CN109651424B - Synthesis method of 7-protecting group-4- (1-hydrogen-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine - Google Patents
Synthesis method of 7-protecting group-4- (1-hydrogen-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine Download PDFInfo
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- CN109651424B CN109651424B CN201710941803.0A CN201710941803A CN109651424B CN 109651424 B CN109651424 B CN 109651424B CN 201710941803 A CN201710941803 A CN 201710941803A CN 109651424 B CN109651424 B CN 109651424B
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- Prior art keywords
- pyrimidine
- pyrrole
- reaction
- protecting group
- hydro
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- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims abstract description 108
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 239000003513 alkali Substances 0.000 claims abstract description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 13
- 125000006239 protecting group Chemical group 0.000 claims abstract description 11
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 10
- BPENHADWRBUXPN-UHFFFAOYSA-N 4-cyano-3-oxobutanoic acid Chemical compound OC(=O)CC(=O)CC#N BPENHADWRBUXPN-UHFFFAOYSA-N 0.000 claims abstract description 9
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006298 dechlorination reaction Methods 0.000 claims abstract description 6
- 238000006704 dehydrohalogenation reaction Methods 0.000 claims abstract description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 4
- 238000007069 methylation reaction Methods 0.000 claims abstract description 4
- -1 acetal diol Chemical class 0.000 claims description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 43
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 claims description 41
- 239000002904 solvent Substances 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 235000011056 potassium acetate Nutrition 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 claims description 5
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims description 5
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 claims description 4
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- DJOJFYVMGCYKJV-UHFFFAOYSA-N ethyl 4-cyano-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CC#N DJOJFYVMGCYKJV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- KZHKHYJBEOOUAJ-UHFFFAOYSA-N methyl 4-cyano-3-oxobutanoate Chemical compound COC(=O)CC(=O)CC#N KZHKHYJBEOOUAJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- LQXDLNIXFFSOSU-UHFFFAOYSA-N tert-butyl 4-cyano-3-oxobutanoate Chemical compound CC(C)(C)OC(=O)CC(=O)CC#N LQXDLNIXFFSOSU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 3
- FLZPTLSRDKJVLE-UHFFFAOYSA-N 1,2-dimethoxyethane-1,2-diol Chemical compound COC(O)C(O)OC FLZPTLSRDKJVLE-UHFFFAOYSA-N 0.000 claims description 2
- CRZJPEIBPQWDGJ-UHFFFAOYSA-N 2-chloro-1,1-dimethoxyethane Chemical compound COC(CCl)OC CRZJPEIBPQWDGJ-UHFFFAOYSA-N 0.000 claims description 2
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000002349 favourable effect Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000011987 methylation Effects 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 239000007791 liquid phase Substances 0.000 description 17
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 108010024121 Janus Kinases Proteins 0.000 description 4
- 102000015617 Janus Kinases Human genes 0.000 description 4
- 239000004327 boric acid Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 3
- 208000017733 acquired polycythemia vera Diseases 0.000 description 3
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- 229910001220 stainless steel Inorganic materials 0.000 description 3
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- OVXJWSYBABKZMD-UHFFFAOYSA-N 2-chloro-1,1-diethoxyethane Chemical compound CCOC(CCl)OCC OVXJWSYBABKZMD-UHFFFAOYSA-N 0.000 description 2
- WHNQTHDJEZTVHS-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-yl)propanoic acid Chemical compound C1=CC=C2SC(CCC(=O)O)=NC2=C1 WHNQTHDJEZTVHS-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 2
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229950000971 baricitinib Drugs 0.000 description 2
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- XQSJHQXYQAUDFC-UHFFFAOYSA-N 4,6-dichloropyrimidine-5-carbaldehyde Chemical compound ClC1=NC=NC(Cl)=C1C=O XQSJHQXYQAUDFC-UHFFFAOYSA-N 0.000 description 1
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical compound OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 description 1
- GOJNFUXEBVBARW-UHFFFAOYSA-N 4-amino-6-chloropyrimidine-5-carbaldehyde Chemical compound NC1=NC=NC(Cl)=C1C=O GOJNFUXEBVBARW-UHFFFAOYSA-N 0.000 description 1
- BWDWLJXFUOPRSD-UHFFFAOYSA-N COC(C)OC.[Br] Chemical compound COC(C)OC.[Br] BWDWLJXFUOPRSD-UHFFFAOYSA-N 0.000 description 1
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- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 1
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- 230000032050 esterification Effects 0.000 description 1
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- 230000026030 halogenation Effects 0.000 description 1
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- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- NHDHVHZZCFYRSB-UHFFFAOYSA-N pyriproxyfen Chemical compound C=1C=CC=NC=1OC(C)COC(C=C1)=CC=C1OC1=CC=CC=C1 NHDHVHZZCFYRSB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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Abstract
The invention discloses a simple synthesis method of 7-protecting group-4- (1-hydrogen-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine. The method utilizes cyanoacetoacetate and haloacetaldehyde acetal dehydrohalogenation reaction to prepare a compound (IV), and then the compound (IV) is condensed with formamidine hydrochloride and alkali to prepare a compound (V); protecting amino group by a protecting group reagent, performing DMFDMA (methyl division multiple access) methylation, and condensing hydrazine hydrate to prepare a compound (VIII); then reacting with chloro reagent to prepare compound (IX); then catalytic hydrogenation dechlorination is carried out to obtain 7-protective substituent-4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (X). The method has the advantages of cheap and easily obtained raw materials, one-pot operation by two times, high environmental protection, simple and convenient process route, convenient reaction operation, high reaction selectivity, high purity of the obtained product, high yield and low cost, and is favorable for green industrial production.
