JP2017529371A - (シクロペンチル[d]ピリミジン−4−イル)ピペラジン化合物を調製する方法 - Google Patents
(シクロペンチル[d]ピリミジン−4−イル)ピペラジン化合物を調製する方法 Download PDFInfo
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- JP2017529371A JP2017529371A JP2017516092A JP2017516092A JP2017529371A JP 2017529371 A JP2017529371 A JP 2017529371A JP 2017516092 A JP2017516092 A JP 2017516092A JP 2017516092 A JP2017516092 A JP 2017516092A JP 2017529371 A JP2017529371 A JP 2017529371A
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 title abstract description 10
- 150000004885 piperazines Chemical class 0.000 title abstract description 9
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 278
- -1 cyclopenta [d] pyrimidin-4-yl Chemical group 0.000 claims abstract description 125
- 238000000034 method Methods 0.000 claims abstract description 118
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims description 228
- 238000006243 chemical reaction Methods 0.000 claims description 79
- 239000003795 chemical substances by application Substances 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 50
- 238000005893 bromination reaction Methods 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- 125000006239 protecting group Chemical group 0.000 claims description 35
- 230000008569 process Effects 0.000 claims description 29
- 239000007795 chemical reaction product Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 230000002255 enzymatic effect Effects 0.000 claims description 23
- 230000031709 bromination Effects 0.000 claims description 22
- 125000001246 bromo group Chemical group Br* 0.000 claims description 18
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 108010033272 Nitrilase Proteins 0.000 claims description 16
- 238000007363 ring formation reaction Methods 0.000 claims description 16
- 238000005660 chlorination reaction Methods 0.000 claims description 14
- 239000006227 byproduct Substances 0.000 claims description 13
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 11
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 11
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 11
- 239000012320 chlorinating reagent Substances 0.000 claims description 11
- 229910052744 lithium Inorganic materials 0.000 claims description 11
- NKKMVIVFRUYPLQ-NSCUHMNNSA-N crotononitrile Chemical compound C\C=C\C#N NKKMVIVFRUYPLQ-NSCUHMNNSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 238000004821 distillation Methods 0.000 claims description 9
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical class NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims description 8
- 108090001060 Lipase Proteins 0.000 claims description 8
- 102000004882 Lipase Human genes 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 150000002902 organometallic compounds Chemical group 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005545 phthalimidyl group Chemical group 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 3
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims 1
- YNLPNVNWHDKDMN-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CC[CH-]C YNLPNVNWHDKDMN-UHFFFAOYSA-M 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- GRZXWCHAXNAUHY-NSISKUIASA-N (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1-piperazinyl]-3-(propan-2-ylamino)-1-propanone Chemical compound C1([C@H](C(=O)N2CCN(CC2)C=2C=3[C@H](C)C[C@@H](O)C=3N=CN=2)CNC(C)C)=CC=C(Cl)C=C1 GRZXWCHAXNAUHY-NSISKUIASA-N 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000003153 chemical reaction reagent Substances 0.000 description 38
