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Polymorphic Forms Of Dasatinib
Abstract: The present invention provides for the dasatinib- thymine co-crystal and dasatinib-adenine co-crystal. The present invention further provides dasatinib-butanediol solvate. The present invention further provides for crystalline dasatinib-(±) – 1, 2-Butane diol, crystalline dasatinib (R)-1, 2-Butanediol, crystalline dasatinib (S)-1, 2-Butanediol and crystalline dasatinib (±)-2, 3-Butanediol and processes for preparation thereof. The present invention also provides for a process for preparation of amorphous dasatinib using dasatinib- butanediol solvate. The present invention further provides for the preparation of anhydrous dasatinib. The present invention also provides for a process for preparation of dasatinib monohydrate from anhydrous dasatinib
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Notices, Deadlines & Correspondence
Patent Information
Application #
Filing Date
07 February 2020
Publication Number
10/2020
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
patent@ralegal.co.in
Parent Application
Applicants
BIOCON LIMITED
20th KM, Hosur Road, Electronic City, Karnataka,
Bangalore 560 100
Inventors
1. BHAT, Ramakrishna, Parameshwar
Kadekodi, Po: Dhareshwar, Ta: Kumta, Karnataka,
Dist: Uttara Kannada 581327
2. RAGHUNADHACHETTY, Jithendrababu
No.7-138/D/10, Aragonda, Thavanam Palli Mandal, Andhra Pradesh,
Chittoor District 517129
3. KALIAPPAN, Mariappan
Sri Sangili Matha Stores, Keelakuyilkudi Villakku, Theni Main Road, Nagamalai, Tamilnadu,
Madurai 625019
4. PALLE, Venkata, Raghavendracharyulu
194/A, Mythri Nagar, Madinaguda, Miyapur, Telangana,
Hyderabad 500049
5. REGALLA, VijayBhaskar, Reddy
H.No: 1-102-1, Chatrai (mandal & Post), Burugugudem Road, Andhra Pradesh,
Krishna District 521214
Specification
This application claims the benefit of priority of our Indian patent applications IN 201741024067 filed on July 07, 2017, IN 201741029965 filed on August 24, 2017, IN 201841001249 filed on January 1 1 , 2018 and IN 201841007613 filed on February 28, 2018 which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to polymorphic forms of dasatinib. In particular, the invention relates to co-crystals and solvates of dasatinib and processes for the preparation thereof.
i ·: !· :ί1 t
BACKGROUND AND PRIOR ART OF THE DISCLOSURE
SPRYCEL® (Dasatinib monohydrate) is a kinase inhibitor. The chemical name for Dasatinib monohydrate is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl] amino] -thiazolecarboxamide, monohydrate which is having molecular Formula C22H26CIN7O2S . H2O and molecular weight 506.02 (monohydrate) and its structural Formula is as follows,
SPRYCEL is a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, adults with chronic, accelerated or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
Dasatinib which was disclosed in PCT Publication No. WO 00/62778 and in U.S. Pat. No. 6,596,746. Dasatinib, chemically N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide.
Dasatinib is known to exist in various solid-state forms: a monohydrate, four anhydrous and unsolvated forms which are described in U.S. Pat. No. 7,491,725 B2, US2006/0004067A1, U.S. Pat. No. 7,973,045 B2 and WO2010/067374 and therein referred to as forms N-6, T1H1-7, B and I.
US. Patent No. 8,067,423 B2 discloses an amorphous form and solvates of IPA, THF, 2-MeTHF, 1,4-Dioxane, Pyridine, Toluene, MIBK, Mono acetone, 2-Butanol-DMSO, IPA-DMF, «-Propanol-DMF, «-Propanol, 2-Butanol-DMF, 2-Butanol, «-Butanol-DMSO, DMF-water, DMF, MIPK, Dimethoxy ethane, Cellosolve, Methyl acetate, Methanol, Ethyl acetate, 2-Pentanone, Dimethyl carbonate, Isopropyl acetate, Dichloromethane, Methyl formate, Z-Butanol, MEK, Monochloro benzene, PGME, Cyclopentyl methyl ether, MTBE, Amyl alcohol, Dimethyl carbonate, Ethylene glycol and glycerol.
PCT publication WO2007/035874 Al discloses crystalline form of a mono-hydrochloric acid salt of Dasatinib comprising Form CA-2, second crystalline form of a mono-hydrochloric acid salt of Dasatinib comprising Form HAC2-1, crystalline form of a di-hydrochloric acid salt of Dasatinib comprising Form H3-1, crystalline form of a monosulfuric acid salt of Dasatinib comprising Form SB-2, second crystalline form of a monosulfuric acid salt of Dasatinib comprising Form SD-2, crystalline form of a hemisulfuric acid salt of Dasatinib comprising Form SA-I, second crystalline form of a hemisulfuric acid salt of Dasatinib comprising Form SC-I, crystalline form of an acetic acid salt of Dasatinib comprising Form NMP-I, a crystalline form of a phosphoric acid salt of Dasatinib comprising Form SA-I, a crystalline form of a hydrobromic acid salt of Dasatinib comprising Form HI .5-1, a crystalline form of a fumaric acid salt of Dasatinib comprising Form TO-I, a crystalline form of a salicylic acid salt of Dasatinib comprising Form SS-2, a crystalline form of a tartaric acid salt of Dasatinib, a crystalline form of a methanesulfonic acid salt of Dasatinib comprising Form PG-I, a crystalline form of a maleic acid salt of Dasatinib comprising Form E-I, a crystalline form of a maleic acid salt of Dasatinib comprising Form H3-2 and a crystalline form of a / toluenesulfonic acid salt of Dasatinib comprising Form N-I.
Chinese patent CN102030745 discloses a crystalline solvate YE of Dasatinib and isopropyl ether.
