KR830010065A - Manufacturing method of therapeutic agent - Google Patents

Manufacturing method of therapeutic agent Download PDF

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KR830010065A
KR830010065A KR1019820001506A KR820001506A KR830010065A KR 830010065 A KR830010065 A KR 830010065A KR 1019820001506 A KR1019820001506 A KR 1019820001506A KR 820001506 A KR820001506 A KR 820001506A KR 830010065 A KR830010065 A KR 830010065A
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에드워드 제퍼리 제임스
코즈릭 안토닌
챨스 윌름셜스트 에릭
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데렉 노르만 에드먼슨
너 부츠 캄파니 피 엘시
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Abstract

내용 없음No content

Description

치료제의 제조방법Manufacturing method of therapeutic agent

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음Since this is an open matter, no full text was included.

Claims (13)

일반식(Ⅴ)의 케톤을 환원적 아미드화하여 n=0, R2=H, R4=CHO 인 일반식(Ⅰ)화합물을 제조하거나 일반식(Ⅵ)의 케톤 또는 알데히이드를 환원적 아미드화하여 n=1, R4=CHO, R8=H인 일반식(Ⅰ)화합물을 제조함을 특징으로 하여 일반식(Ⅰ)의 화합물 및 그의 약제학적으로 허용할 수 있는 염을 제조하는 방법.Reductive amidation of the ketone of formula (V) to prepare a compound of formula (I) wherein n = 0, R 2 = H, R 4 = CHO or reductively convert ketone or aldehyde of formula (VI) Amidation to prepare a compound of formula (I) wherein n = 1, R 4 = CHO, R 8 = H, to prepare a compound of formula (I) and pharmaceutically acceptable salts thereof Way. 상기식에서, n=0 또는 1이며, n=0일때, R1은 1내지 6개의 탄소원자를 함유하는 직쇄 또는 측쇄 알킬그룹, 3내지 7개의 탄소원자를 함유하는 사이클로알킬그룹, 사이클로알킬알킬그룹, (이때 사이클로알킬그룹은 3내지 6개의 탄소원자를 함유하며 알킬그룹은 1내지 3개의 탄소원자를 함유한다). 2내지 6개의 탄소원하를 함유하는 알케닐 또는 알키닐 그룹, 또는 다음 일반식(Ⅱ)의 그룹이며,Wherein n = 0 or 1 and when n = 0, R 1 is a straight or branched chain alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms, a cycloalkylalkyl group, ( Wherein the cycloalkyl group contains 3 to 6 carbon atoms and the alkyl group contains 1 to 3 carbon atoms). An alkenyl or alkynyl group containing 2 to 6 carbon atoms, or a group of the following general formula (II), 이때, R9와 R10은 같거나 다를 수 있으며 H, 할로 또는 1내지 3개의 탄소원자를 가지는 알콕시그룹이다.In this case, R 9 and R 10 may be the same or different and are H, halo or an alkoxy group having 1 to 3 carbon atoms. n=1일때, R1은 H 또는 1내지 3개의 탄소원자를 함유하는 알킬그룹이며, R2는 H 또는 1내지 3개의 탄소원자를 함유하는 알킬그룹이고, R3와 R4는 같거나 다를수 있으며, H, 1내지 4개의 탄소원자를 함유하는 알케닐그룹, 3내지 6개의 탄소원자를 가지는 알키닐그룹, 환이 3내지 7개의 탄소원자를 함유한 직쇄 또는 측쇄 알킬그룹, 3내지 6개의 탄소원자를 함유하는 사이클로알킬그룹, 일반식 R11CO그룹(이때 R11은 H이다)이거나, R3및 R4는 이들이 결합되어 있는 질소원자와 함께 환중에 5 또는 6개의 원자를 가지는 임의 치환된 헤테로사이클환을 형성하는데 이때 환은 질소원자 이외에 다른 헤테로원자를 함유할 수도 있으며; R5와 R6는 같거나 다를수 있으며, H, 할로, 트리플루오로메틸, 1내지 3개의 탄소원자를 가지는 알킬그룹, 1내지 3개의 탄소원자를 함유하는 알콕시 또는 알킬티오그룹, 페닐그룹이거나, R5및 R6는 이들이 결합된 탄소원자와 함께 하나이상의 할로그룹, 1내지 4개의 탄소원자를 함유하는 알킬 또는 알콕시그룹에 의해 임의 치환된 제2의 벤젠환을 형성하거나 제2벤젠환의 치환체는 이들이 결합되어 있는 2개의 탄소원자와 함께 또 다른 벤젠환을 형성할 수 있으며, R7과 R8은 같거나 다를수 있으며, H 또는 1내지 3개의 탄소원자를 함유하는 알킬그룹이다.when n = 1, R 1 is H or an alkyl group containing 1 to 3 carbon atoms, R 2 is H or an alkyl group containing 1 to 3 carbon atoms, and R 3 and R 4 may be the same or different, H, an alkenyl group containing 1 to 4 carbon atoms, an alkynyl group containing 3 to 6 carbon atoms, a straight or branched chain alkyl group containing 3 to 7 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms Group, a general formula R 11 CO group wherein R 11 is H, or R 3 and R 4 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle ring having 5 or 6 atoms in the ring; The ring may contain other heteroatoms in addition to the nitrogen atom; R 5 and R 6 may be the same or different, H, halo, trifluoromethyl, an alkyl group having 1 to 3 carbon atoms, an alkoxy or alkylthio group containing 1 to 3 carbon atoms, a phenyl group, or R 5 And R 6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by one or more halo groups, alkyl or alkoxy groups containing 1 to 4 carbon atoms, or substituents of the second benzene ring to which they are attached Together with the two carbon atoms present, another benzene ring may be formed, and R 7 and R 8 may be the same or different and are H or an alkyl group containing 1 to 3 carbon atoms. 