KR20140147252A - Process for the preparation of pramipexole - Google Patents

Process for the preparation of pramipexole Download PDF

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KR20140147252A
KR20140147252A KR1020130070142A KR20130070142A KR20140147252A KR 20140147252 A KR20140147252 A KR 20140147252A KR 1020130070142 A KR1020130070142 A KR 1020130070142A KR 20130070142 A KR20130070142 A KR 20130070142A KR 20140147252 A KR20140147252 A KR 20140147252A
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tetrahydrobenzo
formula
butyl
amino
carbamate
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KR101546713B1 (en
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김은정
김혜주
김재영
문종택
박규종
장관영
김재섭
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(주)국전약품
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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
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings

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Abstract

The present invention relates to a method for economically and efficiently manufacturing pramipexole used as a treating agent of Parkinson disease, and to a novel intermediate product for the same. The manufacturing method of the present invention comprises the steps of: (i) protecting (S)- 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine with t-butoxy carbonyl to obtain (S)-t-butyl 2-amino-4,5,6,7- tetrahydrobenzo[d]thiazole-6-yl carbamate; (ii) reacting (S)-t-butyl-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl carbamate with a compound of chemical formula VII to obtain (S)-t-butyl-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl(propyl)carbamate; and (iii) reacting (S)-t-butyl-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl(propyl)carbamate with hydrochloric acid to deprotecting t-butoxycarbonyl.

Description

프라미펙솔의 제조방법 {PROCESS FOR THE PREPARATION OF PRAMIPEXOLE}PROCESS FOR THE PREPARATION OF PRAMIPEXOLE [0002]

본 발명은 파킨슨병의 치료제로 사용되는 프라미펙솔의 신규한 제조방법에 관한 것이다. 보다 구체적으로, 본 발명은 경제적이고 효율적으로 프라미펙솔을 제조하는 방법 및 이를 위한 신규한 중간체에 관한 것이다.The present invention relates to a novel method for producing pramipexole used as a therapeutic agent for Parkinson's disease. More particularly, the present invention relates to a process for preparing pramipexole economically and efficiently, and to novel intermediates therefor.

프라미펙솔은 뇌의 도파민 수용체(dopamine receptor)를 자극하여 파킨슨병을 치료하는 도파민 대항물질(dopamine antagonist)로 작용하는 약물로서, 프라미펙솔 이염산염의 형태로 사용되며 하기 화학식 I의 구조를 가진다. Pramipexole is a drug acting as a dopamine antagonist that stimulates dopamine receptors in the brain to treat Parkinson's disease and is used in the form of pramipexole dihydrochloride and has the structure of Formula I .

[화학식 I](I)

Figure pat00001
Figure pat00001

프라미펙솔은 하기 반응식 1에 나타낸 바와 같이, 화학식 IV의 (S)-4,5,6,7-테트라하이드로벤조[d]티아졸-2,6-디아민으로부터 화학식 V의 (S)-N-(2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일)프로피온아미드를 거쳐 제조할 수 있는 것으로 알려져 있다[참고문헌: J. Med. Chem. 1987, 30, 494]. Pramipexole can be prepared from ( S ) -4,5,6,7-tetrahydrobenzo [d] thiazole-2,6-diamine of formula IV as ( S ) -N - (2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl) propionamide [Reference: J. Med. Chem. 1987 , 30 , 494].

[반응식 1][Reaction Scheme 1]

Figure pat00002
Figure pat00002

그러나 상기한 방법은 화학식 V의 (S)-N-(2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일)프로피온아미드를 환원시키기 위해 B2H6-THF를 사용하는데, 이때 필요한 무수 조건이 대규모 생산에 유리하지 않다는 단점이 있다.However, the above-described method (V) of (S) - B 2 H 6 for reducing propionamide (2-amino-4,5,6,7-tetrahydro-benzo [d] thiazol-6-yl) - N -THF, which has the disadvantage that the necessary anhydrous conditions are not advantageous for large-scale production.

