CN116178304A - Synthesis method of pramipexole dihydrochloride - Google Patents
Synthesis method of pramipexole dihydrochloride Download PDFInfo
- Publication number
- CN116178304A CN116178304A CN202310228213.9A CN202310228213A CN116178304A CN 116178304 A CN116178304 A CN 116178304A CN 202310228213 A CN202310228213 A CN 202310228213A CN 116178304 A CN116178304 A CN 116178304A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- pramipexole dihydrochloride
- synthesizing
- tetrahydrobenzothiazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VQMNWIMYFHHFMC-UHFFFAOYSA-N tert-butyl 4-hydroxyindole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=CC2=C1O VQMNWIMYFHHFMC-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229960002652 pramipexole dihydrochloride Drugs 0.000 title claims abstract description 33
- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 238000005893 bromination reaction Methods 0.000 claims abstract description 13
- 125000006239 protecting group Chemical group 0.000 claims abstract description 13
- 230000031709 bromination Effects 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 10
- WIYDBHSVURZSJV-UHFFFAOYSA-N 2-amino-5,7-dihydro-4h-1,3-benzothiazol-6-one Chemical compound C1CC(=O)CC2=C1N=C(N)S2 WIYDBHSVURZSJV-UHFFFAOYSA-N 0.000 claims abstract description 9
- FASDKYOPVNHBLU-UHFFFAOYSA-N N6-Propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine Chemical compound C1C(NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000009833 condensation Methods 0.000 claims abstract description 9
- 230000005494 condensation Effects 0.000 claims abstract description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 7
- POMVSFNBRWJNLM-UHFFFAOYSA-N cyclohexane-1,4-dione;ethane-1,2-diol Chemical compound OCCO.O=C1CCC(=O)CC1 POMVSFNBRWJNLM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000006227 trimethylsilylation reaction Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 117
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 105
- 238000006243 chemical reaction Methods 0.000 claims description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 20
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 10
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- VKRKCBWIVLSRBJ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-8-one Chemical compound C1CC(=O)CCC21OCCO2 VKRKCBWIVLSRBJ-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000001358 L(+)-tartaric acid Substances 0.000 claims description 6
- 235000011002 L(+)-tartaric acid Nutrition 0.000 claims description 6
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 238000005580 one pot reaction Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 238000006266 etherification reaction Methods 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 8
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 20
- 238000003786 synthesis reaction Methods 0.000 abstract description 20
- 238000009776 industrial production Methods 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
- 239000007787 solid Substances 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- 238000003756 stirring Methods 0.000 description 45
- 239000012074 organic phase Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 238000005406 washing Methods 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 20
- 238000001914 filtration Methods 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 238000001035 drying Methods 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 12
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 229960003089 pramipexole Drugs 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 229910000085 borane Inorganic materials 0.000 description 5
- 238000006482 condensation reaction Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical class Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 239000003810 Jones reagent Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000002360 explosive Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000007603 infrared drying Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 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 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IMLXLGZJLAOKJN-UHFFFAOYSA-N 4-aminocyclohexan-1-ol Chemical compound NC1CCC(O)CC1 IMLXLGZJLAOKJN-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108050004812 Dopamine receptor Proteins 0.000 description 2
- 102000015554 Dopamine receptor Human genes 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000027089 Parkinsonian disease Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ALUQMCBDQKDRAK-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1,3-benzothiazole Chemical compound C1C=CC=C2SCNC21 ALUQMCBDQKDRAK-UHFFFAOYSA-N 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 229940098778 Dopamine receptor agonist Drugs 0.000 description 1
- 101150097070 Drd3 gene Proteins 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 238000003445 Hantzsch reaction Methods 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DCZFGQYXRKMVFG-UHFFFAOYSA-N cyclohexane-1,4-dione Chemical compound O=C1CCC(=O)CC1 DCZFGQYXRKMVFG-UHFFFAOYSA-N 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960004279 formaldehyde Drugs 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QXKCTWPNUINDQK-UHFFFAOYSA-N n-(2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)acetamide Chemical compound C1C(NC(=O)C)CCC2=C1SC(N)=N2 QXKCTWPNUINDQK-UHFFFAOYSA-N 0.000 description 1
- YMFBUTYXVRUNAR-UHFFFAOYSA-N n-(2-oxocyclohexyl)acetamide Chemical compound CC(=O)NC1CCCCC1=O YMFBUTYXVRUNAR-UHFFFAOYSA-N 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- QMNWXHSYPXQFSK-KLXURFKVSA-N pramipexole hydrochloride anhydrous Chemical compound Cl.Cl.C1[C@@H](NCCC)CCC2=C1SC(N)=N2 QMNWXHSYPXQFSK-KLXURFKVSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
The invention discloses a synthesis method of pramipexole dihydrochloride, which comprises the following steps: taking 1, 4-cyclohexanedione monoethylene glycol ketal a as a raw material, and generating a compound b through trimethylsilylation reaction; in an organic solvent, sequentially carrying out carbonyl alpha-position bromination, hantzsch condensation and ketal protecting group removal on a compound b to obtain an intermediate 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole c; the intermediate c is subjected to reductive amination to generate 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole d; and resolving the compound d to form salt to obtain pramipexole dihydrochloride. The synthesis method has the advantages of low-cost and easily-obtained raw materials, short synthesis route, high total yield, simple operation, mild conditions, environment friendliness and suitability for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of pramipexole dihydrochloride.
