IL315864A - תהליכים וחומרי ביניים לסינתזה של אדאגראסיב - Google Patents

תהליכים וחומרי ביניים לסינתזה של אדאגראסיב

Info

Publication number: IL315864A
Authority: IL; Israel
Prior art keywords: base; reacting; produce; polar aprotic; aprotic solvent
Prior art date: 2022-04-18

Application number

IL315864A

Other languages

English (en)

Inventor

Thomas Scattolin

Yonghong Gan

Cheng Chen

Chengsheng Chen

Original Assignee

Mirati Therapeutics Inc

Thomas Scattolin

Yonghong Gan

Cheng Chen

Chengsheng Chen

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2022-04-18

Filing date

2023-04-17

Publication date

2024-11-01

2023-04-17 Application filed by Mirati Therapeutics Inc, Thomas Scattolin, Yonghong Gan, Cheng Chen, Chengsheng Chen filed Critical Mirati Therapeutics Inc

2024-11-01 Publication of IL315864A publication Critical patent/IL315864A/he

Links

238000000034 method Methods 0.000 title claims description 113
230000015572 biosynthetic process Effects 0.000 title description 10
238000003786 synthesis reaction Methods 0.000 title description 8
239000000543 intermediate Substances 0.000 title description 6
230000008569 process Effects 0.000 title description 6
239000002585 base Substances 0.000 claims description 206
PEMUGDMSUDYLHU-ZEQRLZLVSA-N 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile Chemical compound ClC=1C=CC=C2C=CC=C(C=12)N1CC=2N=C(N=C(C=2CC1)N1C[C@@H](N(CC1)C(C(=C)F)=O)CC#N)OC[C@H]1N(CCC1)C PEMUGDMSUDYLHU-ZEQRLZLVSA-N 0.000 claims description 153
229940124988 adagrasib Drugs 0.000 claims description 150
239000003880 polar aprotic solvent Substances 0.000 claims description 136
150000003839 salts Chemical class 0.000 claims description 94
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 87
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 77
150000001875 compounds Chemical class 0.000 claims description 77
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 76
230000002194 synthesizing effect Effects 0.000 claims description 65
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 60
239000003795 chemical substances by application Substances 0.000 claims description 52
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 51
239000002904 solvent Substances 0.000 claims description 51
TYCFGHUTYSLISP-UHFFFAOYSA-N 2-fluoroprop-2-enoic acid Chemical compound OC(=O)C(F)=C TYCFGHUTYSLISP-UHFFFAOYSA-N 0.000 claims description 50
239000007822 coupling agent Substances 0.000 claims description 48
JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 47
229910052751 metal Inorganic materials 0.000 claims description 47
239000002184 metal Substances 0.000 claims description 47
239000003513 alkali Substances 0.000 claims description 45
230000003213 activating effect Effects 0.000 claims description 41
-1 (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate Chemical compound 0.000 claims description 39
TVKAZNBVXZKTAV-LURJTMIESA-N 2-[(2s)-piperazin-2-yl]acetonitrile Chemical compound N#CC[C@H]1CNCCN1 TVKAZNBVXZKTAV-LURJTMIESA-N 0.000 claims description 39
239000002798 polar solvent Substances 0.000 claims description 35
239000000654 additive Substances 0.000 claims description 33
230000000996 additive effect Effects 0.000 claims description 33
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 30
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 30
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 28
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
150000007529 inorganic bases Chemical class 0.000 claims description 25
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 25
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 19
VCOJPHPOVDIRJK-LURJTMIESA-N [(2s)-1-methylpyrrolidin-2-yl]methanol Chemical compound CN1CCC[C@H]1CO VCOJPHPOVDIRJK-LURJTMIESA-N 0.000 claims description 19
125000000217 alkyl group Chemical group 0.000 claims description 19
125000003118 aryl group Chemical group 0.000 claims description 19
PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 18
239000002253 acid Substances 0.000 claims description 18
239000007800 oxidant agent Substances 0.000 claims description 15
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 14
239000003054 catalyst Substances 0.000 claims description 14
230000002152 alkylating effect Effects 0.000 claims description 13
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
239000012467 final product Substances 0.000 claims description 12
MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 11
SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 11
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 11
150000001447 alkali salts Chemical class 0.000 claims description 11
229910052794 bromium Inorganic materials 0.000 claims description 11
OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 claims description 11
229910052801 chlorine Inorganic materials 0.000 claims description 10
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 10
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 10
WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 10
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 9
235000019439 ethyl acetate Nutrition 0.000 claims description 8
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
150000008064 anhydrides Chemical class 0.000 claims description 7
XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims description 7
150000004703 alkoxides Chemical class 0.000 claims description 6
229910052731 fluorine Inorganic materials 0.000 claims description 6
150000007530 organic bases Chemical class 0.000 claims description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
QKIHLPFZYGFMDK-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F QKIHLPFZYGFMDK-UHFFFAOYSA-N 0.000 claims description 5
BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 5
UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 claims description 5
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
229910006080 SO2X Inorganic materials 0.000 claims description 5
239000003153 chemical reaction reagent Substances 0.000 claims description 5
BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 5
JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 claims description 5
150000003461 sulfonyl halides Chemical class 0.000 claims description 5
125000003944 tolyl group Chemical group 0.000 claims description 5
229910052740 iodine Inorganic materials 0.000 claims description 4
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
QLZHNIAADXEJJP-UHFFFAOYSA-N Phenylphosphonic acid Chemical compound OP(O)(=O)C1=CC=CC=C1 QLZHNIAADXEJJP-UHFFFAOYSA-N 0.000 claims description 3
150000001350 alkyl halides Chemical class 0.000 claims description 3
150000008052 alkyl sulfonates Chemical class 0.000 claims description 3
125000005228 aryl sulfonate group Chemical group 0.000 claims description 3
239000007844 bleaching agent Substances 0.000 claims description 3
150000001718 carbodiimides Chemical class 0.000 claims description 3
MWSPFHZPVVWJCO-UHFFFAOYSA-M hydron;methyl(trioctyl)azanium;sulfate Chemical compound OS([O-])(=O)=O.CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC MWSPFHZPVVWJCO-UHFFFAOYSA-M 0.000 claims description 3
