CN112321538A - Method for synthesizing monoamine-protected piperazine- (R/S) 2-formate - Google Patents
Method for synthesizing monoamine-protected piperazine- (R/S) 2-formate Download PDFInfo
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- CN112321538A CN112321538A CN202011168801.0A CN202011168801A CN112321538A CN 112321538 A CN112321538 A CN 112321538A CN 202011168801 A CN202011168801 A CN 202011168801A CN 112321538 A CN112321538 A CN 112321538A
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- China
- Prior art keywords
- carboxylic acid
- monoamine
- synthesis
- protected piperazine
- piperazine
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 38
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000006239 protecting group Chemical group 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims abstract description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims abstract description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000003222 pyridines Chemical class 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 238000003786 synthesis reaction Methods 0.000 claims description 37
- 230000015572 biosynthetic process Effects 0.000 claims description 36
- -1 amino-protected piperazine formic acid Chemical class 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000004537 pulping Methods 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 125000001033 ether group Chemical group 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- GEJJWYZZKKKSEV-UONOGXRCSA-N (1r,2s)-2-amino-1,2-diphenylethanol Chemical compound C1([C@@H](O)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-UONOGXRCSA-N 0.000 claims description 2
- GEJJWYZZKKKSEV-KGLIPLIRSA-N (1s,2r)-2-amino-1,2-diphenylethanol Chemical compound C1([C@H](O)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-KGLIPLIRSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- GVIUATGDXSWMPN-UHFFFAOYSA-N piperazin-1-ium;formate Chemical compound [O-]C=O.C1C[NH2+]CCN1 GVIUATGDXSWMPN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 229960001404 quinidine Drugs 0.000 claims description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract description 9
- 239000000047 product Substances 0.000 abstract description 9
- 150000001412 amines Chemical class 0.000 abstract description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 125000003368 amide group Chemical group 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 abstract description 3
- 150000001263 acyl chlorides Chemical class 0.000 abstract description 3
- 125000003158 alcohol group Chemical group 0.000 abstract description 3
- 150000008064 anhydrides Chemical class 0.000 abstract description 3
- 235000019445 benzyl alcohol Nutrition 0.000 abstract description 3
- 229940113088 dimethylacetamide Drugs 0.000 abstract description 3
- 235000019253 formic acid Nutrition 0.000 abstract description 3
- 238000007142 ring opening reaction Methods 0.000 abstract description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 150000007530 organic bases Chemical class 0.000 abstract description 2
- 125000006242 amine protecting group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- IIZGWFQKLVCLLA-UHFFFAOYSA-N 1,4-bis[(2-methylpropan-2-yl)oxycarbonyl]piperazine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(O)=O)C1 IIZGWFQKLVCLLA-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- IIZGWFQKLVCLLA-SNVBAGLBSA-N (2r)-1,4-bis[(2-methylpropan-2-yl)oxycarbonyl]piperazine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(O)=O)C1 IIZGWFQKLVCLLA-SNVBAGLBSA-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
- 238000010586 diagram Methods 0.000 description 3
- 238000012827 research and development Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- QUKAHFCVKNRRBU-UHFFFAOYSA-N 1-o-tert-butyl 3-o-methyl piperazine-1,3-dicarboxylate Chemical compound COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1 QUKAHFCVKNRRBU-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- QUKAHFCVKNRRBU-MRVPVSSYSA-N 1-o-tert-butyl 3-o-methyl (3r)-piperazine-1,3-dicarboxylate Chemical compound COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1 QUKAHFCVKNRRBU-MRVPVSSYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- WNSDZBQLMGKPQS-UHFFFAOYSA-N hydron;piperazine-2-carboxylic acid;dichloride Chemical compound Cl.Cl.OC(=O)C1CNCCN1 WNSDZBQLMGKPQS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940056729 sodium sulfate anhydrous Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for synthesizing piperazine- (R/S) 2-formic ether protected by monoamine, which comprises the steps of taking 2-piperazine formate as a raw material, protecting amines at 1 and 4 positions by using different protecting groups, salifying and splitting different chiral amines to obtain a single chiral compound, using pyridine analogs such as pyridine or DMAP (dimethyl acetamide) and the like as alkali, reacting similar acyl chlorides such as oxalyl chloride, triphosgene, phosgene and thionyl chloride and the like in solvents such as anhydrous tetrahydrofuran, 2-methyltetrahydrofuran or toluene and the like, and finally adding alcohol reagents such as methanol, ethanol, isopropanol, benzyl alcohol and the like to generate an amine protecting group capable of positioning and removing the ortho position of carboxylic acid and esterifying carboxylic acid to obtain a target product. According to the invention, through simple three-step reaction, the amido on piperazine is separately protected, chiral resolution is carried out by utilizing the characteristics of acid, finally, a protonated intermediate is formed through organic base and carboxylic acid, anhydride is formed with ortho amido, and formic acid is esterified by utilizing alcohol substitution ring opening to obtain the final product.