한편, 유럽 특허 제186087호에 따르면 하기 반응식 2에 나타낸 바와 같이, 화학식 IV의 (S)-4,5,6,7-테트라하이드로벤조[d]티아졸-2,6-디아민을 프로피온알데하이드와 환원성아민화(reductive amination)하여 제조하거나, 화학식 VII의 좋은 이탈기를 가지는 화합물(R= 할로겐, OMs, OTs 등)과 반응시켜 제조할 수 있는 것으로 보고되어 있다.On the other hand, according to EP 186087, ( S ) -4,5,6,7-tetrahydrobenzo [d] thiazole-2,6-diamine of formula IV is reacted with propionaldehyde and Can be prepared by reductive amination or by reacting with a compound having a good leaving group (R = halogen, OMs, OTs, etc.) of formula (VII).

[반응식 2][Reaction Scheme 2]

Figure pat00003
Figure pat00003

그러나 상기한 방법은 디프로필레이션에 의한 부반응물의 생성을 피할 수 없는 문제점이 있다.
However, the above method has a problem in that it is inevitable to generate an adduct by dipropylation.

또한 문헌[Organic Process Research & Development 2010, 14, 1125]에는 하기 반응식 3에 나타낸 바와 같이, 화학식 IV의 (S)-4,5,6,7-테트라하이드로벤조[d]티아졸-2,6-디아민에 o-니트로벤젠설포닐(nitrobenzenesulfonyl)을 도입하여 프라미펙솔을 제조하는 방법이 개시되어 있다.Further literature [Organic Process Research & Development 2010, 14, 1125] as shown in Scheme 3 include, (S) -4,5,6,7- tetrahydro-benzo of formula IV [d] thiazol-2,6 - o the diamine-introduced nitrobenzene sulfonyl (nitrobenzenesulfonyl) there is disclosed a method for preparing pramipexole.

[반응식 3][Reaction Scheme 3]

Figure pat00004
Figure pat00004

그러나 상기한 방법은 고가의 o-니트로벤젠설포닐 클로리드를 사용하고, 악취의 황화합물을 사용하는 문제가 있다.
However, the above method has a problem in that expensive o -nitrobenzenesulfonyl chloride is used and sulfur compounds of odor are used.

다른 한편으로, 미국 특허 제6,770,761호에는 하기 반응식 4에 도시된 바와 같이, 화학식 X의 화합물을 이용하여 환원성아민화(reductive amination)한 후, 마지막 단계에서 키랄 분리(chiral resolution)하여 프라미펙솔을 제조하는 방법이 보고되어 있다.On the other hand, U.S. Patent No. 6,770,761 discloses a method of reductive amination using a compound of formula X as shown in Scheme 4 below, followed by chiral resolution at the last step to produce pramipexole Have been reported.

[반응식 4][Reaction Scheme 4]

Figure pat00005
Figure pat00005

그러나 상기한 방법은 환원성아민화(reductive amination)시 발생하는 부반응물과 최종 단계에서 키랄 분리(chiral resolution)를 하게 되어 제조 비용이 증가하게 되는 단점이 있다.However, the above-mentioned method has disadvantages in that the manufacturing cost is increased due to the chiral resolution at the final stage with the side reactants generated during reductive amination.

본 발명자들은 프라미펙솔의 제조에 있어 상기한 문제점을 해결하고자 예의 연구 검토한 결과, 프라미펙솔을 보다 효율적이고 경제적으로 제조할 수 있는 새로운 방법을 개발하였다. The inventors of the present invention have conducted intensive studies to solve the above problems in the production of pramipexole, and as a result, they have developed a new method for producing pramipexole more efficiently and economically.

따라서 본 발명의 목적은 고순도의 프라미펙솔을 경제적이고 효율적으로 제조하는 방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a method for economically and efficiently preparing high purity pramipexole.

본 발명의 다른 목적은 프라미펙솔의 제조를 위한 신규한 중간체를 제공하는 것이다. It is another object of the present invention to provide novel intermediates for the preparation of pramipexole.