150000004965 peroxy acids Chemical class 0.000 claims description 3
AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 claims description 3
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 2
125000005500 uronium group Chemical group 0.000 claims description 2
239000007821 HATU Substances 0.000 claims 1
CJJTVVBERSDQIB-UHFFFAOYSA-N [Na].OC(=O)C(F)=C Chemical compound [Na].OC(=O)C(F)=C CJJTVVBERSDQIB-UHFFFAOYSA-N 0.000 claims 1
239000000203 mixture Substances 0.000 description 108
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 48
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 40
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 39
239000007787 solid Substances 0.000 description 39
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
238000006243 chemical reaction Methods 0.000 description 27
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
229910000404 tripotassium phosphate Inorganic materials 0.000 description 22
235000019798 tripotassium phosphate Nutrition 0.000 description 22
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 20
101150105104 Kras gene Proteins 0.000 description 18
229910052757 nitrogen Inorganic materials 0.000 description 17
239000000243 solution Substances 0.000 description 17
229910019142 PO4 Inorganic materials 0.000 description 16
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 16
239000010452 phosphate Substances 0.000 description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
239000008213 purified water Substances 0.000 description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
229910000856 hastalloy Inorganic materials 0.000 description 14
125000004432 carbon atom Chemical group C* 0.000 description 13
238000003556 assay Methods 0.000 description 12
ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 12
229910000396 dipotassium phosphate Inorganic materials 0.000 description 12
235000019797 dipotassium phosphate Nutrition 0.000 description 12
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 11
239000011541 reaction mixture Substances 0.000 description 11
239000002002 slurry Substances 0.000 description 11
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
239000012074 organic phase Substances 0.000 description 10
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
229910000041 hydrogen chloride Inorganic materials 0.000 description 9
DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 8
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 8
206010028980 Neoplasm Diseases 0.000 description 8
239000008346 aqueous phase Substances 0.000 description 8
125000003710 aryl alkyl group Chemical group 0.000 description 8
239000000460 chlorine Substances 0.000 description 8
239000012065 filter cake Substances 0.000 description 8
238000001914 filtration Methods 0.000 description 8
239000007858 starting material Substances 0.000 description 8
238000003756 stirring Methods 0.000 description 8
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 7
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
229910052744 lithium Inorganic materials 0.000 description 7
229910052700 potassium Inorganic materials 0.000 description 7
239000011591 potassium Substances 0.000 description 7
102200006538 rs121913530 Human genes 0.000 description 7
238000000926 separation method Methods 0.000 description 7
239000011734 sodium Substances 0.000 description 7
229910052708 sodium Inorganic materials 0.000 description 7
239000004135 Bone phosphate Substances 0.000 description 6
YHCNTTLRKUTDRD-ILKKLZGPSA-N Cl.Cl.N#CC[C@H]1CNCCN1 Chemical compound Cl.Cl.N#CC[C@H]1CNCCN1 YHCNTTLRKUTDRD-ILKKLZGPSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
125000003342 alkenyl group Chemical group 0.000 description 6
125000000304 alkynyl group Chemical group 0.000 description 6
201000011510 cancer Diseases 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 6
NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 6
239000000047 product Substances 0.000 description 6
JGPFVCNXUUKNDS-UHFFFAOYSA-M sodium;2-fluoroprop-2-enoate Chemical compound [Na+].[O-]C(=O)C(F)=C JGPFVCNXUUKNDS-UHFFFAOYSA-M 0.000 description 6
229910001220 stainless steel Inorganic materials 0.000 description 6
239000010935 stainless steel Substances 0.000 description 6
UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 6
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 5
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 5
229910000147 aluminium phosphate Inorganic materials 0.000 description 5
125000000753 cycloalkyl group Chemical group 0.000 description 5
238000001035 drying Methods 0.000 description 5
229910052500 inorganic mineral Inorganic materials 0.000 description 5
239000011707 mineral Substances 0.000 description 5
235000010755 mineral Nutrition 0.000 description 5
229910017604 nitric acid Inorganic materials 0.000 description 5
150000007524 organic acids Chemical class 0.000 description 5
239000011975 tartaric acid Substances 0.000 description 5
235000002906 tartaric acid Nutrition 0.000 description 5
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
238000003109 Karl Fischer titration Methods 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
235000011054 acetic acid Nutrition 0.000 description 4
125000001931 aliphatic group Chemical group 0.000 description 4
235000001014 amino acid Nutrition 0.000 description 4
150000001413 amino acids Chemical group 0.000 description 4
235000010323 ascorbic acid Nutrition 0.000 description 4
239000011668 ascorbic acid Substances 0.000 description 4
239000013078 crystal Substances 0.000 description 4
238000002425 crystallisation Methods 0.000 description 4
230000008025 crystallization Effects 0.000 description 4
229940093915 gynecological organic acid Drugs 0.000 description 4
125000000623 heterocyclic group Chemical group 0.000 description 4
229910052739 hydrogen Inorganic materials 0.000 description 4
239000001257 hydrogen Substances 0.000 description 4
239000012046 mixed solvent Substances 0.000 description 4
230000035772 mutation Effects 0.000 description 4
230000007935 neutral effect Effects 0.000 description 4
235000005985 organic acids Nutrition 0.000 description 4
239000002245 particle Substances 0.000 description 4
239000012071 phase Substances 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
238000001556 precipitation Methods 0.000 description 4
159000000000 sodium salts Chemical class 0.000 description 4
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125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
230000002110 toxicologic effect Effects 0.000 description 1
231100000759 toxicological effect Toxicity 0.000 description 1
230000007704 transition Effects 0.000 description 1
125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
238000011144 upstream manufacturing Methods 0.000 description 1
229940116269 uric acid Drugs 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
230000003612 virological effect Effects 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- 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