Furthermore, Dasatinib solvates are known from US2006/0004067A, WO2010/062715, and in particular, patent application WO 2010/062715 includes the solvates of isosorbide dimethyl ether, NN'-dimethylethylene urea and NN'-dimethyl-NN'-propylene urea. Isosorbide dimethyl ether is used in cosmetic and pharmaceutical Formulations.
PCT publication WO2013/ 186726 A2 discloses various co-crystals with Dasatinib such as Dasatinib-Methyl-4-hydroxy-benzoate co-crystal (3: 1), Dasatinib-Nicotinamide co-crystal (3: 1), Dasatinib-Ethyl gallate co-crystal (3: 1), Dasatinib- Vanillin co-crystal (3: 1), Dasatinib-Methyl gallate co-crystal (3: 1) and Dasatinib-(lR,2S,5R)-(-)-Menthol co-crystal (3: 1).
This invention as disclosed in WO2013/186726 A2 suffers from following disadvantages.
Dasatinib and co-former molar ratio in co-crystal is the same as the molar ratio of input.
> The volume of the solvent used is huge (>75 vol) which may not be suitable for the scale up.
The isolation procedure involves the complete evaporation of the reaction mass under dry nitrogen flow which may not be suitable for scale up.
The input for the formation of Dasatinib co-crystals is Dasatinib monohydrate.
PCT publication WO2016/001025 Al discloses various co-crystals such as Dasatinib-(lR,2S,5R)-(-)-Menthol co-crystal (2: 1) and Dasatinib- Vanillin co-crystal (1 : 1).
This invention as disclosed in WO2016/001025 Al suffers from following disadvantages.
The process for the preparation of Dasatinib-(lR,2S,5R)-(-)-Menthol co-crystal (2: 1) involves heating to 120 °C under neat condition which may not be suitable for scale up.
The process for the preparation of Dasatinib-(lR,2S,5R)-(-)-Menthol co-crystal (2: 1) involves filtration at 90 °C which may not be suitable for scale up.
The process for the preparation of Dasatinib-Vanillin co-crystal (1 : 1) involves heating to 120 °C under neat condition which may not be suitable for scale up. The input for the formation of Dasatinib co-crystals is Dasatinib monohydrate.
PCT publication WO2017/002131 Al discloses Dasatinib- 1 ,2-Propanediol solvate and process for the preparation of Dasatinib- 1,2-Propanediol solvate.
This invention as disclosed in WO2017/002131 Al suffers from following disadvantages.
> Solvent required to prepare and get Dasatinib- 1,2-Propanediol solvate is huge as around 21 volume of solvent is used.
> Process involves wet solid isolation followed by 40 volume of solvent usage to get the pure solvate, which means an impure wet solid is used.
PCT Publication WO 20171/034615 Al also discloses Dasatinib- 1,2-Propanediol solvate and process for the preparation of Dasatinib- 1,2-Propanediol solvate.
Dasatinib- 1,2-Propanediol solvate formation requires 12 volumes of solvent, which again is not economical.
BHT is used in the solvate formation to prevent the formation of N-oxide related impurities.
SUMMARY OF THE INVENTION
Aspects of the present application provides co-crystals and solvates of dasatinib and safe, simpler & economical processes for the preparation thereof. Each step of the process disclosed herein are contemplated both in the context of the multistep sequences described and individually.
First aspect of the present invention is crystalline Dasatinib-Thymine co-crystal of Formula la.
Formula la
Second aspect of the present invention, the crystalline Dasatinib-Thymine co-crystal of Formula la is characterized by ¾ NMR which is in accordance with the Figure- 1.
Third aspect of the present invention, the crystalline Dasatinib-Thymine co-crystal of Formula la is further characterised by DSC having endotherm at around 260 °C and the DSC pattern in accordance with the Figure-2.
Fourth aspect of the present invention, the crystalline Dasatinib-Thymine co-crystal of Formula la is further characterised by PXRD having the main 2-theta values 6.83±0.2, 7.15±0.2, 12.15±0.2, 13.27±0.2, 13.64±0.2, 14.29±0.2, 16.31±0.2, 16.67±0.2, 17.30±0.2, 18.32±0.2, 18.78±0.2, 19.18±0.2, 20.56±0.2, 21.42±0.2, 21.90±0.2, 22.40±0.2, 23.94±0.2, 24.39±0.2, 26.76±0.2, 27.37±0.2, 27.70±0.2, 28.77±0.2, 29.28±0.2, 30.21±0.2, 31.39±0.2, 34.32±0.2, 36.14±0.2, 43.75±0.2 and the PXRD pattern in accordance with the Figure-3.
Fifth aspect of the present invention provides the process for the preparation of crystalline Dasatinib-Thymine co-crystal of Formula la.
Formula la
wherein the process does not involve the isolation of Dasatinib as intermediate.
Sixth aspect of the present invention provides the process for the preparation of crystalline Dasatinib-Thymine co-crystal of Formula la.
Formula la
comprising the following steps,
Treating the Dichloro intermediate of Formula II
Formula II
with 2-(piperazin- 1 -yl)ethan- 1 -ol of Formula III
Formula III
in a suitable organic solvent at a suitable temperature to obtain Formula I in situ
Formula ϊ
treating with Thymine in a suitable solvent/s at a suitable temperature,
to obtain crystalline Dasatinib-Thymine co-crystal of Formula la.
