ES2292333B1 - IMPROVEMENTS IN THE OBJECT OF THE MAIN PATENT N. 200401850, BY "MIXED SOLVATO OF OLANZAPINE, PROCEDURE FOR OBTAINING AND PROCEDURE FOR OBTAINING THE FORM I OF OLANZAPINE FROM THE SAME". - Google Patents
IMPROVEMENTS IN THE OBJECT OF THE MAIN PATENT N. 200401850, BY "MIXED SOLVATO OF OLANZAPINE, PROCEDURE FOR OBTAINING AND PROCEDURE FOR OBTAINING THE FORM I OF OLANZAPINE FROM THE SAME". Download PDFInfo
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- ES2292333B1 ES2292333B1 ES200600059A ES200600059A ES2292333B1 ES 2292333 B1 ES2292333 B1 ES 2292333B1 ES 200600059 A ES200600059 A ES 200600059A ES 200600059 A ES200600059 A ES 200600059A ES 2292333 B1 ES2292333 B1 ES 2292333B1
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- olanzapine
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- water
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- 229960005017 olanzapine Drugs 0.000 title claims abstract description 45
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000012453 solvate Substances 0.000 claims abstract description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 22
- FHPIXVHJEIZKJW-UHFFFAOYSA-N 4'-N-desmethylolanzapine Chemical compound S1C(C)=CC2=C1NC1=CC=CC=C1N=C2N1CCNCC1 FHPIXVHJEIZKJW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000007069 methylation reaction Methods 0.000 claims abstract description 5
- 230000011987 methylation Effects 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZTTWQKYKGNLCCA-UHFFFAOYSA-N 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine Chemical compound N1C2=CC=CC=C2N=C(N)C2=C1SC(C)=C2 ZTTWQKYKGNLCCA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000742 histaminergic effect Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- -1 olanzapine alcohols Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Mejoras en el objeto de la patente principal nº
P
200401850, por "Solvato mixto de olanzapina,
procedimiento para su obtención y procedimiento de obtención de la
forma I de olanzapina a partir del mismo".Improvements in the subject of main patent No. P
200401850, for "Olanzapine mixed solvate, procedure for obtaining it and procedure for obtaining form I of olanzapine from it".
Se proporciona un procedimiento mejorado para la
obtención de un solvato mixto de
olanzapina/agua/tetrahidrofu-
rano en una proporción
1:1:1/2.An improved procedure is provided for obtaining a mixed solvate of olanzapine / water / tetrahydrofu
rano in a 1: 1: 1/2 ratio.
Dichas mejoras se caracterizan por el hecho de que se lleva a cabo la obtención de dicho solvato mixto, esencialmente, mediante la metilación de la N-desmetilolanzapina con sulfato de dimetilo, utilizando tetrahidrofurano y agua como disolventes.These improvements are characterized by the fact that obtaining said mixed solvate is carried out, essentially, by methylation of the N-desmethylolanzapine with dimethyl sulfate, using tetrahydrofuran and water as solvents.
Description
Mejoras en el objeto de la patente principal nº P 200401850, por "Solvato mixto de olanzapina, procedimiento para su obtención y procedimiento de obtención de la forma I de olanzapina a partir del mismo".Improvements in the subject of the main patent nº P 200401850, for "Olanzapine mixed solvate, procedure for its obtaining and procedure for obtaining form I of olanzapine from it ".
La presente invención se refiere a mejoras en el objeto de la patente principal núm. 200401850, por "Solvato mixto de olanzapina, procedimiento para su obtención y procedimiento para la obtención de la forma I de olanzapina a partir del mismo".The present invention relates to improvements in the object of main patent no. 200401850, for "Solvato mixed olanzapine, procedure for obtaining and procedure for obtaining form I of olanzapine a from it. "
En particular, la presente invención se refiere a un procedimiento mejorado para la obtención de dicho solvato mixto de olanzapina/agua/tetrahidrofurano en una proporción 1:1:1/2.In particular, the present invention relates to an improved procedure for obtaining said solvate mixed olanzapine / water / tetrahydrofuran in a proportion 1: 1: 1/2.
