Process for preparing 2,3-dihydro-benzofuranol derivatives
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-405/06
C07D-307/81
C07D-307/83
출원번호
US-0612366
(1996-03-07)
우선권정보
EP-0400518 (1995-03-10)
발명자
/ 주소
Marciniak Gilbert (Dachstein FRX) Schnettler Richard A. (Cincinnati OH) Ayers Timothy A. (Loveland OH) Krysan Damian J. (Cincinnati OH)
출원인 / 주소
Hoechst Marion Roussel, Inc. (Cincinnati OH 02)
인용정보
피인용 횟수 :
14인용 특허 :
0
초록
This invention relates to a novel process for preparing 2,3-dihydro-benzofuranol derivatives and to the novel intermediates produced thereby.
대표청구항▼
A process for preparing 2,3-dihydro-benzofuranol derivatives of formula (I) [Figure] (I) including stereoisomers, enantiomers, optically active and racemic mixtures thereof, or their pharmaceutically acceptable salts thereof, wherein R2 is C1-4 alkyl each R2 moiety being independently C1-4 alkyl or
A process for preparing 2,3-dihydro-benzofuranol derivatives of formula (I) [Figure] (I) including stereoisomers, enantiomers, optically active and racemic mixtures thereof, or their pharmaceutically acceptable salts thereof, wherein R2 is C1-4 alkyl each R2 moiety being independently C1-4 alkyl or both R2 moleties, when taken together with the carbon atom to which they are attached, form a C5-6 cyclic hydrocarbyl moiety; R4 is C1-6 alkyl; R5 is H or C(O)R with R being H or C1-9 alkyl; R6 is C1-6 alkyl; R7 is H or C1-6 alkyl; X is COOR8, CH2OH, halomethyl, C(O)A or CH2A; A is NR7R9, -N�R6R6R6-Q, pyrrolidino, piperidino, morpholino, [Figure] R8 is H, C1-6alkyl, or -(CH2)m-A with m being 2,3 or 4; R9 is [Figure] n is 1, 2, 3 or 4, p is 1, 2, or 3; R10 is H, C1-8 alkyl, C2-6 alkenyl, C4-6 cycloalkyl, cyclohexylmethyl, hydroxyalkyl (C2-6), dihydroxyalkyl (C3-6), C2-9 acyloxyalkyl (C2-6), C1-4 alkoxyalkyl (C1-6), (CH2)2-6O(CH2)2-4OH, [Figure] t being 0, 1 or 2, or pyrimidinyl, with the proviso that when Y is other than H then R10 is H; Y is H, CH3 or COOR7; R11 is H, C1-4 alkoxy, C1-4 alkyl or halogeno; R12 is ortho C1-4 alkoxy, ortho C1-4 alkyl or p-halo; and Q is a halide, or sulfonate ion -SO3R1 with R1 being H, C1-6 alkyl, aryl or aralkyl, comprising the steps of: (a) reacting a hydroquinone of formula (3)wherein R4, R6 and R7 are defined above and Pg is hydrogen or a suitable protecting group, [Figure] (3) with a 2-halogeno-2-(C1-4)alkyl(C1-6)acylhalide or a 2-halogeno-2-(C1-4)alkyl(C1-6)acid of formula R2-C(W)(R2)C(O)V wherein R2 is as defined above, W is halogen such as iodide, bromide, chloride or fluoride and more preferably bromide or chloride and V is halogen as defined above or hydroxy (-OH) using Friedel-Crafts reaction conditions, optionally saponifying or deprotecting the so-produced compound, thereby producing a benzofuranone of formula (6), wherein R2, R4, R6 and R7 are as defined above, [Figure] (6) (b) protecting the 5-hydroxy moiety of so-produced benzofuranone (6)with a suitable protecting group and converting the ketone moiety to exo-methylene moiety thereby producing the benzofuran of formula (8), wherein R2, R4, R6 and Pg are as defined above, [Figure] (8) (c) converting by hydroboration/oxidation the exo-methylene group of the so-produced benzofuran (8) into 3-hydroxymethyl group thereby producing compound of formula (9) wherein R2, R4, R6, R7 and Pg are as defined above, [Figure] (9) optionally, (d) resolving the alcohol (9) to obtain the (R) and (S) optically active compounds (9), optionally, (e) deprotecting the 5-hydroxy group of compound (9), thereby producing the benzofuranol of formula (I) wherein X is CH2OH and R5 is H, optionally, (f) oxidizing 3-hydroxymethyl of compound (9) into 3-carboxylic acid of formula (12) [Figure] (12) optionally, (g) resolving the racemic acid of formula (12) to obtain the (S) and (R) optically active compounds (12), optionally, (h) deprotecting the 5-hydroxy group of the acid (12), thereby producing the benzofuranol of formula (I) wherein X is COOH and R5 is H, optionally, (i) esterifying the carboxylic acid of formula (12) and optionally deprotecting the hydroxy group, thereby producing the benzofuranol of formula (I) wherein X is COOR8 and R5 is H, optionally, (j) reacting the desired amino group with the carboxylic acid of formula (12) and optionally deprotecting the hydroxy group, thereby producing the benzofuranol of formula (I) wherein X is C(O)A and R5 is H, optionally, (k) reducing the carboxylic acid (12) thereby producing compound of formula (9), optionally, (l) optionally deprotecting the hydroxy of compound (9) and converting the hydroxy of the 3-hydroxymethyi group to an halogen, thereby producing the benzofuranol of formula (I) wherein X is halomethyl and R5 is H, optionally, (m) deprotecting optionally the hydroxy group of compound (9)and converting the hydroxy of the 3-hydroxymethyl group to a leaving group, thereby producing the benzofuranol of formula (10), [Figure] (10) (n) substituting the leaving group of compound (10) by desired amino group and deprotecting optionally the hydroxy group to obtain the product of formula (I) wherein X is CH2A and R5 is H, optionally, (o) esterifying the 5-hydroxy group of compound of formula (I) wherein R5 is H, to give compound of formula (I) wherein R5 is C(O)R, R being C1-9 alkyl and optionally converting said product to pharmaceutically acceptable salt thereof.
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