Further, the present invention relates to the process for the preparation for crystalline Dasatinib-Thymine co-crystal of Formula la comprising following steps,
a) Charging Dichloro intermediate of Formula II into a reactor
b) Adding 2-(piperazin-l-yl) ethan-l-ol of Formula III
c) Adding a suitable organic solvent
d) Heating the reaction mass to a suitable temperature
e) Maintaining the reaction mass at a suitable temperature
f) Cooling the reaction mass to a suitable temperature
g) Adding Thymine at a suitable temperature
h) Adding a suitable organic solvent to the reaction mass at a suitable temperature i) Heating the reaction mixture to a suitable temperature
j) Maintaining the reaction mixture at a suitable temperature
k) Cooling the reaction mixture to a suitable temperature
1) Stirring the reaction mixture at a suitable temperature
m) Adding water to the reaction mixture at a suitable temperature
n) Stirring the reaction mixture at a suitable temperature
o) Filtering the reaction mixture under vacuum
p) Washing the solid with a suitable organic solvent
q) Suck drying the wet solid under vacuum
r) Drying the wet solid at a suitable temperature under vacuum to obtain crystalline
Dasatinib-Thymine co-crystal of Formula la.
Further, according to step c), as described above, a suitable organic solvent is selected from the group consisting of solvents selected from NN-Dimethylacetamide, NN-Dimethylformamide and the like.
Further, according to step d) and step e), suitable temperature is selected from the range consisting of 40 to 80 °C, preferably 70 to 80 °C.
Further, in step f), step g) and step h), a suitable temperature is selected from the range consisting of 20 to 60 °C, preferably 20 to 40 °C, more preferably 20 to 30 °C.
Further, in step i) and step j), a suitable temperature is selected from the range consisting of 30 to 62 °C, preferably 50 to 62 °C.
Further, in step k), step 1), step m) and step n), a suitable temperature is selected from the range consisting of 10 to 40 °C, preferably 10 to 30 °C, more preferably 20 to 30 °C.
Further, in step h) and step p), a suitable organic solvent is selected from the group consisting of Alcoholic solvents selected from methanol, ethanol, propanol, «-butanol & isopropanol.
Further, in step r), a suitable temperature is selected from the range consisting of 30 to 65 °C, preferably 45 to 65 °C, more preferably 50 to 60 °C.
Seventh aspect of the present invention provides the process for the preparation of crystalline Dasatinib-Thymine co-crystal of Formula la.
Formula la
comprising the following steps,
Treating the Dichloro intermediate of Formula II
Formula II
with 2-(piperazin-l-yl)ethan-l-ol of Formula III
Formula III
in a suitable organic solvent at a suitable temperature and isolating Formula I as a wet solid using a suitable organic solvent at a suitable temperature.
i¾rssiwja I (wet mlM
Treating the wet solid of Formula I with Thymine
In a suitable solvent/s at a suitable temperature, to obtain crystalline Dasatinib-Thymine co-crystal of Formula la,
Formula la
Eighth aspect of the present invention relates to the alternate process for the preparation of a crystalline Dasatinib-Thymine co-crystal of Formula la, comprising the following steps,
Treating the Dichloro intermediate of Formula II
Formula II
with 2-(piperazin-l-yl)ethan-l-ol of Formula III
Formula III
and Thymine,
in a suitable solvent at a suitable temperature, to obtain a crystalline Dasatinib-Thymine co-crystal of Formula la,
Formula la
Further, the present invention relates to the alternate process for the preparation of crystalline Dasatinib-Thymine co-crystal of Formula la, comprising the following steps,
a) charging Dichloro intermediate of Formula II into a reactor
b) adding 2-(piperazin- l -yl)ethan- l-ol of Formula III
c) adding Thymine at a suitable temperature
d) adding a suitable organic solvent
e) heating I the reaction mass to a suitable temperature
*) maintaining the reaction mass at a suitable temperature
g) adding a suitable organic solvent at a suitable temperature
h) maintaining the reaction mass at a suitable temperature
i) cooling I the reaction mass to a suitable temperature
j) stirring I the reaction mixture at a suitable temperature
k) filtering the reaction mixture under vacuum
1) washing the solid with a suitable organic solvent
m) suck drying the wet solid under vacuum
n) drying the wet solid at a suitable temperature under vacuum to obtain a
crystalline Dasatinib-Thymine co-crystal of Formula la
Further, in step d), step g) and step 1), a suitable organic solvent is selected from the group consisting of alcoholic solvents, preferably Methanol.
Further, in step e), step f), step g) and step h), a suitable temperature is selected from the range consisting of 30 to 69 °C, preferably 50 to 69°C, more preferably 65 to 69 °C.
Further, in step i) and step j), a suitable temperature is selected from the range consisting of 10 to 40 °C, preferably 10 to 30 °C, more preferably 20 to 30 °C.
Further, in step n), a suitable temperature is selected from the range consisting of 30 to 65 °C, preferably 45 to 65 °C, more preferably 50 to 60 °C
Ninth aspect of the present invention is crystalline Dasatinib-Adenine co-crystal of Formula lb.
Formula lb
Tenth aspect of the present invention, the crystalline Dasatinib-Adenine co-crystal of Formula lb is characterized by ¾ NMR which is in accordance with the Figure-4.
Eleventh aspect of the present invention, the crystalline Dasatinib-Adenine co-crystal of Formula lb is further characterized by DSC having endotherm at around 274.4 °C and the DSC pattern in accordance with the Figure-5.
Twelfth aspect of the present invention, the crystalline Dasatinib-Adenine co-crystal of Formula lb is further characterized by PXRD having the main 2-theta values 6.91±0.2, 7.25±0.2, 12.37±0.2, 13.25±0.2, 13.78±0.2, 14.47±0.2, 15.99±0.2, 16.57±0.2, 16.74±0.2,
17.21±0.2, 18.53±0.2, 19.25±0.2, 20.99±0.2, 21.89±0.2, 22.07±0.2, 22.51±0.2, 23.12±0.2, 23.82±0.2, 24.31±0.2, 24.82±0.2, 25.29±0.2, 27.99±0.2, 32.22±0.2, 38.72±0.2. and the PXRD pattern in accordance with the Figure-6.