Description
Technical Field
The invention belongs to the technical field of synthetic methods, and particularly relates to a synthetic method for gradually completing chiral resolution, removing ortho-protecting groups of formic acid and esterifying by taking piperazine-2-formic acid as a raw material.
Background
Taking the synthesis of (S/R) 1-BOC-3-piperazine methyl formate as an example, the molecular formula is C11H20N2O4And the molecular weight is 244.29. As shown in fig. 1, fig. 1 is a synthesis path diagram in the prior art, in the synthesis route in the prior art document, methyl groups on hazardous reagents such as diazomethane are used, and Pd/C is also used for reduction, so that the route is long, the cost is high, and based on the above defects in the prior art, there is a need to invent an improved synthesis route, which uses conventional cheap reagents, avoids using hazardous reagents, can perform chiral resolution to obtain a single configuration, is simple to operate, has high yield, is suitable for commercial amplification production, and greatly reduces the research and development cost.
Disclosure of Invention
The invention provides a method for synthesizing piperazine- (R/S) 2-formic ether protected by monoamine, which is simple in post-treatment, low in research and development cost and convenient for commercial scale-up production, and aims to overcome the defects in the prior art.
The invention is realized by the following technical scheme: the invention discloses a method for synthesizing piperazine- (R/S) 2-formic ether protected by monoamine, which specifically comprises the following steps:
the first step is as follows: adding piperazine-2-formic acid and a solvent into a reaction flask, uniformly stirring, adding alkali, adding a protective group R1 solution, controlling the temperature, stirring for 2-3h after dripping, then adding a protective group R2 solution additionally, continuously stirring for 2-3h, washing and layering by using a saturated sodium bicarbonate aqueous solution, washing an organic phase twice, concentrating under reduced pressure, and carrying out column chromatography to obtain the amino-protected piperazine formic acid.
The second step is that: dissolving the obtained amino-protected piperazine formic acid in a reaction solvent at room temperature, adding a resolution reagent, gradually separating out a solid under stirring, continuously stirring at room temperature for 1 hour after the addition is finished, filtering, recrystallizing the obtained solid to obtain white to off-white amino-protected piperazine formic acid amine salt with a single configuration, acidifying with acid water, adding an organic solvent, extracting, washing, drying, and concentrating under reduced pressure to obtain the white to off-white amino-protected piperazine formic acid with the single configuration.
The third step: adding piperazine formic acid with single configuration and protected by amino and a reaction solvent into a reaction flask, uniformly stirring, adding alkali, cooling to a specified temperature, then dropwise adding a chlorinated reagent, controlling the dropwise adding temperature, stirring at the specified temperature after dropwise adding, finally adding alcohol to continue reacting until the raw materials disappear, after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove the reaction solvent, adding an organic solvent to dissolve, adjusting the pH to 9-10 by using an alkali solution, extracting and separating the reaction liquid, continuing extracting the water phase by using the organic solvent, combining the organic phases, concentrating under reduced pressure, and pulping by using the solvent to obtain piperazine- (R/S) 2-formate with 4 different protecting groups.
In the first step, the R1 group is one or more of Boc, Cbz, Ts, Bn, Bz, F-moc or Ac. The R2 group is one or more of Boc, Cbz, formyl methyl ester, formyl ethyl ester or formyl isopropyl ester. The R3, R4 and R5 groups are one or more of H, methyl, ethyl, methoxy, ethoxy, alkyl, nitro or benzyl. The base is one or more of triethylamine, pyridine, diisopropylethylamine or sodium hydroxide. The solvent is one or more of dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate or DMF. The reaction temperature is 0-10 ℃, 20-30 ℃ or 40-60 ℃.
