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NZ761156B2 - Improved process for preparing aminopyrimidine derivatives - Google Patents
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NZ761156B2 - Improved process for preparing aminopyrimidine derivatives - Google Patents

Improved process for preparing aminopyrimidine derivatives

Info

Publication number
NZ761156B2
NZ761156B2 NZ761156A NZ76115618A NZ761156B2 NZ 761156 B2 NZ761156 B2 NZ 761156B2 NZ 761156 A NZ761156 A NZ 761156A NZ 76115618 A NZ76115618 A NZ 76115618A NZ 761156 B2 NZ761156 B2 NZ 761156B2
Authority
NZ
New Zealand
Prior art keywords
process according
phenyl
reacting
pyrimidinyl
methyl
Prior art date
Application number
NZ761156A
Other versions
NZ761156A (en
Inventor
Yoon Ah Hwang
Hyun Ju
Ja Heouk Khoo
Seong Ran Lee
Jong Chul Lim
Sang Ho Oh
Dae Gyu Park
Su Min Park
Woo Seob Shin
Original Assignee
Yuhan Corporation
Filing date
Publication date
Application filed by Yuhan Corporation filed Critical Yuhan Corporation
Priority claimed from PCT/KR2018/008379 external-priority patent/WO2019022485A1/en
Publication of NZ761156A publication Critical patent/NZ761156A/en
Publication of NZ761156B2 publication Critical patent/NZ761156B2/en

Links

Classifications

    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2284—Compounds with one or more Sn-N linkages

Abstract

The present invention provides an improved process for preparing an aminopyrimidine derivative or pharmaceutically acceptable salt thereof having a selective inhibitory activity against protein kinases, especially against the protein kinases for mutant epidermal growth factor receptors. And also, the present invention provides novel intermediates useful for said process and processes for preparing the same.

Claims (45)

