WO2015107533A1 - A process for preparation of 1h-purine-2,6-dione, 8-[(3r)-3-amino-1-piperidinyl]-7 (2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2quinazolinyl) methyl] and its pharmaceutically acceptable salts - Google Patents
A process for preparation of 1h-purine-2,6-dione, 8-[(3r)-3-amino-1-piperidinyl]-7 (2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2quinazolinyl) methyl] and its pharmaceutically acceptable salts Download PDFInfo
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- WO2015107533A1 WO2015107533A1 PCT/IN2014/000567 IN2014000567W WO2015107533A1 WO 2015107533 A1 WO2015107533 A1 WO 2015107533A1 IN 2014000567 W IN2014000567 W IN 2014000567W WO 2015107533 A1 WO2015107533 A1 WO 2015107533A1
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- Prior art keywords
- methyl
- dione
- purine
- dihydro
- amino
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- -1 4-methyl-2quinazolinyl Chemical group 0.000 title claims abstract description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 52
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- FAIAJSOSTNJZCI-UHFFFAOYSA-N purine-2,6-dione Chemical compound O=C1NC(=O)C2=NC=NC2=N1 FAIAJSOSTNJZCI-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 150000003839 salts Chemical class 0.000 title description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- 150000003892 tartrate salts Chemical class 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- RCZJXCXNYGHNSR-UHFFFAOYSA-N 8-bromo-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione Chemical compound C1=CC=CC2=NC(CN3C(=O)N(C)C=4N=C(Br)N(C=4C3=O)CC#CC)=NC(C)=C21 RCZJXCXNYGHNSR-UHFFFAOYSA-N 0.000 claims description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 229960001270 d- tartaric acid Drugs 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- GGPNYXIOFZLNKW-ZJIMSODOSA-N (3r)-piperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CCCNC1 GGPNYXIOFZLNKW-ZJIMSODOSA-N 0.000 claims description 5
- 239000000010 aprotic solvent Substances 0.000 claims description 5
- 239000011928 denatured alcohol Substances 0.000 claims description 5
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000003759 ester based solvent Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000012267 brine Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- PEUGKEHLRUVPAN-RXMQYKEDSA-N (3r)-piperidin-3-amine Chemical compound N[C@@H]1CCCNC1 PEUGKEHLRUVPAN-RXMQYKEDSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZFQWSCZYQLPFFZ-UHFFFAOYSA-N 8-bromo-3,7-dihydropurine-2,6-dione Chemical compound N1C(=O)NC(=O)C2=C1N=C(Br)N2 ZFQWSCZYQLPFFZ-UHFFFAOYSA-N 0.000 description 1
- WUOQXNWMYLFAHT-UHFFFAOYSA-N CC(C)(C)OC(NC1CNCCC1)=O Chemical compound CC(C)(C)OC(NC1CNCCC1)=O WUOQXNWMYLFAHT-UHFFFAOYSA-N 0.000 description 1
- VFWDPMGOXULTSH-YSKBWJPDSA-N CC(C)(C)OC(N[C@H](CCC1)CN1c1nc(N(C)C(N(CC(N=C(C)/C2=C/C)=N/C2=C/C)C2=O)=O)c2[n]1CC#CC)=O Chemical compound CC(C)(C)OC(N[C@H](CCC1)CN1c1nc(N(C)C(N(CC(N=C(C)/C2=C/C)=N/C2=C/C)C2=O)=O)c2[n]1CC#CC)=O VFWDPMGOXULTSH-YSKBWJPDSA-N 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BXHWWPNRUOHACS-MRVPVSSYSA-N tert-butyl (3r)-1-aminopiperidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1 BXHWWPNRUOHACS-MRVPVSSYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention discloses the process for preparation of 1H-Purine-2,6-dione, 8- [(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl- 2quinazolinyl) methyl].
Description
"A process for preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7- (2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyI) methyl] and its pharmaceutically acceptable salts"
FIELD OF INVENTION:
The present invention relates to process for preparation of lH-Purine-2,6-dione, 8-[(3R)- 3 -amino- 1 -piperidiriyl] -7-(2-butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 - [(4-methyl- 2quinazolinyl) methyl] (Formula- 1) with high purity and high yield.
BACKGROUND OF INVENTION:
DPP-IV inhibitor is described chemically as 1 H-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] (Forumula-1). lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7- dihydro-3 -methyl- l-[(4-methyl-2quinazolinyl) methyl] is used for the treatment of type- II diabetes mellitus.
