ES2547897T3 - Procedimiento de síntesis enzimática de (7S)-1-(3,4-dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il) N-metilmetanoamina y su utilización en la síntesis de ivabradina y de sus sales - Google Patents
Procedimiento de síntesis enzimática de (7S)-1-(3,4-dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il) N-metilmetanoamina y su utilización en la síntesis de ivabradina y de sus sales Download PDFInfo
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Abstract
Procedimiento de síntesis del compuesto de fórmula (IX):**Fórmula** donde R1representa un grupo alquilo(C1-C6) lineal o ramificado, alilo o bencilo, por acilación enzimática enantioselectiva de la amina racémica de fórmula (IV):**Fórmula** con ayuda de una lipasa (EC 3.1.1.3 en la clasificación internacional de las enzimas): con un carbonato de fórmula R1O-(CO)-OR1donde R1 tiene el significado anteriormente definido, en una cantidad que presenta de 1 a 15 equivalentes molares con respecto a la amina de fórmula (IV), en un disolvente orgánico, acuoso, una mezcla de disolventes orgánicos o una mezcla de disolventes orgánicos y acuosos, a una concentración de 5 a 500 g/l del compuesto de fórmula (IV) por litro de disolvente o mezcla de disolventes, en una relación E/S de 10/1 a 1/100, a una temperatura de 25ºC a 40ºC.
Description
E13176588
21-09-2015
El medio de reacción se analiza mediante HPLC en fase inversa y la enantioselectividad (ee) del carbamato y de la amina se controla mediante HPLCV en fase quiral según los métodos descritos más abajo:
Condiciones de fase inversa: columna Phenomenex® LUNA HST 50*3 C18(2)
5 2,5 µm 0% a 100% de B en 8 min 0,8 ml.min 40ºC A (1000 agua + 25 ACN + 1 ATFA) B (1000 ACN + 25 agua + 1 ATFA)
Condiciones de fase quiral: columna Chiralpak® IC 250*4.6
10 50% isopropanol + 0,1% DEA + 50% heptano + 0,1% DEA 1ml.min 25ºC 288 nm
- Tiempo (h)
- Conversión (%) Ee (carbamato) (%) Ee amina (%) E
- 24
- 58 90 87 12
En un reactor se cargan, bajo nitrógeno, hidruro de litio y aluminio (1,41 kg), y tetrahidrofurano (32,5 l), y después se añade gota a gota a 20ºC una solución de {[(7S)-3,4-dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il]metil}carbamato de etilo(5 kg) en tetrahidrofurano (50 l). La mezcla se calienta a reflujo durante 1 hora y
20 después se enfría a una temperatura inferior a 15ºC para hidrolizar la mezcla de reacción con agua (1 l), una disolución acuosa 5N de hidróxido de sodio (1 l) y después agua (1 l). Luego se filtra el sólido obtenido. La fase orgánica se seca. Se recupera el producto indicado en el título en forma de un aceite con un rendimiento de un 93%.
25 1H RMN (DMSO-d6, ppm / TMS) = 2,60 (m; 3H); 2,85 (m; 1H); 3,15 (m; 1H); 3,25 (dd; 1H); 3,30 (m; 1H); 3,62 (m; 1H); 3,70 (s; 6H); 6,82 (s; 1H); 6,89 (s; 1H); 8,48 (sl; 1H).
30 En un reactor se carga (7S)-3,4-dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il]-N-metilmetanoamina (5 kg), acetato de etilo (40 l) y etanol (10 l). La carga se agita a
E13176588
21-09-2015
20ºC durante 30 minutos, después se añade a través de la válvula del fondo de reactor o a través de un tubo de inmersión ácido clorhídrico gaseoso (1,012 kg). La suspensión obtenida se agita a 15-20ºC durante 1 hora y después se filtra o centrifuga. El precipitado se lava con una mezcla de acetato de etilo/etanol 4/1 (2 x 5 l) y después se seca para obtener el producto indicado en el título con un rendimiento de un 92%.
En un autoclave se cargan 5,5 kg de 3-[2-(1,3-dioxolan-2-il)etil]-7,8-dimetoxi-1,3dihidro-2H-3-benzacepin-2-ona, 27,5 l de etanol y 550 g de paladio sobre carbono.
La mezcla se purga con nitrógeno y después con hidrógeno, se calienta a 55ºC y luego se hidrogena a esta temperatura bajo una presión de 5 bar hasta la absorción de la cantidad teórica de hidrógeno.