Description
Technical Field
The invention relates to a synthesis method of a pyrrolopyrimidine heterocyclic compound which is a key intermediate required for preparing rucotinib and barrecetinib, in particular to a simple synthesis method of 7-protecting group-4- (1-hydrogen-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (X), belonging to the field of pharmaceutical biochemical engineering.
Background
The Ruxolitinib, also known as Ruxolitinib, is an antitumor drug developed by nova, and is mainly used for Myelofibrosis (MF) treatment. Myelofibrosis is a clonal disease of hematopoietic stem cells characterized by myelogenous hyperplasia, including Primary Myelofibrosis (PMF), Polycythemia Vera (PV), myelofibrosis after polycythemia vera (post-PV MF), myelofibrosis after primary thrombocythemia (post-ET MF), Janus kinase (JAK)/Signal Transduction and Activator of Transcription (STAT) signaling pathways play an important role in the pathogenesis of MF, with about 65% of PMF, 55% of post-ET MF, and 96% of post-PV MF 617 having JAK 2V 617F gene mutations. The lucertinib is a potent JAK1/JAK2 inhibitor, and random control studies (COMFORT-I and COMFORT-II) conducted by Nowa in the United states and Europe all show that the lucertinib has good therapeutic effect when orally administered, and is approved by the European Union and the United states for the treatment of MF.
Baricitinib, a selective irreversible inhibitor of Janus kinase 1(JAK1) and Janus kinase 2(JAK 2). Baricitinib, jointly developed by Incyte and Li Lai, was approved by the European drug administration for marketing at 13.2.2017, and later approved by the Japanese pharmaceutical medical device integration agency (PMDA) at 3.7.2017 under the trade name Oleumiant, and was approved for the treatment of mild to moderate rheumatoid arthritis in adult patients who respond poorly or intolerantly to other anti-arthritis drugs.
The related compound has the following structural formula:
patent US20100190981 discloses a preparation method of luccotinib, 4, 6-dihydroxypyrimidine, phosphorus oxychloride and DMF are formylated and are simultaneously chlorinated to prepare 4, 6-dichloro-5-formylpyrimidine, then the 4-amino-6-chloro-5-formylpyrimidine is prepared by substituting ammonia methanol amino, 4-amino-6-chloro-5-formylpyrimidine is reacted with Wittig reagent to obtain 4-amino-6-chloro-5- (-2-methoxy) vinyl pyrimidine, concentrated hydrochloric acid is refluxed and cyclized to obtain 4-chloro-7-hydropyrrole [2,3-d ] pyrimidine, then 7-position is protected, and then the protected 7-position is coupled with 1- (1-ethoxyethyl) -1-hydropyrazole-4-boric acid ester under the catalysis of tetrakis (triphenylphosphine) palladium to remove a pyrazole ring protecting group, obtaining a key intermediate 7-protecting group-4- (1-hydrogen-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (X), then carrying out addition and chiral resolution on the key intermediate and 3-cyclo-penteylonitrile or asymmetric addition on the key intermediate and 3-cyclo-penteylonitrile under a chiral catalyst, carrying out deprotection and phosphoric acid salification to prepare the lucocotinib. The chemical reaction equation is depicted as scheme 1.
Synthesis scheme 1
Wherein the 1- (1-ethoxyethyl) -1-hydropyrazole-4-boric acid ester is obtained by utilizing pyrazole to carry out selective halogenation, 1-position protection, Grignard reagent or metal lithiation and boric acid esterification, and a chemical reaction equation is described as a synthetic route 2.
Synthesis scheme 2
Patents WO2009114512, WO2016125080, US2009233903 and patent CN102026999A also use 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (x) as starting material to prepare barrectin, the reaction process is a mixture of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine and 2- (1- (ethylsulfonyl) azetidin-3-ylidene) acetonitrile and/or 2- (3-chloro-1- (ethylsulfonyl) azetidin-3-yl) acetonitrile, and deprotection is used to prepare barrectin, and the chemical reaction equation is described as scheme 3.
Synthesis scheme 3
In summary, the compound of formula X, i.e. the 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine, is a key intermediate of efectinib and barremictinib in the existing synthetic routes, but the prior art preparation methods thereof have the following disadvantages: the preparation process is complicated, the waste water amount is large, and the atom economy is low; the required Wittig reaction, the tetrakis (triphenylphosphine) palladium catalytic coupling reaction, the Grignard reagent or the metal lithiation have high operation requirement; the used raw materials of 4-chloro-7-hydropyrrolo [2,3-d ] pyrimidine, 1- (1-ethoxyethyl) -1-hydropyrrole-4-boric acid ester and tetrakis (triphenylphosphine) palladium have high price, long preparation process, are not favorable for cost reduction, need for multiple column chromatography separation and are not favorable for industrial implementation.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of a pyrrolopyrimidine heterocyclic compound which is a key intermediate required for preparing the ricotinib and the barrecetinib, namely a simple synthesis method of 7-protecting group-4- (1-hydrogen-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (X), in order to prepare the ricotinib and the barrecetinib by using cheap and easily-obtained raw materials and a simplified process flow.