본 발명은 하기 화학식 I의 프라미펙솔의 제조방법에 관한 것으로, 본 발명의 제조방법은The present invention relates to a process for preparing pramipexole of the formula (I)

(i) 화학식 IV의 (S)-4,5,6,7-테트라하이드로벤조[d]티아졸-2,6-디아민을 t-부톡시카보닐로 보호화하여 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트를 수득하는 단계;(i) protecting the ( S ) -4,5,6,7-tetrahydrobenzo [d] thiazole-2,6-diamine of formula IV with t -butoxycarbonyl to give ( S ) - t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl carbamate;

(ii) 상기 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트를 화학식 VII의 화합물과 반응시켜 화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트를 수득하는 단계; 및(ii) reacting the ( S ) -t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-ylcarbamate of formula II with a compound of formula VII to form a compound of formula III Of ( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl (propyl) carbamate; And

(iii) 상기 화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트를 염산과 반응시켜 t-부톡시카보닐을 탈보호화하는 단계를 포함한다.(iii) reacting the ( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl (propyl) carbamate of formula III with hydrochloric acid to give t - < / RTI > butoxycarbonyl.

[화학식 IV](IV)

Figure pat00006
Figure pat00006

[화학식 II]≪ RTI ID = 0.0 &

Figure pat00007
Figure pat00007

[화학식 VII](VII)

Figure pat00008
Figure pat00008

[화학식Ⅲ][Formula (III)

Figure pat00009
Figure pat00009

[화학식 I](I)

Figure pat00010
Figure pat00010

상기 식에서,In this formula,

R1은 이탈기, 구체적으로는 브롬(Br), 요오드(I), 염소(Cl), 메실레이트(OMs) 또는 토실레이트(OTs)이다.
R 1 is a leaving group, specifically bromine, iodine, chlorine, mesylate or tosylate.

이하, 본 발명의 제조방법을 하기 반응식 5를 참조로 보다 상세히 설명한다.Hereinafter, the production method of the present invention will be described in more detail with reference to Reaction Scheme 5 below.

[반응식 5][Reaction Scheme 5]

Figure pat00011

Figure pat00011

제1단계 : 화학식 II의 화합물의 합성Step 1: Synthesis of Compound of Formula II

화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트는 화학식 IV의 (S)-4,5,6,7-테트라하이드로벤조[d]티아졸-2,6-디아민을 t-부톡시카보닐(Boc)로 보호화하여 제조한다.Formula II of (S) - t - butyl 2-amino-4,5,6,7-tetrahydro-benzo [d] thiazol-6-yl-carbamate of the formula IV (S) -4,5,6, Tetrahydrobenzo [d] thiazole-2,6-diamine with t -butoxycarbonyl (Boc).

상기 보호화는 디-t-부틸디카보네이트(Boc2O) 등을 사용하여 수행할 수 있으나, 이에 한정되는 것은 아니다. The protection may be performed using di- t -butyl dicarbonate (Boc 2 O) or the like, but is not limited thereto.

상기 보호화 반응은 용매를 사용하거나 사용하지 않을 수 있다. 용매로는 메틸렌클로라이드, 클로로포름, 디클로로에탄, 메탄올, 에탄올, 이소프로필알콜, 테트라하이드로푸란, 디메틸포름아미드, 디메틸아세트아미드 등을 사용할 수 있다.The protecting reaction may or may not use a solvent. As the solvent, methylene chloride, chloroform, dichloroethane, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dimethylformamide, dimethylacetamide and the like can be used.

반응온도는 -20℃ 내지 50℃일 수 있고, 반응시간은 30분 내지 24시간일 수 있다. The reaction temperature may be from -20 占 폚 to 50 占 폚, and the reaction time may be from 30 minutes to 24 hours.

본 발명의 일 실시형태로, 메탄올 용매를 사용하고, 0℃ 내지 10℃의 온도 범위에서, 약 2시간 내지 24시간 동안 반응시켜 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트를 제조할 수 있다.
In one embodiment of the present invention, a methanol solvent is used and reacted in a temperature range of 0 to 10 캜 for about 2 to 24 hours to obtain (S ) -t -butyl 2-amino-4,5 , 6,7-tetrahydrobenzo [d] thiazol-6-yl carbamate can be prepared.

제2단계 : 화학식 III의 화합물의 합성Step 2: Synthesis of compound of formula (III)

화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트는 상기 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트를 화학식 VII의 화합물과 반응시켜 수득한다.Of formula III (S) - t - butyl-2-amino-4,5,6,7-tetrahydro-benzo [d] thiazol-6-yl (propyl) carbamate is (S) of the general formula II - t -Butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-ylcarbamate with the compound of formula VII.