Formula-1
US 7,407,955 describes synthesis of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] and its pharmaceutically tolerable salts which involves condensation reaction of 8-bromo xanthine with 3-(R)-BOC amino piperidine resulting in protected lH-Purine-2,6-dione, 8- [(3R)-3-amino- 1 -piperidinyl]-7-(2-butyn- 1 -yl)-3 ,7-dihydro-3-methyl- 1 -[(4-methyl- 2quinazolinyl) methyl] which is converted to lH-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn-l -yl)-3,7-dihydro-3 -methyl- 1 -[(4-methyl-2quinazolinyl) methyl] by deprotection process.
Trifluoro acetic acid
IP A . HC1
Formula -1
Scheme-1
The said process is tedious, time consuming and expensive. Further the said process involves impurities which are difficult to remove on industrial scale.
PCT publication WO2013098775 discloses process for preparation of lH-Purine-2,6- dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4- methyl-2quinazolinyl) methyl] comprising reacting (R)-piperidine-3 -amine of formula II or an acid addition salt thereof with 1 -[(4-methyl-quinazolin-2-yl)methyl]-3- methyl-7- (2-butyn-l -yl)-8-bromoxanthine of formula III in presence of a suitable base in an inert organic solvent. The reaction reported in this publication has disadvantages such as longer reaction periods, less yields and purity.
Thus there is a need in the art to develop cost-effective, time saving and eco-friendly process for preparing lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l- yl)-3,7-dihydro-3 -methyl- l-[(4-methyl-2quinazolinyl) methyl] .
Therefore, the object of the present invention is to provide an insitu process for preparing lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3- methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)-tartrate salt to avoid multistep synthesis reported in prior art. Another object of the present invention is to provide suitable catalyst which increases the rate of reaction and decreases the reaction time which results in obtaining Formula- 1 with high yield and high purity.
Thus the present invention provides economical, safe and commercially applicable process for preparing lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l- yl)-3 ,7-dihydro-3 -methyl- 1 - [(4-methyl-2quinazolinyl) methyl] .
SUMMARY OF THE INVENTION:
The present invention discloses cost-effective and improved process for preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3- methyl-l-[(4-methyl-2quinazolinyl) methyl] of formula- 1.
In a preferred aspect, the invention provides insitu process for preparing lH-Purine-2,6- dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4- methyl-2quinazolinyl) methyl] -(D)-Tartrate salt which comprises:
(a) Reacting 8-bromo-7-(but-2-yn- 1 -yl)-3 -methyl- 1 -[(4-methylquinazolin-2- yl)methyl]-3,7-dihydro-lH-purine-2,6-dione of formula-2 with (3R)-piperidin-3- amine dihydrochloride of formula-3 in presence of base, wherein, the reaction is characterized by the use of suitable catalyst and ester solvent or mixture of ester solvents with dipolar aprotic solvents at 85-125°C;
(b) Reacting the crude lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2- butyn-l-yl)-3,7-dihydro-3 -methyl- l-[(4-methyl-2quinazolinyl) methyl]with D- tartaric acid using mixture of alcohol solvent with 0.5 to 50% denatured alcohol (herein after DNS) at a temperature from 35 to 75°C; and
(c) Isolating lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)- 3 ,7-dihydro-3 -methyl- l-[(4-methyl-2quinazolinyl) methyl] -D-tartrate salt.
In another aspect, the invention provides a process for isolation of pure lH-Purine-2,6- dione, 8- [(3 R)-3 -amino- 1 -piperidinyl] -7-(2-butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 - [(4- methyl-2quinazolinyl) methyl] from lH-Purine-2,6-dione, 8-[(3R)-3-aminO-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)-Tartrate salt which comprises:
(a) hydrolyzing the Tartrate salt of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 -[(4-methyl-2quinazolinyl) methyl] in presence of solvent by maintaining pH at 11-12 with a suitable base in water at a temperature range of 25-55°C;
(b) optionally repeating the process of preparing lH-Purine-2,6-dione, 8-[(3R)-3- amino- 1 -piperidinyl] -7-(2-butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 -[(4-methyl- 2quinazolinyl) methyl] -(D)-tartrate salt obtained from step (a), isolating tartrate salt and hydrolyzing tartrate salt and
(c) Isolating pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn- 1-yl)- 3, 7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl].