Background
Pramipexole (Pramipexole), alias mirapare, CAS number: 104632-26-0, chemical name: (S) -2-amino-6-propylamine-4, 5,6, 7-tetrahydrobenzothiazole. Pramipexole hcl, CAS no: 104632-25-9, which has the following structural formula:
pramipexole dihydrochloride is a non-ergot selective D2/D3 dopamine receptor agonist developed by the company bolognathan, germany, approved by the FDA in the united states in 1997, licensed in the european union in 2002, licensed in the chinese in 2005, and marketed in china under the trade name "forest formol". Pramipexole, as a first line of treatment for parkinson's disease, binds to the D2 subfamily of dopamine receptors with a high degree of selectivity and specificity and has complete intrinsic activity. The pramipexole has longer half-life period, can avoid the pulse-like stimulation of the postsynaptic membrane dopamine receptor of the striatum, and can reduce and delay the occurrence of the movement complications. The pramipexole is rapidly and completely absorbed by oral administration, has absolute bioavailability higher than 90%, is the best choice for treating early parkinsonism, and can also be used for the combined treatment of late parkinsonism.
At present, the synthesis method of pramipexole dihydrochloride mainly comprises the following steps:
route one: taking acetamido cyclohexanone as a raw material, firstly generating bromine bromination at a carbonyl alpha-position, then carrying out Hantzsch condensation reaction on the brominated bromine and thiourea to form a ring to generate 2-amino-6-acetamido-4, 5,6, 7-tetrahydrobenzothiazole, and then carrying out HBr deacetylation, tartaric acid resolution, propionic anhydride acylation, borane reduction and hydrochloric acid salification to obtain pramipexole hydrochloride. The overall yield of this route is 5.27% (see J. Med. Chem. 1987, 30, 494-499).
The starting material of the route is relatively expensive, the route is longer, the material loss is large, and the yield is low; the use of highly toxic, explosive borane gases for the reduction of amides makes this route difficult to adapt to large-scale industrial production.
Route two: the p-aminocyclohexanol is used as a starting material, and pramipexole hydrochloride is synthesized by phthalic anhydride protection amino, jones reagent oxidation, bromine bromination, hantzsch condensation reaction to form a ring, hydrazine deprotection, tartaric acid resolution, reductive amination and hydrochloric acid salification in sequence (see patent EP 186087).
This route is subjected to two separate reaction steps of phthalic anhydride protection and deprotection, making the route longer and less efficient in terms of atom utilization. Meanwhile, the high-pollution Jones reagent and the explosive tubular reagent hydrazine hydrate are used in the route, so that the large-scale industrialized popularization of the route is difficult to realize.
Route three: 1, 4-cyclohexanedione is used as a starting material, and is subjected to ketal single-protection carbonyl, bromous-tion, hantzsch condensation reaction to form a ring, hydrochloric acid deprotection, reductive amination and tartaric acid resolution in sequence to obtain pramipexole (see U.S. Pat. No. 3,182).
The method has short steps and high atom utilization rate, and does not use high-toxicity and high-pollution reagents except liquid bromine. However, this route, reported in patent CN109232471, was repeated several times, and failure to repeat the literature report, may be related to the stability of the substrate.
Route four: the pramipexole is obtained by taking p-aminocyclohexanol as a starting material and sequentially carrying out propionic anhydride protection, hydroxyl oxidation, bromination and Hantzsch reaction to form a ring, borane reduction and tartaric acid resolution, wherein the total yield of the pramipexole is 8.7% (see WO 2006117614).