La olanzapina es una tienobenzodiazepina de fórmula (I):Olanzapine is a thienobenzodiazepine of formula (I):
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que actúa como antagonista sobre receptores de la dopamina D1, D2, D3, D4 y D5; de la serotonina 5-HT2 y 5HT3; alfa-1-adrenérgicos, colinérgicos e histaminérgicos H1.that acts as an antagonist on dopamine receptors D1, D2, D3, D4 and D5; of serotonin 5-HT2 and 5HT3; alpha-1-adrenergic, cholinergic e histaminergic H1.
La olanzapina se describe, por primera vez, en la patente EP0454436B1, en donde dicha tienobenzodiazepina se obtiene a partir de 4-amino-2-metil-10H-tieno[2,3-b][1,5]benzodiazepina y N-metilpiperazina en DMSO/tolueno y aislando, a continuación, la olanzapina mediante adición de agua y cristalización con acetonitrilo.Olanzapine is described, for the first time, in EP0454436B1, wherein said thienobenzodiazepine is gets from 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine and N-methylpiperazine in DMSO / toluene and isolating, to then olanzapine by adding water and crystallization with acetonitrile.
En la patente EP0733635A1 se describen dos formas polimórficas de la olanzapina: la Forma I (metaestable) y la Forma II (estable), siendo la Forma I la obtenida en la primera patente EP0454436B1.In EP0733635A1 two are described polymorphic forms of olanzapine: Form I (metastable) and Form II (stable), Form I being the one obtained in the first EP0454436B1.
El carácter metaestable de la Forma I se refiere a una variación en el color en condiciones ambientales de almacenamiento.The metastable character of Form I refers to to a variation in color in environmental conditions of storage.
Las patentes EP0733634A1, US5703232 y EP0831098A2 reivindican la obtención de especies hidratadas y de solvatos de alcoholes de la olanzapina y su uso para la obtención de la Forma II (estable) de la olanzapina, si bien en la patente US 5703232 se llama Forma I a la forma estable (cuando, en los demás documentos se refieren a la Forma estable como Forma II).EP0733634A1, US5703232 and EP0831098A2 claim the obtaining of hydrated species and of Solvates of olanzapine alcohols and their use for obtaining of Form II (stable) of olanzapine, although in US Pat. 5703232 Form I is called the stable form (when, in others Documents refer to the Stable Form as Form II).
En la patente US5637584 se reivindica el solvato de diclorometano de la olanzapina y un procedimiento para su obtención.In US5637584 the solvate is claimed of olanzapine dichloromethane and a procedure for its obtaining.
Finalmente en las patentes WO0218390A1,
WO03097650A1, WO03055438A2, WO03101997 y WO2004006933
A2 se
reivindica la obtención de olanzapina Forma I. En la patente
WO0218390A1 se obtiene la Forma I de la olanzapina a partir del
dihidrato I, del monohidrato I o a partir de la Forma II, por
cristalización en diclorometano. En la patente WO03097650A1 se
obtiene la Forma I por extracción y posterior purificación con
diclorometano de la olanzapina obtenida mediante condensación del
4-amino-2-metil-10H-tieno[2,3-b][1,5]benzodiazepina
y N-metilpiperazina. En dicha patente se reivindica
un solvato mixto de diclorometano/agua y un solvato mixto de
DMSO/agua. En la patente WO03055438A2 se obtiene la Forma I por
sucesivas cristalizaciones y decoloraciones en alcoholes
C1-C4. En la patente WO03101997 se obtiene la Forma
I por precipitación en una mezcla de un disolvente orgánico en
medio básico como tolueno y sosa metanólica sembrando con la propia
Forma I. En la patente WO2004006933A2 se obtiene la Forma I por
cristalización de una mezcla de disolventes que contienen IPA. En
algunas de las anteriores patentes, se describe la Forma I obtenida
como estable frente a cambios de color.Finally in patents WO0218390A1, WO03097650A1, WO03055438A2, WO03101997 and WO2004006933
A2 claims to obtain Form I olanzapine. In WO0218390A1, Form I of olanzapine is obtained from dihydrate I, monohydrate I or from Form II, by crystallization from dichloromethane. In WO03097650A1, Form I is obtained by extraction and subsequent purification with dichloromethane of olanzapine obtained by condensation of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine and N- methylpiperazine In said patent a mixed dichloromethane / water solvate and a mixed DMSO / water solvate are claimed. In WO03055438A2, Form I is obtained by successive crystallizations and discolorations in C1-C4 alcohols. In WO03101997, Form I is obtained by precipitation in a mixture of an organic solvent in basic medium such as toluene and methanolic soda by sowing with Form I. In WO2004006933A2, Form I is obtained by crystallization of a solvent mixture that contain IPA In some of the previous patents, Form I obtained as stable against color changes is described.