DETAILED DESCRIPTION OF THE INVENTION:
The present invention discloses a process for preparing 1 H-Purine-2,6-dione. 8-[(3R)-3- amino- 1 -piperidinyl]-7-(2-butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 - [(4-methyl-2quinazolinyl) methyl]. (Forumula-1)
Formula-1
In an embodiment, the invention discloses insitu process for preparing lH-Purine-2,6- dione, 8-[(3R)-3-amino- 1 -piperidinyl] -7-(2-butyn- 1 -yl)-3,7-dihydro-3 -methyl- 1 -[(4- methyl-2quinazolinyl) methyl] -(D)-Tartrate salt which comprises:
(a) Reacting 8-bromo-7-(but-2-yn- 1 -yl)-3 -methyl- 1 -[(4-methylquinazolin-2- yl)methyl]-3,7-dihydro-lH-purine-2,6-dione of formula-2 with (3R)-piperidin-3- amine dihydrochloride of formula-3 in presence of a base, wherein, the reaction is characterized by the use of suitable catalyst and ester solvent or mixture of ester solvents with dipolar aprotic solvents at 85-125°C to obtain crude 1H- Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro- 3-methyl-l-[(4-methyl-2quinazolinyl) methyl] ;
(b) Reacting the crude lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2- butyn-l-yl)-3,7-dihydro-3 -methyl- l-[(4-methyl-2quinazolinyl) methyl] with D- Tartaric acid using mixture of alcohol solvent with 0.5 to 50% DNS at a temperature from 35 to 75°C; and
(c) Isolating lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)- 3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -D-tartrate salt.
The ester solvent in the said process is selected from the group consisting of N-Butyl acetate, Ethyl acetate, Methyl acetate, Isopropyl acetate. The dipolar aprotic solvent is selected from N-methylmorpholine, Morpholine, N-methyl-2-pyrrolidone, Dimethylformamide, Dimethylacetamide, Dimethylsulfoxide. The base is selected from alkali and alkaline earth metal carbonates like Potassium carbonate, Sodium carbonate, Potassium bi carbonate, Sodium bi carbonate. The suitable catalyst is selected from Potassium iodide and Sodium iodide.
The alcohol solvent is selected from Methanol, Ethanol, n-Propanol, Isopropanol, n- Butanol. The denatured alcohol (DNS) is with 0.5-50% Ethyl acetate, 0.5-50% Toluene, 0.5-50% Acetone or mixture of them.
The HPLC purity of the lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn- l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)-Tartrate salt thus obtained is 99-99.95%.
In another embodiment, the invention discloses process for isolation of pure 1H-Purine- 2,6-dione, 8-[(3R)-3-amino- l-piperidinyl]-7-(2-butyn- 1 -yl)-3,7-dihydro-3 -methyl- 1 -[(4- methyl-2quinazolinyl) methyl] from lH-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)-Tartrate salt which comprises:
(a) hydrolyzing the Tartrate salt of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 -[(4-methyl-2quinazolinyl) methyl] in presence of solvent by maintaining pH 11-12 with a suitable base in water at a temperature range of 25-55°C;
(b) optionally repeating the process of preparing lH-Purine-2,6-dione, 8-[(3R)-3- amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl- 2quinazolinyl) methyl] -(D)-tartrate salt obtained from step (a), isolating tartrate salt and hydrolyzing tartrate salt and
(c) Isolating of pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2- butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 - [(4-methyl-2quinazolinyl) methyl] .
The suitable base is selected from Sodium hydroxide, Potassium hydroxide, Lithium hydroxide, Calcium hydroxide. The solvent is selected from toluene, 1 ,4-dioxane, Chloroform, Diethylether, Dichloromethane.
The HPLC purity of the pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2- butyn-l-yl)-3,7-dihydro-3 -methyl- l-[(4-methyl-2quinazolinyl) methyl] thus obtained is
99-99.95%.
The present invention discloses process for preparing Formula-1 according to scheme-2.
