KR100701743B1 - Novel Making Proces of the Bambuterol - Google Patents

Novel Making Proces of the Bambuterol Download PDF

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KR100701743B1
KR100701743B1 KR1020050093346A KR20050093346A KR100701743B1 KR 100701743 B1 KR100701743 B1 KR 100701743B1 KR 1020050093346 A KR1020050093346 A KR 1020050093346A KR 20050093346 A KR20050093346 A KR 20050093346A KR 100701743 B1 KR100701743 B1 KR 100701743B1
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dimethylcarbamoyloxy
bis
bambuterol
acetophenone
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김철주
김정숙
유은경
정진현
강민석
김동명
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주식회사 라이트팜텍
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/40Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/08Separation; Purification; Stabilisation; Use of additives

Abstract

Provided is a novel method for preparing [bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-t-butylaminoethnoal (bambuterol) used as the medicine for asthma which is improved in yield and is simplified. The bis(3',5'-N,N-dimethylcarbamoyloxy)-acetophenone represented by the formula 3 which is an intermediate for the synthesis of the bambuterol represented by the formula 1, is prepared by refluxing the 3,5-dihydroxyacetophenone represented by the formula 4 and dimethylcarbamoyl chloride with sodium hydroxide and tetrabutylammonium bromide as a catalyst. The bambuterol of the formula 1 is prepared by dissolving bis(3',5'-N,N-dimethylcarbamoyloxy)-2-bromo-acetophenone in ethanol; adding sodium cyanoborohydride to it; stirring it at a room temperature; and refluxing the obtained one with t-butylamine.

Description

밤부테롤의 신규한 제조 방법{Novel Making Proces of the Bambuterol}Novel Making Proces of the Bambuterol

..

본 발명은 천식 치료제로서 널리 사용되고 있는 하기 화학식1의 밤부테롤 즉 1- [비스-(3',5'-N,N-디메틸카바모일옥시)페닐] -2-N-t-부틸아미노에탄올의 신규한 제조 방법에 관한 것으로, 3',5'-디하이드록시아세토페논과 디메틸카바모일 클로라이드를 출발 물질로하여 무기염과 테프라부틸 암모니움 브로마이드를 촉매로 하여 비스-3',5'-(N,N-디메틸카바모일옥시)-아세토페논을 제조한 후 브롬화 과정을 통하여 비스-3',5'-(N,N-디메틸카바모일옥시)-2-브로모-아세토페논를 제조 한 후 최종적으로 한 번에 환원반응과 첨가반응을 완료하여 최종 생성 물질을 생산함으로써 양질의 천식 치료제를 간단하면서도 고수율로 합성할 수가 있다.The present invention is a novel novel form of bambuterol of formula (1), namely 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-Nt-butylaminoethanol, which is widely used as a treatment for asthma. A process for the preparation, comprising 3 ', 5'-dihydroxyacetophenone and dimethylcarbamoyl chloride as starting materials, and an inorganic salt and teprabutyl ammonium bromide as catalysts for bis-3', 5 '-(N, N-dimethylcarbamoyloxy) -acetophenone was prepared, and then bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone was prepared through bromination. By completing the reduction and addition reactions in one step to produce the final product, it is possible to synthesize high-quality asthma drugs in a simple and high yield.

Figure 112005512107577-pat00002
Figure 112005512107577-pat00002

밤부테롤은 기관지 확장제로, 기관지 천식, 기관지 경련을 수반하는 만성 기관지염, 폐기종 및 기타 폐관련질환에 유효한 약물이다. 종래의 밤부테롤의 합성은 아스트라사사는 천식치료제 테르부탈린의 전구약인 밤부테롤을 발견한 후 특허를 최초로 출원하였고, 이에 대응하는 개선된 제조방법을 계속하여 출원하였다.(EP 43807, USP 4011258, WO 9108197)Bambuterol is a bronchodilator that is effective for chronic bronchitis, emphysema, and other lung-related diseases involving bronchial asthma, bronchial spasms. In the conventional synthesis of bambuterol, Astrasa first applied for a patent after discovering bambuterol, a prodrug of the asthma drug terbutalin, and continued to apply the corresponding improved manufacturing method (EP 43807, USP 4011258). , WO 9108197)