상기 반응은 염기의 존재하에 수행하는 것이 바람직하다. 염기로는 트리에틸아민, 디에틸아이소프로필아민, 피리딘 등을 단독으로 또는 혼합하여 사용할 수 있으며, 소듐하이드리드, 소듐비카보네이트, 소듐카보네이트, 포타슘카보네이트, 수산화칼륨, 수산화나트륨 등의 무기 염기도 사용할 수 있다. 바람직하게는 소듐하이드리드를 사용할 수 있다.The reaction is preferably carried out in the presence of a base. As the base, triethylamine, diethyl isopropylamine, pyridine, etc. may be used alone or in combination. An inorganic base such as sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide, have. Preferably, sodium hydride can be used.

반응용매로는 극성 용매, 비극성 용매 또는 이들의 혼합 용매를 사용할 수 있으며, 바람직하게는 테트라하이드로푸란, 디옥산, 메틸렌클로라이드, 1,2-디클로로에탄, 1,1,1-트리클로로에탄 등을 사용할 수 있다.The reaction solvent may be a polar solvent, a nonpolar solvent or a mixed solvent thereof, preferably tetrahydrofuran, dioxane, methylene chloride, 1,2-dichloroethane, 1,1,1-trichloroethane, Can be used.

반응온도는 -20℃ 내지 50℃, 바람직하게는 -10℃ 내지 10℃일 수 있으며, 반응시간은 약 1시간 내지 12시간, 바람직하게는 1시간 내지 2시간일 수 있다.
The reaction temperature may be -20 ° C to 50 ° C, preferably -10 ° C to 10 ° C, and the reaction time may be about 1 hour to 12 hours, preferably 1 hour to 2 hours.

제3단계 : 화학식 I의 화합물의 합성Step 3: Synthesis of compounds of formula (I)

화학식 I의 프라미펙솔은 상기 화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트를 염산과 반응시켜 제조한다.The pramipexole of formula (I) is prepared by reacting ( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol- ≪ / RTI >

반응용매로는 메탄올, 에탄올, 프로판올, 부탄올, 정제수, 초산에틸, 메틸렌클로라이드, 클로로포름, 테트라하이드로푸란 등을 사용할 수 있다. As the reaction solvent, methanol, ethanol, propanol, butanol, purified water, ethyl acetate, methylene chloride, chloroform, tetrahydrofuran and the like can be used.

반응온도는 -20℃ 내지 60℃, 반응시간은 1시간 내지 24시간일 수 있다. 본 발명의 일 실시형태로, 0 내지 5℃에서 6시간 내지 8시간 동안 교반하여 프라미펙솔을 수득할 수 있다.
The reaction temperature may be -20 ° C to 60 ° C, and the reaction time may be 1 hour to 24 hours. In one embodiment of the present invention, pramipexole can be obtained by stirring at 0 to 5 占 폚 for 6 hours to 8 hours.

다른 한편으로, 본 발명은 프라미펙솔의 제조를 위한 신규한 중간체인 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트에 관한 것이다.On the other hand, the present invention relates to ( S ) -t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazole-6 - Iso carbamate.

[화학식 II]≪ RTI ID = 0.0 &

Figure pat00012

Figure pat00012

또 다른 한편으로, 본 발명은 프라미펙솔의 제조를 위한 신규한 중간체인 화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트에 관한 것이다.( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazole of formula III, which is a novel intermediate for the preparation of pramipexole, -6-yl (propyl) carbamate.