The use of propionyl protection in this route eliminates the deprotection step, but also uses highly contaminating Jones reagent and highly toxic, explosive borane gas, and the route is low in yield and not suitable for industrial mass production.
Furthermore, the above routes share the disadvantage that: the bromination reaction uses highly toxic controlled reagent liquid bromine; at the same time, bromine bromination may occur at the same time at two equivalent reaction sites, resulting in a reduced yield.
The existing synthesis method of pramipexole dihydrochloride still has a plurality of defects. Therefore, the development of the synthesis method which is short in synthesis route, high in yield, simple and convenient to operate, mild in condition, environment-friendly and suitable for industrial production has important significance.
Disclosure of Invention
The invention aims to: aiming at overcoming the defects of the prior art, the invention provides a synthesis method of pramipexole dihydrochloride, which has the advantages of low-cost and easily obtained raw materials, short synthesis route, high total yield, simple operation, mild condition, environment friendliness and suitability for large-scale industrial production.
The technical scheme is as follows: the aim of the invention is achieved by the following technical scheme:
the invention provides a synthesis method of pramipexole dihydrochloride, which comprises the following steps:
(1) Taking 1, 4-cyclohexanedione monoethylene glycol ketal a as a raw material, and generating a compound b through trimethylsilylation reaction;
(2) In an organic solvent, sequentially carrying out carbonyl alpha-position bromination, hantzsch condensation and ketal protecting group removal on a compound b to obtain an intermediate 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole c;
(3) The intermediate c is subjected to reductive amination to generate 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole d;
(4) And resolving the compound d to form salt to obtain pramipexole dihydrochloride.
A preferred embodiment of the invention is: the synthesis method of pramipexole dihydrochloride comprises the following steps:
(1) Under the existence of TMSOTF and triethylamine, carrying out trimethylsilylation reaction on 1, 4-cyclohexanedione monoethylene ketal a in chlorinated hydrocarbon solvent to generate a silicon etherification product b of carbonyl;
(2) In an organic solvent, the compound b is subjected to one-pot boiling method to sequentially generate NBS bromination, condensation with thiourea Hantzsch and removal of ketal protecting group by HCl in the presence of Acona to obtain an intermediate 2-amino-6-oxo-4, 5,6,7-
Tetrahydrobenzothiazole c;
wherein, the HCl is removed to remove ketal protecting group and HBr byproduct generated by Hantzsch condensation reaction is utilized.
(3) The intermediate c and n-propylamine are subjected to reductive amination in the presence of sodium cyanoborohydride to generate 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole d;
(4) The compound d is resolved by L- (+) -tartaric acid and salified to obtain pramipexole dihydrochloride.
Further preferably, in step (1), the chlorinated hydrocarbon solvent is one of dichloromethane, chloroform or 1, 2-dichloroethane.
Still further, the chlorinated hydrocarbon solvent is methylene chloride.
Further preferably, in step (1), the molar ratio of 1, 4-cyclohexanedione monoethylene glycol ketal a, TMSOtf and triethylamine is 1:1.1 to 1.5:3 to 4.
Still further, the molar ratio of 1, 4-cyclohexanedione monoethylene glycol ketal a, TMSOtf and triethylamine was 1:1.2:3.
Further preferably, in the step (1), the reaction temperature is-30 to 5 ℃ and the reaction time is 0.5 to 1h.
Further, the reaction temperature is-10-0 ℃ and the reaction time is 30-40 min.
Further preferably, in the step (2), the organic solvent is a mixed solvent of water and THF, and the volume ratio of the two is 0-3:1.
Further, the volume ratio of water to THF was 1:1.
Further preferably, in the step (2), the reaction temperature of the NBS bromination is 10-40 ℃ and the reaction time is 1-2 h; the reaction temperature of the Hantzsch condensation is 50-80 ℃ and the reaction time is 3-5 h; the reaction temperature for removing ketal protecting group from HCl is 50-80 ℃ and the reaction time is 1-2 h.
Further, the NBS bromination reaction temperature is 20-30 ℃ and the reaction time is 1-1.5 h;
the reaction temperature of the Hantzsch condensation is 65-75 ℃ and the reaction time is 3-4 h.
The reaction temperature for removing ketal protecting group from HCl is 65-75 ℃ and the reaction time is 1.5-2 h.