아스트라사의 원방법 및 개선된 방법은 3,5-디하이드록시아세토페논을 출발물질로 N,N-디메틸 카바모일 클로라이드을 작용시킨 후, 브로민과 반응시켜 핵심 중간체인 화합물 2를 제조하였고, 화합물 2에 N-벤질-t-부틸아민을 반응시키고, 라니 니켈과 같은 유사한 금속을 작용시켜 밤부테롤을 제조하였다.Astrasa's original and improved methods were prepared by reacting N, N-dimethyl carbamoyl chloride with 3,5-dihydroxyacetophenone as a starting material and then reacting with bromine to produce Compound 2, a key intermediate. N-benzyl-t-butylamine was reacted with a similar metal such as Raney nickel to prepare bambuterol.

그러나 이 방법은 브로민을 작용시킬 때 다이할라이드 화합물이 다량 생성되는 단점을 가지고 있으며, 아미노기가 보호된 벤질기를 제거할 때 공업적으로 사용하기에는 매우 위험한 금속을 사용하는 단점을 지니고 있다.However, this method has a disadvantage in that a large amount of dihalide compounds are produced when the bromine is functionalized, and a metal that is very dangerous for industrial use is used when the benzyl group in which the amino group is protected is removed.

Figure 112005512107577-pat00003
Figure 112005512107577-pat00003

상기와 같이 종래의 밤부테롤 합성방법은 각 단계의 반응 조건이 까다로와 공업화 하는데 있어서 설비와 비용이 많이 들게된다.As described above, the conventional bambuterol synthesis method requires a lot of equipment and cost in industrialization due to the difficult reaction conditions of each step.

따라서, 본 발명에서는, 밤부테롤 즉, 1- [비스-(3',5'-N,N-디메틸카바모일옥시)페닐] -2-N-t-부틸아미노에탄올의 새로운 방법에 의하여 제조 방법의 단점을 개선한 것으로, 3',5'-디하이드록시아세토페논과 디메틸카바모일 클로라이드를 출발 물질로하여 무기염과 테프라부틸 암모니움 브로마이드를 촉매로 하여 비스-3',5'-(N,N-디메틸카바모일옥시)-아세토페논을 제조한 후 브롬화 과정을 통하여 비스-3',5'-(N,N-디메틸카바모일옥시)-2-브로모-아세토페논를 제조한 후 최종적으로 한 번에 환원반응과 첨가반응을 완료하여 최종 생성물질을 생산함으로써 양질의 천식 치료제를 간단하면서도 고수율로 합성할 수가 있다.Therefore, in the present invention, the disadvantages of the production process by a novel method of bambuterol, i.e., 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-Nt-butylaminoethanol 3 ', 5'-dihydroxyacetophenone and dimethylcarbamoyl chloride were used as starting materials, and bis-3', 5 '-(N, N) was used as a catalyst with inorganic salts and teprabutyl ammonium bromide. -Dimethylcarbamoyloxy) -acetophenone was prepared, and then bis-3 ', 5'-(N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone was prepared by bromination. By completing the reduction and addition reactions at once, the final product can be produced to synthesize high-quality asthma drugs in a simple and high yield.

본 발명은 일반명 밤부테롤의 신규한 제조 방법 및 재결정화법에 의해 을 정제하는 방법에 관한 것이다.The present invention relates to a novel process for the production of the common name bambuterol and to a process for refining by.

이하, 본 발명을 실시 예에 의거하여 보다 상세하게 설명하고자 하나, 이는 본 발명의 구성 및 작용의 이해를 돕기 위한 것일 뿐이며 본 발명의 범위가 이들 실시 예에 한정 되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only intended to help the understanding of the structure and operation of the present invention and the scope of the present invention is not limited to these examples.

[반응식 1]Scheme 1

Figure 112005512107577-pat00004
Figure 112005512107577-pat00004

구체적인 반응 공정을 실시예1에 나타내었다.The specific reaction process is shown in Example 1.