일반식(Ⅴ)의 케톤을 환원적 아민화하여 n=0, R2=H인 일반식(Ⅰ) 화합물을 제조하거나 일반식(Ⅵ)의 케톤 또는 알데하이드를 환원적 아민화하여 n=1, R8=H인 일반식(Ⅰ)화합물을 제조함을 특징으로 하여 일반식(Ⅰ)화합물을 제조하는 방법.Reductive amination of the ketone of formula (V) to prepare a compound of formula (I) wherein n = 0, R 2 = H or reductive amination of a ketone or aldehyde of formula (VI) to n = 1, A process for preparing a compound of formula (I), characterized in that to produce compound of formula (I) wherein R 8 = H. 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같다.Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1. 일반식(Ⅶ)의 화합물을 환원시킴을 특징으로 하여 일반식(Ⅰ)의 화합물을 제조하는 방법.A method for preparing a compound of formula (I), characterized by reducing the compound of formula (VII). 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같고,Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1, a) Z 가 일반식 -CR1=NOH그룹 또는)그외 에스테르 또는 에테르인 경우, n=0이고 R2,R3및 R4가 H인 일반식(Ⅰ)의 화합물이 수득되고,a) when Z is a general formula -CR 1 = NOH group or) or other esters or ethers, a compound of formula (I) is obtained wherein n = 0 and R 2 , R 3 and R 4 are H, b) Z 가 일반식 -CR1=NR3의 그룹인 경우, n=0이고 R2및 R4가 H인 일반식(Ⅰ)의 화합물이 수득되고b) when Z is a group of the formula -CR 1 = NR 3 , a compound of formula (I) is obtained in which n = 0 and R 2 and R 4 are H; c) Z 가 일반식 -CR1=NY의 그룹(Y는 유기금속 시약으로부터 유도된 금속함유 잔기를 나타낸다)인 경우, n=0이고 R2,R3및 R4가 H인 일반식(I)의 화합물이 수득되고c) when Z is a group of the formula -CR 1 = NY (Y represents a metal-containing moiety derived from an organometallic reagent), where n = 0 and R 2 , R 3 and R 4 are H (I ) Compound is obtained d) Z 가 일반식 -CR1R2CN의 그룹인 경우, n=1이고 R3,R4,R7및 R8이 H인 일반식(Ⅰ)의 화합물이 수득되고d) when Z is a group of the formula -CR 1 R 2 CN, a compound of formula (I) is obtained wherein n = 1 and R 3 , R 4 , R 7 and R 8 are H; e) Z 가 일반식 -CR1R2CR7=NOH 또는 그의 에스테르 또는 에테르인 경우, n=1이고, R2,R4및 R8이 H인 일반식(Ⅰ)의 화합물이 수득되고e) when Z is the formula -CR 1 R 2 CR 7 = NOH or its ester or ether, a compound of formula (I) is obtained in which n = 1 and R 2 , R 4 and R 8 are H; f) Z 가 일반식 -CR1R2CR7=NR3의 그룹인 경우 n=1이고, R4및 R8이 H인 일반식(Ⅰ)의 화합물이 수득되고f) when Z is a group of the formula -CR 1 R 2 CR 7 = NR 3 , a compound of formula (I) is obtained wherein n = 1 and R 4 and R 8 are H; g) Z 가 일반식 -CR1R2CR3CR7=NY(Y는 유기금속 시약으로부터 유도된 금속함유잔기를 나타낸다)의 그룹인 경우, n=1이고 R3,R4및 R8은 H인 일반식(Ⅰ)의 화합물이 수득된다.g) when Z is a group of the general formula —CR 1 R 2 CR 3 CR 7 = NY (Y represents a metal-containing residue derived from an organometallic reagent), n = 1 and R 3 , R 4 and R 8 are A compound of formula (I) is obtained, which is H. h) Z 가 일반식 -CR1R2CONR3R4의 그룹인 경우, n=1이고 R7및 R8은 H인 일반식(I)의 화합물이 수득된다.h) When Z is a group of the formula -CR 1 R 2 CONR 3 R 4 , a compound of formula (I) is obtained wherein n = 1 and R 7 and R 8 are H. 제3항에 있어서, Y가 MgBr 또는 Li임이 특징인 방법.The method of claim 3, wherein Y is MgBr or Li. 유기금속 시약을 일반식(Ⅶ)의 이민과 반응시킨후 생성물을 가수분해 시킴을 특징으로하여 n이 O인 일반식(Ⅰ)화합물을 제조하는 방법.A method of preparing a compound of formula (I) wherein n is O, characterized by reacting an organometallic reagent with an imine of general formula and then hydrolyzing the product. 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같다.Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1. 제5항에 있어서, 유기금속 시약이 일반식 R1MgBr인 그리나드 시약이거나 일반식 R1Li인 유기리튬 화합물임이 특징인 방법.The method of claim 5, wherein the organometallic reagent is a Grignard reagent of the general formula R 1 MgBr or an organolithium compound of the general formula R 1 Li. 유기금속 시약을 일반식(Ⅸ)의 이민과 반응시킨후 생성물을 가수분해시킴을 특징으로하여 n이 1인 일반식(Ⅰ)화합물을 제조하는 방법.A method of preparing a compound of formula (I), wherein n is 1, by reacting an organometallic reagent with an imine of general formula and then hydrolyzing the product. 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같다.Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1. 제7항에 있어서, 유기 금속 시약이 일반식 R7MgBr인 그리나드 시약이거나 일반식 R7Li인 유기리튬 화합물임이 특징인 방법.8. The method of claim 7, wherein the organometallic reagent is a Grignard reagent of general formula R 7 MgBr or an organolithium compound of general formula R 7 Li. 일반식(Ⅹ)의 아미드를 탈카복실화적으로 전위시켜 n=0인 일반식(Ⅰ)의 아민을 제조하거나, 일반식(XI)의 아미드를 탈카복실화 적으로 전위시켜 n=1인 일반식(Ⅰ)의 아민을 제조하거나, 나트륨 이자이드를 일반식(XⅡ)의 산 클로라이드와 반응시켜 생성된 아실아자이드를 탈카복실화적으로 전위시켜 n=0인 일반식(Ⅰ)의 아민을 제조하거나, 나트륨 이자이드를 일반식(XⅢ)의 산 클로라이드와 반응시켜 생성된 아실 아자이드를 탈카복실화적으로 전위시켜 n=1인 일반식(Ⅰ)의 아민을 제조함을 특징으로하여 일반식(Ⅰ)의 화합물을 제조하는 방법.The amide of general formula (VII) is decarboxylated to prepare an amine of general formula (I) having n = 0, or the amide of general formula (XI) is decarboxylated to general formula of n = 1. Preparing an amine of formula (I), or reacting sodium iside with an acid chloride of formula (XII) to decarboxylate the resulting acyl azide to prepare an amine of formula (I) with n = 0; , By reacting sodium iside with acid chloride of general formula (XIII) to decarboxylating the resulting acyl azide to produce an amine of general formula (I) with n = 1. To prepare a compound. 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같다.Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1. 하이드라조 산을 일반식(XⅣ)의 카복실산과 반응시켜 n=0인 일반식(Ⅰ)의 아민을 제조하거나, 하이드라조산을 일반식(XV)의 카복실산과 반응시켜 n=1인 일반식(Ⅰ)의 아민을 제조함을 특징으로 하여 일반식(Ⅰ)의 화합물을 제조하는 방법.Hydrazoic acid is reacted with a carboxylic acid of formula (XIV) to prepare an amine of formula (I) with n = 0, or hydrazonic acid is reacted with a carboxylic acid of formula (XV) with n = 1 A process for preparing a compound of formula (I), characterized by preparing an amine of I). 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같다.Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1. R4가 -CHO인 일반식(Ⅰ)화합물을 가수분해 시킴을 특징으로 하여 R4가 수소인 일반식(Ⅰ)화합물을 제조하는 방법.A method for producing a compound of formula (I) wherein R 4 is hydrogen, characterized by hydrolysis of compound of formula (I) wherein R 4 is -CHO. 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같다.Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1. R4가 -CHO인 일반식(Ⅰ)화합물을 환원시킴을 특징으로 하여 R4가 메틸인 일반식(Ⅰ)화합물을 제조하는 방법.A process for preparing the compound of formula (I) wherein R 4 is methyl, characterized in that the compound of formula (I) wherein R 4 is -CHO is reduced. 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같다.Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1. R3및 R4중의 하나 또는 둘다다 수소인 일반식(Ⅰ)화합물을 목적하는 화합물로 전환시킴을 특징으로 하여 R3및 R4중의 하나 또는 둘다다 수소이외의 기인 일반식(Ⅰ)화합물을 제조하는 방법.R 3 and R 4 is one or both of the hydrogen in the general formula (Ⅰ) one or both are a group other than hydrogen in a by R 3 and R 4 characterized in Sikkim converted to the compound of interest of the compound formula (Ⅰ) compound How to manufacture. 상기식에서, n,R1,R2,R3,R4,R5,R6,R7및 R8은 제1항에서 정의된 바와 같다.Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1. ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
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