ZA200504476B - Process for the preparation of pyrimidine compounds. - Google Patents
Process for the preparation of pyrimidine compounds. Download PDFInfo
- Publication number
- ZA200504476B ZA200504476B ZA200504476A ZA200504476A ZA200504476B ZA 200504476 B ZA200504476 B ZA 200504476B ZA 200504476 A ZA200504476 A ZA 200504476A ZA 200504476 A ZA200504476 A ZA 200504476A ZA 200504476 B ZA200504476 B ZA 200504476B
- Authority
- ZA
- South Africa
- Prior art keywords
- formula
- compound
- group
- alkyl
- aryl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 35
- 238000002360 preparation method Methods 0.000 title claims description 24
- 150000003230 pyrimidines Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 83
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- -1 alkaline earth metal carbonate Chemical class 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims description 8
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 6
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000011369 resultant mixture Substances 0.000 description 6
- 229960000789 guanidine hydrochloride Drugs 0.000 description 5
- HNNFDXWDCFCVDM-UHFFFAOYSA-N methyl 4-methyl-3-oxopentanoate Chemical compound COC(=O)CC(=O)C(C)C HNNFDXWDCFCVDM-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- QLXLISAWVGPSSW-UHFFFAOYSA-N ethyl 2-amino-4-(4-fluorophenyl)-6-propan-2-ylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=C(C(C)C)N=C(N)N=C1C1=CC=C(F)C=C1 QLXLISAWVGPSSW-UHFFFAOYSA-N 0.000 description 3
- UGYAOPGIMIOTOE-UHFFFAOYSA-N ethyl 2-amino-6-(4-fluorophenyl)-4-propan-2-yl-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1=C(N)NC(C(C)C)C(C(=O)OCC)=C1C1=CC=C(F)C=C1 UGYAOPGIMIOTOE-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 229940001593 sodium carbonate Drugs 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 101100113485 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) chs-3 gene Proteins 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- XCLDSQRVMMXWMS-UHFFFAOYSA-N ethyl 4-methyl-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(C)C XCLDSQRVMMXWMS-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000543 intermediate Chemical class 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- UWAQJFHCXKILSF-UHFFFAOYSA-N methyl 2-amino-6-(4-fluorophenyl)-4-propan-2-yl-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1=C(N)NC(C(C)C)C(C(=O)OC)=C1C1=CC=C(F)C=C1 UWAQJFHCXKILSF-UHFFFAOYSA-N 0.000 description 2
- ZMDDIBOTLBHGNY-UHFFFAOYSA-N methyl 6-(4-fluorophenyl)-4-propan-2-yl-2-pyrazol-1-yl-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1C(C(C)C)C(C(=O)OC)=C(C=2C=CC(F)=CC=2)N=C1N1C=CC=N1 ZMDDIBOTLBHGNY-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- LYTQYZZPBCKFTK-UHFFFAOYSA-N propan-2-yl 2-amino-6-(4-fluorophenyl)-4-propan-2-yl-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1=C(N)NC(C(C)C)C(C(=O)OC(C)C)=C1C1=CC=C(F)C=C1 LYTQYZZPBCKFTK-UHFFFAOYSA-N 0.000 description 2
- RSNLWQKJOHYEAJ-UHFFFAOYSA-N propan-2-yl 4-methyl-3-oxopentanoate Chemical compound CC(C)OC(=O)CC(=O)C(C)C RSNLWQKJOHYEAJ-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- XQYAEIDOJUNIGY-UHFFFAOYSA-N (2-iodo-5-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(I)C(B(O)O)=C1 XQYAEIDOJUNIGY-UHFFFAOYSA-N 0.000 description 1
- WBNTUGPRADFXAL-UHFFFAOYSA-N 1H-pyrazole-5-carboximidamide Chemical compound NC(=N)C=1C=CNN=1 WBNTUGPRADFXAL-UHFFFAOYSA-N 0.000 description 1
- 150000005006 2-aminopyrimidines Chemical class 0.000 description 1
- VIQUKKCAYSMRHC-UHFFFAOYSA-N 4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-amine Chemical compound NC1=NC(C(C)C)=CC(C=2C=CC(F)=CC=2)=N1 VIQUKKCAYSMRHC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- MJBWDEQAUQTVKK-IAGOWNOFSA-N aflatoxin M1 Chemical compound C=1([C@]2(O)C=CO[C@@H]2OC=1C=C(C1=2)OC)C=2OC(=O)C2=C1CCC2=O MJBWDEQAUQTVKK-IAGOWNOFSA-N 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005599 alkyl carboxylate group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- ZZCNKSMCIZCVDR-UHFFFAOYSA-N barium(2+);dioxido(dioxo)manganese Chemical compound [Ba+2].[O-][Mn]([O-])(=O)=O ZZCNKSMCIZCVDR-UHFFFAOYSA-N 0.000 description 1
- 150000004054 benzoquinones Chemical class 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- QWDLWJHZPSTJKL-UHFFFAOYSA-N ethyl 4-(4-fluorophenyl)-2-(methylamino)-6-propan-2-ylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=C(C(C)C)N=C(NC)N=C1C1=CC=C(F)C=C1 QWDLWJHZPSTJKL-UHFFFAOYSA-N 0.000 description 1
- JTXOTDJQFWHXEA-UHFFFAOYSA-N ethyl 6-(4-fluorophenyl)-2-(methylamino)-4-propan-2-yl-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1=C(NC)NC(C(C)C)C(C(=O)OCC)=C1C1=CC=C(F)C=C1 JTXOTDJQFWHXEA-UHFFFAOYSA-N 0.000 description 1