Formula - 1
Scheme-2
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example: 1 Preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7- (2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)- Tartrate salt
To the 1500cc N-butyl acetate charged 0.55 moles Potassium carbonate, O.Olmoles Potassium iodide and 0.275 moles (3R)-piperidin-3-amine dihydrochloride and 0.22 moles 8-bromo-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7- dihydro-lH-purine-2,6-dione. Stirred the reaction mixture for 4-8hrs at 85-125°C. After completion of the reaction, reaction mixture cooled to 5-10°C and charged lOOOcc 10% Acetic acid solution. After stirred for 10-30 min aqueous layer was washed with 300cc
Methyl isobutyl ketone and 300 cc Toluene at 15-45°C. Aqueous layer cooled to 5-10 °C and charged 350cc 10% Sodium hydroxide. Then charged lOOOcc Methylene dichloride and stirred for 20 min. aqueous layer extracted with 350cc Methylene dichloride two times. Organic layer washed with water and brine solution. Solvent distilled out completely. Charged lOOcc Methanol to degassed mass and distilled out Methanol under vaccum.
To thereaction mass added 2500 cc Methanol and 0.5-50% Denatured alcohol charged 0.13 mole D-tartaric acid at reflux temperature for 1 to 3 hrs. Cooled the reaction mixture at 5-15°C and stirred for 2-4 hrs. Filtered the product and washed with solvent. Wet product dried at 25-45°C for 4-8hrs to obtain lH-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3 -methyl- l-[(4-methyl-2quinazolinyl) methyl] Tartrate salt with 78-85% yield.
HPLC purity: 99-99.5%
Example: 2 Preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyI]-7- (2-butyii-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazoIinyl) methyl] -(D)- Tartrate salt
To the mixture of 1300 cc n-butyl acetate and 200 cc n-Methylmorpholine charge 0.55 mole Potassium carbonate, 0.01 mole Potassium iodide, 0.275 mole (3R)-piperidin-3- amine dihydrochloride, 0.22 mole 8-bromo-7-(but-2-yn-l-yl)-3-methyl-l-[(4- methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione. Maintained the reaction mixture for 4-8hrs at 85-125°C. After completion of the reaction, reaction mixture cooled to 5-10°C and charged lOOOcc of 10% Acetic acid solution. After stirred for 10-30 min aqueous layer was washed with 300cc Methyl isobutyl ketone and 300 cc Toluene at 15-45°C. Aqueous layer cooled to 5-10 °C and charged 350cc 10% Sodium hydroxide. Then charged lOOOcc Methylene dichloride and stirred for 20 min. aqueous layer extracted with 350cc Methylene dichloride two times. Organic layer washed with water and brine solution. Solvent distilled out completely. Charged lOOcc Methanol to degassed mass and distilled out Methanol under vaccum.
To the reaction mass added 2500 cc Methanol and 0.5-50% Denatured alcohol .charged 0.13mole D-tartaric acid at reflux temperature for 1 to 3 hrs. Cooled the reaction mixture at 5-15°C and stirred for 2-4 hrs. Filtered the product and washed with solvent. Wet product dried at 25-45°C for 4-8hrs to obtain lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-
piperidinyl]-7-(2-butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 - [(4-methyl-2quinazolinyl) methyl] Tartrate salt with 78-85% yield.
HPLC purity: 99-99.5%
Example: 3 Preparation of pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-buryn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl]
In 1500cc water, charged lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyi]-7-(2- butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 - [(4-methyl-2quinazolinyl) methyl] Tartrate salt and 2000cc Toluene at temperature of 25-55°C.pHwas adjusted to 11-12 with 10% Sodium hydroxide solution. Stirred for 45-75 min and washed organic layer with water and brine solution. Distilled out the organic layer at 40-45°C.
To the reaction mass added 1650cc Methanol and 0.5-50%o DNS charged 0.14 mole purified lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7- dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] in first purification at a temperature 35-75 °C. Charged 0.1 mole D-tartaric acid in 350 cc Methanol with 0.5-50% DNS at reflux temperature for 1 to 3 hrs. Cooled the reaction mixture at 5-15°C and stirred for 2-4 hrs. Filtered the product and washed with solvent. Wet product dried at 25- 45°C for 4-8hrs to obtain lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2- butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] Tartrate salt. In 975cc water charge lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l- yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] Tartrate salt and 1300cc Toluene at temperature 25-55°C.pH adjusted 11-12 with 10% Sodium hydroxide solution. « Stirred for 45-75 min and washed organic layer with water and brine solution. Distilled out solvent at 40-45°C. Charged DNS at a temperature 45-85°C and stirred for 30 min. cooled the mixture at 15-35 °C and filtered to obtain pure lH-Purine-2,6-dione, 8-[(3R)- 3-amino- 1 -piperidinyl] -7-(2-butyn- 1 -yl)-3 ,7-dihy dro-3 -methyl- 1 - [(4-methyl- 2quinazolinyl) methyl] with 47% yield.