[화학식Ⅲ][Formula (III)

Figure pat00013
Figure pat00013

본 발명의 제조방법에 따르면, 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트가 결정성이 우수하여 저순도의 화학식 IV의 (S)-4,5,6,7-테트라하이드로벤조[d]티아졸-2,6-디아민을 사용하더라도 컬럼 크로마토그래피 등 시간과 비용이 많이 소요되는 정제 공정 없이 고순도의 프라미펙솔을 용이하게 제조할 수 있다. 아울러 보호화된 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트에 프로필기를 도입함으로써 디프로필레이션에 의한 부반응물의 생성을 피할 수 있고, 염산으로 간단하게 탈보호화함으로써 별도의 공정 없이 용이하게 프라미펙솔 이염산염을 제조할 수 있다. According to the production process of the present invention, the ( S ) -t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-ylcarbamate of the formula (II) Even if ( S ) -4,5,6,7-tetrahydrobenzo [d] thiazole-2,6-diamine of the low purity is used, high purity Of pramipexole can be easily produced. And by introducing a propyl group into the protected ( S ) -t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl carbamate of formula (II) It is possible to avoid the formation of side reaction products, and by simple deprotection with hydrochloric acid, the pramipexole dihydrochloride can be easily produced without any additional process.

이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It should be apparent to those skilled in the art that these embodiments are for illustrative purpose only and that the scope of the present invention is not limited to these embodiments.

실시예 1: (Example 1: ( SS )-) - tt -부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트(화학식 II의 화합물)의 합성-Butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl carbamate (compound of formula II)

화학식 IV의 (S)-4,5,6,7-테트라하이드로벤조[d]티아졸-2,6-디아민 100g에 메탄올 100mL를 가하였다. 0 내지 5℃를 유지하면서 디-t-부틸디카보네이트 155g을 천천히 가한 후, 20 내지 25℃에서 1시간 동안 교반하였다. 반응물을 농축한 다음 톨루엔 300mL를 넣고 2시간 동안 상온에서 방치한 후, 냉동실에서 4시간 동안 방치하였다. 여과 후 건조하여 흰색의 고체인 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트 143g(수율 90%)을 얻었다. 100 g of methanol was added to 100 g of ( S ) -4,5,6,7-tetrahydrobenzo [d] thiazole-2,6-diamine of the formula IV. 155 g of di- t -butyl dicarbonate was added slowly while maintaining the temperature at 0 to 5 占 폚, followed by stirring at 20 to 25 占 폚 for 1 hour. After the reaction was concentrated, 300 mL of toluene was added and the mixture was allowed to stand at room temperature for 2 hours, and then left in a freezer for 4 hours. Filtered and dried to obtain 143 g (yield 90%) of ( S ) -t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-ylcarbamate of formula (II) ≪ / RTI >

1H NMR (CDCl3, 400MHz) δ 4.74(1H, brs), 4.05(1H, brs), 2.95(1H, dd), 2.64(2H, brs), 2.47(1H, dd), 2.07~1.96(1H, m), 1.89~1.81(1H, m), 1.46(9H, s) 1 H NMR (CDCl 3, 400MHz ) δ 4.74 (1H, brs), 4.05 (1H, brs), 2.95 (1H, dd), 2.64 (2H, brs), 2.47 (1H, dd), 2.07 ~ 1.96 (1H , m), 1.89-1.81 (1H, m), 1.46 (9H, s)

실시예 2: (Example 2: ( SS )-) - tt -부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트(화학식 III의 화합물)의 합성Synthesis of butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl (propyl) carbamate

화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트 27g과 테트라하이드로푸란 120mL을 혼합한 후, 브로모프로판 18.2mL를 가하고 -10℃로 냉각하였다. 소듐하이드리드 7g을 천천히 가한 후 2시간 동안 교반하였다. 정제수 100ml를 천천히 가한 후 메틸렌클로라이드 100mL로 2회 추출하고 농축하여 무색의 고체인 화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트 28.3g(수율 91%)을 얻었다.27 g of ( S ) -t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-ylcarbamate of the formula (II) and 120 ml of tetrahydrofuran were mixed, 18.2 mL was added and the mixture was cooled to -10 ° C. 7 g of sodium hydride was slowly added thereto, followed by stirring for 2 hours. 100 ml of purified water was slowly added and extracted twice with 100 ml of methylene chloride and concentrated to give ( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thia 6-yl (propyl) carbamate (yield: 91%).