Further preferably, in step (2), the reaction system for removing ketal protecting group by HCl has a pH <1. In the invention, the pH value of a reaction system is regulated by adopting concentrated hydrochloric acid to remove ketal protecting groups from HCl; the reaction also utilizes HBr by-product produced by Hantzsch condensation reaction, resulting in reduced amounts of hydrochloric acid.
Further preferably, in step (2), the molar ratio of the compound b, NBS, acONa to thiourea is 1:1.05 to 1.3:0.1 to 0.2:1.1 to 1.5.
Still further, the molar ratio of compound b, NBS, acONa to thiourea was 1:1.1:0.16:1.1.
Further preferably, in step (3), the reaction solvent for reductive amination is one of methanol, 1, 2-dichloroethane, tetrahydrofuran or dichloromethane; the molar ratio of the compound c to the n-propylamine to the sodium cyanoborohydride is 1:1.5-2:2-3.
Still further, the reductive amination reaction solvent is methanol; the molar ratio of the compound c to the n-propylamine to the sodium cyanoborohydride is 1:1.5:2.
A further preferred embodiment of the invention is: in the step (2), after the reaction is completed, the intermediate c is extracted from the aqueous phase by using an organic solvent, wherein the organic solvent is tetrahydrofuran or one of mixed solvents of dichloromethane and methanol (dichloromethane: methanol=10-20:1, v/v).
Further, the organic solvent is a mixed solvent of dichloromethane and methanol (v/v=10-20:1).
A further preferred embodiment of the invention is: purifying and refining the compounds c and d, adding the obtained crude product into an organic solvent of hydrogen chloride, stirring to obtain a hydrochloride form of the compound c or d, filtering, and washing with the organic solvent to remove impurities.
Further, the organic solvent of hydrogen chloride is saturated ethyl acetate solution of hydrogen chloride or 1, 4-dioxane solution of 4M hydrogen chloride.
Further, the organic solvent of hydrogen chloride is saturated ethyl acetate solution of hydrogen chloride.
The beneficial effects are that:
(1) The invention takes 1, 4-cyclohexanedione monoethylene glycol ketal as a raw material to synthesize pramipexole dihydrochloride. The method has the advantages of cheap and easily obtained raw materials, simple operation, 99.2 percent of product purity, optical rotation [ alpha ] D= -63.8 degrees (c=1 in methanol) and total yield of 26.14 percent.
(2) The synthesis method of the invention avoids the use of toxic, high-pollution and explosive reagents such as liquid bromine, jones reagent, borane, hydrazine hydrate and the like, is environment-friendly and mild in condition, and has wide prospect and industrial application value.
(3) The invention synthesizes the key intermediate 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole by a one-pot method, wherein, the ketal protecting group removes and utilizes HBr byproducts generated by Hantzsch condensation, thereby greatly shortening the synthetic route and improving the yield.
Drawings
FIG. 1 shows nuclear magnetic hydrogen spectrum of pramipexole dihydrochloride 1 H-NMR)。
FIG. 2 shows nuclear magnetic carbon spectrum of pramipexole dihydrochloride 13 C-NMR)。
Detailed Description
The technical scheme of the present invention is described in detail below through specific examples, but the scope of the present invention is not limited to the examples.
In the specific embodiment of the invention, the synthetic route of pramipexole dihydrochloride is as follows:
example 1
(1) Synthesis of Compound b
1, 4-cyclohexanedione monoethylene ketal (8.0 g,51.22 mmol) was dissolved in 140mL dichloromethane under nitrogen protection in a 250mL three-necked flask, triethylamine (21.36 mL,153.66 mmol) was added, stirred and cooled in an ice salt bath at-5℃for 20min, and TMSOTF (11.12 mL,61.46 mmol) was slowly added dropwise. After the completion of the dropwise addition, the reaction was continued with stirring for 30min under heat preservation, and the TLC monitored the reaction (petroleum ether: ethyl acetate volume ratio=9:1 as developing agent, phosphomolybdic acid in ethanol as color developing agent) until the raw material reaction was complete. Saturated sodium bicarbonate solution 60, mL was added to the reaction, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane (2×100 mL), and the organic phases were combined. The organic phase was washed successively with water (3×50 mL), saturated brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound b (pale yellow oil, 11.49 g, crude yield 98.2%) which was directly carried on to the next step without further purification.