The technical scheme of the invention is as follows:
a simple synthesis method of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (x), comprising the steps of:
(1) in the presence of a solvent and a base 1, carrying out dehydrohalogenation reaction on cyanoacetoacetate (II) and haloacetaldehyde acetal diol (III) to prepare 1, 1-dialkoxy-3-cyano-4-oxo-hexanoate (IV), and in the presence of a base 2, condensing the 1, 1-dialkoxy-3-cyano-4-oxo-hexanoate (IV) and formamidine hydrochloride to prepare 2- (7-hydropyrrole [2,3-d ] pyrimidin-4-yl) acetate (V);
(2) preparing 2- (7-protecting substituent pyrrole [2,3-d ] pyrimidine-4-yl) acetate (VI) by protecting amino with a protecting group reagent in the presence of a solvent and alkali by using 2- (7-hydrogen pyrrole [2,3-d ] pyrimidine-4-yl) acetate (V); filtering, and performing a methylation reaction on the obtained 2- (7-protective substituent pyrrole [2,3-d ] pyrimidine-4-yl) acetate (VI) filtrate and N, N-dimethylformamide dimethyl acetal (DMFDMA) to obtain 2- (7-protective substituent pyrrole [2,3-d ] pyrimidine-4-yl) -2-dimethylamine methylene acetate (VII); then carrying out condensation reaction with hydrazine hydrate to prepare 7-protective substituent-4- (1-hydrogen-3-hydroxypyrazole-4-yl) pyrrole [2,3-d ] pyrimidine (VIII);
(3) preparing 7-protective substituent-4- (1-hydrogen-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) by the action of 7-protective substituent-4- (1-hydrogen-3-hydroxypyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (VIII) and a chlorinated reagent;
(4) and (3) carrying out catalytic hydrogenation dechlorination on 7-protective substituent-4- (1-hydro-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) in a solvent, alkali and a catalyst to obtain 7-protective substituent-4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (X).
Wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl or other C4H9A group; x is chlorine or bromine; PG is trimethylsiloxyethyl methyl, triisopropyl silyl or benzyloxy methyl.
In accordance with a preferred aspect of the present invention,
the cyanoacetoacetate ester (II) in the step (1) is cyanoacetoacetate methyl ester, cyanoacetoacetate ethyl ester or cyanoacetoacetate tert-butyl ester;
the haloacetaldehyde acetal diol (III) in the step (1) is chloroacetaldehyde dimethyl acetal, chloroacetaldehyde diethyl alcohol, bromoacetaldehyde dimethyl acetal or bromoacetaldehyde diethyl acetal;
the solvent in the step (1) is N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or any mixed solvent thereof; the mass ratio of the solvent to the cyanoacetoacetic ester is (4-15) to 1;
in the step (1), the alkali 1 and the alkali 2 are both one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium methoxide methanol solution or sodium ethoxide ethanol solution or a mixture thereof;
in the step (1), the molar weight ratio of the alkali 1, the cyano-acetoacetic ester (II) and the halogen-acetaldehyde acetal diol (III) is (1.0-1.5) to (1.0-1.5): 1;
in the step (1), the dehydrohalogenation reaction temperature is-10-80 ℃, the reaction is carried out for 2-10 hours, the reaction temperature is further preferably 10-40 ℃, and the reaction is carried out for 4-7 hours;
in the step (1), the molar weight ratio of the alkali 2, the formamidine hydrochloride and the cyanoacetoacetate (II) is (1.0-1.5) to (1.0-1.5): 1;
in the step (1), the condensation reaction temperature is 0-80 ℃, the reaction is carried out for 2-10 hours, and the reaction temperature is further preferably 30-60 ℃, and the reaction is carried out for 3-6 hours.
In accordance with a preferred aspect of the present invention,
the solvent in the step (2) is tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxy ethylene glycol, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or any mixed solvent thereof; the mass ratio of the solvent to the 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate (V) is (4-15) to 1;
the protecting group reagent in the step (2) is 2- (chloromethoxy) ethyl) trimethylsilane, triisopropylsilicon chloride and benzyl chloromethyl ether;
in the step (2), the alkali is sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate or a mixture thereof, and the molar weight ratio of the alkali, the protecting group reagent and the 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate (V) is (1.0-2.0) to (1.0-1.5): 1;
in the step (2), the reaction temperature of the 2- (7-hydropyrrolo [2,3-d ] pyrimidine-4-yl) acetate (V) and a protecting group reagent for protecting amino is 20-80 ℃, and the reaction lasts for 2-8 hours;
the molar weight ratio of DMFDMA to 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate (V) in step (2) is (1.0-2.0): 1;
in the step (2), the temperature of the methylene reaction is 60-120 ℃, the reaction is carried out for 2-9 hours, the reaction temperature is further preferably 80-100 ℃, and the reaction is carried out for 3-6 hours;
the molar weight ratio of the hydrazine hydrate to the 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate (V) in the step (2) is (1.0-2.0): 1;
in the step (2), the condensation reaction temperature is 30-120 ℃, the reaction time is 2-9 hours, the reaction temperature is further preferably 70-100 ℃, and the reaction time is 3-7 hours.