1H NMR (CDCl3, 400MHz) δ 0.07(2H, brs), 2.70~2.70(4H, m), 2.05~1.90(2H, m), 1.60~1.51(2H, m), 1.47(9H, s), 0.87(3H, t) 1 H NMR (CDCl 3, 400MHz ) δ 0.07 (2H, brs), 2.70 ~ 2.70 (4H, m), 2.05 ~ 1.90 (2H, m), 1.60 ~ 1.51 (2H, m), 1.47 (9H, s) , 0.87 (3 H, t)

실시예 3: 프라미펙솔(화학식 I의 화합물)의 합성Example 3: Synthesis of pramipexole (compound of formula I)

화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트 20g을 conc. HCl 5ml와 THF 50ml에 녹인 후, 20 내지 25℃에서 12시간 동안 교반하였다. 생성된 고체를 여과 건조하여 화학식 I의 프라미펙솔 16.5g(수율 85%)를 얻었다. 20 g of ( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl (propyl) carbamate of formula III was dissolved in conc. HCl (5 ml) and THF (50 ml), and the mixture was stirred at 20 to 25 ° C for 12 hours. The resulting solid was filtered and dried to give 16.5 g (85% yield) of pramipexole of formula (I).

Claims (7)

(i) 화학식 IV의 (S)-4,5,6,7-테트라하이드로벤조[d]티아졸-2,6-디아민을 t-부톡시카보닐로 보호화하여 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트를 수득하는 단계;
(ii) 상기 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트를 화학식 VII의 화합물과 반응시켜 화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트를 수득하는 단계; 및
(iii) 상기 화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트를 염산과 반응시켜 t-부톡시카보닐을 탈보호화하는 단계를 포함하는 하기 화학식 I의 프라미펙솔의 제조방법:
[화학식 IV]
Figure pat00014

[화학식 II]
Figure pat00015

[화학식 VII]
Figure pat00016

[화학식Ⅲ]
Figure pat00017

[화학식 I]
Figure pat00018

상기 식에서,
R1은 이탈기이다.(i) protecting the ( S ) -4,5,6,7-tetrahydrobenzo [d] thiazole-2,6-diamine of formula IV with t -butoxycarbonyl to give ( S ) - t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl carbamate;
(ii) reacting the ( S ) -t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-ylcarbamate of formula II with a compound of formula VII to form a compound of formula III Of ( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl (propyl) carbamate; And
(iii) reacting the ( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl (propyl) carbamate of formula III with hydrochloric acid to give t Lt; RTI ID = 0.0 > (I) < / RTI > comprising deprotecting < RTI ID = 0.0 &
(IV)
Figure pat00014

≪ RTI ID = 0.0 &
Figure pat00015

(VII)
Figure pat00016

[Formula (III)
Figure pat00017

(I)
Figure pat00018

In this formula,
R 1 is a leaving group. 제1항에 있어서, R1이 브롬(Br), 요오드(I), 염소(Cl), 메실레이트(OMs) 또는 토실레이트(OTs)인 것을 특징으로 하는 제조방법.The process according to claim 1, wherein R 1 is bromine (Br), iodine (I), chlorine (Cl), mesylate (OMs) or tosylate (OTs). 제1항에 있어서, 단계 (i)에서 보호화가 디-t-부틸디카보네이트(Boc2O)를 사용하여 수행되는 것을 특징으로 하는 제조방법.The process according to claim 1, wherein in step (i) the deprotection is carried out using di- t -butyl dicarbonate (Boc 2 O). 제1항에 있어서, 단계 (ii)의 반응이 염기의 존재하에 수행되는 것을 특징으로 하는 제조방법.The process according to claim 1, wherein the reaction of step (ii) is carried out in the presence of a base. 제4항에 있어서, 염기가 소듐하이드리드인 것을 특징으로 하는 제조방법.The process according to claim 4, wherein the base is sodium hydride. 하기 화학식 II의 (S)-t-부틸 2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일카바메이트:
[화학식 II]
Figure pat00019
( S ) -t -butyl 2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-ylcarbamate of formula II:
≪ RTI ID = 0.0 &
Figure pat00019
 하기 화학식 III의 (S)-t-부틸-2-아미노-4,5,6,7-테트라하이드로벤조[d]티아졸-6-일(프로필)카바메이트:
[화학식Ⅲ]
Figure pat00020
( S ) -t -butyl-2-amino-4,5,6,7-tetrahydrobenzo [d] thiazol-6-yl (propyl) carbamate of formula III:
[Formula (III)
Figure pat00020
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