- QJKIIKVRMCMCEO-UHFFFAOYSA-N ethyl 6-(4-fluorophenyl)-2-(methylamino)-4-propan-2-yl-1,4-dihydropyrimidine-5-carboxylate;2-methylguanidine;hydrochloride Chemical compound Cl.CN=C(N)N.N1C(NC)=NC(C(C)C)C(C(=O)OCC)=C1C1=CC=C(F)C=C1 QJKIIKVRMCMCEO-UHFFFAOYSA-N 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229960004198 guanidine Drugs 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- RMYXELUYVYVDAI-UHFFFAOYSA-N methyl 2-amino-4-(4-fluorophenyl)-6-propan-2-ylpyrimidine-5-carboxylate Chemical compound COC(=O)C1=C(C(C)C)N=C(N)N=C1C1=CC=C(F)C=C1 RMYXELUYVYVDAI-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical group P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003555 thioacetals Chemical class 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Description
COMPOUNDS AND PROCESSES
The present invention concerns a process for the preparation of pyrimidines and intermediate compounds useful in the preparation thereof.
Substituted pyrimidine compounds are valuable compounds for use in particularly the pharmaceutical industry. Certain 2-aminopyrimidine compounds are intermediates - used in the preparation of pharmaceutical compounds useful in the treatment of, inter alia, hypercholesterolemia, hyperlipoproteinemia and artherosclerosis. Synthetic routes to substituted pyrimidine compounds have been disclosed in EP-A-O0 521 471 and
WOQO01/04100. Nevertheless, it remains desirable to identify alternative routes for the preparation of substituted pyrimidine compounds.
According to a first aspect of the present invention, there is provided a process for the preparation of a compound of Formula (1):
E
A
RY A
Formula (1) which comprises a) reacting a compound of formula R'-CO-CH,-E with a compound of formula R>-CHX'X? in the presence of a compound of formula R®°R*N-C(=NH)NH, and a catalyst, thereby to form a dihydropyrimidine; and b) oxidising the dihydropyrimidine produced in step a) to form the compound of Formula (1) wherein
R'is H or an alkyl group;
R? is H or an alkyl or aryl group;
R® and R* are each independently H, alkyl or aryl, or R® and R* are linked to form, together with the nitrogen to which they are attached, a 5 to 7 membered heterocyclic * ring;
E is H, an unsubstituted alkyl group, an aryl group or an electron withdrawing group; and . 30 X" and X? are each independently leaving groups, or X' and X? together represent =O.
Dihydropyrimidines formed in step a) can be represented by the Formula (2):
E
1 2
SN
N N
WY
. 2 Ns
Formula (2)
It will be recognised that the compounds of Formula (2) can exist in a number of tautomeric forms in which the double bonds are delocalised into other positions in the molecule, notably into different positions around the pyrimidine ring. Without wishing to be bound by any theory, it is believed that for certain compounds of Formula 2, the predominant tautomeric form is of Formula (2a):
E
Zz
NaN
Tw
N
R¥ Ng
Formula (2a)
Alkyl groups which may be represented by R' include linear, branched and cyclic alkyl groups commonly comprising from 1 to 8 carbon atoms. Preferred cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Preferred linear and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl and tert-butyl groups. Most preferably, R' represents isopropyl.
Alkyl groups which may be represented by R? are as described above for R’.
Aryl groups which may be represented by R® include both homoaryl and heteroaryl groups, and commonly comprise at least one 5 to 7 membered aromatic ring. Examples of aryl groups include phenyl, naphthyl and pyridyl groups. Most preferably, R® represents a phenyl group.
Alkyl and aryl groups which may be represented by R® and R* are as described above for R' and R?. In certain preferred embodiments, R® represents methyl and R* . 25 represents H. In other preferred embodiments, both of R® and R* are H.
Alkyl and aryl groups which may be represented by R', R% R® and R* may be . unsubstituted or substituted by one or more substituents. Examples of substituents include optionally substituted atkoxy (preferably C,4-alkoxy), optionally substituted alkyl (preferably C4-alkyl), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), optionally substituted heterocyclyl, polyalkylene oxide (preferably polyethylene oxide or polypropylene oxide), carboxy, oxo, phosphato, sulpho,
nitro, cyano, halo, especially chloro and fluoro, ureido, -SO;F, hydroxy, ester, -NR°R®, i -COR?, -CONR®R?®, -NHCOR?, carboxyester, sulphone, and -SO,NR®R® wherein R? and R® are each independently H, optionally substituted alkyl (especially C,4-alkyl) or optionally substituted aryl (preferably phenyl), or, in the case of -NR?R®, -CONR®R® and -SO.NR?R®,
R® and R® together with the nitrogen atom to which they are attached may represent an aliphatic or aromatic ring system. Optional substituents for any of the substituents ) described may be selected from the same list of substituents.