HPLC purity: 99-99.95%
Single large unknown impurity: less than 0.07 %
Claims
(1) A process for preparation of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl]
Formula-1
(a) Reacting insitu 8-bromo-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2- yl)methyl]-3,7-dihydro-lH-purine-2,6-dione of formula-2 with (3R)-piperidin-3- amine dihydrochloride of formula-3 in presence of base, wherein the reaction is characterized by the use of suitable catalyst and ester solvent or mixture of ester solvents with dipolar aprotic solvents at 85-125°C to obtain crude lH-Purine-2,6- dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l- [(4-methyl-2quinazolinyl) methyl] ;
(b) Reacting insitu crude lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2- butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] with D- tartaric acid in mixture of alcohol solvent and 0.5 to 50% DNS at a temperature from 35 to 75°C; and
(c) Isolating lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)- 3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] -D-tartrate salt.
(2) The process according to claim 1, wherein the process for preparing pure 1H- Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3- methyl-l-[(4-methyl-2quinazolinyl) methyl] which comprises:
(a) hydrolyzing tartrate salt of lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]- 7-(2-butyn-l-yl)-3,7-dihydro-3 -methyl- l-[(4-methyl-2quinazolinyl) methyl] in presence of solvent by maintaining pH at 11-12 with a suitable base in water at a temperature range of 25-55°C;
(b) optionally repeating the process of preparing lH-Purine-2,6-dione, 8-[(3R)-3- amino- 1 -piperidinyl]-7-(2-butyn- 1 -yl)-3 ,7-dihydro-3-methyl- 1 -[(4-methyl- 2quinazolinyl) methyl] -(D)-tartrate salt obtained from step (a)* isolating tartrate salt and hydrolyzing tartrate salt and
(c) Isolating pure lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l- yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2quinazolinyl) methyl] .
(3) The process according to claim 1 , wherein the ester solvent is selected from the group consisting of N-butyl acetate, Ethyl acetate, Methyl acetate and Isopropyl acetate.
(4) The process according to claim 1, wherein the dipolar aprotic solvent is selected from the group consisting of N-methylmorpholine, Morpholine, N-methyl-2- pyrrolidone, Dimethylformamide, Dimethylacetamide and Dimethylsulfoxide.
(5) The process according to claim 1, wherein the base used in step (a) is selected from the group consisting of alkali and alkaline earth metal carbonates like Potassium carbonate, Sodium carbonate, Potassium bi carbonate and Sodium bi carbonate.
(6) The process according to claim 1, wherein the suitable catalyst is selected from Potassium iodide or Sodium iodide.
(7) The process according to claim 1 , wherein the alcohol solvent used in step(b) is selected from Methanol or Ethanol.
(8) The process according to claim 1 , wherein the DNS used in step (b) is selected from denatured alcohol with 0.5 to 50% Ethyl acetate, 0.5-50 %Toluene, 0.5- 50% Acetone or mixture of them.
(9) The process according to any of the preceding claims, wherein purity of 1H- Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3- methyl-l-[(4-methyl-2quinazolinyl) methyl] -(D)-tartrate salt and pure 1H-Purine-
2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-niethyl- l-[(4-methyl-2quinazolinyl) methyl] is 99-99.95%.
(10) The process according to any of the preceding claims, wherein single largest unknown impurity is less than 0.07%.
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| IN137/MUM/2014 | 2014-01-15 | ||
| IN137MU2014 | 2014-01-15 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7407955B2 (en) * | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| US7820815B2 (en) * | 2004-11-05 | 2010-10-26 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines |
| WO2013098775A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Improved process for preparation of pure linagliptin |
| CN103319483A (en) * | 2012-10-19 | 2013-09-25 | 药源药物化学（上海）有限公司 | Preparation method of important intermediate of linagliptin |
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2014
- 2014-09-01 WO PCT/IN2014/000567 patent/WO2015107533A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7407955B2 (en) * | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| US7820815B2 (en) * | 2004-11-05 | 2010-10-26 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines |
| WO2013098775A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Improved process for preparation of pure linagliptin |
| CN103319483A (en) * | 2012-10-19 | 2013-09-25 | 药源药物化学（上海）有限公司 | Preparation method of important intermediate of linagliptin |
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