(2) Synthesis of 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole (intermediate c)
Compound b (10.0 g,43.79 mmol) was dissolved in a mixed solvent of THF: H2O volume ratio=1:1 (160 mL) in a 250mL three-necked flask, NBS (8.57 g,48.17 mmol), acONa (0.57 g,7.0 mmol) were added in sequence, the reaction was stirred at 20 ℃ for 1H, tlc monitored the reaction (petroleum ether: ethyl acetate volume ratio=7:1 as developing agent, phosphomolybdic acid in ethanol as color developer) until the starting material was completely reacted. Thiourea (3.67 g,48.17 mmol) was added to the reaction system in portions, the temperature was raised to 70℃to continue the reaction 4. 4h, cooled to room temperature, concentrated hydrochloric acid was added dropwise with stirring to give a pH of the reaction system of <1, and the reaction was continued to be heated at 70℃to 1.5. 1.5 h. After the reaction, the reaction mixture was cooled to room temperature, THF was removed under reduced pressure, saturated sodium bicarbonate solution was added dropwise to the ice bath, ph=9 of the system was adjusted, the mixture of dcm: meoh (volume ratio=10:1) was extracted (3×100 mL), the organic phases were combined, and the organic phase was successively washed with water (3×30 mL), saturated brine (3×60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a reddish brown oily substance.
The above reddish brown oily substance was dissolved in a mixed solvent of 60mL dichloromethane/methanol (volume ratio=5:1), and an ethyl acetate solution of 20mL saturated hydrogen chloride was added dropwise under stirring until no more significant solid was produced, suction filtration was performed, the filter cake was washed with dichloromethane, and dried to obtain a pale yellow solid.
The solid was added to 40mL of 15% by mass aqueous sodium hydroxide solution, stirred at room temperature for 30min, filtered, and the cake was washed with ice water and dried under vacuum to give compound c (5.47 g, purity 99.1%, yield 74.3%).
1 H NMR(300MHz,CDCl 3 )δ4.88(s,2H),3.44(s,2H),2.96(t,J＝7.0Hz,2H),2.71(t,J＝6.9Hz,2H)。
(3) Synthesis of 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole (Compound d)
Under the protection of nitrogen, the compound c (5.20 g,30.91 mmol) is dissolved in 135mL of absolute methanol, cooled in an ice bath for 10min, n-propylamine (5.39 mL,46.38 mmol) and glacial acetic acid are sequentially added, the stirring reaction is continued in the ice bath for 40min, and then NaCNBH is slowly added in batches 3 (3.88 g,61.82 mmol). After the addition, the reaction was carried out at room temperature for 6 hours. Adding 30mL of hydrochloric acid with the mass fraction of 10% for quenching reaction, adding saturated sodium bicarbonate to adjust the pH to 8-9, removing most of methanol under reduced pressure, extracting with dichloromethane (3X 80 mL), combining organic phases, washing the organic phases with supersaturated salt water (3X 60 mL), drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude solid.
The crude product is dissolved in 40mL of dichloromethane, 10mL of saturated hydrogen chloride ethyl acetate solution is added dropwise under stirring, suction filtration is carried out, a filter cake is washed by dichloromethane, and a white solid is obtained after drying.
The white solid was added to 30mL of an aqueous solution of 20% by mass of potassium carbonate, stirred at room temperature for 30min, filtered, and the cake was washed with ice water and dried under vacuum to give compound d (5.52 g, purity 98.4%, yield 84.5%).
1 H NMR(300MHz,CDCl 3 )δ4.79(bs,2H),3.05-2.92(m,1H),2.92-2.79(m,1H),2.72-2.55(m,4H),2.33-2.44(m,2.3Hz,1H),2.08-1.95(m,1H),1.63-1.76(m,1H),1.48-1.58(m,2H),0.93(t,J＝7.4Hz,3H)。
(4) Synthesis of pramipexole dihydrochloride (Compound e)
Compound d (5.30 g,25.08 mmol) was dissolved in 25mL of methanol, heated to complete dissolution, then concentrated hydrochloric acid (2.07 mL,25.08 mmol) was added dropwise, stirring was continued for 20min, filtration, washing of the filter cake with cold methanol, and drying to give 6.09g of a white solid.