Unsubstituted alkyl groups which may be represented by E are those unsubstituted alkyl groups as described above for R'.
Aryl groups which may be represented by E are as described above for R>.
Electron withdrawing groups which may be represented by E include nitro groups; nitrile groups; perhaloalkyl groups, such as trifluoromethyl and pentafluoroethyl; ester groups, especially alkyl carboxylate groups; sulphonamide groups; keto groups; amide groups; and aldehyde groups, especially formyl groups.
E may also represent a group of formula -CHX®X®, wherein X* and X° each independently represents a halo, especially a chloro or bromo group, an alkoxy group, especially a C,4alkoxy, such as a methoxy or ethoxy group, an alkylthio group, especially a Cisalkyithio group, or X® and X° are linked to form a cyclic acetal or thioacetal commonly comprising, with the carbon to which X? and X® are bonded, from 5 to 7 atoms in the ring. When E represents a group of formula -CHX?X®, it is preferred that X? is the same as X°.
Further groups which may be represented by E are groups of formula -CH,E?, wherein E? represents halo, especially bromo or chloro, or a phosphorus-containing moiety, such as a phosphate ester, for example of formula -OP(=0)(OR°®),, a phosphonate ester, for example of formula -P(=0)(OR®),, a phosphite, for example of formula -P(OR°),, a phosphine, for example of formula -P(R®),, or a phosphine oxide, for example of formula -P(=0)(R®), in each of which R® represents an alkyl, such as a C,_4 alkyl, or an aryl, such as a phenyl, group. When E? represents a phosphorus-containing moiety, it is preferably a phosphine oxide of formula -P(=0)(R?), wherein R? represents methyl, ethyl or phenyl.
E may also represent a group of formula -CR*=CR'R?, wherein R*, R* and R? each independently represent H, alkyl or aryl. Preferably, R* and RY represent H, and R? represents an optionally substituted Cis alkyl chain. R® is preferably substituted by two ) hydroxy groups, commonly present as a protected 1,3-dihydroxy moiety. R? preferably comprises a terminal carboxyl group, especially a carboxy ester group. R® is most : 35 preferably a group of formula:
’ A _eor wherein R'is an alkyl group, preferably a tert-butyl group.
A particular compound of formula R'-CO-CH,-E is of formula: oo 5 0 Xs
HAA or wherein R'is an alkyl group, preferably a tert-butyl group.
Preferably, E represents a group of formula -CO»(Ci4alkyl), and especially -CO Me, -CO;Et or -CO;iPr.
Leaving groups which can be represented by X' and X? include chloro, bromo and iodo, especially chloro, groups, and alkoxy groups, especially Cijalkoxy, such as methoxy, groups. Commonly when X' and X? are leaving groups, either both are selected from chloro, bromo or iodo, or both are alkoxy. It is most preferred that X' and X? together represent =O.
Oxidising agents which may be employed in the process according to the present invention include those oxidising agents known in the art to oxidise dihydropyrimidines to pyrimidines. Examples of suitable oxidising agents include quinones, such as chloranil, and particularly substituted benzoquinones such as 2,3-dichloro-5,6-dicyano-1,4- benzoquinone; halogens, such as bromine, transition metal oxidants such as barium manganate, copper chloride, optionally in the presence of phenanthroline, and manganese dioxide; metallic oxidants, such as palladium on charcoal or other suitable platinum group metals; and elemental sulfur. The most preferred oxidants are elemental sulfur and manganese dioxide.
In certain embodiments of the present invention, particularly when E represents H or unsubstituted alkyl, and especially H, the product of the reaction obtained from step (a) is the substituted pyrimidine rather than a dihydropyrimidine. Without wishing to be bound . by any theory, it is believed that any dihydropyrimidine formed is autoxidised to the pyrimidine by the presence of oxygen, or the dihydropyrimidine self-oxidises or ] 30 disproportionates.
Preferred compounds of formula R'-CO-CH,-E are compounds of formula (C,. salkyl)-CO-CH,CO,R®, wherein R® represents a Cy alkyl group, especially a methyl, ethyl or isopropyl group. Most preferred compounds of formula R'-CO-CH,-E are compounds of formulae:
g-oncoon, —g-crcoca and gcng—o—( ) 0 0 0 0 : Compounds of formula (CH3),CH-CO-CH,-CO.-C3H;, preferably (CH;),CH-CO-
CH,-CO,-CH(CHs3)., form another aspect of the present invention. Such compounds may i 5 be prepared by methods analogeus to those known in the art for the preparation of similar compounds, such as methyl isobutyrylacetate and ethyl isobutyrylacetate.
Preferred compounds of formula R2-CHX'X? are compounds of formula: xX) wherein X® represents a substituent, especially halo, and n is 0 or 1-5. Preferably x2 is chloro or fluoro, alkyl, preferably methyl, or alkoxy, preferably methoxy. Most preferably n is 1, and X°® is present at the 4-position. Especially preferred is 4-fluorobenzaldehyde.