El objeto de la presente invención es proporcionar un procedimiento alternativo y mejorado para la obtención del solvato mixto de olanzapina/agua/tetrahidrofurano en una proporción 1:1:1/2 (I):The object of the present invention is provide an alternative and improved procedure for obtaining the mixed solvate of olanzapine / water / tetrahydrofuran in a 1: 1: 1/2 ratio (I):
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En consecuencia, un primer aspecto de la presente invención se refiere a mejoras en el objeto de la patente principal núm. 200401850, por "Solvato mixto de olanzapina, procedimiento para su obtención y procedimiento para la obtención de la forma I de olanzapina a partir del mismo", caracterizadas por el hecho de que se proporciona un nuevo procedimiento para la obtención de dicho solvato mixto que consiste, esencialmente, en la metilación de la N-desmetilolanzapina con sulfato de dimetilo, utilizando tetrahidrofurano y agua como disolventes.Consequently, a first aspect of the The present invention relates to improvements in the object of the patent main no. 200401850, for "Olanzapine mixed solvate, procedure for obtaining and procedure for obtaining of the form I of olanzapine from it ", characterized by the fact that a new procedure is provided for the obtaining said mixed solvate consisting essentially of the methylation of N-desmethylolanzapine with sulfate of dimethyl, using tetrahydrofuran and water as solvents
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Para mayor comprensión de las mejoras del objeto de la presente invención, se incluye a continuación un breve resumen del objeto de la patente principal núm. 200401850.For greater understanding of object improvements of the present invention, a brief is included below summary of the object of the main patent no. 200401850
La patente principal tiene por objeto proporcionar un solvato mixto de olanzapina/agua/tetrahidrofurano en una proporción 1:1:1/2 de fórmula (I):The main patent is intended provide a mixed solvate of olanzapine / water / tetrahydrofuran in a 1: 1: 1/2 ratio of formula (I):
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
que se identifica por su difractograma de Rayos X en polvo. En la Tabla 1 de más adelante se muestran los picos observados en un difractograma de Rayos X utilizando un difractómetro automático para polvo cristalino X'Pert de PHILIPS provisto de un tubo de Cu y un monocromador secundario de grafito (longitud de onda K\alpha Cu, 1,5419 \ring{A}).that is identified by its X-ray powder diffractogram. In Table 1 below, show the peaks observed in an X-ray diffractogram using an automatic diffractometer for crystalline powder X'Pert PHILIPS equipped with a Cu tube and a secondary monochromator graphite (wavelength Kα Cu, 1.5419 \ ring {A}).
El difractograma de Rayos X del solvato se caracteriza por la posición(º2\theta), las distancias interplanares d y las intensidades relativas I/I_{0}. Dicho difractograma revela como picos característicos de dicho solvato mixto.The X-ray diffractogram of the solvate is characterized by position (º2 \ theta), distances interplanes d and the relative intensities I / I_ {0}. Saying diffractogram reveals as characteristic peaks of said solvate mixed.