In accordance with a preferred aspect of the present invention,
the chlorinated reagent in the step (3) is phosphorus oxychloride, phosphorus pentachloride or thionyl chloride; the molar weight ratio of the chlorinated reagent to the 7-protective substituent-4- (1-hydrogen-3-hydroxypyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (VIII) is (1.0-20.0): 1.
in the step (3), the chlorination reaction temperature is 30-150 ℃, the reaction is carried out for 2-20 hours, and the reaction temperature is preferably 50-140 ℃, and the reaction is carried out for 3-16 hours.
In accordance with a preferred aspect of the present invention,
the solvent in the step (4) is one of tetrahydrofuran, 2-methyltetrahydrofuran and glycol dimethyl acetal or any mixed solvent thereof, and the mass ratio of the solvent to the 7-protective substituent-4- (1-hydrogen-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) is (4-20): 1.
The alkali in the step (4) is one of sodium carbonate, potassium carbonate, sodium acetate and potassium acetate or a mixture of the sodium carbonate, the potassium carbonate, the sodium acetate and the potassium acetate in any proportion, and is used for neutralizing hydrogen chloride generated by catalytic hydrodechlorination, and the molar ratio of the alkali to 7-protective substituent-4- (1-hydrogen-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) is (1.0-2.0): 1.
the catalyst in the step (4) is palladium carbon or Raney nickel, the mass ratio of the added amount of the catalyst to the 7-protective substituent-4- (1-hydrogen-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) is 0.5-10.0%, the hydrogen pressure is 0.2-1.0 MPa, the catalytic hydrogenation dechlorination reaction temperature is 30-100 ℃, the reaction time is 2-9 hours, and the reaction time is preferably 40-80 ℃ and 3-7 hours.
The invention uses cyanoacetoacetate (II) and halogen aldehyde acetal diol (III) to prepare 1, 1-dialkoxy-3-cyano-4-oxo-n-hexanoate (IV) by dehydrohalogenation reaction under the action of solvent and alkali, and then the 1, 1-dialkoxy-3-cyano-4-oxo-n-hexanoate is condensed with formamidine hydrochloride and alkali to prepare 2- (7-hydropyrrole [2,3-d ] pyrimidine-4-yl) acetate (V); the obtained 2- (7-hydrogen pyrrole [2,3-d ] pyrimidine-4-yl) acetate (V) is subjected to amino protection by a protecting group reagent, DMFDMA methylation and hydrazine hydrate condensation to prepare 7-protecting substituent-4- (1-hydrogen-3-hydroxy pyrazole-4-yl) pyrrole [2,3-d ] pyrimidine (VIII); then 7-protecting substituent-4- (1-hydrogen-3-hydroxypyrazole-4-yl) pyrrole [2,3-d ] pyrimidine (VIII) and a chlorinated reagent act to prepare 7-protecting substituent-4- (1-hydrogen-3-chloropyrazole-4-yl) pyrrole [2,3-d ] pyrimidine (IX); then catalytic hydrogenation dechlorination is carried out to obtain 7-protective substituent-4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (X). The compound is a key intermediate for preparing the reecotinib and the barrectin benzoate, and can be used for preparing the reecotinib and the barrectin benzoate.
The structural formula and the synthetic route 4 of the compound related in the preparation method are as follows:
synthesis scheme 4
Wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl or other C4H9A group; x is chlorine or bromine; PG is trimethylsiloxyethyl methyl, triisopropyl silyl or benzyloxy methyl.
The invention has the beneficial effects that:
the raw materials used in the invention are cheap and easily available, and the cost is low; the operation of one-pot method is utilized twice, the process route is simple and convenient, and the reaction operation is convenient; the reaction selectivity is high, the byproducts are few, the reaction is stable and controllable, the purity of the obtained product is high, the yield is high, the purity can reach more than 99 percent, and the total yield is as high as more than 72.2 percent; the method has the advantages of high reaction atom economy, environmental protection and contribution to industrial production.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified.
Example 1: 2- (7-Hydropyrrole [2,3-d ]]Pyrimidin-4-yl) acetic acid methyl ester (V)1) Preparation of
150 g of N, N-dimethylformamide, 15.5 g (0.11 mol) of methyl cyanoacetoacetate, 24.0 g (0.12 mol) of 27% sodium methoxide methanol solution, 17.0 g (0.1 mol) of bromoacetaldehyde dimethyl acetal is added dropwise at the temperature of between 20 and 25 ℃ in a 500 ml four-neck flask, the dropwise addition is finished within about 30 minutes, then the reaction is carried out at the temperature of between 20 and 25 ℃ for 6 hours, the reaction of the bromoacetaldehyde dimethyl acetal is detected in a gas phase, and the methyl 1, 1-dimethoxy-3-cyano-4-oxo-hexanoate (IV) is obtained1). 10.0 g (0.12 mol) of formamidine hydrochloride and 24.0 g (0.12 mol) of 27% sodium methoxide methanol solution are added to react at 40-45 ℃ for 4 hours, 20 g of saturated aqueous ammonium chloride solution is added to adjust the pH value to 3-4, and the mixture is stirred at 40-45 ℃ for 2 hours. The reaction liquid was added to 500 g of ice water, filtered, and the filter cake was recrystallized from 90 g of isopropyl alcohol to obtain 17.1 g of 2- (7-hydropyrrolo [2,3-d ]]Pyrimidin-4-yl) acetic acid methyl ester, liquid phase purity 99.8%, yield 89.5%.