Preferred compounds of formula R®R*N-C(=NH)NH, are guanidine and methylguanidine. The compounds of formula R®*R*N-C(=NH)NH, can be employed as the free base, but in many embodiments are advantageously employed as a salt, such as a nitrate, carbonate or sulphate salt, and especially a hydrochloride salt.
Preferred catalysts which can be employed in the present invention are bases.
Bases which can be employed in the process of the present invention are preferably inorganic bases. Examples of inorganic bases include alkali and alkaline earth metal carbonates and hydrogencarbonates, particularly sodium or potassium hydrogencarbonate and most preferably sodium or potassium carbonate.
Step a) of the process according to the present invention preferably employs a solvent which is inert under the reaction conditions employed. In many embodiments, a polar solvent is employed, preferably a polar aprotic solvent, for example including dichloromethane, dimethylsulphoxide and tetrahydrofuran. Preferred solvents are amides, such as N-methylpyrrolidinone and especially dimethylformamide and dimethylacetamide.
Mixtures of solvents may be employed if desired.
In many preferred embodiments of the present invention, a mixture comprising the . 30 compound of formula R'-CO-CH,-E, compound of formula R*-CHX'X? and compound of formula R’R*N-C(=NH)NH, is formed, optionally in the presence of a solvent, and the . catalyst added to this mixture.
It will be recognised that the reaction conditions employed in Step a) of the present invention the process may be varied over a wide range, depending for example on the nature of the reagents and/or solvent employed. Step a) commonly employs a reaction temperature in the range of from about 50°C to about 80°C, such as from about 55° to
65°C. In many embodiments, a mole ratio of compound of formula R*’R*N-C(=NH)NH. to } compound of formula R'-CO-CH,-E of from about 1.5 : 1 to about 3.5 : 1, such as about 2 : 1, can be advantageously employed. In many embodiments, a stoichiometric mole ratio, or a small molar excess, such as up to about 1.2 : 1, of compound of formula R-CHX'X? to compound of formula R'-CO-CH,-E is employed.
Step b) of the process preferably employs a solvent which is inert under the oT reaction conditions employed. The solvent is selected according to the nature of the oxidising agent employed, and may include the solvents described above for step a).
Further solvents which may be employed in step b) include non-polar solvents, for example hydrocarbons, such as toluene, and dialkylethers, such as methyl tertiary-butyl ether. Mixtures of solvents may be employed if desired.
It will be recognised that the reaction conditions employed in Step b) of the process according to the present invention may be varied over a wide range, depending for example on the nature of the oxidant and/or solvent employed. Step b) commonly employs a reaction temperature in the range of from about 50°C to about 140°C, such as from about 100°C to 120°C. In many embodiments, a stoichiometric mole ratio, or a molar excess of oxidant to dihydropyrimidine is employed. In certain highly preferred embodiments, the oxidant employed is MnO, and azeotropic conditions are employed, most preferably employing toluene as solvent, with a mole ratio of MnO, to dihydropyrimidine of from about 2: 1 to 4 : 1 being especially preferred.
Compounds of Formula (2) and tautomers thereof, especially compounds of
Formula (2a), wherein E is not H, R® and R* are not both unsubstituted alkyl groups and
R'is not -CH; when R? is unsubstituted phenyl or o-nitropheny! are novel, and accordingly form a second aspect of the present invention. In such compounds, it is preferred that at least one of R® and R* represents H, and that R? preferably represents a phenyl group substituted by one or more halogens, and most preferably represents a 4-fluorophenyl group.
Step a) of the process according to the first aspect of present invention forms a third aspect of the present invention.
Step b) of the process according to the first aspect of present invention forms a fourth aspect of the present invention.
When either or both of R® and R* is H, the compounds of Formulae (1) or (2) may ’ be reacted with reagents to introduce a substituent onto the exocyclic nitrogen, especially “to introduce an alkyl, especially a methyl, or an alkyl- or arylsulfonyl, especially a mesyl, . 35 substituent.
In a particularly preferred aspect of the present invention, there is provided a process for the preparation of a compound of Formula (3):
E i 2 Ngo
Formula (3) - which comprises a) reacting a compound of formula R'-CO-CH-E with a compound of formula R:-CHX'X? in the presence of a compound of formula R’'HN-C(=NH)NH, and a catalyst, thereby to form a dihydropyrimidine, which may be represented by a compound of formula (2) or (2a) as described above but in which R® represents R” and R* is H; b) oxidising the dihydropyrimidine produced in step a) to form a compound of Formula (4)
E i
Sa
Formula (4) and c) reacting the compound of Formula (4) with a compound of formula R°SO,-X* to give a compound of Formula (3); wherein
R', R% E, X" and X? are as previously described;
R° represents alky or aryl, preferably methyl;
Ris H, alkyl or aryl; and
X* represents a leaving group, preferably Cl or Br.
Alkyl and aryl groups which may be represented by R’ are as described above for
R®. In many embodiments, R’ represents H or a methyl group.
Preferred features for R', R% E, X' and X? are as previously described.
