 80 ml of purified water, and 160 ml of methanol and the wet solid obtained above were added with stirring, followed by heating and stirring at 70-75 ° C. for 4 hours. The reaction solution was filtered hot, the filtrate was cooled, 480 ml of methanol was added at 20 to 25 ° C., and hydrochloric acid (20%) was slowly added dropwise to pH 6.8, followed by stirring for 2 hours. 400 ml of purified water was added to the reaction mixture, which was then stirred for 2 hours. The resulting crystals were filtered, washed sequentially with 320 ml of purified water and 80 ml of methanol, and dried to obtain 75.49 g of the target compound telmisartan as an almost white solid (yield 89.3%).
Claims (3)
축합반응은 반응용매로서 디메틸설폭시드와 이소프로판올의 혼합용매를 화학식 2 화합물의 사용량을 기준으로 디메틸설폭시드 0.5~1.5배, 이소프로판올 1.5~4.5배를 사용하여 중간체 화합물인 화학식 4 화합물을 제조하며, 가수분해반응은 반응용매로서 화학식 4 화합물의 사용량을 기준으로 메탄올 7~9배와 정제수 5~7배의 혼합용매에서 반응하는 것을 특징으로 하는 하기 화학식 1 화합물인 텔미사탄의 제조방법.
<화학식 1>
<화학식 2>
<화학식 3>
<화학식 4>
In the method of preparing a compound of the general formula (1) and telmisartan by the condensation reaction of the compound of formula (2) and the compound of formula (3) to produce a compound of formula (4) as an intermediate compound
In the condensation reaction, a mixed solvent of dimethyl sulfoxide and isopropanol is used as a reaction solvent to prepare a compound of formula 4, which is an intermediate compound, using 0.5 to 1.5 times of dimethyl sulfoxide and 1.5 to 4.5 times of isopropanol based on the amount of the compound of formula (2). The decomposition reaction is a method for preparing telmisartan, which is a compound of Formula 1, characterized in that the reaction is carried out in a mixed solvent of 7 to 9 times methanol and 5 to 7 times purified water based on the amount of the compound of Formula 4 as a reaction solvent.
<Formula 1>
<Formula 2>
<Formula 3>
<Formula 4>
The method of claim 1, wherein after the completion of the condensation reaction, 4 to 7 times the amount of purified water is added based on the amount of the compound of formula 2 to prepare a telmisartan compound of the formula (1) characterized in that to precipitate and crystallize the crystal of the compound of formula (4) Way.
The method for preparing telmisartan according to claim 1, wherein the compound of Formula 1 is hydrolyzed using the compound of Formula 4 in a wet state without drying after preparing the compound of Formula 4.
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| KR1020100014346A KR20110094751A (en) | 2010-02-17 | 2010-02-17 | An improved process for preparing telmisartan |
| PCT/KR2011/001041 WO2011102645A2 (en) | 2010-02-17 | 2011-02-17 | An improved process for preparing telmisartan |
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| KR1020100014346A KR20110094751A (en) | 2010-02-17 | 2010-02-17 | An improved process for preparing telmisartan |
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| WO2015099327A1 (en) * | 2013-12-24 | 2015-07-02 | 주식회사 파마코스텍 | Novel method for preparing telmisartan |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2414019A (en) * | 2004-05-11 | 2005-11-16 | Cipla Ltd | One-step preparation of telmisartan by condensation and hydrolysis |
| KR20070061583A (en) * | 2004-10-15 | 2007-06-13 | 테바 파마슈티컬 인더스트리즈 리미티드 | Process for preparing telmisartan |
| US7943781B2 (en) * | 2004-10-18 | 2011-05-17 | Dr. Reddy's Laboratories Limited | Process for preparing telmisartan |
| JP2006321798A (en) * | 2005-05-18 | 2006-11-30 | Chemagis Ltd | Improved method for producing high-purity telmisartan form a suitable for pharmaceutical composition |
-
2010
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| WO2015099327A1 (en) * | 2013-12-24 | 2015-07-02 | 주식회사 파마코스텍 | Novel method for preparing telmisartan |
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| WO2011102645A2 (en) | 2011-08-25 |
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