A continuación se lleva de vuelta a temperatura ambiente y después se descomprime el autoclave.
A continuación se añaden 4 kg de clorhidrato de (7S)-3,4dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il]-N-metilmetanoamina, 11 l de etanol, 5,5 l de agua y 1 kg de paladio sobre carbono.
La mezcla se purga con nitrógeno y después con hidrógeno, se calienta a 85ºC y luego se hidrogena a esta temperatura bajo una presión de 30 bar hasta la absorción de la cantidad teórica de hidrógeno.
A continuación se lleva de vuelta a temperatura ambiente y se purga el autoclave. Luego se filtra la mezcla de reacción, se destilan los disolventes y se aísla el clorhidrato de ivabradina mediante cristalización en una mezcla de tolueno/1metil-2-pirrolidinona.
De este modo se obtiene el clorhidrato de ivabradina con un rendimiento de un 85% y una pureza química superior a un 99%.
Ejemplo 8:Selección de lipasas para la acilación enzimática de 1-(3,4dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il)metanoamina
La 1-(3,4-dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il)metanoamina racémica (5 mg; c = 10 g/l) y el carbamato de fórmula R1O-(CO)-OR1 (10 eq) se solubilizan en 0,5 ml de TBME.
E13176588
21-09-2015
Después se añaden 5 mg (c = 10 g/l) de la lipasa a estudiar al medio (relación E/S=1/1). El medio de reacción se mantiene a 30ºC, bajo agitación rotatoria a 250 rpm, durante 24 horas.
Los medios de reacción se analizan mediante HPLC en fase quiral para el control de la enantioselectividad según el método:
columna Chiralpak® IC 20 um, 250*4.6 Acetonitrilo/propan-2-ol/DEA 90/10/0,1%; 1,3 ml.min; 30ºC 288 nm
Los resultados se resumen en la siguiente tabla:
- Lipasa
- Carbonato Producto Conversión c (%) ee (%) Amina (R) ee (%) Carbamato (S) E
- Pseudomonas cepacia lipasa II Pseudomonas fluorescens Lipasa PS 'Amano' SD Lipasa PS 'Amano' IM
-
imagen10 IXa 59 14 4 52 >99,9 12,3 3,9 91,6 69,8 73,8 83,2 83,5 40 7 11 36
- Pseudomonas cepacia lipasa II Pseudomonas fluorescens Lipasa PS 'Amano' IM
-
imagen11 IXb 57 5 33 97,0 3,9 44,4 73,4 78,2 89,0 26 8 27
- Pseudomonas cepacia lipasa II Pseudomonas fluorescens Lipasa PS 'Amano' IM
-
imagen12 IXc 16 3 12 17,7 2,2 11,2 89,6 66,1 84,6 22 5 13
- IXa: R1 = alilo IXb: R1 = bencilo IXc: R1 = etilo
E13176588
21-09-2015
- Lipasa
- Carbonato Producto Conversión c (%) ee (%) Amina (R) ee (%) Carbamato (S) E
- aExceso enantiomérico ee (en %) = % enantiómero E2 -% enantiómero E1 / % enantiómero E2 + % enantiómero E1 (siendo el enantiómero E2 el enantiómero mayoritario)bCoeficiente de enantioselectividad E = ln[(1-c)(1-ee(S)] / ln[(1-c)(1+ee(S)]; c = tasa de conversión = ee (amina) / [ee (carbamato) + ee (amina)]
Claims (1)
-
imagen1 imagen2 imagen3
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1256913 | 2012-07-17 | ||
FR1256913A FR2993561B1 (fr) | 2012-07-17 | 2012-07-17 | Procede de synthese enzymatique de la (7s)-1-(3,4-dimethoxy bicyclo[4.2.0]octa-1,3,5-triene 7-yl) n-methyl methanamine, et application a la synthese de l'ivabradine et de ses sels |
Publications (1)
Publication Number | Publication Date |
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ES2547897T3 true ES2547897T3 (es) | 2015-10-09 |
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Application Number | Title | Priority Date | Filing Date |
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ES13176588.5T Active ES2547897T3 (es) | 2012-07-17 | 2013-07-16 | Procedimiento de síntesis enzimática de (7S)-1-(3,4-dimetoxibiciclo[4.2.0]octa-1,3,5-trien-7-il) N-metilmetanoamina y su utilización en la síntesis de ivabradina y de sus sales |
Country Status (33)
Country | Link |