In the second step, the reaction solvent is one or more of toluene, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone or methyl tertiary ether. The resolving agent is one or more of S/R-methylbenzylamine, (1R,2S) -2-amino-1, 2-diphenylethanol, (1S,2R) -2-amino-1, 2-diphenylethanol, cinchonidine, quinidine or (R/S) -1- (1-naphthyl) ethylamine. The equivalent weight of resolving agent is between 0.5 and 1.5 relative to the carboxylic acid prior to resolution. The organic solvent is one or more of toluene, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone or methyl tertiary ether. The crystallization temperature is 0-15 deg.C, 15-30 deg.C or 30-45 deg.C. The acid used in the second acidification step is an aqueous solution of hydrochloric acid or sulfuric acid.
In the third step, the reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, dichloromethane, methyl tert-butyl ether or ethyl acetate. The equivalent weight of the solvent relative to the single configuration of the amino-protected piperazine carboxylic acid is between 3 and 15 volumes. The alkali is one or more pyridine compounds selected from pyridine, DMAP and 2, 6-dimethylpyridine. The equivalent of base is between 0.3 and 2.3 equivalents relative to the amino-protected piperazine carboxylic acid of a single configuration. The designated temperature is any interval of 0-50 ℃. The room temperature means 20-30 ℃.
The chlorinating reagent in the third step is one or more of oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosgene or triphosgene. The equivalent of the chlorinating agent is between 0.3 and 2.3 equivalents relative to the amino-protected piperazine carboxylic acid of a single configuration. The dropping temperature is any temperature in the range of-15 to 30 ℃. The alcohol used for esterification is one or more of methanol, ethanol, isopropanol or benzyl alcohol, and the equivalent weight of the alcohol is between 1.0 and 3.0 equivalent weight relative to the amino-protected piperazine carboxylic acid of a single configuration. The organic solvent is one or more of toluene, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate or methyl tertiary ether. The alkali used for adjusting the pH value to 9-10 is one or more of potassium carbonate, sodium hydroxide or potassium hydroxide. The solvent for subsequent pulping and purification is one or more of toluene, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methyl tert-ether, n-heptane, n-hexane, petroleum ether and water.
The method comprises the steps of taking 2-piperazine formate as a raw material, protecting amines at 1 and 4 positions with different protecting groups, salifying and splitting different chiral amines to obtain a single chiral compound, reacting pyridine analogs such as pyridine or DMAP (dimethyl acetamide) and the like in solvents such as anhydrous tetrahydrofuran, 2-methyltetrahydrofuran or toluene and the like with similar acyl chlorides such as oxalyl chloride, triphosgene, phosgene, thionyl chloride and the like, and finally adding alcohol reagents such as methanol, ethanol, isopropanol, benzyl alcohol and the like to generate an amino protecting group capable of positioning and removing the ortho position of carboxylic acid and esterifying the carboxylic acid to obtain a target product.
Taking a synthesis process of 4-Boc piperazine-2-formic ether as an example, 2-formic acid piperazine is taken as a raw material, and different protecting groups are used for protecting amines at 1 and 4 positions to obtain a compound shown as a general formula 1; and then using different chiral amines (resolving reagents) to form salts, resolving to obtain single chiral amine carboxylate, dissociating to obtain a single chiral compound with a structure shown in a general formula 2, finally using pyridine analogs such as pyridine or DMAP (dimethyl acetamide) and the like as alkali, reacting similar acyl chlorides such as oxalyl chloride, triphosgene, phosgene, thionyl chloride and the like in solvents such as anhydrous tetrahydrofuran, 2-methyltetrahydrofuran or toluene and the like, and finally adding alcohol reagents such as methanol, ethanol, isopropanol, benzyl alcohol and the like to generate an amino protecting group R2 capable of positioning and removing the ortho position of the carboxylic acid, and esterifying the carboxylic acid to obtain a target product. The general formula 1 is a reaction raw material, the general formula 2 is an intermediate with a single or mixed configuration, and the general formula 3 is a product with a single or mixed configuration.
Wherein R1 is a protecting group such as Boc, Cbz or Ts, R2 is an acyl protecting group similar to Boc, R3, R4 and R5 can be alkyl such as H, methyl and ethyl, one or any combination of aromatic groups such as nitro and benzyl, and R is methyl, ethyl, isopropyl, benzyl and the like.
The invention has the beneficial effects that: the invention discloses a chemical synthesis method for synthesizing piperazine- (R/S) -2-formate with different protecting groups at 4 positions by taking piperazine-2-formic acid as a raw material through a series of reactions. The invention selects proper protecting groups to protect amine groups, then uses the acidity of carboxylic acid to form salts with different chiral amines, obtains single configuration by splitting, finally forms intramolecular mixed anhydride under specific conditions, and then obtains target products by alcohol substitution ring opening. The invention develops an improved synthetic route, uses conventional cheap reagents, avoids using dangerous reagents, can carry out chiral resolution to obtain single configuration, has simple operation, higher yield, simple post-treatment and low reaction cost, is suitable for commercial amplification production, and greatly reduces the research and development cost.