The present invention is illustrated further, without limitation, by the following examples. > 25
Example 1. Preparation of Methyl 2-amino-4-(4-fluorophenyl)-6-isopropyl- . pyrimidine-5-carboxylate a) A 100 ml two neck round bottom flask equipped with a condenser and connected to a nitrogen line was charged with p-fluorobenzaldehyde (0.57ml, 5mmol), methyl isobutyrylacetate (“MIBA”, 0.79g, 5.5mmol), guanidine hydrochloride (1.19g, 12.5mmol), potassium carbonate (2.76g, 40mmol) and 10 ml of anhydrous dimethylformamide (DMF).
This mixture was stirred and heated at 70°C for 20h. The reaction mixture changed from ] colourless to yellow during this time. After cooling, DMF was removed under vacuum and the residue partitioned between brine (50ml) and ethyl acetate (200ml). The aqueous ) phase was washed with ethyl acetate (200ml) and the combined organic layers were dried over magnesium sulfate and filtered. The solvent was removed under vacuum to obtain 1g of yellow solid. 'HNMR and LC showed methyl 2-amino-4-(4-fluorophenyl)-6-isopropyl- 1,6-dihydropyrimidine-5-carboxylate as the major component (82%). 'H NMR (250MHz, C,DS0);8 0.95-1.1 (2xd, 6H, CH(CH3);), 3.45 (s, 3H, O-CHj3), 4.0 (septet, 1H, CH(CHs3),), 6.1 (broad s, 2H, NH), 7.1-7.3 (m, 5-H, N-H & 4 C-H aromatic). b) A 25 ml three neck round bottom flask evacuated and back-filled with nitrogen was charged with methyl 2-amino-4-(4-flucrophenyl)-6-isopropyl-1,6-dihydropyrimidine-5- carboxylate (100 mg) and 15 ml of anhydrous THF. 2,3-Dichloro-5,6-dicyano-1,4- benzoquinone (135 mg, 0.45 mmol) was added under nitrogen. The red solution was stirred at room temperature. After 40 min, methyl 2-amino-4-(4-fluorophenyl)-6-isopropyl- pyrimidine-5-carboxylate was observed by HPLC and LC-MS. The product was identified by comparison with a standard of high purity prepared by a different chemical route. Both samples co-eluted by HPLC and showed the same ions by positive and negative electrospray mass spectrometry. : Example 2. Preparation of Methyl 2-amino-4-(4-fluorophenyl)-6-isopropyi-1,6- dihydropyrimidine-5-carboxylate
Guanidine hydrochloride (12.1g), 4-Fiuorobenzaldehyde (7.0g), methyl 4-methyl-3-oxo- pentanoate (8.9g) and DMF (150ml) were charged to a vessel equipped with a condenser and connected to a nitrogen line. The resultant mixture was stirred until a clear solution was obtained. Potassium carbonate (17.5g) is charged and the mixture heated to 70°C for 3 hours. The reaction mixture was cooled to ambient temperature and filtered. It contained methyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5- carboxylate in 55% yield. An analytical sample was prepared by removing the reaction solvents by evaporation under reduced pressure, precipitating the product from the resultant oil in acetonitrlie and recrystallisation from acetonitrile. 'H NMR (250MHz, C,D;S0);5 0.95-1.1 (2xd, 6H, CH(CH3),), 3.45 (s, 3H, O-CH3), 4.0 : 35 (septet, TH, CH(CHa),), 6.1 (broad s, 2H, NH), 7.1-7.3 (m, 5-H, N-H & 4 C-H aromatic).
Example 3. Preparation of Ethyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6- . dihydropyrimidine-5-carboxylate
Guanidine hydrochloride (24.1g), 4-Fluorobenzaldehyde (13.99), ethyl 4-methyl-3-oxo- . pentanoate (16.2g) and DMF (300ml) were charged to a vessel equipped with a 5) condenser and connected to a nitrogen line. The resultant mixture was stirred until a clear solution was obtained. Sodium carbonate (26.89) was charged and the mixture heated to 70°C for 4 hours. The reaction mixture contained ethyl 2-amino-4-(4-fluorophenyl)-6- isopropyl-1,6-dihydropyrimidine-5-carboxylate in 75% yield. DMF was removed by evaporation under reduced pressure until the reaction mixture contained 35-40% DMF by weight. Toluene was charged (112ml) and the temperature adjusted to 55°C. This solution was washed 3 times with 10% aqueous sodium chloride solution, cooled to 10°C, washed with toluene (32ml) and dried in a vacuum oven at 50°C. 'H NMR (250MHz, C.DgSO); & 1.0 (t, 3H, CH,CH3), 1.1 (d, 6H, CH(CHs)), 3.9 (q, 2H,
CH,CH;), 4.05 (septet, 1H, CH(CH3),), 5.2 (s, 1H, N-C-H), 6.1 (broad s, 2H, NH), 7.1 (4, 2H, C-H aromatic), 7.15-7.3 (m, 3H, N-H & 2 C-H aromatic).