Thirteenth aspect of the present invention provides the process for the preparation of crystalline Dasatinib-Adenine co-crystal of Formula lb.
Formula lb
wherein the process does not involve the isolation of Dasatinib.
Fourteenth aspect of the present invention provides the process for the preparation of crystalline Dasatinib-Adenine co-crystal of Formula lb.
Formula lb
Comprising the following steps,
Treating the Dichloro intermediate of Formula II
Formula II
with 2-(piperazin-l-yl)ethan-l-ol of Formula III
Formula III
in a suitable organic solvent at a suitable temperature to obtain Formula I in situ
Formula I (in-situ)
Treating the with Adenine
In a suitable solvent/s at a suitable temperature, to obtain crystalline Dasatinib- Adenine co-crystal of Formula lb,
Formula lb
Further, the present invention relates to the process for the preparation for crystalline Dasatinib- Adenine co-crystal of Formula lb comprising following steps,
a) Charging Dichloro intermediate of Formula II into a reactor
b) Adding 2-(piperazin-l-yl) ethan-l-ol of Formula III
c) Adding a suitable organic solvent
d) Heating the reaction mass to a suitable temperature
e) Maintaining the reaction mass at a suitable temperature
f) Cooling the reaction mass to a suitable temperature
g) Adding Adenine at a suitable temperature
h) Adding a suitable organic solvent to the reaction mass at a suitable temperature i) Heating the reaction mixture to a suitable temperature
j) Maintaining the reaction mixture at a suitable temperature
k) Cooling the reaction mixture to a suitable temperature
1) Stirring the reaction mixture at a suitable temperature
m) Adding water to the reaction mixture at a suitable temperature
n) Stirring the reaction mixture at a suitable temperature
o) Filtering the reaction mixture under vacuum
p) Washing the solid with a suitable organic solvent
q) Suck drying the wet solid under vacuum
r) Drying the wet solid at a suitable temperature under vacuum to obtain crystalline Dasatinib- Adenine co-crystal of Formula lb.
Further, according to step c), as described above, a suitable organic solvent is selected from the group consisting of solvents selected from NN-Dimethylacetamide, NN-Dimethylformamide and the like.
Further, according to step d) and step e), suitable temperature is selected from the range consisting of 40 to 80 °C, preferably 70 to 80 °C.
Further, in step f), step g) and step h), a suitable temperature is selected from the range consisting of 20 to 60 °C, preferably 20 to 40 °C, more preferably 20 to 30 °C.
Further, in step i) and step j), a suitable temperature is selected from the range consisting of 30 to 62 °C, preferably 50 to 62 °C.
Further, in step k), step 1), step m) and step n), a suitable temperature is selected from the range consisting of 10 to 40 °C, preferably, 10 to 30 °C, more preferably 20 to 30 °C.
Further, in step h) and step p), a suitable organic solvent is selected from the group consisting of Alcoholic solvents selected from methanol, ethanol, propanol, «-butanol & isopropanol.
Further, in step r), a suitable temperature is selected from the range consisting of 30 to 65 °C, preferably 45 to 65 °C, more preferably 50 to 60 °C.
Fifteenth aspect of the present invention relates to the alternate process for the preparation of a crystalline Dasatinib- Adenine co-crystal Formula lb, comprising the following steps,
Treating the Dichloro intermediate of Formula II
Formula II
with 2-(piperazin-l-yl)ethan-l-ol of Formula III
Formula III
a suitable organic solvent at a suitable temperature to obtain Formula I (-
Formula I (wet)
treating the wet Formula I with Adenine
in a suitable solvent/s at suitable temperature, to obtain crystalline Dasatinib- Adenine co-crystal of Formula lb,
Further, the present invention relates to the alternate process for the preparation of a crystalline Dasatinib-Adenine co-crystal comprising the following steps,
a) charging Dichloro intermediate of Formula II into a reactor
b) adding 2-(piperazin- 1 -yl)ethan- 1 -ol of Formula III
c) adding a suitable organic solvent
d) heating the reaction mass to a suitable temperature
e) maintaining the reaction mass at a suitable temperature
f) cooling the reaction mass to a suitable temperature
g) adding a suitable organic solvent at a suitable temperature
h) stirring the reaction mixture at a suitable temperature
i) filtering the reaction mixture under vacuum
j) washing the solid with a suitable organic solvent
k) suck drying the wet solid under vacuum
1) transferring the wet solid into a reactor
m) adding Adenine
n) adding a suitable organic solvent
o) heating the reaction mixture to a suitable temperature
p) maintaining the reaction mixture at a suitable temperature
q) cooling the reaction mixture to a suitable temperature
r) stirring the reaction mixture at a suitable temperature
s) adding water to the reaction mixture at a suitable temperature
t) stirring the reaction mixture at a suitable temperature
u) filtering the reaction mixture under vacuum
v) washing the solid with a suitable organic solvent
w) suck drying the wet solid under vacuum
x) drying the wet solid at a suitable temperature under vacuum to obtain crystalline Dasatinib-Adenine co-crystal of Formula lb
Further, in step c), a suitable organic solvent selected from the group consisting of Amide solvents, preferably N,N-Dimethylacetamide.
Further, in step d) and step e), a suitable temperature selected from the range consisting of 40 to 80 °C, preferably 70 to 80 °C, more preferably 73 to 77 °C.
Further, in step f), step g), step h), step q), step r), step s) and step t) a suitable temperature selected from the range consisting of 20 to 60 °C, preferably 20 to 40 °C, more preferably 20 to 30 °C.