La patente principal también se refiere a un procedimiento para la obtención de dicho solvato mixto de olanzapina/agua/tetrahidrofurano en la proporción 1:1:1/2, que comprende solvatar una olanzapina cruda anhidra con una mezcla de tetrahidrofurano/agua en una proporción comprendida entre 1:10 y 10:1 v/v, a una temperatura comprendida entre 20 y 80ºC.The main patent also refers to a procedure for obtaining said mixed solvate of olanzapine / water / tetrahydrofuran in the ratio 1: 1: 1/2, which comprises solvating an anhydrous raw olanzapine with a mixture of tetrahydrofuran / water in a ratio between 1:10 and 10: 1 v / v, at a temperature between 20 and 80 ° C.
Otro procedimiento alternativo que se describe en la patente principal para obtener dicho solvato mixto es partiendo de la condensación del clorhidrato de la 4-amino-2-metil-10H-tieno[2,3-b][1,5]benzodiazepina (II) con un exceso de N-metilpiperacina (III)Another alternative procedure described in the main patent to obtain said mixed solvate is starting from the condensation of the hydrochloride of the 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine (II) with an excess of N-methylpiperacin (III)
seguido de la destilación de la N-metilpiperacina sobrante y, finalmente, el crudo resultante se trata con una mezcla de tetrahidrofurano/agua en una proporción comprendida entre 1:10 y 10:1 v/v, precipitando el solvato mixto de olanzapina/agua/tetrahidrofurano en la proporción 1:1:1/2.followed by distillation of the N-methylpiperacin leftover and finally the crude resulting is treated with a mixture of tetrahydrofuran / water in a ratio between 1:10 and 10: 1 v / v, precipitating the mixed olanzapine solvate / water / tetrahydrofuran in the proportion 1: 1: 1/2.
La patente principal también se refiere a la preparación de la olanzapina Forma I a partir del solvato mixto de olanzapina/agua/tetrahidrofurano en la proporción 1:1:1/2. Dicho procedimiento comprende el secado del solvato al vacío a una presión que oscila entre 1 y 40 mmHg a una temperatura controlada entre 10 y 50ºC.The main patent also refers to the Preparation of olanzapine Form I from the mixed solvate of olanzapine / water / tetrahydrofuran in the ratio 1: 1: 1/2. Saying method comprises drying the solvate under vacuum at a pressure ranging from 1 to 40 mmHg at a controlled temperature between 10 and 50 ° C.
Las mejoras en el objeto de la patente principal núm. 200401850, comprenden un procedimiento alternativo para la obtención del solvato mixto de olanzapina/agua/tetrahidrofurano en la proporción 1:1:1/2, donde dichas mejoras se caracterizan por el hecho de que se llevan a cabo las siguientes etapas:The improvements in the object of the main patent no. 200401850, comprise an alternative procedure for obtaining the mixed solvate of olanzapine / water / tetrahydrofuran in the 1: 1: 1/2 ratio, where these improvements are characterized by the fact that the following stages are carried out:
- a)to)
- Condensación del compuesto de fórmula (IIa) con piperacina de fórmula (IIIa) en presencia de por lo menos un disolvente aprótico, seguido de purificación por cristalización en tolueno anhidro:Condensation of the compound of formula (IIa) with piperazine of formula (IIIa) in the presence of minus an aprotic solvent, followed by purification by crystallization in anhydrous toluene:
- b)b)
- Metilación de la N-desmetilolanzapina de fórmula (IV) con sulfato de dimetilo en presencia de tetrahidrofurano y agua como disolventes:Methylation N-desmethylolanzapine of formula (IV) with sulfate dimethyl in the presence of tetrahydrofuran and water as solvents:
- c)C)
- Obtención directa del solvato mixto de Olanzapina/agua/THFDirect obtaining of the mixed solvate of Olanzapine / water / THF
- d)d)
- Secado y obtención de la forma I de Olanzapina.Drying and obtaining form I of Olanzapine
El producto (IV), N-desmetilolanzapina, es conocido y, por lo tanto, su obtención está al alcance de un conocedor en la materia.The product (IV), N-desmethylolanzapine is known and, therefore, its obtaining is within the reach of a connoisseur in the field.