[실시예1]Example 1

비스-(3',5'-N,N-디메틸카바모일옥시)-아세토페논[화학식 3]의 제조Preparation of Bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) -acetophenone [Formula 3]

3,5-디하이드록시아세토페논[화학식 4] 15.2g, 수산화나트륨 16.0g, 테프라부틸 암모니움 브로마이드 0.5g를 500mL 반응기에 아세톤 300.0mL 과 함께 넣고 상온에서 교반하면서 디메틸카바모일 클로라이드 14.0 g을 적가하였다. 적가완료 후 환류냉각기를 설치한 후 넣고 환류온도에서 5시간 동안 반응시킨 후 냉각하였다. 냉각 후에 증류하여 아세톤으로 제거 한 후 잔류물에 정제수 50mL를 가한 후 에틸아세테이트 300mL로 3회 추출한다. 추출한 에틸아세테이트층을 무수 황산 마그네슘으로 건조 여과하였다. 여액을 농축 한 뒤 이소프로필알코올과 디이소프로필에테르로 재결정하고 진공으로 건조하여 백색 고체의 비스-(3',5'-N,N-디메틸카바모일옥시)-아세토페논[화학식 3] 27.9g(수율 95%)를 얻었다.15.2 g of 3,5-dihydroxyacetophenone [Formula 4], 16.0 g of sodium hydroxide, 0.5 g of teprabutyl ammonium bromide were added together with 300.0 mL of acetone in a 500 mL reactor, and 14.0 g of dimethylcarbamoyl chloride was added dropwise while stirring at room temperature. It was. After completion of the dropwise addition, after installing a reflux condenser, the reaction was carried out at reflux for 5 hours and then cooled. After cooling, distilled and removed with acetone, 50 mL of purified water was added to the residue, followed by extraction three times with 300 mL of ethyl acetate. The extracted ethyl acetate layer was dried and filtered with anhydrous magnesium sulfate. The filtrate was concentrated and recrystallized with isopropyl alcohol and diisopropyl ether and dried in vacuo to give a white solid, bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) -acetophenone 27.9g (Yield 95%) was obtained.

1H NMR (200MHz, CDCl3), δ(ppm) : 2.59(s, 3H), 3.07(s, 12H), 7.40(m, 3H) MS(FAB) ; 295(M++H+) 1 H NMR (200 MHz, CDCl 3 ), δ (ppm): 2.59 (s, 3H), 3.07 (s, 12H), 7.40 (m, 3H) MS (FAB); 295 (M + + H + )

[반응식 2]Scheme 2

Figure 112005512107577-pat00005
Figure 112005512107577-pat00005

구체적인 반응 공정을 실시예2에 나타내었다.The specific reaction process is shown in Example 2.

[실시예2]Example 2

비스-(3',5'-N,N-디메틸카바모일옥시)-2-브로모-아세토페논[화학식 2]의 제조Preparation of Bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone [Formula 2]

실시예1에서 제조 된 비스-(3',5'-N,N-디메틸카바모일옥시)-아세토페논[화학식 3] 29.4g과 디옥산 150.0mL를 500mL 반응기에 넣고 상온에서 교반하였다. 브롬수 20.0g을 디옥산 100mL에 희석한 후 희석액을 1시간 동안 교반하면서 적가하한 후 상온에서 5시간 동안 반응하였다. 반응 액을 증류하여 제거한 후 여액을 이소프로필알코올과 디이소프로필에테르로 재결정하고 진공으로 건조하여 백색 고체의 비스-(3',5'-N,N-디메틸카바모일옥시)-2-브로모-아세토페논[화학식 2] 36.2g(수율 97%)를 얻었다.29.4 g of bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) -acetophenone prepared in Example 1 and 150.0 mL of dioxane were added to a 500 mL reactor and stirred at room temperature. After diluting 20.0 g of bromine water in 100 mL of dioxane, the diluted solution was added dropwise with stirring for 1 hour, and then reacted at room temperature for 5 hours. The reaction solution was distilled off and the filtrate was recrystallized from isopropyl alcohol and diisopropyl ether and dried in vacuo to give a white solid bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) -2-bromo -36.2 g (yield 97%) of acetophenone was obtained.