Further, in step o) and step p), a suitable temperature selected from the range consisting of 30 to 62 °C, preferably 50 to 62 °C, more preferably 58 to 62 °C.
Further, in step g), step j), step n) and step v), a suitable organic solvent selected from the group consisting of Alcoholic solvents, preferably Methanol.
Further, in step x), a suitable temperature selected from the range consisting of 30 to 65 °C, preferably 45 to 65 °C, more preferably 50 to 60 °C.
Sixteenth aspect of the present invention relates to the alternate process for the preparation of a crystalline Dasatinib-Adenine co-crystal Formula lb, comprising the following steps,
Treating the Dichloro intermediate of Formula II
Formula II
with 2-(piperazin-l-yl)ethan-l-ol of Formula III
Formula III
and Adenine,
in a suitable solvent at suitable temperature, to obtain crystalline Dasatinib-Adenine co-crystal of Formula lb,
Further, the present invention relates to the alternate process for the preparation of crystalline Dasatinib-Adenine co-crystal of Formula lb, further comprising the following steps,
a) charging Dichloro intermediate of Formula II into a reactor
b) adding 2-(piperazin- 1 -yl)ethan- 1 -ol of Formula III
c) adding Adenine
d) adding a suitable organic solvent
e) heating the reaction mass to a suitable temperature
f) maintaining the reaction mass at a suitable temperature
g) adding a suitable organic solvent at a suitable temperature
h) maintaining the reaction mass at a suitable temperature
i) cooling the reaction mass to a suitable temperature
j) stirring the reaction mixture at a suitable temperature
k) filtering the reaction mixture under vacuum
1) washing the solid with a suitable organic solvent
m) suck drying the wet solid under vacuum
n) drying the wet solid at a suitable temperature under vacuum to obtain crystalline
Dasatinib- Adenine co-crystal of Formula lb
Further, in step d), step g) and step 1), a suitable organic solvent is selected from the group consisting of alcoholic solvents, preferably Methanol.
Further, in step e), step f), step g) and step h), a suitable temperature is selected from the range consisting of 30 to 62 °C, preferably 50 to 62 °C, more preferably 58 to 62 °C.
Further, in step i) and step j), a suitable temperature is selected from the range consisting of 10 to 40 °C, preferably 10 to 30 °C, more preferably 20 to 30 °C.
Further, in step n), a suitable temperature is selected from the range consisting of 30 to 65 °C, preferably 45 to 65 °C, more preferably 50 to 60 °C
Seventeenth aspect of the present invention provides Dasatinib-alkanediol solvates.
Eighteenth aspect of the present invention provides crystalline Dasatinib-alkanediol solvate.
Nineteenth aspect of the present invention provides alkanediol solvent chosen from linear alkyl chain having carbon length C4-C7.
Twentieth aspect of the present invention provides alkanediol solvent selected preferably from alkyl chain having carbon length C4-C7 wherein the diols are vicinal.
Twenty first aspect of the present invention provides alkanediol solvent selected preferably from alkyl chain having carbon length C4-C7 wherein, the diols can be racemic and/or absolute stereoisomers.
Twenty second aspect of the present invention provides alkanediol solvent was selected preferably from alkyl chain having carbon length C4-C7 and most preferably, alkyl chain having carbon length C4 wherein, the diols can be racemic and/or absolute stereoisomers.
Twenty third aspect of the present invention provides Dasatinib-butanediol solvate.
Twenty fourth aspect of the present invention provides crystalline Dasatinib-butanediol solvate.
Twenty fifth aspect of the present invention provides a process for the preparation of a crystalline Dasatinib-Butanediol solvate of Formula Ic or Formula Id or Formula Ie or Formula Ig, comprising the following steps,
Treating the Dichloro intermediate of Formula II
Formula II
with 2-(piperazin-l-yl)ethan-l-ol of Formula III
Formula III
in the presence of a suitable Butanediol and a suitable organic base at suitable temperature, to obtain corresponding a crystalline Dasatinib-Butanediol solvate of Formula Ic or Formula Id or Formula Ie or Formula Ig
Formnia Ic («r) M (or) Ie (tx) Ig
Wherein, Butanediol = (±) - 1,2-Butane diol or (R)- 1,2 -Butanediol or (5)-l,2-Butanediol or (±) -2,3 -Butanediol
Formula Ic = Dasatinib-(±) - 1,2-Butanediol
Formula Id = Dasatinib-( ?)- 1,2-Butanediol solvate
Formula Ie = Dasatinib-(5)-l,2-Butanediol solvate
Formula Ig = Dasatinib-(±) - 2,3 -Butanediol solvate
Further, the present invention relates to the process for the preparation for crystalline Dasatinib-butane diol solvate of Formula Ic or Formula Id or Formula Ie or Formula Ig comprising following steps,
a) Charging Dichloro intermediate of Formula II into a reactor
b) Adding 2-(piperazin- 1 -yl)ethan- 1 -ol of Formula III
c) Optionally a suitable organic solvent and adding a suitable butanediol d) Optionally adding a suitable organic base
e) Heating the reaction mass to a suitable temperature
f) Maintaining the reaction mass at a suitable temperature
g) Cooling the reaction mass to a suitable temperature
h) Stirring the reaction mixture at a suitable temperature
i) Filtering the reaction mixture under vacuum
j) Suck drying the wet solid under vacuum
k) Optionally washing with wet solid with a suitable organic solvent
1) Optionally drying the wet solid at a suitable temperature under vacuum to obtain corresponding crystalline Dasatinib-butanediol solvate of Formula Ic or Formula
Id or Formula Ie or Formula Ig.
Further according to step c), a suitable organic solvent selected from the group consisting of Amide solvents, preferably N,N-Dimethylacetamide.