En la presente invención la N-desmetilolanzapina se purifica por cristalización para en una segunda etapa someterla a una reacción de metilación con sulfato de dimetilo y así obtener olanzapina en solución de THF. Mediante la adición de agua se forma el solvato mixto de olanzapina/agua/THF que, posteriormente, es aislado.In the present invention the N-desmethylolanzapine is purified by crystallization for a second stage to undergo a methylation reaction with dimethyl sulfate and thus obtain olanzapine in solution of THF. By adding water, the mixed solvate of olanzapine / water / THF which is subsequently isolated.
Las mejoras en el presente procedimiento se basan en el hecho de que la utilización de la N- desmetilolanzapina como producto intermedio permite la purificación de este compuesto por cristalización en tolueno anhidro de forma que se mejora el perfil de impurezas presentes en el solvato mixto de olanzapina/agua/THF lo que a su vez permite la obtención de una olanzapina Forma I de elevada pureza.The improvements in this procedure are based on the fact that the use of N-desmethylolanzapine as intermediate it allows the purification of this compound by crystallization in anhydrous toluene so that the profile of impurities present in the mixed solvate of olanzapine / water / THF which in turn allows obtaining a olanzapine Form I of high purity.
Ventajosamente, la reacción de la etapa a) se lleva a cabo con piperacina en presencia de disolventes apróticos como N-metilpirrolidona (NMP) y/o tolueno o mezclas de ellos, a una temperatura entre 50ºC y 150ºC, preferiblemente entre 120 y 135ºC. El producto obtenido se purifica por cristalización en tolueno anhidro. En la etapa b) la reacción se realiza en presencia de una o más bases inorgánicas como hidróxidos y carbonatos de metales alcalinos, utilizando como disolvente una mezcla de THF y agua. La reacción tiene lugar por adición de un agente metilante, preferiblemente sulfato de metilo, a una temperatura entre 0ºC y 30ºC, preferiblemente entre 5ºC y 15ºC, bajo atmósfera inerte. Una vez finalizada la reacción se realiza un work-up con agua y ácido clorhídrico diluido llegándose a una solución de olanzapina en tetrahidrofurano.Advantageously, the reaction of step a) is carried out with piperazine in the presence of aprotic solvents such as N-methylpyrrolidone (NMP) and / or toluene or mixtures of them, at a temperature between 50 ° C and 150 ° C, preferably between 120 and 135 ° C. The product obtained is purified by crystallization in anhydrous toluene. In step b) the reaction is performs in the presence of one or more inorganic bases as hydroxides and alkali metal carbonates, using as solvent a mixture of THF and water. The reaction takes place by adding a methylating agent, preferably methyl sulfate, at a temperature between 0 ° C and 30 ° C, preferably between 5 ° C and 15 ° C, under inert atmosphere Once the reaction is finished a Work-up with water and dilute hydrochloric acid reaching a solution of olanzapine in tetrahydrofuran.
La obtención del solvato mixto de olanzapina/agua/THF se realiza mediante adición de agua sobre dicha solución.Obtaining the mixed solvate of olanzapine / water / THF is performed by adding water on said solution.
Las etapas de transformación del solvato mixto en olanzapina forma I mediante secado forman parte ya del contenido de la patente principal núm. 200401850.The stages of transformation of the mixed solvate in olanzapine form I by drying they are already part of the content of main patent no. 200401850
A continuación, se incluye una realización de la presente invención que, a título de ejemplo no limitativo, describe la obtención del solvato mixto de olanzapina/THF/agua.Next, an embodiment of the present invention which, by way of non-limiting example, describes obtaining the mixed solvate of olanzapine / THF / water.