1H NMR (200MHz, CDCl3), δ(ppm) : 3.07(s, 12H), 4.43(s, 2H), 7.44(m, 3H) MS(FAB) ; 373(M++H+) 1 H NMR (200 MHz, CDCl 3 ), δ (ppm): 3.07 (s, 12H), 4.43 (s, 2H), 7.44 (m, 3H) MS (FAB); 373 (M + + H + )

[반응식 3]Scheme 3

Figure 112005512107577-pat00006
Figure 112005512107577-pat00006

[실시예3]Example 3

1- [비스-(3',5'-N,N-디메틸카바모일옥시)페닐] -2-N-t-부틸아미노에탄올 [화학식 1]의 제조1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-N-t-butylaminoethanol [Formula 1]

실시예2에서 제조된비스-(3',5'-N,N-디메틸카바모일옥시)-2-브로모-아세토페논 3.7g에 에탄올 30.0mL를에 녹인후 100mL 반응기에 넣고 소디움시아노보로하이드라이드 3.56g를 천천히 적가하였다. 상온에서 2시간동안 교반 후에 메탄올을 증류하여 제거하였다. 여액에 아세토나이트릴 30.0mL를 넣고 t-부틸아민 3.0g을 적가하였다. 적가완료 후 환류 냉각기를 설치한 후 70도에서 10시간 동안 반응한 후 냉각한 액을 여과하고 여액에 2노르말 농도의 염산 이소프로판올액 50mL를 가한 후 3시간 동안 교반하였다. 반응액을 농축한후 이소프로필알코올과 디이소프로필에테르로 재결정하고 진공으로 건조하여 백색 고체의 1-[비스-(3',5'-N,N-디메틸카바모일옥시)페닐] -2-N-t-부틸아미노에탄올[화학식 1]을 2.3g을 얻었다.(수율 64%)In 3.7 g of bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone prepared in Example 2, 30.0 mL of ethanol was dissolved in 100 mL reactor and sodium cyanoboro 3.56 g of hydride was slowly added dropwise. After stirring for 2 hours at room temperature, methanol was distilled off. 30.0 mL of acetonitrile was added to the filtrate, and 3.0 g of t-butylamine was added dropwise. After completion of the dropwise addition, a reflux condenser was installed, and the reaction mixture was reacted at 70 ° C for 10 hours, and then, the cooled liquid was filtered, and 50 mL of isopropanol hydrochloride solution of 2 normal concentration was added to the filtrate, followed by stirring for 3 hours. The reaction solution was concentrated, recrystallized with isopropyl alcohol and diisopropyl ether, and dried in vacuo to yield white solid 1- [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2- 2.3g of Nt-butylaminoethanol [Formula 1] was obtained. (Yield 64%)

1H NMR (200MHz, D2O), δ(ppm) : 1.43(s, 9H), 3.03(d, 12H), 3.17(m, 2H), 4.70(DOH), 5.10(q, 1H), 7.09(m, 3H) 1 H NMR (200 MHz, D 2 O), δ (ppm): 1.43 (s, 9H), 3.03 (d, 12H), 3.17 (m, 2H), 4.70 (DOH), 5.10 (q, 1H), 7.09 (m, 3 H)

이상에서 살펴본 바와 같이 본 발명에 따라 밤부테롤 즉 [비스-(3',5'-N,N-디메틸카바모일옥시)페닐] -2-N-t-부틸아미노에탄올[화학식 1]을 제조하는 과정은 합성에서의 간결함과 중간 물질인 비스-(3',5'-N,N-디메틸카바모일옥시)-2-브로모-아세토페논의 생산에 있어서 비용, 안전 및 생태학적 요구에 대한 준수를 겸비하고 있다. 화학적 과정은 양질의 최종 생산물로 인도하는 간단하고 고수율인 합성 단계를 통해서 대규모로 쉽게 재현이 가능한 것이다.As described above, the process of preparing bambuterol according to the present invention, that is, [bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-Nt-butylaminoethanol [Formula 1] Combines simplicity in the synthesis with compliance with cost, safety and ecological requirements in the production of the intermediate bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone Doing. Chemical processes are easily reproducible on a large scale through simple, high-yield synthesis steps that lead to quality end products.

