NZ773226B2 - Salts of pi3k inhibitor and processes for their preparation - Google Patents
Salts of pi3k inhibitor and processes for their preparation Download PDFInfo
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- NZ773226B2 NZ773226B2 NZ773226A NZ77322616A NZ773226B2 NZ 773226 B2 NZ773226 B2 NZ 773226B2 NZ 773226 A NZ773226 A NZ 773226A NZ 77322616 A NZ77322616 A NZ 77322616A NZ 773226 B2 NZ773226 B2 NZ 773226B2
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- 238000000034 method Methods 0.000 title claims abstract 52
- 150000003839 salts Chemical class 0.000 title claims abstract 15
- 239000012828 PI3K inhibitor Substances 0.000 title 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 43
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 9
- 239000002904 solvent Substances 0.000 claims 8
- 150000003512 tertiary amines Chemical class 0.000 claims 8
- BOSVWXDDFBSSIZ-UHFFFAOYSA-N 2-(1-ethoxyethylidene)propanedinitrile Chemical compound CCOC(C)=C(C#N)C#N BOSVWXDDFBSSIZ-UHFFFAOYSA-N 0.000 claims 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 4
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims 4
- 239000003054 catalyst Substances 0.000 claims 3
- 238000005984 hydrogenation reaction Methods 0.000 claims 3
- 239000007800 oxidant agent Substances 0.000 claims 3
- 230000001590 oxidative effect Effects 0.000 claims 3
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical group [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 claims 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 2
- LLJITAAISCMRAR-UHFFFAOYSA-N bis[4-(trifluoromethyl)phenyl]phosphane Chemical compound C1=CC(C(F)(F)F)=CC=C1PC1=CC=C(C(F)(F)F)C=C1 LLJITAAISCMRAR-UHFFFAOYSA-N 0.000 claims 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical group C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims 2
- 238000002955 isolation Methods 0.000 claims 2
- -1 ptoluenesulfonic acid monohydrate Chemical class 0.000 claims 2
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 claims 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 claims 1
- OWIUPIRUAQMTTK-UHFFFAOYSA-M n-aminocarbamate Chemical compound NNC([O-])=O OWIUPIRUAQMTTK-UHFFFAOYSA-M 0.000 claims 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- ZQPDJCIXJHUERQ-QWRGUYRKSA-N (4r)-4-[3-[(1s)-1-(4-amino-3-methylpyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl]pyrrolidin-2-one Chemical compound CCOC1=C([C@H](C)N2C3=NC=NC(N)=C3C(C)=N2)C=C(Cl)C(F)=C1[C@@H]1CNC(=O)C1 ZQPDJCIXJHUERQ-QWRGUYRKSA-N 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 150000003906 phosphoinositides Chemical class 0.000 abstract 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The present application provides processes for preparing (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, which is useful as an inhibitor phosphoinositide 3-kinase-delta (PI3Kd), as well as a salt form and intermediates related thereto.
Claims (50)
1. A process, sing reacting a compound of Formula XVI: with formamidine acetate to form a compound of a I:
2. The process of claim 1, wherein said reacting of the compound of Formula XVI with formamidine acetate is conducted in a solvent component comprising 1,2- ethanediol.
3. The process of claim 1 or 2, wherein said reacting of the compound of Formula XVI with formamidine acetate is performed at a temperature of from about 100 oC to about 105 oC.
4. The process of any one of claims 1 to 3, n about 8 to about 10 equivalents of formamidine acetate is used based on 1 equivalent of the compound of Formula XVI.
5. The process of any one of claims 1 to 4, further sing preparing the compound of Formula XVI by a process comprising reacting a compound of Formula with (1-ethoxyethylidene)malononitrile in the presence of a tertiary amine.
6. The process of claim 5, wherein said tertiary amine is ylpyrrolidinone.
7. The process of claim 5 or 6, wherein said reacting of the nd of Formula XV with with (1-ethoxyethylidene)malononitrile is performed at about room temperature.