1. A process for preparing N-(5-((4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)amino)m 5 ethoxymorpholinophenyl)acrylamide or a pharmaceutically acceptable salt thereof, the process comprising (a) reacting N1-(4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)methoxy morpholinobenzene-1,3-diamine with a compound of Formula 4 to obtain a compound of 10 Formula 2; and (b) reacting the compound of Formula 2 with a base to obtain N-(5-((4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)amino)m ethoxymorpholinophenyl)acrylamide: wherein, X is halogen. 20
2. The process according to claim 1, wherein the reacting of Step (a) is carried out in the presence of one or more base(s) selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo[5.4.0]undecene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]nonene, pyridine, triethylamine, diisopropylamine and diisopropylethylamine.
3. The process according to claim 1, wherein the reacting of Step (a) is carried out in 5 the presence of a solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C ~C alcohol, toluene, ethyl acetate, isopropyl acetate, diethyl ether, water and a mixture thereof.
4. The process according to claim 3, wherein the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, dichloromethane, water and a mixture thereof. 15
5. The process according to claim 1, wherein the base used in Step (b) is one or more selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo[5.4.0]undecene, 1,4-diazabicyclo[2.2.2]octane, 20 1,5-diazabicyclo[4.3.0]nonene, pyridine, triethylamine, diisopropylamine and diisopropylethylamine.
6. The process according to claim 5, wherein the base is one or more selected from the group consisting of sodium hydroxide, triethylamine and diisopropylamine.
7. The process according to claim 1, wherein the reacting of Step (b) is carried out in the presence of a solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C1~C5 30 alcohol, toluene, ethyl acetate, isopropyl acetate, diethyl ether, water and a mixture thereof.
8. The process according to claim 7, wherein the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, dichloromethane, water and a mixture thereof.
9. The process according to claim 1, wherein Step (a) and Step (b) are carried out in a one-pot reaction.
10. The process according to any one of claims 1 to 9, wherein the 10 N1-(4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)methoxy morpholinobenzene-1,3-diamine in Step (a) is obtained by a process comprising (i) reacting 4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)-N-(2-methoxymorpholinon itrophenyl)pyrimidinamine with tin chloride in the presence of hydrochloric acid to 15 obtain a complex of Formula 5 and (ii) reacting the complex of Formula 5 with a base to obtain N1-(4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)methoxy morpholinobenzene-1,3-diamine: 20 .
11. The process according to claim 10, wherein the reacting of Step (i) is carried out in the presence of one or more solvent(s) selected from the group consisting of water, C1~C10 alcohol, dichloromethane, tetrahydrofuran, acetonitrile and ethyl acetate.
12. The process according to claim 10, wherein the base used in Step (ii) is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, 5 and sodium phosphate.
13. The process according to claim 10, wherein the 4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)-N-(2-methoxymorpholinon itrophenyl)pyrimidinamine is obtained by reacting 10 1-(2-((2-methoxymorpholinonitrophenyl)amino)pyrimidinyl)phenyl-1H-pyrazol ecarbaldehyde with dimethylamine or a salt thereof.
14. The process according to claim 13, wherein the reacting is carried out in the presence of one or more reducing agent(s) selected from the group consisting of sodium 15 triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride.
15. The process according to claim 13, wherein the 1-(2-((2-methoxymorpholinonitrophenyl)amino)pyrimidinyl)phenyl-1H-pyrazol ecarbaldehyde is obtained by reacting 20 4-chloro-N-(2-methoxymorpholinonitrophenyl)pyrimidinamine with 3-phenyl-1H-pyrazolecarbaldehyde.
16. The process according to claim 15, wherein the 4-chloro-N-(2-methoxymorpholinonitrophenyl)pyrimidinamine is obtained by 25 reacting N-(2-methoxymorpholinonitrophenyl)formamide with 4-chloro(methylsulfonyl)pyrimidine.
17. The process according to claim 16, wherein the N-(2-methoxymorpholinonitrophenyl)formamide is obtained by performing a 30 formylation of 2-methoxymorpholinonitroaniline.
18. The process according to claim 17, wherein the formylation is carried out with a mixture of acetic acid and formic acid.
19. The process according to claim 16, wherein the 5 4-chloro(methylsulfonyl)pyrimidine is obtained by performing an oxidation of 4-chloro(methylthio)pyrimidine.
20. The process according to claim 19, wherein the oxidation is carried out with one or more oxidizing agent(s) selected from the group consisting of potassium permanganate, 10 chromic acid, oxygen, hydrogen peroxide and 3-chloroperbenzoic acid.
21. The process according to claim 13, wherein the 1-(2-((2-methoxymorpholinonitrophenyl)amino)pyrimidinyl)phenyl-1H-pyrazol ecarbaldehyde is obtained by reacting 15 N-(2-methoxymorpholinonitrophenyl)formamide with 1-(2-(methylsulfonyl)pyrimidinyl)phenyl-1H-pyrazolecarbaldehyde.
22. The process according to claim 21, wherein the reacting is carried out in the presence of one or more base(s) selected from the group consisting of sodium C1~C6 20 alkoxide, potassium C ~C alkoxide, sodium carbonate, potassium carbonate, and potassium phosphate.
23. The process according to claim 21, wherein the reacting is carried out in the presence of one or more solvent(s) selected from the group consisting of 25 dimethylformamide, dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoramide, C ~C alcohol, diethyl ether, ethyl acetate, acetonitrile and acetone.