Claims (2)

하기 화학식1로 표시되는 [비스-(3',5'-N,N-디메틸카바모일옥시)페닐]-2-N-t-부틸아미노에탄올 즉, 밤부테롤의 제조를 위한 중간 생성물인 비스-(3',5'-N,N-디메틸카바모일옥시)-아세토페논[화학식 3]을 제조하기 위하여 3,5-디하이드록시아세토페논[화학식 4]에 수산화나트륨과 테프라부틸 암모니움 브로마이드를 촉매로 사용하고, 디메틸카바모일 클로라이드를 넣고 환류 시키는 것을 특징으로 하는 방법.[Bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-Nt-butylaminoethanol, ie, bis- (3) To prepare ', 5'-N, N-dimethylcarbamoyloxy) -acetophenone [Formula 3], 3,5-dihydroxyacetophenone [Formula 4] was catalyzed by sodium hydroxide and teprabutyl ammonium bromide. Using, dimethylcarbamoyl chloride is added and refluxed.
Figure 112006509273185-pat00008
Figure 112006509273185-pat00008
[화학식 1][Formula 1]
Figure 112006509273185-pat00009
Figure 112006509273185-pat00009
[화학식 3][Formula 3]
Figure 112006509273185-pat00010
Figure 112006509273185-pat00010
[화학식 4][Formula 4]
제1항의 [비스-(3',5'-N,N-디메틸카바모일옥시)페닐]-2-N-t-부틸아미노에탄올 즉, 밤부테롤[화학식 1]을 제조하기 위하여, 비스-(3',5'-N,N-디메틸카바모일옥시)-2-브로모-아세토페논[화학식 2]를 에탄올에 녹이고 소디움시아노보로하이드라이드를 첨가하여 상온에서 교반한 후, t-부틸아민을 넣어 환류시키는 것을 특징으로 하는 밤부테롤의 제조 방법.To prepare the bis- (3 ', 5'-N, N-dimethylcarbamoyloxy) phenyl] -2-Nt-butylaminoethanol, namely bambuterol [Formula 1] of claim 1, bis- (3' Dissolve 5,5-N, N-dimethylcarbamoyloxy) -2-bromo-acetophenone [Formula 2] in ethanol, and add sodium cyanoborohydride and stir at room temperature, then add t-butylamine. Method for producing bambuterol, characterized in that reflux.
Figure 112006509273185-pat00011
Figure 112006509273185-pat00011
[화학식 2][Formula 2]
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100803291B1 (en) 2006-09-08 2008-02-13 (주)팜스웰 Improved preparation method of bambuterol hydrochloride

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0456799B1 (en) 1989-12-01 1994-06-01 Aktiebolaget Astra Improved method of preparing an intermediate for the manufacture of bambuterol
KR20030085658A (en) * 2002-04-30 2003-11-07 한올제약주식회사 An improved synthetic method of bambuterol
US20050171197A1 (en) 2002-08-08 2005-08-04 Dr. Wen Tan R-bambuterol, its preparation and therapeutic uses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0456799B1 (en) 1989-12-01 1994-06-01 Aktiebolaget Astra Improved method of preparing an intermediate for the manufacture of bambuterol
KR20030085658A (en) * 2002-04-30 2003-11-07 한올제약주식회사 An improved synthetic method of bambuterol
US20050171197A1 (en) 2002-08-08 2005-08-04 Dr. Wen Tan R-bambuterol, its preparation and therapeutic uses

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Title
1999, 30(4)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100803291B1 (en) 2006-09-08 2008-02-13 (주)팜스웰 Improved preparation method of bambuterol hydrochloride

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