Example 4. Preparation of Isopropyl 4-methyl-3-oxo-pentanoate
Methyl 4-methyl-3-oxo-pentanoate (304g), isopropyl! alcohol (500ml) and p-toluenesulfonic acid (3.8g) were stirred together and heated to reflux at 90°C. After 3 hours, 400ml of solvent was collected by distillation at atmospheric pressure. Fresh isopropyl alcohol was added and the mixture refluxed for a further 3 hours. The cycle of distillation, addition of fresh solvent and refluxing was continued until the conversion had reached 95%, determined by a peak area ratio of product : starting material of 95 : 5 measured by LC.
The remaining volatile solvents were removed by distillation and the resultant liquid washed with 10% sodium carbonate solution and dried over anhydrous sodium sulfate and filtered to give isopropyl 4-methyl-3-oxo-pentanoate as a clear liquid (301g, 83%). 'H NMR (250MHz, C,D¢SO); § 1.05, 1.2 (2xd, 12H, C-CH(CHs),, O-CH(CHas).), 2.7 (septet, 1H, C-CH(CHj3).), 3.6 (s, 2H, CH,),4.05 (septet, 1H, O-CH(CH;),)
Example 5. Preparation of Isopropyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6- dihydropyrimidine-5-carboxylate : Guanidine hydrochloride (12.1g), 4-Fluorobenzaldehyde (7.0g), isopropyl 4-methyl-3-oxo- : 35 pentanoate (8.99) and DMF (150ml) were charged to a vessel equipped with a condenser and connected to a nitrogen line. The resultant mixture was stirred until a clear solution was obtained. Potassium carbonate (17.5g) was charged and the mixture heated to 70°C for 3 hours. The reaction mixture was cooled to ambient temperature, filtered, and the solvents removed by evaporation under reduced pressure. The resultant oil was triturated in water at 80°C and cooled to give a slurry that was filtered and dried to give isopropyl 2- amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate in 67% yield. 'H NMR (250MHz, C,DsSO); 8 0.9-1.15 (d, 12H, C-CH(CHa);, O-CH(CH3),), 4.0 (septet, 1H, C-CH(CHas),), 4.75 (septet, 1H, O-CH(CH,).), 5.2 (s, 1H, N-C-H), 6.1 (broad s, 2H,
NH,), 7.1 (t, 2H, C-H aromatic), 7.2 (m, 3H, N-H & 2 C-H aromatic). Co
Example 6. Preparation of Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methylamino-1,6- dihydropyrimidine-5-carboxylate 1-Methylguanidine hydrochloride (8.25g), 4-Fluorobenzaldehyde (4.29), ethyl 4-methyl-3- oxo-pentanoate (5.0g) and DMF (100ml) were charged to a vessel equipped with a condenser and connected to a nitrogen line. The resultant mixture stirred until a clear solution is obtained. Sodium carbonate (4.0g) was charged and the mixture heated to 70°C for 2 hours. The reaction mixture was cooled to ambient temperature, filtered, and the solvents removed by evaporation under reduced pressure. The resultant oil was triturated in water at 50°C and cooled to give a slurry that was filtered and dried to give ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methylamino-1,6-dihydropyrimidine-5-carboxylate in 63% yield. 'H NMR (250MHz, C,DeSO); & 0.95-1.1 (m, 9H, CH,CH; & CH(CHj3).), 2.7 (s, 3H, NH-
CH), 3.9 (q, 2H, CH:CHzs), 4.0 (septet, 1H, CH(CHa)2), 5.2 (s, 1H, N-C-H), 6.4 (broad s, 1H, NH-CHs), 7.1 (1, 2H, C-H aromatic), 7.2 (m, 3H, N-H & 2 C-H aromatic).
Example 7. Preparation of Methyl 4-(4-fluorophenyl} -6-isopropyl -2-(1-pyrazolyl) -1,6-dihydropyrimidine-5-carboxylate 1H-Pyrazole carboxamidine (prepared according to the method of Bernatowicz, Wu and
Matsueda; J. Org. Chem., 52, 2497-2502, 1992; 0.919), 4-Fluorobenzaldehyde (0.379), methyl 4-methyl-3-oxo-pentanoate (0.4g), potassium carbonate (1.38g) and DMF (10ml) were charged to a small vessel. The resultant mixture was heated to 85°C for 6 hours.
The reaction mixture was cooled to ambient temperature, filtered, and the solvents removed by evaporation under reduced pressure. The resultant oil was triturated in water to give a slurry that was filtered, washed and dried. The major component isolated by ) column chromatography was Methyl 4-(4-fluorophenyl) -6-isopropyl -2-(1-pyrazolyl) -1,6- dihydropyrimidine-5-carboxylate. : 35 'H NMR (250MHz, C.DsSO); & 1.05-1.2 (2xd, 6H, CH(CHs),), 3.55 (s, 3H, O-CHs), 4.0 (septet, 1H, CH(CH,),), 5.5 (s, 1H, N-C-H), 6.55 (m, 1H, pyrazolyl C-H), 7.0 (t, 2H, phenyl!
C-H), 7.3 (m, 3H, N-H & 2 phenyt C-H), 7.7 (m, 1H, pyrazolyl C-H), 8.4 (m, 1H, pyrazolyl
C-H).