- 125000000623 heterocyclic group Chemical group 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- 239000002904 solvent Substances 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 26
- 125000000753 cycloalkyl group Chemical group 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 125000003342 alkenyl group Chemical group 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 125000000304 alkynyl group Chemical group 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- 230000035484 reaction time Effects 0.000 description 12
- 239000002002 slurry Substances 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 239000000839 emulsion Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 125000006413 ring segment Chemical group 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 150000002825 nitriles Chemical class 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 0 C[C@](CC1=O)c2c1ncnc2N1CCN(*)CC1 Chemical compound C[C@](CC1=O)c2c1ncnc2N1CCN(*)CC1 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000007806 chemical reaction intermediate Substances 0.000 description 4
- 238000010931 ester hydrolysis Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 125000001979 organolithium group Chemical group 0.000 description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- CWTRWPGRAQQDOY-UHFFFAOYSA-N 4,6-dichloropyrimidine-2-carbonitrile Chemical compound ClC1=CC(Cl)=NC(C#N)=N1 CWTRWPGRAQQDOY-UHFFFAOYSA-N 0.000 description 3
- KIGYEIRDVXHKMG-MRVPVSSYSA-N C[C@@H]1CC(C=2N=CN=C(C=21)N1CCNCC1)=O Chemical compound C[C@@H]1CC(C=2N=CN=C(C=21)N1CCNCC1)=O KIGYEIRDVXHKMG-MRVPVSSYSA-N 0.000 description 3
- UMMBRZLJMBSFAJ-RXMQYKEDSA-N ClC1=NC=NC(=C1[C@@H](CC#N)C)Cl Chemical compound ClC1=NC=NC(=C1[C@@H](CC#N)C)Cl UMMBRZLJMBSFAJ-RXMQYKEDSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- ZUZDORNNKJYZFE-RXMQYKEDSA-N OC1=NC=NC(=C1[C@@H](CC#N)C)O Chemical compound OC1=NC=NC(=C1[C@@H](CC#N)C)O ZUZDORNNKJYZFE-RXMQYKEDSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000002051 biphasic effect Effects 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- HASCQPSFPAKVEK-UHFFFAOYSA-N dimethyl(phenyl)phosphine Chemical compound CP(C)C1=CC=CC=C1 HASCQPSFPAKVEK-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000004744 fabric Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000006192 iodination reaction Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical group NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000006227 trimethylsilylation reaction Methods 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Chemical group 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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
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- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract
Description
本出願は、2014年9月26日に出願された米国仮出願第62/055,893号からの優先権を主張する。この仮出願の全内容はこれにより本明細書において参照として援用される。
本開示の分野
本開示は、(シクロペンチル[d]ピリミジン−4−イル)ピペラジン化合物を調製する方法に関し、より特定すれば(R)−4−(5−メチル−7−オキソ−6,7−ジヒドロ−5H−シクロペンタ[d]ピリミジン−4−イル)ピペラジンおよびそのN−保護誘導体を調製する方法に関し、これらは、イパタセルチブ(すなわち、(S)−2−(4−クロロフェニル)−1−(4−((5R,7R)−7−ヒドロキシ−5−メチル−6,7−ジヒドロ−5H−シクロペンタ[d]ピリミジン−4−イル)ピペラジン−1−イル)−3−(イソプロピルアミノ)−プロパン−1−オン)の合成に中間体として使用できる。本開示は、これらの方法に用いられる中間体である様々な化合物にさらに関する。