8. The process of any one of claims 5 to 7, further comprising preparing the compound of Formula XV by a process comprising reacting a compound of Formula XIV-a: XIV-a with ine in the presence of a tertiary amine, wherein P1 is C1-6 alkylsulfonyl.
9. The process of claim 8, wherein said tertiary amine is N-methylpyrrolidinone.
10. The process of claim 8 or 9, wherein said reacting of the compound of Formula XIV-a with ine is performed at a temperature of from about 35 oC to about 60 oC.
11. The s of any one of claims 8 to 10, n said reacting of the compound of Formula XIV-a with hydrazine is conducted in a solvent component comprising dichloromethane.
12. The process of any one of claims 8 to 11, wherein P1 is esulfonyl group.
13. The process of any one of claims 8 to 12, r comprising preparing the compound of Formula XIV-a by a process comprising reacting a compound of Formula XIII: with C1-6 alkylsulfonylhalide in the presence of a tertiary amine.
14. The process of claim 13, wherein said C1-6 alkylsulfonylhalide is methanesulfonyl chloride.
15. The process of claim 13 or 14, wherein said tertiary amine is N,N- diisopropylethylamine.
16. The process of any one of claims 13 to 15, wherein about 1.1 to about 1.5 equivalents of alkylsulfonylhalide is used based on 1 equivalent of the compound of Formula XIII.
17. The process of any one of claims 13 to 16, wherein said reacting of said compound of Formula XIII with C1-6 alkylsulfonylhalide is performed at a temperature of from about -10 oC to about 5 oC.
18. The s of any one of claims 13 to 17, wherein said reacting of said compound of Formula XIII with C1-6 alkylsulfonylhalide is performed in a solvent component comprising dichloromethane.
19. The process of any one of claims 1 to 18, wherein the steps of: (i) reacting of said nd of Formula XIII with C1-6 alkylsulfonylhalide; (ii) reacting said nd of Formula XIV-a with ine in the presence of a tertiary amine to form a compound of Formula XV; and (iii) reacting said compound of Formula XV with formamidine e to form a compound of Formula XVI are conducted in the same pot without isolation of the compound of Formula XIV-a or the compound of Formula XV.
20. The process of any one of claims 1 to 4, further comprising preparing the nd of Formula XVI by a process comprising reacting a salt of Formula XV-a: with (1-ethoxyethylidene)malononitrile in the presence of a ry amine, wherein TsOH is p-toluenesulfonic acid.
21. The process of claim 20, wherein said tertiary amine is N,N- diisopropylethylamine.
22. The process of claim 20 or 21, wherein said reacting a salt of Formula XV-a with with (1-ethoxyethylidene)malononitrile is performed at about room temperature.
23. The process of any one of claims 20 to 22, wherein about 1.3 to about 1.6 equivalents of (1-ethoxyethylidene)malononitrile is used based on 1 lent of the salt of Formula XV-a.
24. The process of any one of claims 20 to 23, wherein said reacting of the salt of Formula XV-a with (1-ethoxyethylidene)malononitrile is conducted in a solvent ent comprising ethanol.
25. The process of any one of claims 20 to 24, further comprising preparing the salt of Formula XV-a by a process comprising reacting a compound of Formula XXI: with p-toluenesulfonic acid, wherein Boc is tert-butoxycarbonyl.
26. The process of claim 25, wherein said p-toluenesulfonic acid is ptoluenesulfonic acid monohydrate.
27. The process of claim 25 or 26, wherein about 1.3 to about 1.6 equivalents of ptoluenesulfonic acid is used based on 1 equivalent of the compound of Formula XXI.
28. The process of any one of claims 25 to 27, wherein said reacting of said nd of Formula XXI with enesulfonic acid is performed at a temperature of from about 45 oC to about 65 oC.
29. The process of any one of claims 25 to 28, wherein reacting of said compound of Formula XXI with p-toluenesulfonic acid is conducted in a solvent ent sing ethanol.