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EjemploExample
A una disolución preenfriada a 10ºC de 0,125 Kg (3,125 moles) de hidróxido sódico y 0,261 Kg (1,891 moles) de carbonato potásico en 1,66 L de agua se añaden 8 L de tetrahidrofurano y 1,0 Kg (3,160 moles) de 2-metil-4-(1-piperazinil)-10H-tieno[2,3-b][1,5]benzodiazepina (N-desmetilolanzapina purificada por cristalización en tolueno anhidro). A la suspensión resultante se adicionan a 10ºC y bajo atmósfera de nitrógeno 0,484 Kg de sulfato de dimetilo disueltos en 0.83 L de tetrahidrofurano a lo largo de 2-3 horas. Acabada la adición se mantiene la agitación a 10ºC durante 5 horas y seguidamente se calienta a 30ºC y se mantiene la agitación durante 30 min. Se añaden 0,666 L de agua y 0,075 L de ácido clorhídrico acuoso del 35% y se calienta la suspensión a 50ºC hasta disolución total, obteniéndose una mezcla bifásica. Se decanta la fase acuosa inferior y se filtra la fase orgánica superior a 45-50ºC. Se destilan 4,6 L de tetrahidrofurano a vacío, se añaden 4,3 L de agua a se completa la destilación del tetrahidrofurano. Se añaden 1,85 L de tetrahidrofurano y se calienta a reflujo. Se enfría a 5ºC y se filtra el sólido resultante, que se lava dos veces con 1 L de agua.At a precooled solution at 10 ° C of 0.125 kg (3,125 moles) of sodium hydroxide and 0.261 kg (1,891 moles) of potassium carbonate in 1.66 L of water is added 8 L of tetrahydrofuran and 1.0 kg (3,160 moles) of 2-methyl-4- (1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (C-crystallization purified N-desmethylolanzapine in anhydrous toluene). To the resulting suspension are added to 10 ° C and under nitrogen atmosphere 0.484 kg of dimethyl sulfate dissolved in 0.83 L of tetrahydrofuran throughout 2-3 hours Once the addition is finished, the stirring at 10 ° C for 5 hours and then heat to 30 ° C and stirring is maintained for 30 min. 0.666 L of water and 0.075 L of 35% aqueous hydrochloric acid and the suspension at 50 ° C until complete dissolution, obtaining a mixture biphasic The lower aqueous phase is decanted and the phase is filtered. organic higher than 45-50 ° C. 4.6 L of distilled tetrahydrofuran in vacuo, 4.3 L of water are added to the completion of the tetrahydrofuran distillation. 1.85 L of tetrahydrofuran and heated to reflux. It is cooled to 5 ° C and filter the resulting solid, which is washed twice with 1 L of Water.
El sólido obtenido se seca en la estufa de aire a 40ºC hasta peso constante, obteniéndose 0,85 Kg (73%) del solvato mixto de olanzapina/agua/tetrahidrofurano en la proporción 1:1:1/2.The solid obtained is dried in the air stove at 40 ° C to constant weight, obtaining 0.85 kg (73%) of mixed olanzapine solvate / water / tetrahydrofuran in the proportion 1: 1: 1/2.
Si se desea el solvato obtenido se purifica por
disolución a reflujo en 3,4 L de THF seguido de adición de 0,85 L
agua. Después de enfriar a 20-25ºC durante una hora
y, a continuación, a 0ºC durante una hora más, se filtra el sólido
y se seca en una estufa de aire a 42ºC hasta peso constante
obteniendo 750 g de solvato mixto de olanzapina/
agua/tetrahidrofurano en la proporción 1:1:1/2 con menos de un 0,2%
de impurezas totales por HPLC.If desired, the solvate obtained is purified by refluxing in 3.4 L of THF followed by the addition of 0.85 L of water. After cooling to 20-25 ° C for one hour and then at 0 ° C for another hour, the solid is filtered and dried in an air oven at 42 ° C to constant weight to obtain 750 g of mixed olanzapine solvate /
water / tetrahydrofuran in the ratio 1: 1: 1/2 with less than 0.2% total impurities by HPLC.