AKT(タンパク質キナーゼBとしても公知)は、ある特定のヒト腫瘍で過剰発現するセリン/トレオニンタンパク質キナーゼである。イパタセルチブは、現在、固形腫瘍、胃がんおよび前立腺がんを処置するための臨床試験で評価されているAKT阻害剤である。イパタセルチブは、例えば、米国特許第8,063,050号(例えば、実施例14を参照されたい)、ならびに国際特許出願公開第2008/006040号で開示されている。
本開示は、(シクロペンチル[d]ピリミジン−4−イル)ピペラジン化合物、より特定すれば、(R)−4−(5−メチル−7−オキソ−6,7−ジヒドロ−5H−シクロペンタ[d]ピリミジン−4−イル)ピペラジンならびにそのN−保護誘導体、例えばtert−ブチル−(R)−4−(5−メチル−7−オキソ−6,7−ジヒドロ−5H−シクロペンタ[d]ピリミジン−4−イル)ピペラジン−1−カルボキシレートを調製する改善した方法を提供する。本開示は、AKT阻害剤、特に、イパタセルチブを調製する方法、これらの(シクロペンチル[d]ピリミジン−4−イル)ピペラジン化合物およびそのN−保護誘導体を調製する、改善した方法の使用をさらに提供する。
本明細書において以下でさらに詳述されているように、本開示は、一般的に、(シクロペンチル[d]ピリミジン−4−イル)ピペラジン化合物を調製する、改善した方法を対象とし、より特定すれば、(R)−4−(5−メチル−7−オキソ−6,7−ジヒドロ−5H−シクロペンタ[d]ピリミジン−4−イル)ピペラジン、ならびにそのN−保護誘導体、例えば、一般的に以下のスキーム2で例示されているtert−ブチル−(R)−4−(5−メチル−7−オキソ−6,7−ジヒドロ−5H−シクロペンタ[d]ピリミジン−4−イル)ピペラジン−1−カルボキシレートを調製する、改善した方法を対象とする:
A.(シクロペンタ[d]ピリミジン−4−イル)ピペラジン化合物
1.環化ステップ
2.ピペラジン添加ステップ
3.臭素化ステップ
4.塩素化ステップ
5.ピリミジン合成ステップ
6.共役付加ステップおよび酵素的分割ステップ
7.一貫プロセス改善および全プロセス効率
8.例示的な実施形態
B.AKT阻害剤合成
C.反応生成物および中間体化合物
D.定義
(実施例2):酵素的分割
(実施例3):ピリミジン合成
(実施例4):塩素化−臭素化−SNAr一貫プロセス
(実施例5):グリニャール環化
(実施例6):比較例−グリニャールの試行
クロロ−ニトリルで置換されている類似体化合物の環化
(実施例7):比較例−HBrを使用した臭素化反応の試行
Claims (39)
- Yがブロモである、請求項2に記載の方法。
- Lvが、水素およびハロゲンから選択され、R1が、アセチル、トリフルオロアセチル、フタルイミジル、ベンジル、トリフェニルメチル、ベンジリデニル、p−トルエンスルホニル、p−メトキシベンジル、tertブチルオキシカルボニル、9−フルオレニルメチルオキシカルボニルおよびカルボベンジルオキシから選択される、請求項2または請求項3に記載の方法。
- 式IVの前記化合物またはその塩が、約1モル当量から約1.5モル当量の前記ピペラジン化合物と接触させられる、請求項2から4のいずれか一項に記載の方法。
- 式IVの前記化合物またはその塩が、前記ピペラジン化合物と、室温で接触させられる、請求項2から5のいずれか一項に記載の方法。
- 各Xがクロロである、請求項7に記載の方法。
- 各Xがヒドロキシルである、請求項7に記載の方法。
- 前記臭素化剤が、臭素、ブロモトリメチルシラン、オキシ臭化リン、N−ブロモスクシンイミドおよび三臭化リンから選択される、請求項7から9のいずれか一項に記載の方法。
- 式Vの前記化合物またはその塩が、約2モル当量から約7モル当量の前記臭素化剤と接触させられる、請求項7から10のいずれか一項に記載の方法。
- 前記臭素化反応が、約70℃から約75℃の温度で実行される、請求項7から11のいずれか一項に記載の方法。
- 式IVの前記化合物または塩が、式Vの前記化合物または塩の前記臭素化の後で、および前記ピペラジン化合物との反応の前に単離されない、請求項7から12のいずれか一項に記載の方法。
- 臭素化反応中に、揮発性副生成物を除去するために蒸留が使用される、請求項7から13のいずれか一項に記載の方法。
- 式Vcの前記化合物または塩が、Vbの前記化合物または塩の前記塩素化の後で、および臭素化の前に単離されない、請求項15に記載の方法。
- 塩素化剤が、オキシ塩化リンおよび三塩化リンから選択される、請求項15または請求項16に記載の方法。
- 式Vbの前記化合物またはその塩が、約1.5モル当量から約5モル当量の前記塩素化剤の前記と接触させられる、請求項15から17のいずれか一項に記載の方法。
- 式VIbの前記化合物または塩をホルムアミジン塩と接触させて、式VIbの前記化合物またはその塩を環化するステップを含む、請求項19に記載の方法。
- 分離が、酵素的分割により達成され、さらに、前記酵素的分割が、式IVaおよび式VIbの前記化合物、またはそれらの塩を含む前記異性体混合物を、ニトリラーゼ酵素またはリパーゼ酵素と接触させるステップにより達成される、請求項21に記載の方法。
- 酵素的分割が、ニトリラーゼ酵素を使用することにより達成される、請求項22に記載の方法。
- 前記異性体混合物が、酵素的分割の前に、反応生成混合物から単離されない、請求項22または請求項23に記載の方法。
- 前記クロトノニトリルが、約1から約1.5モル当量のマロネートと接触させられる、請求項21から24のいずれか一項に記載の方法。
- R1がアミノ保護基である、請求項1から25のいずれか一項に記載の方法。
- R1が、アセチル、トリフルオロアセチル、フタルイミジル、ベンジル、トリフェニルメチル、ベンジリデニル、p−トルエンスルホニル、p−メトキシベンジル、tertブチルオキシカルボニル、9−フルオレニルメチルオキシカルボニルおよびカルボベンジルオキシから選択される、請求項26に記載の方法。
- メタル化剤が有機金属化合物である、請求項1から27のいずれか一項に記載の方法。
- 前記有機金属化合物が、マグネシウムまたはリチウムを含む、請求項28に記載の方法。
- 前記有機金属化合物が、イソプロピルマグネシウムクロリド、イソプロピルマグネシウムクロリド塩化リチウム錯体、sec−ブチルマグネシウムクロリド、n−ブチルリチウム、sec−ブチルリチウム、t−ブチルリチウム、リチウムトリ−n−ブチルマグネシエート、リチウムトリイソプロピルマグネシエートおよびリチウム(イソプロピル)(ジ−n−ブチル)マグネシエートから選択される、請求項29に記載の方法。
- 式IIIの前記化合物またはその塩が、約1モル当量から約1.5モル当量の前記メタル化剤の前記と接触させられる、請求項1から30のいずれか一項に記載の方法。
- 先行する請求項のいずれか一項に記載の方法により調製される、式Iの化合物。
- 式IX:
(i)式III
(ii)式Iの前記化合物またはその塩を還元して、式VIIa:
(iii)式VIIaの前記化合物またはその塩を、任意選択で脱保護して、式VIIb:
(iv)式VIIbの前記化合物またはその塩を、式VIII:
- 請求項33に記載の方法により調製される、式IXの化合物。
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