In experiments, the synthetic method greatly shortens the synthetic route of the compound, reduces the cost for synthesizing the compound, avoids using dangerous metal-containing reagents such as Pd/C and the like, has extremely low emission of three wastes, is environment-friendly and is convenient for commercial production. The invention provides a new synthesis idea, which can separately protect amido on piperazine through simple three-step reaction, performs chiral resolution by utilizing the characteristics of acid, forms a protonated intermediate through organic base and carboxylic acid, forms anhydride with ortho-position amido, and esterifies formic acid by utilizing alcohol substitution ring opening to obtain a final product.
Drawings
FIG. 1 is a diagram of the synthetic pathway of a target product in the prior art;
FIG. 2 is a diagram of the improved synthesis path of the present invention.
Detailed Description
The invention is described in detail below with reference to the figures and the detailed description.
Example 1:
1, 4-bis-Boc piperazine-2-carboxylic acid synthesis: to a 1.0L reaction flask, piperazine-2-carboxylic acid dihydrochloride (50g) was added, NaOH (39.4g) was dissolved in water (500mL) and added to the above solid and dissolved with stirring, temperature was controlled at 0-10 deg.C, Boc anhydride (134.2g) was dissolved in THF (100mL) and added dropwise to the above reaction flask, and the reaction was carried out at 20-30 deg.C for 16 h. And (3) post-treatment: adding methyl tert-butyl ether (400mL) into the system for extraction and liquid separation, taking an aqueous phase, adjusting the pH of the aqueous phase to 2-3 with 3NHCl (150mL), separating out solids, pulping at 0-10 ℃ for 1-2h, then carrying out suction filtration, washing a filter cake with water, and drying in vacuum to constant weight to obtain a solid: (75.1g, molar yield: 92.3%).
1HNMR(400MHz,DMSO-d6):1.37(d,18H),2.94(m,3H),3.64(d,1H),3.81(s,1H),4.35(m,2H),12.88(s,1H)。
Example 2:
(R) -1, 4-bis-Boc piperazine-2-carboxylic acid synthesis: adding 1, 4-di-Boc piperazine-2-carboxylic acid (15g) into toluene (150mL) in a 1.0L reaction bottle, adding R (+) -alpha-methylbenzylamine (6.6g), separating out a solid, stirring for crystallization for 1-2h, performing suction filtration, washing filter cake toluene to obtain a crude (R) -1, 4-di-Boc piperazine-2-carboxylic acid amine salt, adding toluene (200mL) into the crude product, pulping for 1-2h, performing suction filtration to obtain (R) -1, 4-di-Boc piperazine-2-carboxylic acid amine salt (9.2g, the yield is 44.9%, ee% > 98.0%), adding (R) -1, 4-di-Boc piperazine-2-carboxylic acid amine salt (9.0g) into water (90mL), adding dichloromethane (90mL), adjusting the pH to 2-3 with 3N hydrochloric acid, after stirring for 10min, the liquid was extracted, the aqueous phase was extracted once more with DCM (90mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R) -1, 4-di-Boc piperazine-2-carboxylic acid (6.2g, yield: 94.2%, ee% > 98.0%).
Example 3:
4-Boc piperazine-2-carboxylic acid methyl ester synthesis: adding 1, 4-di-Boc piperazine-2-carboxylic acid (20g) into a 1.0L reaction bottle, adding anhydrous THF (200mL), uniformly stirring, adding pyridine (7.2g), cooling to 0-10 ℃, dropwise adding a THF (100mL) solution of oxalyl chloride (9.2g), controlling the temperature to be not more than 10 ℃, stirring at 20-30 ℃ for 2-3h after dropwise adding, finally adding methanol (200mL) to continue reacting at 40-50 ℃ for 2-3h, after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove methanol and pyridine, adding ethyl acetate to dissolve, adjusting the pH to 9-10 by using saturated sodium carbonate aqueous solution, extracting and separating liquid, continuing to extract the aqueous phase by EA, combining the organic phase, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography to obtain the target product (12.6g, the molar yield: 85.2%).