Example 2: 2- (7-Hydropyrrole [2,3-d ]]Pyrimidin-4-yl) acetic acid ethyl ester (V)2) Preparation of
Adding 150 g of N, N-dimethylformamide, 15.5 g (0.1 mol) of ethyl cyanoacetoacetate, 27.5 g (0.12 mol) of 30% sodium ethoxide ethanol solution into a 500 ml four-neck flask, dropwise adding 19.5 g (0.1 mol) of bromoacetaldehyde diethyl acetal at the temperature of between 20 and 25 ℃, reacting for 6 hours at the temperature of between 20 and 25 ℃ after dropwise adding is finished for about 30 minutes, detecting the completion of the reaction of the bromoacetaldehyde diethyl acetal in a gas phase manner to obtain 1, 1-diethoxy-3-cyano-4-oxo-N-hexanoate (IV)2). Adding 10.0 g (0.12 mol) formamidine hydrochloride, 27.5 g (0.12 mol) 30% sodium ethoxide ethanol solution, reacting at 40-45 ℃ for 4 hours, adding 20 g saturated ammonium chloride water solution, adjusting pH value to 3-4, and stirring at 30-35 ℃ for 3 hours. The reaction liquid was added to 500 g of ice water, filtered, and the filter cake was recrystallized from 80 g of isopropyl alcohol to give 18.6 g of 2- (7-hydropyrrolo [2,3-d ]]Pyrimidin-4-yl) acetate with a liquid phase purity of 99.5% and a yield of 90.7%.
Example 3: 2- (7-Hydropyrrole [2,3-d ]]Pyrimidin-4-yl) acetic acid tert-butyl ester (V)3) Preparation of
150 g of N, N-dimethylformamide, 18.5 g (0.10 mol) of cyanoacetoacetic acid tert-butyl ester, 6.5 g (0.12 mol) of solid sodium methoxide are added into a 500 ml four-neck flask at the temperature of between 30 and 35 ℃, 15.5 g (0.1 mol) of chloroacetaldehyde diethyl acetal is added dropwise, the dropwise addition is finished within about 30 minutes, then the reaction is carried out at the temperature of between 30 and 35 ℃ for 6 hours, and the reaction of chloroacetaldehyde diethyl acetal is finished by gas phase detection to obtain 1, 1-diethoxy-3-cyano-4-oxo-N-hexyl tert-butyl ester (IV)3). 10.0 g (0.12 mol) of formamidine hydrochloride and 24.0 g (0.12 mol) of 27% sodium methoxide methanol solution are added to react at 40-45 ℃ for 4 hours, 20 g of saturated aqueous ammonium chloride solution is added to adjust the pH value to 3-4, and the mixture is stirred at 40-45 ℃ for 2 hours. The reaction liquid was added to 500 g of ice water, filtered, and the filter cake was recrystallized from 90 g of isopropyl alcohol to give 19.8 g of 2- (7-hydropyrrolo [2,3-d ]]Pyrimidin-4-yl) acetic acid tert-butyl ester, liquid phase purity 99.3%, yield 85.0%.
Example 4: 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d]Pyrimidine (VIII)1) Preparation of
Into a 500 ml four-necked flask, 150 g of N, N-dimethylformamide, 19.1 g (0.1 mol) of methyl 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate, 25.0 g (0.15 mol) of 2- (chloromethoxy) ethyl) trimethylsilane, 20.7 g (0.15 mol) of potassium carbonate were added and stirred at 40 to 45 ℃ for 5 hours, and after completion of the liquid phase detection reaction, the mixture was filtered, the filter cake was washed with 20 g of N, N-dimethylformamide, the filtrates were combined, the obtained filtrate was transferred to another dry 500 ml four-necked flask, 23.8 g (0.2 mol) of DMFDMA was added and stirred at 90 to 95 ℃ for 4 hours. Cooling to 40-45 deg.C, adding 16.0 g (0.2 mol) of 40% hydrazine hydrate, stirring at 40-45 deg.C for 2 hr, and stirring at 90-95 deg.C for 3 hr. The reaction liquid was cooled to 20 to 25 ℃, added to 500 g of ice water, filtered, and the filter cake was recrystallized from 90 g of isopropanol to give 29.6 g of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine in a liquid phase purity of 99.6% and a yield of 89.3%.
Example 5: 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d]Pyrimidine (VIII)1) Preparation of
Into a 500 ml four-necked flask, 150 g of N, N-dimethylformamide, 20.5 g (0.1 mol) of ethyl 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate, 21.5 g (0.13 mol) of 2- (chloromethoxy) ethyl) trimethylsilane, 16.0 g (0.15 mol) of sodium carbonate were added and stirred at 40 to 45 ℃ for 5 hours, and after completion of the liquid phase detection reaction, the reaction mixture was filtered, the filter cake was washed with 20 g of N, N-dimethylformamide, the filtrates were combined, the resulting filtrate was transferred to another dry 500 ml four-necked flask, 23.8 g (0.2 mol) of DMFDMA was added and stirred at 80 to 85 ℃ for 6 hours. Cooling to 40-45 deg.C, adding 16.0 g (0.2 mol) of 40% hydrazine hydrate, stirring at 40-45 deg.C for 2 hr, and stirring at 90-95 deg.C for 3 hr. The reaction liquid was cooled to 20 to 25 ℃, added to 500 g of ice water, filtered, and the filter cake was recrystallized from 90 g of isopropanol to give 29.2 g of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine in a liquid phase purity of 99.7% and a yield of 88.1%.