Example 8. Preparation of 2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine } Guanidine hydrochloride (1.19g), 4-Fluorobenzaldehyde (0.62g), 3-methyl butan-2-one (0.479) and DMF (20ml) were charged to a flask. The resultant mixture was stirred until a clear solution was obtained. Sodium tert-butoxide (2.36g) was charged and the mixture stirred at ambient temperature for 18 hours. The reaction mixture contained 2-amino-4-(4- fluorophenyl)-6-isopropyl-pyrimidine in 30% yield. The major component was isolated by - flash column chromatography on silica, eluting with ethyl acetate/hexanes (1:4). 'H NMR (250MHz, CDCl); § 1.25 (d, 6H, CH(CH3),), 2.8 (septet, 1H, CH(CHzs),), 6.6 (broad s, 2H, NH), 7.35 (t, 2H, C-H aromatic), 8.15 (m, 2 C-H aromatic).
Example 9. Preparation of Ethyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine- 5-carboxylate
Ethyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate (22.69) was dissolved in toluene (150ml) and heated until a solution was obtained. Manganese dioxide (18.89) was added as a slurry in toluene (150ml) and the mixture refluxed under azeotropic conditions for 6 hours until conversion was complete. A small amount of water was collected in the Dean and Stark trap. The slurry was filtered and the solvents removed by evaporation under reduced pressure to give ethyl 2-amino-4-(4-fluorophenyl)- 6-isopropyl-pyrimidine-5-carboxylate as a crystalline solid in 96% yield. 'H NMR (250MHz, C,D6S0); § 0.95 (t, 3H, CH.CH3), 1.2 (d, 6H, CH(CHs)2), 3.1 (septet, 1H, CH(CHsa),), 4.05 (q, 2H, CH,CH3), 7.1 (broad s, 2H, NH), 7.3 (t, 2H, C-H aromatic), 7.55 (m, 2 C-H aromatic).
Example 10. Preparation of Ethyl 2-amino-4-(4-fluorophenyl)-6-isopropyl- pyrimidine-5-carboxylate
The process of Example 9 was repeated, but using elemental sulfur (4.7g) in place of the manganese dioxide, and a reaction time of 24 hours. The product was obtained in a near quantitative conversion.
Example 11. Preparation of Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methylamino- pyrimidine-5-carboxylate : The process of Example 9 was repeated but employing 10mmol of ethyl 4-(4- ‘ 35 fluorophenyl)-6-isopropyl-2-methylamino-1,6-dihydropyrimidine-5-carboxylate in place of ethyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate, with the other reagents and components reduced proportionately. The product was obtained in a near quantitative conversion.
'H NMR (250MHz, C,DsSO); § 0.95 (t, 3H, CH.CH3), 1.2 (d, 6H, CH(CHjs),), 2.85 (d, 3H,
N-CHs), 3.1 (septet, 1H, CH(CH3),), 4.05 (q, 2H, CH,CH3), 7.3 (t, 2H, C-H aromatic), 7.45- 7.65 (broad s, 3-H, N-H & 2 C-H aromatic).
Claims (26)
1. A process for the preparation of a compound of Formula (1): ] E 1 2 NA he N c rR Ng? Formula (1) which comprises a) reacting a compound of formula R'-CO-CH,-E with a compound of formula R*-CHX'X? in the presence of a compound of formula R®’R*N-C(=NH)NH, and a catalyst, thereby to form a dihydropyrimidine; and b) oxidising the dihydropyrimidine produced in step a) to form the compound of Formula (1) wherein R'is H or an alkyl group; R? is H or an alkyl or aryl group; R® and R* are each independently H, alkyl or aryl, or R® and R* are linked to form, together with the nitrogen to which they are attached to form a 5 to 7 membered heterocyclic ring; E is H, an unsubstituted alkyl group, an aryl group or an electron withdrawing group; and X" and X? are each independently leaving groups, or X' and X? together represent =O.
2. A process according to claim 1, wherein the dihydropyrimidine is represented by the Formula (2a), and tautomers thereof: E 1 2 NaN YS AN 3 4 - 25 "OR Formula (2a) wherein R', R%, R?, R* and E are as defined in claim 1.
3. A process according to claim 1 or claim 2, wherein the compound of formula R'- CO-CH,-E is a compound of formulae:
—g-cncocr I—g-cncocn, or —g-ong-o— 0 0 0 fo] . 4. A process according to any preceding claim, wherein the compound of formula Re. CHX'X? is a compound of formula: S - Ores x); wherein X® represents halo, and nis 0 or 1-5, and preferably 4-fluorobenzaldehyde.
5. A process according to any preceding claim, wherein the compound of formula R3R*N-C(=NH)NH; is guanidine or methylguanidine.
6. A process according to claim 5, wherein the compound of formula RPR*N- C(=NH)NH; is employed as a hydrochloride or sulfate salt.