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US (1) | US9045788B2 (es) |
EP (1) | EP2687506B1 (es) |
JP (1) | JP5822880B2 (es) |
KR (1) | KR101495614B1 (es) |
CN (1) | CN103540625B (es) |
AR (1) | AR091765A1 (es) |
AU (1) | AU2013206562B2 (es) |
BR (1) | BR102013017550A2 (es) |
CA (1) | CA2820192C (es) |
CY (1) | CY1116500T1 (es) |
DK (1) | DK2687506T3 (es) |
EA (1) | EA024637B1 (es) |
ES (1) | ES2547897T3 (es) |
FR (1) | FR2993561B1 (es) |
GE (1) | GEP20156422B (es) |
HR (1) | HRP20150906T1 (es) |
HU (1) | HUE025113T2 (es) |
JO (1) | JO3159B1 (es) |
MA (1) | MA34880B1 (es) |
MD (1) | MD4375C1 (es) |
MX (1) | MX341588B (es) |
MY (1) | MY177115A (es) |
NZ (1) | NZ612592A (es) |
PL (1) | PL2687506T3 (es) |
PT (1) | PT2687506E (es) |
RS (1) | RS54082B1 (es) |
SA (1) | SA113340722B1 (es) |
SG (1) | SG196717A1 (es) |
SI (1) | SI2687506T1 (es) |
TW (1) | TWI485250B (es) |
UA (1) | UA113052C2 (es) |
UY (1) | UY34900A (es) |
WO (1) | WO2014013179A1 (es) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6616934B2 (ja) * | 2014-05-22 | 2019-12-04 | 株式会社 資生堂 | レナリドミドの光学分割方法 |
EP3101010A1 (en) | 2015-06-03 | 2016-12-07 | Urquima S.A. | New method for the preparation of highly pure ivabradine base and salts thereof |
CN110656134B (zh) * | 2018-06-29 | 2023-03-28 | 广东东阳光药业有限公司 | 一种单酯的制备方法 |
CN110483312A (zh) * | 2019-08-27 | 2019-11-22 | 北京阳光诺和药物研究有限公司 | 一种高纯度盐酸伊伐布雷定及其中间体的制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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IE52768B1 (en) * | 1981-04-06 | 1988-02-17 | Boots Co Ltd | 1-arylcyclobutylalkylamine compounds useful as therapeutic agents |
FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
US5981267A (en) * | 1996-01-24 | 1999-11-09 | The Scripps Research Institute | Enantioselection of amines using homocarbonates with hydrolase |
CN100412062C (zh) * | 2001-09-12 | 2008-08-20 | 阿诺麦德股份有限公司 | 对映体纯的氨基取代稠合双环的合成 |
KR100510379B1 (ko) * | 2003-07-31 | 2005-08-25 | 동부아남반도체 주식회사 | 트렌치 소자 분리 형성 방법 |
FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2868775B1 (fr) * | 2004-04-13 | 2008-04-11 | Servier Lab | Nouveau procede de synthese de derives de la 1,3,4,5- tetrahydro-2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2870537A1 (fr) * | 2004-05-19 | 2005-11-25 | Servier Lab | Nouveau procede de synthese du (1s)-4,5-dimethoxy-1-(methyl aminomethyl-)-benzocyclobutane et de ses sels d'addition, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2935381B1 (fr) * | 2008-08-29 | 2010-12-17 | Servier Lab | Nouveau procede de resolution des enantiomerees du (3,4-dimethoxy-bicyclo°4.2.0!octa-1,3,5-trien-7-yl)nitrile et application a la synthese de l'ivabradine |
CN102264689B (zh) * | 2008-12-22 | 2014-12-31 | 新梅斯托克尔卡公司 | 制备伊伐布雷定的方法 |
HUP1000245A2 (en) * | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
EP2495237A1 (en) * | 2011-03-04 | 2012-09-05 | Alembic Pharmaceuticals Limited | An improved process for the preparation of highly pure ivabradine hydrochloride |
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- 2013-07-16 CN CN201310298217.0A patent/CN103540625B/zh not_active Expired - Fee Related
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- 2013-07-16 KR KR20130083669A patent/KR101495614B1/ko active IP Right Grant
- 2013-07-16 PT PT131765885T patent/PT2687506E/pt unknown
- 2013-07-16 PL PL13176588T patent/PL2687506T3/pl unknown
- 2013-07-16 SI SI201330063T patent/SI2687506T1/sl unknown
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2015
- 2015-07-06 CY CY20151100587T patent/CY1116500T1/el unknown
- 2015-08-27 HR HRP20150906TT patent/HRP20150906T1/hr unknown
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