30. The process of any one of claims 25 to 29, wherein the steps of: (i) ng said compound of Formula XXI with p-toluenesulfonic acid to form a salt of Formula XV-a; and (ii) reacting said salt of Formula XV-a with (1- ethoxyethylidene)malononitrile are ted in the same pot without isolation of the salt of a XV-a.
31. The process of any one of claims 25 to 30, r comprising preparing the compound of Formula XXI by a process comprising reacting a compound of Formula with hydrogen gas in the presence of one or more independently selected hydrogenation catalysts, wherein Boc is t-butoxycarbonyl.
32. The process of claim 31, wherein said reacting of the compound of Formula XX with hydrogen gas is performed in the presence of two independently selected hydrogenation catalysts.
33. The process of claim 32, wherein one hydrogenation catalyst is bis(1,5- cyclooctadiene)rhodium(I)tetrafluoroborate and the other is (R)-(-){(S)[bis(4- trifluoromethylphenyl)phosphine]ferrocenyl}ethyl-di-t-butylphosphine.
34. The process of claim 33, wherein about 13.5 to about 14.5 equivalents of the compound of a XX are used based on 1 lent of the bis(1,5- cyclooctadiene)rhodium(I)tetrafluoroborate.
35. The process of claim 33 or 34, wherein about 12 to about 13 equivalents of the compound of Formula XX are used based on 1 equivalent of the (R)-(-){(S) [bis(4-trifluoromethylphenyl)phosphine]ferrocenyl}ethyl-di-t-butylphosphine.
36. The process of any one of claims 31 to 35, wherein said reacting of the compound of Formula XX with hydrogen gas is performed at about room temperature.
37. The process of any one of claims 31 to 36, wherein said reacting of the compound of Formula XX with hydrogen gas is conducted in a solvent ent comprising methanol.
38. The s of any one of claims 31 to 37, r comprising preparing the compound of Formula XX by a process comprising reacting a compound of Formula with l carbazate.
39. The process of claim 38, wherein said reacting of the nd of Formula XIX with t-butyl carbazate is performed at a temperature of from about 60 oC to about 70 oC.
40. The process of claim 38 or 39, wherein said reacting of the compound of Formula XIX with t-butyl carbazate is conducted in a solvent component comprising methanol.
41. The process of any one of claims 38 to 40, further comprising preparing the compound of Formula XIX by a process comprising oxidizing a nd of Formula XIII-a: XIII-a in the presence of an oxidizing agent.
42. The process of claim 41, n said oxidizing agent is Dess-Martin periodinane.
43. The process of claim 41 or 42, wherein about 1.2 to about 1.7 equivalents of said oxidizing agent is used based on 1 equivalent of the compound of a XIII-
44. The process of any one of claims 41 to 43, wherein said oxidizing of the compound of Formula XIII-a is performed at about room temperature.
45. The process of any one of claims 41 to 44, n said oxidizing of the compound of Formula XIII-a is conducted in a solvent component comprising dichloromethane.
46. A compound of Formula XIV: or a pharmaceutically acceptable salt thereof.
47. A compound of Formula XV: or a pharmaceutically acceptable salt thereof.
48. A compound of Formula XVI: or a pharmaceutically acceptable salt thereof.
49. A nd of Formula XX: or a ceutically acceptable salt thereof.
50. A compound of Formula XXI: or a ceutically acceptable salt thereof. com AOL 3:: 98m? mmbom F . .0."— am: >>o_ “— A926 SUBSTITUTE SHEET (RULE 26) mm-- AOOV > "I N 525 .0."— 8% IIIIII-g EswwmQEmko F >SJQI u 3283?: 28 0 Im mm. vNor on. —— (%) %1u6!e/V
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562121697P | 2015-02-27 | 2015-02-27 | |
| NZ734993A NZ734993B2 (en) | 2016-02-26 | Salts of pi3k inhibitor and processes for their preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ773226A NZ773226A (en) | 2024-03-22 |
| NZ773226B2 true NZ773226B2 (en) | 2024-06-25 |
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