Example 6: 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d]Pyrimidine (VIII)1) Preparation of
Into a 500 ml four-necked flask, 150 g of N, N-dimethylformamide, 23.5 g (0.1 mol) of tert-butyl 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate, 26.5 g (0.16 mol) of 2- (chloromethoxy) ethyl) trimethylsilane, 27.5 g (0.2 mol) of potassium carbonate were added and stirred at 40 to 45 ℃ for 5 hours, and after completion of the liquid phase detection reaction, the reaction mixture was filtered, the filter cake was washed with 20 g of N, N-dimethylformamide, the filtrates were combined, the obtained filtrate was transferred to another dry 500 ml four-necked flask, 23.8 g (0.2 mol) of DMFDMA was added and stirred at 90 to 95 ℃ for 4 hours. Cooling to 40-45 deg.C, adding 16.0 g (0.2 mol) of 40% hydrazine hydrate, stirring at 40-45 deg.C for 2 hr, and stirring at 90-95 deg.C for 3 hr. The reaction liquid was cooled to 20 to 25 ℃, added to 500 g of ice water, filtered, and the filter cake was recrystallized from 90 g of isopropanol to give 30.4 g of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine in a liquid phase purity of 99.5% and a yield of 91.8%.
Example 7: 7- ((2-triisopropylsilyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d]Pyrimidine (VIII)2) Preparation of
Into a 500 ml four-necked flask, 150 g of N, N-dimethylformamide, 19.1 g (0.1 mol) of methyl 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate, 29.0 g (0.15 mol) of triisopropylchlorosilane, 20.7 g (0.15 mol) of potassium carbonate were added, and the mixture was stirred at 40 to 45 ℃ for 5 hours, and after completion of the liquid phase detection reaction, the mixture was filtered, and the filter cake was washed with 20 g of N, N-dimethylformamide, and the filtrates were combined, and the obtained filtrate was transferred to another dry 500 ml four-necked flask, and 23.8 g (0.2 mol) of DMFDMA was added, and the mixture was stirred at 90 to 95 ℃ for 4 hours. Cooling to 40-45 deg.C, adding 16.0 g (0.2 mol) of 40% hydrazine hydrate, stirring at 40-45 deg.C for 2 hr, and stirring at 90-95 deg.C for 3 hr. Cooling to 20-25 ℃, adding the reaction liquid into 500 g of ice water, filtering, and recrystallizing a filter cake with 90 g of isopropanol to obtain 31.6 g of 7- ((2-triisopropylsilyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrole [2,3-d ] pyrimidine, wherein the liquid phase purity is 99.4% and the yield is 88.5%.
Example 8: 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-chloropyrazol-4-yl) pyrrolo [2,3-d]Pyrimidine (IX)1) Preparation of
A500 ml four-neck flask equipped with a thermometer, mechanical stirring and reflux condenser was charged with 46.0 g (0.3 mol) of phosphorus oxychloride, 16.5 g (0.05 mol) of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine, stirred at 140 ℃ for 3 hours, slightly cooled, and recovered under reduced pressure at 60-80 ℃, the reaction system was poured into 200 g of ice water while it was hot, sufficiently stirred, then extracted with dichloromethane (3X 80 g), the organic phases were combined, washed successively with a saturated sodium bicarbonate solution (30 g) and a saturated saline solution (30 g), dried over anhydrous sodium sulfate, and recovered by distillation dichloromethane to obtain 16.2 g of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-chloro-methane Pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine, the yield is 92.5 percent, and the liquid phase purity is 99.7 percent.
Example 9: 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-chloropyrazol-4-yl) pyrrolo [2,3-d]Pyrimidine (IX)1) Preparation of
A500-ml four-neck flask equipped with a thermometer, mechanical stirring and reflux condenser was charged with 71.5 g (0.6 mol) of thionyl chloride, 16.5 g (0.05 mol) of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine, stirred at 60-65 ℃ for reaction for 15 hours, slightly cooled, and recovered at 40-50 ℃ under reduced pressure, the reaction system was poured into 200 g of ice water while it was hot, sufficiently stirred, then extracted with dichloromethane (3X 80 g), the organic phases were combined, washed successively with a saturated sodium bicarbonate solution (30 g) and a saturated saline solution (30 g), then dried over anhydrous sodium sulfate, and recovered by distillation of dichloromethane, to give 14.6 g of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-chloro) 4 Pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine, the yield is 83.5 percent, and the liquid phase purity is 99.6 percent.