Further according to step c), the suitable butanediol is selected from the group of vicinal Butanediol, preferably isomer and isomeric mixture of 1 ,2-butane diols or 2,3-butanediol, more preferably (±)- l,2-butanediol or (R)- l,2-butanediol or (S)- l,2-butanediol or (±)-2,3-butanediol
Further according to step e) and step f), a suitable temperature is selected from the range consisting of 90 to 120 °C, preferably 100 to 120 °C, more preferably 1 10 to 120 °C.
Further according to step g) and step h), a suitable temperature is selected from the range consisting of 30 to 65 °C, preferably 50 to 65 °C, more preferably 55 to 65 °C.
Further according to step k), a suitable organic solvent is selected from the group consisting of Ether solvents, Hydrocarbon solvents preferably, hydrocarbon solvent, more preferably Toluene.
Further according to step 1), a suitable temperature is selected from the range consisting of 20 to 45 °C, preferably 30 to 45 °C, more preferably 35 to 45 °C.
Twenty sixth aspect of the present invention provides an alternate process for the preparation of crystalline Dasatinib-Butanediol solvate of Formula Ic or Formula Id or Formula Ie or Formula Ig comprising the following steps,
Treating the Dichloro intermediate of Formula II
Formula II
with 2-(piperazin- l -yl)ethan- l -ol of Formula III
Formula III
in the presence of suitable organic solvent and a suitable organic base at a suitable temperature to obtain Formula I (In-situ)
Formula I (in-situ)
treating the mass containing the Formula I with a suitable Butanediol at a suitable temperature, to obtain crystalline Dasatinib-Butanediol solvate of Formula Ic or Formula Id or Formula Ie or Formula Ig,
Formala Ic (erj M (OF) le ■ A U'nSiSi
General procedure: To a glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II, Formula III and a suitable first organic solvent and the mass was heated to suitable temperature. The resulting reaction mass (containing Formula I) was cooled and a co-former selected from Thymine or Adenine was added to the reaction mass. A suitable second organic solvent was added to the reaction mass at constant rate under stirring. The mass was heated to a suitable temperature and the resulting suspension was maintained at the same temperature under stirring. The mass was cooled and Water was added to the reaction mass at a constant rate under stirring. The reaction mass was maintained at 25±5 °C. The mass was filtered and the solid was washed, suck dried and dried under vacuum to obtain Dasatinib- co-crystal of Formula B as a crystalline solid.
Example la: Preparation of Dasatinib-Thymine co-crystal of Formula la from Formula II (using DMAc and Methanol as the solvents) One-pot synthesis
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To a 100 mL glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II (2.00 g, 0.0051 mol, 1.00 equiv.), Formula III (6.00 mL, 3.00 vol) and N,N- dimethyl acetamide (2.00 mL, 1.00 vol) and the mass was heated to 75±2 °C. The reaction mass was maintained at 75±2 °C under stirring. The resulting reaction mass (containing Formula I) was cooled to 25±5 °C and Thymine (0.96 g, 0.007 mol, 1.50 equiv.) was added to the reaction mass at 25±5 °C under stirring. Methanol (60.0 mL, 30.0 vol) was added to the reaction mass at constant rate at 25±5 °C under stirring. The mass was heated to 60±2 °C and the resulting suspension was maintained at the same temperature under stirring. The mass was cooled to 25±5 °C and maintained at the same temperature. Water (15 mL, 7.50 vol) was added to the reaction mass at a constant rate under stirring. The reaction mass was maintained at 25±5 °C. The mass was filtered and the solid was washed with Methanol (10.0 mL, 5.00 vol), suck dried and dried at 50±5 °C under vacuum to obtain Dasatinib-Thymine co-crystal of Formula la as a crystalline solid.
Example-lb: Preparation of Dasatinib-Adenine co-crystal of Formula lb from Formula II (using DMAc and Methanol as the solvents) - One-pot synthesis
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To a 500 mL glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II (10.0 g, 0.0254 mol, 1.00 equiv.), Formula III (30.0 mL, 3.00 vol) and N, N-dimethyl acetamide (10.0 mL, 1.00 vol) and the mass was heated to 75±5 °C. The reaction mass was maintained at 75±5 °C under stirring. The reaction mass was cooled to 25±5 °C and Adenine (5.14 g, 0.038 mol, 1.50 equiv.) was added to the reaction mass at 25±5 °C under stirring. Methanol (300 mL, 30.0 vol) was added to the reaction mass at constant rate at 25±5 °C under stirring. The mass was heated to 60±2 °C and the resulting suspension was maintained at the same temperature under stirring. The mass was cooled to 25±5 °C and maintained at the same temperature. Water (130 mL, 13.0 vol) was added to the reaction mass at a constant rate under stirring. The reaction mass was maintained at 25±5 °C. The mass was filtered and the solid was washed with Methanol (70.0 mL, 7.00 vol), suck dried and dried at 50±5 °C under vacuum to obtain Dasatinib-Adenine co-crystal of Formula lb as a crystalline solid.
Example-lc:
To a 3L glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II (50.0 g, 0.127 mol, 1.00 equiv.), Formula III (150 mL, 3.00 vol) and N,N-dimethyl acetamide (50.0 mL, 1.00 vol) and the mass was heated to 75±5 °C. The reaction mass was maintained at 75±5 °C under stirring. The reaction mass was cooled to 25±5 °C and Adenine (25.7 g, 0.190 mol, 1.50 equiv.) was added to the reaction mass at 25±5 °C under stirring. Methanol (1500 mL, 30.0 vol) was added to the reaction mass at constant rate at 25±5 °C under stirring. The mass was heated to 60±2 °C and the resulting suspension was maintained at the same temperature under stirring. The mass was cooled to 25±5 °C and maintained at the same temperature. Water (650 mL, 13.0 vol) was added to the reaction mass at a constant rate under stirring. The reaction mass was maintained at 25±5 °C. The mass was filtered and the solid was washed with Methanol (350 mL, 7.00 vol), suck dried and dried at 50±5 °C under vacuum to obtain Dasatinib-Adenine co-crystal of Formula lb as a crystalline solid.