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Epidemiology (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)

IL315864A 2022-04-18 2023-04-17 תהליכים וחומרי ביניים לסינתזה של אדאגראסיב IL315864A (he)

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US202263332181P	2022-04-18	2022-04-18
PCT/US2023/018809 WO2023205074A1 (en)	2022-04-18	2023-04-17	Processes and intermediates for synthesis of adagrasib

Publications (1)

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IL315864A true IL315864A (he)	2024-11-01

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Country Status (6)

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EP (1)	EP4511372A1 (he)
KR (1)	KR20250003858A (he)
CN (1)	CN119072477A (he)
AU (1)	AU2023257901A1 (he)
IL (1)	IL315864A (he)
WO (1)	WO2023205074A1 (he)

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* Cited by examiner, † Cited by third party
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TW202428280A (zh) *	2022-09-28	2024-07-16	美商米拉蒂醫療公司	組合療法

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN111989321B (zh) *	2017-11-15	2024-05-14	米拉蒂治疗股份有限公司	Kras g12c抑制剂
US10647715B2 (en) *	2017-11-15	2020-05-12	Mirati Therapeutics, Inc.	KRas G12C inhibitors
TWI752580B (zh) *	2019-08-07	2022-01-11	大陸商北京加科思新藥研發有限公司	Kras突變蛋白抑制劑
CA3163218A1 (en) *	2019-12-02	2021-06-10	Shanghai Yingli Pharmaceutical Co., Ltd	Oxygen-containing heterocyclic compound, preparation method therefor and use thereof

2023
- 2023-04-17 AU AU2023257901A patent/AU2023257901A1/en active Pending
- 2023-04-17 IL IL315864A patent/IL315864A/he unknown
- 2023-04-17 KR KR1020247038122A patent/KR20250003858A/ko active Pending
- 2023-04-17 WO PCT/US2023/018809 patent/WO2023205074A1/en active Application Filing
- 2023-04-17 EP EP23792376.8A patent/EP4511372A1/en active Pending
- 2023-04-17 CN CN202380035098.1A patent/CN119072477A/zh active Pending

Also Published As

Publication number	Publication date
KR20250003858A (ko)	2025-01-07
AU2023257901A1 (en)	2024-10-10
CN119072477A (zh)	2024-12-03
EP4511372A1 (en)	2025-02-26
WO2023205074A1 (en)	2023-10-26

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NZ539390A (en)	2007-05-31	Azaindole derivatives as inhibitors of p38 kinase
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IL225808A (he)	2016-08-31	ססקווי–הידרט של 1–{ (s 2)–2–אמינו–4–[4,2–ביס(טריפלואורומתיל)– 8,5–דיהידרופירידו[4,3–d]פירימידינ–7(h6)–יל]–4–אוקסובוטיל}–5,5–דיפלואורו–פיפרידינ–2–ון טרטראט, תהליך להכנתו ותכשירי רוקחות המכילים אותו לטיפול בסכרת והשמנת יתר
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