Example 10: 7- ((2-triisopropylsilyl) -4- (1-hydro-3-chloropyrazol-4-yl) pyrrolo [2,3-d]Pyrimidine (IX)2) Preparation of
A500 ml four-neck flask which is provided with a thermometer, a mechanical stirring device and a reflux condenser is added with 46.0 g (0.3 mol) of phosphorus oxychloride, 17.9 g (0.05 mol) of 7- ((2-triisopropylsilyl) -4- (1-hydro-3-hydroxypyrazol-4-yl) pyrrole [2,3-d ] pyrimidine, the mixture is stirred and reacted at 130 ℃ and 140 ℃ for 3 hours, the mixture is cooled slightly, the phosphorus oxychloride is recovered under reduced pressure at 60-80 ℃, the reaction system is poured into 200 g of ice water while the reaction system is hot, the mixture is fully stirred, dichloromethane is used for extraction (3 multiplied by 80 g), organic phases are combined, the organic phases are washed by saturated sodium bicarbonate solution (30 g) and saturated saline solution (30 g), then the anhydrous sodium sulfate is used for drying, the dichloromethane is recovered by distillation, and 17.5 g of 7- ((2-triisopropylsilyl) -4- (1-hydro-3-chloropyrazol-4-yl) pyriproxyfen are obtained Pyrrole [2,3-d ] pyrimidine, yield 93.2%, liquid phase purity 99.5%.
Example 11: 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d]Pyrimidine (X)1) Preparation of
Adding 50 g of tetrahydrofuran, 2.0 g of potassium carbonate, 3.5 g (10 mmol) of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine and 0.05 g of 5 percent palladium carbon into a 250 ml stainless steel pressure kettle, replacing 3 times by nitrogen, charging hydrogen to 0.05-0.1MPa, carrying out catalytic hydrogenation reaction at 50-55 ℃ for 5 hours, cooling to room temperature after the hydrogenation reaction is finished, filtering, recovering the solvent, recrystallizing the residue by using 20 g of methyl tert-butyl ether to obtain 3.1 g of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine, the purity of the liquid phase is 99.9 percent, the yield is 98.4 percent, and the total yield is 72.2 percent (calculated by the bromine acetaldehyde dimethyl acetal).
1HNMR(DMSO-d6,400MHz):13.30(bs,1H),8.76(s,1H),8.66(bs,1H),8.36(bs,1H),7.74(d,1H),7.11(d,1H),5.62(s,2H),3.51(t,2H),0.82(t,2H),0.15(s,9H)。
Example 12: 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d]Pyrimidine (X)1) Preparation of
Adding 50 g of ethylene glycol dimethyl acetal, 2.0 g of sodium acetate, 3.5 g (10 mmol) of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine and 0.15 g of 50% Raney nickel into a 250 ml stainless steel pressure kettle, replacing 3 times with nitrogen, charging hydrogen to 0.05-0.1MPa, carrying out catalytic hydrogenation reaction at 50-55 ℃ for 5 hours, cooling to room temperature after the hydrogenation reaction is finished, filtering, recovering the solvent, recrystallizing the residue with 20 g of methyl tert-butyl ether to obtain 3.0 g of 7- ((2- (trimethylsilyl) ethoxy) methyl) -4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine, the purity of the liquid phase is 99.8 percent, and the yield is 95.1 percent.
Example 13: 7- ((2-triisopropylsilyl) -4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d]Pyrimidine (X)2) Preparation of
To a 250 ml stainless steel autoclave, 50 g of tetrahydrofuran, 3.0 g of potassium acetate, 3.75 g (10 mmol) of 7- ((2-triisopropylsilyl) -4- (1-hydro-3-chloropyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine, 0.05 g of 5% palladium on carbon, and after 3 times of replacement with nitrogen, the pressure of the charging gas is 0.05 to 0.1MPa, the catalytic hydrogenation reaction is carried out for 5 hours at the temperature of between 50 and 55 ℃, after the hydrogenation reaction is finished, the temperature is reduced to room temperature, the filtration is carried out, the solvent is recovered, and the remainder is recrystallized by 20 g of methyl tertiary butyl ether to obtain 3.36 g of 7- ((2-triisopropylsilyl) -4- (1-hydrogen-3-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine, the liquid phase purity is 99.8 percent, and the yield is 98.5 percent.
Claims (10)
1. A process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (x), comprising the steps of:
(1) in the presence of a solvent and a base 1, carrying out dehydrohalogenation reaction on cyanoacetoacetate (II) and haloacetaldehyde acetal diol (III) to prepare 1, 1-dialkoxy-3-cyano-4-oxo-hexanoate (IV), and in the presence of a base 2, condensing the 1, 1-dialkoxy-3-cyano-4-oxo-hexanoate (IV) and formamidine hydrochloride to prepare 2- (7-hydropyrrole [2,3-d ] pyrimidin-4-yl) acetate (V);
(2) preparing 2- (7-protecting substituent pyrrole [2,3-d ] pyrimidine-4-yl) acetate (VI) by protecting amino with a protecting group reagent in the presence of a solvent and alkali by using 2- (7-hydrogen pyrrole [2,3-d ] pyrimidine-4-yl) acetate (V); filtering, and performing a methylation reaction on the obtained 2- (7-protective substituent pyrrole [2,3-d ] pyrimidine-4-yl) acetate (VI) filtrate and N, N-dimethylformamide dimethyl acetal (DMFDMA) to obtain 2- (7-protective substituent pyrrole [2,3-d ] pyrimidine-4-yl) -2-dimethylamine methylene acetate (VII); then carrying out condensation reaction with hydrazine hydrate to prepare 7-protective substituent-4- (1-hydrogen-3-hydroxypyrazole-4-yl) pyrrole [2,3-d ] pyrimidine (VIII);
(3) preparing 7-protective substituent-4- (1-hydrogen-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) by the action of 7-protective substituent-4- (1-hydrogen-3-hydroxypyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (VIII) and a chlorinated reagent;
(4) carrying out catalytic hydrogenation dechlorination on 7-protective substituent-4- (1-hydro-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) in a solvent, alkali and a catalyst to obtain 7-protective substituent-4- (1-hydro-3-pyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (X);
wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl or other C4H9A group; x is chlorine or bromine; PG is trimethylsiloxyethyl methyl, triisopropyl silyl or benzyloxy methyl.