1HNMR(400MHz,CDCl3):1.42(d,9H),2.73(d,1H),3.10(m,3H),3.46(d,1H),3.72(m,4H),3.99(m,1H)；MS(m/z,ESI+):145&189, M + H, Boc fragmented in the system.
Example 4:
4-Boc piperazine-2-carboxylic acid methyl ester synthesis: adding 1, 4-di-Boc piperazine-2-carboxylic acid (20g) into a 1.0L reaction bottle, adding anhydrous THF (200mL), uniformly stirring, adding pyridine (7.2g), cooling to 0-10 ℃, adding triphosgene (21.6g), stirring for 2-3h at 40-45 ℃, finally adding methanol (200mL) to continue reacting for 2-3h at 40-50 ℃, after the reaction is finished, concentrating the reaction solution under reduced pressure to remove methanol and pyridine, adding ethyl acetate to dissolve, adjusting the pH to 9-10 by using saturated sodium carbonate aqueous solution, extracting and separating, continuing extracting the aqueous phase by EA, combining the organic phases, drying by using sodium sulfate anhydrous, concentrating under reduced pressure, adding dichloromethane and n-heptane, and pulping to obtain a target product (11.9g, wherein the molar yield is 80.5%).
1HNMR(400MHz,CDCl3):1.41(d,9H),2.70(d,1H),3.00(m,3H),3.41(d,1H),3.68(m,4H),3.93(m,1H)；MS(m/z,ESI+):145&189, M + H, Boc fragmented in the system.
Example 5:
(R) -4-Boc piperazine-2-carboxylic acid methyl ester synthesis: adding (R) -1, 4-di-Boc piperazine-2-formic acid (20g) into a 1.0L reaction bottle, adding anhydrous THF (200mL), stirring uniformly, adding pyridine (7.2g), cooling to 0-10 ℃, dropwise adding a THF (100mL) solution of oxalyl chloride (9.2g), controlling the temperature to be not more than 10 ℃, stirring for 2-3h at 20-30 ℃ after dropwise adding, finally adding methanol (200mL), continuing to react for 2-3h at 40-50 ℃, and after the reaction is finished, the reaction mixture was concentrated under reduced pressure to remove methanol and pyridine, and ethyl acetate was added to dissolve the mixture, and the pH was adjusted to 9 to 10 using a saturated aqueous solution of sodium carbonate, followed by extraction and liquid separation, and the aqueous phase was further extracted with EA, and the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and slurried with dichloromethane and n-heptane to give the objective product (11.8g, molar yield: 79.8%).
1HNMR(400MHz,CDCl3):1.41(d,9H),2.70(d,1H),3.00(m,3H),3.41(d,1H),3.68(m,4H),3.93(m,1H)；MS(m/z,ESI+):145&189, M + H, Boc fragmented in the system.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (25)
1. A method for synthesizing monoamine-protected piperazine- (R/S) 2-formate, characterized by: the method for synthesizing the piperazine- (R/S) 2-formic ether protected by monoamine specifically comprises the following steps:
the first step is as follows: adding piperazine-2-formic acid and a solvent into a reaction flask, uniformly stirring, adding alkali, adding a protective group R1 solution, controlling the temperature, stirring for 2-3h after dripping, then adding a protective group R2 solution additionally, continuously stirring for 2-3h, washing and layering by using a saturated sodium bicarbonate aqueous solution, washing an organic phase twice, concentrating under reduced pressure, and carrying out column chromatography to obtain the amino-protected piperazine formic acid.
The second step is that: dissolving the obtained amino-protected piperazine formic acid in a reaction solvent at room temperature, adding a resolution reagent, gradually separating out a solid under stirring, continuously stirring at room temperature for 1 hour after the addition is finished, filtering, recrystallizing the obtained solid to obtain white to off-white amino-protected piperazine formic acid amine salt with a single configuration, acidifying with acid water, adding an organic solvent, extracting, washing, drying, and concentrating under reduced pressure to obtain the white to off-white amino-protected piperazine formic acid with the single configuration.
The third step: adding piperazine formic acid with single configuration and protected by amino and a reaction solvent into a reaction flask, uniformly stirring, adding alkali, cooling to a specified temperature, then dropwise adding a chlorinated reagent, controlling the dropwise adding temperature, stirring at the specified temperature after dropwise adding, finally adding alcohol to continue reacting until the raw materials disappear, after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove the reaction solvent, adding an organic solvent to dissolve, adjusting the pH to 9-10 by using an alkali solution, extracting and separating the reaction liquid, continuing extracting the water phase by using the organic solvent, combining the organic phases, concentrating under reduced pressure, and pulping by using the solvent to obtain piperazine- (R/S) 2-formate with 4 different protecting groups.
2. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the first step, the R1 group is one or more of Boc, Cbz, Ts, Bn, Bz, F-moc or Ac.
3. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the first step, the R2 group is one or more of Boc, Cbz, formyl methyl ester, formyl ethyl ester or formyl isopropyl ester.
4. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: the R3, R4 and R5 groups are one or more of H, methyl, ethyl, methoxy, ethoxy, alkyl, nitro or benzyl.
5. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the first step, the kind of the base is one or more of triethylamine, pyridine, diisopropylethylamine or sodium hydroxide.
6. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the first step, the solvent is one or more of dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate or DMF.
7. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the first step, the reaction temperature is 0-10 ℃, 20-30 ℃ or 40-60 ℃.
8. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the second step, the reaction solvent is one or more of toluene, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone or methyl tertiary ether.
9. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the second step, the resolving agent is one or more of S/R-methylbenzylamine, (1R,2S) -2-amino-1, 2-diphenylethanol, (1S,2R) -2-amino-1, 2-diphenylethanol, cinchonidine, quinidine or (R/S) -1- (1-naphthyl) ethylamine.
10. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the second step, the equivalent weight of the resolving agent is between 0.5 and 1.5 relative to the carboxylic acid before resolution.
11. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the second step, the organic solvent is one or more of toluene, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone or methyl tertiary ether.
12. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the second step, the crystallization temperature is 0-15 ℃, 15-30 ℃ or 30-45 ℃.
13. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: the acid used in the second acidification step is an aqueous solution of hydrochloric acid or sulfuric acid.
14. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, dichloromethane, methyl tert-butyl ether or ethyl acetate.
15. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the solvent equivalent is between 3 and 15 volumes relative to the single configuration of the amino-protected piperazine carboxylic acid.
16. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the alkali is one or more pyridine compounds selected from pyridine, DMAP and 2, 6-dimethylpyridine.
17. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the equivalent of base is between 0.3 and 2.3 equivalents relative to the amino-protected piperazine carboxylic acid of a single configuration.
18. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the designated temperature is any interval temperature of 0-50 ℃.
19. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: the chlorinating reagent in the third step is one or more of oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosgene or triphosgene.
20. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the equivalent of the chlorinating agent is between 0.3 and 2.3 equivalents relative to the amino-protected piperazine carboxylic acid of a single configuration.
21. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: and in the third step, the dripping temperature is any temperature in the range of-15 to 30 ℃.
22. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the alcohol used for esterification is one or more of methanol, ethanol, isopropanol or benzyl alcohol, and the equivalent of the alcohol is between 1.0 and 3.0 equivalents relative to the amino-protected piperazine carboxylic acid of a single configuration.
23. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the organic solvent is one or more of toluene, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate or methyl tert-ether.
24. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the alkali used for adjusting the pH value to 9-10 is one or more of potassium carbonate, sodium hydroxide or potassium hydroxide.
25. A process for the synthesis of monoamine protected piperazine- (R/S) 2-carboxylic acid esters according to claim 1, wherein: in the third step, the solvent for subsequent pulping and purification is one or more of toluene, methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methyl tert-ether, n-heptane, n-hexane, petroleum ether and water.
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| US5856485A (en) * | 1994-04-20 | 1999-01-05 | Lonza Ag | Process for preparing 2-piperazinecarboxylic acid derivatives |
| US6310095B1 (en) * | 1995-11-06 | 2001-10-30 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
| CN1744930A (en) * | 2002-12-17 | 2006-03-08 | 先灵公司 | 17 beta-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases |
| US20060183919A1 (en) * | 2003-04-09 | 2006-08-17 | Jean-Claude Souvie | Novel method for the synthesis of s-indoline-2- carboxylic acid and application thereof in the synthesis of perindopril |
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| US5856485A (en) * | 1994-04-20 | 1999-01-05 | Lonza Ag | Process for preparing 2-piperazinecarboxylic acid derivatives |
| US6310095B1 (en) * | 1995-11-06 | 2001-10-30 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
| CN1744930A (en) * | 2002-12-17 | 2006-03-08 | 先灵公司 | 17 beta-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases |
| US20060183919A1 (en) * | 2003-04-09 | 2006-08-17 | Jean-Claude Souvie | Novel method for the synthesis of s-indoline-2- carboxylic acid and application thereof in the synthesis of perindopril |
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