Scheme-2: Preparation of Dasatinib-co-crystal of Formula B from Formula II (using wet Dasatinib)
To a glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II, Formula III and a suitable first organic solvent and the mass was heated to a suitable temperature. The reaction mass was cooled and a suitable second organic silvent was added at a constant rate under stirring. The mass was filtered. Formula I (wet), was charged into a glass vessel equipped with a stirrer, condenser and a thermometer probe. Co-former selected from Thymine or adenine was added. The mass was heated to a suitable tmperature and the resulting suspension was maintained at the same temperature under stirring. The mass was cooled and Water was added to the reaction mass at a constant rate under stirring. The mass was filtered and the solid was washed with Methanol, suck dried and dried under vacuum to obtain Dasatinib- co-crystal of Formula B as a crystalline solid.
Example 2a: Preparation of Dasatinib-Thymine co-crystal of Formula la from Formula II (using wet Dasatinib)
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To a 100 mL glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II (2.00 g, 0.0051 mol, 1.00 equiv.), Formula III (6.00 mL, 3.00 vol) and NN- dimethyl acetamide (2.00 mL, 1.00 vol) and the mass was heated to 75±2 °C. The reaction mass was maintained at 75±2 °C under stirring. The reaction mass was cooled to 25±5 °C and Methanol (50.0 mL, 25.0 vol) was added at a constant rate under stirring. The resulting slurry was stirred at 25±5 °C. The mass was filtered and the solid was washed with Methanol (10.0 mL, 5.00 vol). Formula I (wet) (2.00 g, 0.0041 mol), was charged into a 100 mL glass vessel equipped with a stirrer, condenser and a thermometer probe. Thymine (0.77 g, 0.006 mol, 1.50 equiv.) and Methanol (60.0 mL, 30.0 vol) were added at 25±5 °C. The mass was heated to 60±2 °C and the resulting suspension was maintained at the same temperature under stirring. The mass was cooled to 25±5 °C and maintained at the same temperature. Water (15 mL, 7.50 vol) was added to the reaction mass at a constant rate under stirring. The reaction mass was maintained at 25±5 °C. The mass was filtered and the solid was washed with Methanol (10.0 mL, 5.00 vol), suck dried and dried at 50±5 °C under vacuum to obtain Dasatinib-Thymine co-crystal of Formula la as a crystalline solid.
Scheme-3: Preparation of Dasatinib-co-crystal of Formula B from Formula II (using Methanol as the solvent) One-pot synthesis
To a glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II, Formula III, a suitable coformer selected from Thymine or adenine and Methanol. The reaction mass was heated to a suitable temperature. The mass was cooled and filtered and the solid was washed with Methanol, suck dried and dried under vacuum to obtain Dasatinib- co-crystal of Formula B as a crystalline solid.
Example 3a: Preparation of Dasatinib-Thymine co-crystal of Formula la from Formula II (using Methanol as the solvent) One-pot synthesis
To a 1 L glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II (50.0 g, 0.127 mol, 1.00 equiv.), Formula III (200 mL, 4.00 vol), Thymine (15.99 g, 0.127 mol, 1.00 equiv.) and Methanol (300 mL, 6.00 vol). The reaction mass was heated to 67±2 °C. The reaction mass was maintained at 65±2 °C under stirring. After completion of the reaction, Methanol (200 mL, 4.00 vol) was added to the reaction mass at constant rate. The reaction mass was maintained at the same temperature under stirring. The mass was cooled to 25±5 °C and maintained at the same temperature. The mass was filtered and the solid was washed with Methanol (250 mL, 5.00 vol), suck dried and dried at 50±5 °C under vacuum to obtain Dasatinib-Thymine co-crystal of Formula la as a crystalline solid (57.5 g, 91.38% w.r.t Formula II, 99.91% AUC, N-Oxide impurity: < 0.15% AUC, N-Deshydroxyethyl impurity: < 0.15% AUC).
Scheme-4: Preparation of Dasatinib-butane diol solvates of Formula Ic, Id, Ie & Ig from Anhydrous Dasatinib (using Butanediol as the solvent) - One-pot synthesis
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FsHnsls l = Das atia.i -¾-=}-l, 2-¾atass*dM iefcaie
ί orffiy.ia ki = BasstiaiMSJ-I, "i-B¾ta¾ idislia * ate
To a glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula I, and Butanediol and the mass was heated to 1 15±5 °C. The reaction mass was maintained at 115±5 °C under stirring. The reaction mass was cooled to 60±5 °C and maintained at the same temperature. The mass was filtered and dried under vacuum to obtain Dasatinib-Butanediol solvate of Formula Ic or Id or Ie or Ig as a crystalline solid.
Example 4a: Preparation of crystalline Dasatinib-(±)-l,2-Butanediol solvate of Formula Ic from Anhydrous Dasatinib
To a 50 mL glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula I (1.00 g, 0.002 mol), and (±)-l ,2-Butanediol (10.0 mL, 10.0 vol) and the mass was heated to 1 15±5 °C. The reaction mass was maintained at 1 15±5 °C under stirring. The reaction mass was cooled to 60±5 °C and maintained at the same temperature. The mass was filtered and dried under vacuum to obtain Dasatinib-(±)-l,2-Butanediol solvate of Formula Ic as a crystalline solid.