2. A process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
the cyanoacetoacetate ester (II) in the step (1) is cyanoacetoacetate methyl ester, cyanoacetoacetate ethyl ester or cyanoacetoacetate tert-butyl ester;
the haloacetaldehyde acetal diol (III) in the step (1) is chloroacetaldehyde dimethyl acetal, chloroacetaldehyde diethyl alcohol, bromoacetaldehyde dimethyl acetal or bromoacetaldehyde diethyl acetal;
in the step (1), the alkali 1 and the alkali 2 are both one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium methoxide methanol solution or sodium ethoxide ethanol solution or a mixture thereof.
3. A process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
the solvent in the step (1) is N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or any mixed solvent thereof; the mass ratio of the solvent to the cyanoacetoacetic ester is (4-15) to 1;
in the step (1), the molar weight ratio of the alkali 1, the cyano-acetoacetic ester (II) and the halogen-acetaldehyde acetal diol (III) is (1.0-1.5) to (1.0-1.5): 1;
in the step (1), the molar weight ratio of the alkali 2, the formamidine hydrochloride and the cyanoacetoacetate (II) is (1.0-1.5) to (1.0-1.5): 1.
4. a process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
in the step (1), the dehydrohalogenation reaction temperature is-10-80 ℃, and the reaction is carried out for 2-10 hours;
in the step (1), the condensation reaction temperature is 0-80 ℃, and the reaction lasts for 2-10 hours.
5. A process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
the solvent in the step (2) is tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxy ethylene glycol, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or any mixed solvent thereof; the mass ratio of the solvent to the 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate (V) is (4-15) to 1;
the protecting group reagent in the step (2) is 2- (chloromethoxy) ethyl) trimethylsilane, triisopropylsilicon chloride and benzyl chloromethyl ether;
in the step (2), the alkali is sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate or a mixture thereof, and the molar weight ratio of the alkali, the protecting group reagent and the 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate (V) is (1.0-2.0) to (1.0-1.5): 1.
6. a process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
the molar weight ratio of DMFDMA to 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate (V) in step (2) is (1.0-2.0): 1;
the molar weight ratio of the hydrazine hydrate to the 2- (7-hydropyrrolo [2,3-d ] pyrimidin-4-yl) acetate (V) in the step (2) is (1.0-2.0): 1.
7. a process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
in the step (2), the reaction temperature of the 2- (7-hydropyrrolo [2,3-d ] pyrimidine-4-yl) acetate (V) and a protecting group reagent for protecting amino is 20-80 ℃, and the reaction lasts for 2-8 hours;
in the step (2), the temperature of the methylene reaction is 60-120 ℃, and the reaction lasts for 2-9 hours;
in the step (2), the condensation reaction temperature is 30-120 ℃, and the reaction lasts for 2-9 hours.
8. A process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
the chlorinated reagent in the step (3) is phosphorus oxychloride, phosphorus pentachloride or thionyl chloride; the molar weight ratio of the chlorinated reagent to the 7-protective substituent-4- (1-hydrogen-3-hydroxypyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (VIII) is (1.0-20.0): 1;
in the step (3), the chlorination reaction temperature is 30-150 ℃, and the reaction is carried out for 2-20 hours.
9. A process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
the solvent in the step (4) is one of tetrahydrofuran, 2-methyltetrahydrofuran and glycol dimethyl acetal or any mixed solvent thereof, and the mass ratio of the solvent to 7-protective substituent-4- (1-hydrogen-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) is (4-20): 1;
the alkali in the step (4) is one of sodium carbonate, potassium carbonate, sodium acetate and potassium acetate or a mixture of the sodium carbonate, the potassium carbonate, the sodium acetate and the potassium acetate in any proportion, and the mol ratio of the alkali to the 7-protective substituent-4- (1-hydrogen-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) is (1.0-2.0): 1.
10. a process for the synthesis of 7-protecting group-4- (1-hydro-pyrazol-4-yl) pyrrolo [2,3-d ] pyrimidine (X) according to claim 1,
the catalyst in the step (4) is palladium carbon or Raney nickel, the mass ratio of the added amount of the catalyst to the 7-protective substituent-4- (1-hydrogen-3-chloropyrazol-4-yl) pyrrole [2,3-d ] pyrimidine (IX) is 0.5-10.0%, the hydrogen pressure is 0.2-1.0 MPa, the catalytic hydrogenation dechlorination reaction temperature is 30-100 ℃, and the reaction time is 2-9 hours.
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