Claims (7)
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- a)to)
- Condensación del compuesto de fórmula (IIa) con piperacina de fórmula (IIIa) en presencia de por lo menos un disolvente aprótico, seguido de purificación por cristalización en tolueno anhidro:Condensation of the compound of formula (IIa) with piperazine of formula (IIIa) in the presence of minus an aprotic solvent, followed by purification by crystallization in anhydrous toluene:
- b)b)
- Metilación de la N-desmetilolanzapina de fórmula (IV) con sulfato de dimetilo en presencia de tetrahidrofurano y agua como disolventes:Methylation N-desmethylolanzapine of formula (IV) with sulfate dimethyl in the presence of tetrahydrofuran and water as solvents:
- c)C)
- Obtención directa del solvato mixto de Olanzapina/agua/THF, yDirect obtaining of the mixed solvate of Olanzapine / water / THF, and
- d)d)
- Secado y obtención de la forma I de Olanzapina.Drying and obtaining form I of Olanzapine
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ES200600059A ES2292333B1 (en) | 2004-07-27 | 2006-01-05 | IMPROVEMENTS IN THE OBJECT OF THE MAIN PATENT N. 200401850, BY "MIXED SOLVATO OF OLANZAPINE, PROCEDURE FOR OBTAINING AND PROCEDURE FOR OBTAINING THE FORM I OF OLANZAPINE FROM THE SAME". |
AT06841525T ATE489390T1 (en) | 2006-01-05 | 2006-12-20 | METHOD FOR PRODUCING A MIXED OLANCEPINE SOLVATE |
JP2008548969A JP2009522319A (en) | 2006-01-05 | 2006-12-20 | Method for producing mixed solvate of olanzapine |
ES06841525T ES2356135T3 (en) | 2006-01-05 | 2006-12-20 | PROCEDURE FOR OBTAINING SOLVATO MIXTO DE OLANZAPINA. |
EP06841525A EP1968983B1 (en) | 2006-01-05 | 2006-12-20 | Method for preparing a mixed solvate of olanzapine |
PCT/EP2006/070028 WO2007077134A1 (en) | 2006-01-05 | 2006-12-20 | Method for preparing a mixed solvate of 0lanzapine |
PL06841525T PL1968983T3 (en) | 2006-01-05 | 2006-12-20 | Method for preparing a mixed solvate of olanzapine |
DE602006018527T DE602006018527D1 (en) | 2006-01-05 | 2006-12-20 | INSOLVATS |
PT06841525T PT1968983E (en) | 2006-01-05 | 2006-12-20 | Method for preparing a mixed solvate of olanzapine |
US12/160,004 US8129522B2 (en) | 2006-01-05 | 2006-12-20 | Method for preparing a mixed solvate of olanzapine |
KR1020087019172A KR20080107359A (en) | 2006-01-05 | 2006-12-20 | Method for preparing a mixed solvate of olanzapine |
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ES200600059A ES2292333B1 (en) | 2004-07-27 | 2006-01-05 | IMPROVEMENTS IN THE OBJECT OF THE MAIN PATENT N. 200401850, BY "MIXED SOLVATO OF OLANZAPINE, PROCEDURE FOR OBTAINING AND PROCEDURE FOR OBTAINING THE FORM I OF OLANZAPINE FROM THE SAME". |
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Title |
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D. O. CALLIGARO et al. "The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053)", Bioorg. & Med. Chem Lett., 1997, vol. 7, nº 1, páginas 25-30. * |
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