Example 4b: Preparation of crystalline Dasatinib-(i?)-l, 2-Butanediol solvate of Formula Id from Anhydrous Dasatinib
To a 50 mL glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula I (1.00 g, 0.002 mol), and (R)- l, 2-Butanediol (10.0 mL, 10.0 vol) and the mass was heated to 1 15±5 °C. The reaction mass was maintained at 1 15±5 °C under stirring. The reaction mass was cooled to 60±5 °C and maintained at the same temperature. The mass was filtered and dried under vacuum to obtain Dasatinib-(R)- 1 , 2-Butanediol solvate of Formula Id as a crystalline solid.
Example 4c: Preparation of crystalline Dasatinib-(±)-2,3-Butanediol solvate of Formula Ig from Anhydrous Dasatinib
To a 50 mL glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula I (2.00 g, 0.0021 mole, 1.00 equiv.), and (±)-2,3-butanediol (15.0 mL, 15.0 vol) and the mass was heated to 1 15±5 °C. The reaction mass was maintained at 1 15±5 °C under stirring for 1 to 2 h (Clear solution). The reaction mass was cooled to 60±5 °C and maintained at the same temperature for 3 to 4 h. The mass was filtered and dried under vacuum for 10- 15 h to obtain Dasatinib-2, 3 -butanediol solvate of Formula Ig as a crystalline solid.
Scheme-5: Preparation of Dasatinib-butanediol solvates of Formula Ic, Id, Ie and Ig from Formula II (using DIPEA and Butanediol as the solvent) - One-pot synthesis
To a glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula-II, Formula-Ill, N,N-Diisopropyl ethyl amine and Butanediol was added and the mass was heated to a suitable temperature. The mass was cooled and filtered. The solid was washed, suck dried under vacuum to obtain Dasatinib-Butanediol solvate of Formula-Ic or Id or Ie or Ig as a crystalline solid.
Example 5a: Preparation of crystalline Dasatinib-(5)-l,2-Butanediol solvate of Formula Ie from Formula II (using DIPEA and Butanediol as the solvent) - One-pot synthesis:
To a 5L glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula-II (300.0 g, 0.7608 mol.), Formula-Ill (300 mL, 1.00 vol), NJf-Diisopropyl ethyl amine (688 g, 5.32 mol) and (S)- l,2-Butanediol (1500 mL, 5.00 vol) was added and the mass was heated to 1 15±5 °C. The reaction mass was maintained at 1 15±5 °C under stirring for 13 to 15h. The mass was cooled to 60±5 °C and maintained at the same temperature for 1 to 2h. The mass was filtered and the solid was washed with Diisopropyl ether (1500 mL, 5.00 vol), suck dried under vacuum for l -2h and material was dried at 40 °C under vacuum for 12- 15h to obtain Dasatinib-(S)- 1 ,2-Butanediol solvate of Formula-Ie as a crystalline solid.
Scheme-6: Preparation of Dasatinib-Butanediol solvates of Formula Ic, Id, Ie and Ig from Formula II (using Butanediol and DMAc as the solvents) - One-pot synthesis
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To a glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II, Formula III, NN-dimethyl acetamide and Butanediol and the mass was heated to a suitable temperature. The reaction mass was cooled and Butanediol was added. The mass was heated again to a suitable temperature. The mass was cooled and filtered and the solid and dried under vacuum obtain Dasatinib-Butanediol solvate of Formula Ic or Id or Ie or Ig as a crystalline solid.
Example 6a: Preparation of crystalline Dasatinib-(±)-l,2-Butanediol solvate of Formula Ic from Formula II (One-pot synthesis)
To a 100 mL glass vessel equipped with a stirrer, condenser and a thermometer probe were added the Formula II (5.00 g, 0.0127 mol), Formula III (5.00 mL, 1.00 vol), NN-dimethyl acetamide (2.50 mL, 0.50 vol) and (±)-l ,2-Butanediol (5.00 mL, 1.00 vol) and the mass was heated to 1 15±5 °C. The reaction mass was maintained at 1 15±5 °C under stirring. The reaction mass was cooled to 25±5 °C and (±)- l,2-Butanediol (20.0 mL, 4.00 vol) was added. The mass was heated to 1 15±5 °C and the resulting mass was maintained at the same temperature under stirring. The mass was cooled to 60±5 °C and maintained at the same temperature. The mass was filtered and the solid was washed with (±)- l ,2-Butanediol (5.00 mL, 1.00 vol), dried under vacuum obtain Dasatinib-(±)- l,2-Butanediol solvate of Formula Ic as a crystalline solid.
Scheme-7: Preparation of Dasatinib-butanediol solvates of Formula Ic, Id, Ie and Ig from Formula II via in-situ Formula I (using DMAc and butane diols as the solvents) ne-pot synthesis)
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| 1 | 202017005477.pdf | 2020-02-07 |
| 2 | 202017005477-TRANSLATIOIN OF PRIOIRTY DOCUMENTS ETC. [07-02-2020(online)].pdf | 2020-02-07 |
| 3 | 202017005477-STATEMENT OF UNDERTAKING (FORM 3) [07-02-2020(online)].pdf | 2020-02-07 |
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| 9 | 202017005477-FORM-26 [20-02-2020(online)].pdf | 2020-02-20 |
| 10 | 202017005477-FORM 3 [21-05-2021(online)].pdf | 2021-05-21 |
| 11 | 202017005477-FORM 18 [02-07-2021(online)].pdf | 2021-07-02 |
| 12 | abstract.jpg | 2021-10-19 |
| 13 | 202017005477-Power of Attorney-250220.pdf | 2021-10-19 |
| 14 | 202017005477-OTHERS-250220.pdf | 2021-10-19 |
| 15 | 202017005477-FER.pdf | 2021-10-19 |
| 16 | 202017005477-Correspondence-250220.pdf | 2021-10-19 |
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