7. A process according to any preceding claim, wherein the catalyst is a base.
8. A process according to claim 7, wherein the base is an alkali or alkaline earth metal carbonate or hydrogencarbonate.
9. A process according to any preceding claim, wherein the oxidising agent is manganese dioxide.
10. A compound of Formula (2a), and tautomers thereof: E 1 2 NaN DERE N RY Ng Formula (2a) : wherein : R'is H or an alkyl group; R2 is H or an alkyl or aryl group; R® and R* are each independently H, alkyl or aryl, provided that R® and R* are not both unsubstituted alkyl; and
E is an unsubstituted alkyl group, an aryl group or an electron withdrawing group, further provided that R' is not -CH; when R? is unsubstituted phenyl or o-nitrophenyl. ) 11. A compound according to claim 10, wherein R? represents a phenyl group substituted by one or more halogens.
12. A compound according to claim 10 or 11, wherein at least one of R® and R* is H.
13. A compound according to any one of claims 10 to 12, wherein R' represents isopropyl and R? represents 4-fluorophenyl.
14. A compound according to any one of claims 10 to 13, wherein R® is H or methyl and R*is H.
15. A compound according to anyone of claims 10 to 14, wherein E represents a group of formula -CO,(C.salkyl).
16. A process for the preparation of a compound of Formula (2a) and tautomers thereof: E 1 2
SY . NaN Tw AN Rw Formula (2a) which comprises a) reacting a compound of formula R'-CO-CH.-E with a compound of formula R-CHX'X? in the presence of a compound of formula R’R*N-C(=NH)NH, and a catalyst, thereby to form the compound of Formula (2a) wherein R'is an H or an alkyl group; : R? is an H or an alkyl or aryl group; R® and R* are each independently H, alkyl or aryl, or R® and R* are linked to form, . together with the nitrogen to which they are attached to form a 5 to 7 membered heterocyclic ring; E is H, an unsubstituted alkyl group, an aryl group or an electron withdrawing group; and X' and X? are each independently leaving groups, or X" and X? together represent =O.
17. A process according to claim 16, wherein R' represents isopropyl, R? represents 4- fluorophenyl, and R® and R* each independently represents H or methyl.
18. A process according to claim 17, wherein R® is methyl and R* is H.
19. A process for the preparation of a compound of Formula (1): E NAT he 2 N Formula (1) which comprises oxidising a compound of Formula (2a): E SA NaN Tw N PC Ng Formula (2a) wherein R'is H or an alkyl group; R%is an H, an alkyl or aryl group; R® and R* are each independently H, alkyl or aryl, or R® and R* are linked to form, together with the nitrogen to which they are attached to form a 5 to 7 membered heterocyclic ring; and E is H, an unsubstituted alkyl group, an ary! group or an electron withdrawing group.
20. A process according to claim 19, wherein R’ represents isopropyl, R? represents 4- fluorophenyl, and R® and R* each independently represents H or methyl. . 25
21. A process according to claim 19 or 20, wherein the oxidation employs manganese dioxide.
22. A process for the preparation of a compound of Formula (3): ’ E ’ A AN R SO,R® Formula (3) which comprises a) reacting a compound of formula R'-CO-CH,-E with a compound of formula R?*-CHX'X? in the presence of a compound of formula R'HN-C(=NH)NH, and a catalyst, thereby to form a dihydropyrimidine; b) oxidising the dihydropyrimidine produced in step a) to form a compound of Formula (4) E i ay Formula (4) and c) reacting the compound of Formula (4) with a compound of formula R®S0,-X* to give a compound of Formula (3); wherein R', R% E, X' and X? are as defined in claim 1; R® represents alky or aryl, preferably methyl; Ris H, alkyl or aryl; and X* represents a leaving group, preferably Cl or Br.
23. A process for the preparation of a compound of Formula (3):
E . NA oo #7 Ngo Formula (3)
which comprises A a) reacting a compound of formula R'-CO-CH-E with a compound of formula R-CHX'X? in the presence of a compound of formula R’HN-C(=NH)NH, and a catalyst, thereby to } form a dihydropyrimidine comprising an exocyclic group formula -NHR; b) reacting the compound of Formula (4) with a compound of formula R°SO,-X* to form a dihydropyrimidine comprising an exocyclic group formula -N(R")SO.R®; ¢) oxidising the dinydropyrimidine produced in step b) to form a compound of Formula (3); wherein R', RZ E, X" and X* are as defined in claim 1; R® represents alky or aryl, preferably methyl; Ris H, alkyl or aryl; and X* represents a leaving group, preferably Cl or Br.
24. A process according to claim 22 or 23, wherein R' represents isopropyl, R? represents 4-fluorophenyl, X' and X? together represent =O, R® represents methyl, E represents a group of formula -CO»(C alkyl), and R” is H or methyl.
25. A compound of formula (CH;),CH-CO-CH2-CO,-CsH;
26. A compound according to claim 25, of formula: —g-ong—o—( noe 0 lo}
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GB0229243A GB0229243D0 (en) | 2002-12-16 | 2002-12-16 | Compounds and process |
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CN104592130A (en) * | 2014-12-30 | 2015-05-06 | 江苏阿尔法药业有限公司 | Novel method for preparing rosuvastatin main chain |
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2003
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GB0229243D0 (en) | 2003-01-22 |
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