24. The process according to claim 21, wherein the 30 1-(2-(methylsulfonyl)pyrimidinyl)phenyl-1H-pyrazolecarbaldehyde is obtained by reacting 1-(2-(methylthio)pyrimidinyl)phenyl-1H-pyrazolecarbaldehyde with an oxidizing agent.
25. The process according to claim 24, wherein the oxidizing agent is one or more 5 selected from the group consisting of potassium permanganate, chromic acid, oxygen, hydrogen peroxide and 3-chloroperbenzoic acid.
26. The process according to claim 24, wherein the reacting is carried out in the presence of one or more solvent(s) selected from the group consisting of C1~C5 alcohol, 10 carbon tetrachloride, chloroform, dichloromethane, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, cyclohexane, petroleum ether, kerosene, toluene, xylene, mesitylene and benzene. 15
27. The process according to claim 24, wherein the 1-(2-(methylthio)pyrimidinyl)phenyl-1H-pyrazolecarbaldehyde is obtained by reacting 4-chloro(methylthio)pyrimidine with 3-phenyl-1H-pyrazolecarbaldehyde.
28. The process according to claim 27, wherein the reacting is carried out in the 20 presence of one or more base(s) selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo[5.4.0]undecene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]nonene, pyridine, triethylamine, diisopropylamine and 25 diisopropylethylamine.
29. The process according to claim 27, wherein the reacting is carried out in the presence of one or more solvent(s) selected from the group consisting of dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl 30 sulfoxide, tetrahydrofuran, C ~C alcohol, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile and toluene.
30. A compound of Formula 2 or salt thereof: 5 wherein, X is halogen.
31. A complex of Formula 5:
32. 1-(2-(methylsulfonyl)pyrimidinyl)phenyl-1H-pyrazolecarbaldehyde.
33. 1-(2-(methylthio)pyrimidinyl)phenyl-1H-pyrazolecarbaldehyde. 15
34. A process according to claim 1, for preparing N-(5-((4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)amino)m ethoxymorpholinophenyl)acrylamide or a pharmaceutically acceptable salt thereof, the process comprising (a) reacting N1-(4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)methoxy morpholinobenzene-1,3-diamine with a compound of Formula 4 in acetonitrile in the 5 presence of sodium hydroxide to obtain a compound of Formula 2; and (b) reacting the compound of Formula 2 with triethylamine in n-propanol to obtain N-(5-((4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)amino)m ethoxymorpholinophenyl)acrylamide: wherein, X is halogen. 15
35. The process according to claim 34, wherein Step (a) and Step (b) are carried out in a one-pot reaction.
36. The process according to claim 1, wherein the N1-(4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)methoxy 20 morpholinobenzene-1,3-diamine in Step (a) is obtained by a process comprising (i) reacting 4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)-N-(2-methoxymorpholinon itrophenyl)pyrimidinamine with tin chloride dihydrate in the presence of hydrochloric acid to obtain a complex of Formula 5 and (ii) reacting the complex of Formula 5 with sodium hydroxide to obtain N1-(4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)pyrimidinyl)methoxy morpholinobenzene-1,3-diamine: 5
37. The process according to claim 36, wherein the 10 4-(4-((dimethylamino)methyl)phenyl-1H-pyrazolyl)-N-(2-methoxymorpholinon itrophenyl)pyrimidinamine is obtained by reacting 1-(2-((2-methoxymorpholinonitrophenyl)amino)pyrimidinyl)phenyl-1H-pyrazol ecarbaldehyde with dimethylamine hydrochloride and sodium triacetoxyborohydride in N,N dimethylacetamide and acetonitrile.
38. The process according to claim 37, wherein the 1-(2-((2-methoxymorpholinonitrophenyl)amino)pyrimidinyl)phenyl-1H-pyrazol ecarbaldehyde is obtained by reacting 4-chloro-N-(2-methoxymorpholinonitrophenyl)pyrimidinamine with 20 3-phenyl-1H-pyrazolecarbaldehyde in N,N-dimethylformamide under basic conditions using potassium carbonate.
39. The process according to claim 38, wherein the 4-chloro-N-(2-methoxymorpholinonitrophenyl)pyrimidinamine is obtained by reacting N-(2-methoxymorpholinonitrophenyl)formamide with 4-chloro(methyl sulfonyl) pyrimidine.
40. The process according to claim 39, wherein the 5 N-(2-methoxymorpholinonitrophenyl)formamide is obtained by performing a formylation of 2-methoxymorpholinonitroaniline.
41. The process according to claim 40, wherein the formylation is carried out with a mixture of acetic acid and formic acid.
42. The process according to claim 39, wherein the 4-chloro(methylsulfonyl)pyrimidine is obtained by performing an oxidation of 4-chloro(methylthio)pyrimidine. 15
43. The process according to claim 42, wherein the oxidation is carried out with one or more oxidizing agent(s) selected from the group consisting of potassium permanganate, chromic acid, oxygen, hydrogen peroxide and 3 -chloroperbenzoic acid.
44. A compound of Formula II according to claim 30: or a salt thereof.
45. A process as claimed in any one of claims 1-29 and 34-43, or a compound as claimed in any one of claims 30-33 and 44, substantially as described herein and with reference to any example thereof.
NZ761156A 2018-07-25 Improved process for preparing aminopyrimidine derivatives NZ761156B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20170096212 2017-07-28
PCT/KR2018/008379 WO2019022485A1 (en) 2017-07-28 2018-07-25 Improved process for preparing aminopyrimidine derivatives

Publications (2)

Publication Number Publication Date
NZ761156A NZ761156A (en) 2024-01-26
NZ761156B2 true NZ761156B2 (en) 2024-04-30

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