The white solid is fully dissolved in 65mL of methanol, heated to be dissolved, then L- (+) -tartaric acid (3.70 g,24.58 mmol) is added, stirring is continued until the white solid appears, cooling is carried out, crystallization is carried out at 0 ℃ for 12h, filtering, washing with cold methanol, infrared drying is carried out, and the obtained solid methanol is recrystallized once, thus obtaining 4.31g of white solid.
The solid was dissolved in 25mL of water, cooled to 5℃and 10mL of 30% by mass KOH aqueous solution was added, followed by stirring for 20min, filtration, washing of the cake with cold water and vacuum drying to give 2.29g of a white solid.
The above solid was dissolved in 15mL of ethyl acetate, 8mL of ethyl acetate solution of saturated hydrogen chloride was added dropwise with stirring at room temperature, and after stirring for 30min, filtration, washing with ethyl acetate, and vacuum drying, to give compound e (3.02 g, total yield of compound e from compound D: 42.4%) with a purity of 99.2% and an optical rotation [ αd= -63.8 ° (c=1 in methanol).
The nuclear magnetic hydrogen spectrum of pramipexole dihydrochloride is shown in figure 1, and the nuclear magnetic carbon spectrum is shown in figure 2.
1 H NMR(300MHz,DMSO-d 6 )δ0.91(t,J＝7.5Hz,3H),1.64-1.76(m,J＝7.5Hz,2H),1.88-2.01(m,1H),2.24-2.33(m,1H),2.55-2.67(m,2H),2.73-2.81(m,1H),2.82-2.95(m,2H),2.96-3.06(m,1H),3.47(m,1H),9.50(m,4H)。
13 C NMR(75MHz,DMSO-d 6 )δ169.25,133.50,111.37,52.71,46.42,25.27,23.92,21.38,19.58,11.68。
Example 2
(1) Synthesis of Compound b
1, 4-cyclohexanedione monoethylene ketal (6.5 g,41.62 mmol) was dissolved in 120mL of methylene chloride under nitrogen protection in a 250mL three-necked flask, triethylamine (20.25 mL,145.67 mmol) was added, and TMSOTF (8.28 mL,45.78 mmol) was slowly added dropwise with stirring and cooling in a low temperature reactor at-30℃for 20 min. After the completion of the dropwise addition, the reaction was continued with stirring for 1h under heat preservation, and the reaction was monitored by tlc (petroleum ether: ethyl acetate=9:1 as developing agent, and phosphomolybdic acid in ethanol as color developing agent) until the reaction of the starting materials was complete. To the reaction was added 50mL of saturated sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane (2X 100 mL), and the organic phases were combined. The organic phase was washed successively with water (3X 40 mL), saturated brine (3X 40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound b (9.31 g, crude yield 98.0%) as pale yellow oil, which was directly carried out in the next step without further purification.
(2) Synthesis of 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole (Compound c)
Compound b (9.0 g,39.41 mmol) was dissolved in 140mL THF in a 250mL three-necked flask, NBS (7.36 g,41.38 mmol), acONa (0.65 g,7.88 mmol) and stirred at 10deg.C for 2h, TLC monitored reaction (petroleum ether: ethyl acetate=7:1 as developing agent, phosphomolybdic acid in ethanol as color developing agent) was added until the starting material was complete. Thiourea (3.30 g,43.35 mmol) was added to the reaction system in portions, the temperature was raised to 50℃for further reaction for 4 hours, cooled to room temperature, concentrated hydrochloric acid was added dropwise with stirring to give a pH of the reaction system of <1, and the reaction was continued at 60℃for 1 hour. After the reaction, the reaction mixture was cooled to room temperature, THF was removed under reduced pressure, saturated sodium bicarbonate solution was added dropwise to the ice bath, ph=9 of the system was adjusted, a mixed solvent of dcm: meoh (volume ratio=15:1) was extracted (3×100 mL), the organic phases were combined, and the organic phase was successively washed with water (3×30 mL), saturated brine (3×60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a reddish brown oily substance.
The above reddish brown oily substance was dissolved in 50mL of a mixed solvent of dichloromethane/methanol (volume ratio=5:1), 20mL of a 1, 4-dioxane solution of 4m hydrogen chloride was added dropwise under stirring, suction filtration was performed, and the filter cake was washed with dichloromethane and dried to obtain a pale yellow solid.
The solid was added to 15% by mass aqueous sodium hydroxide solution, stirred at room temperature for 30min, filtered, and the cake was washed with ice water and dried under vacuum to give compound c (4.87 g, purity 98.5%, yield 73.4%).
(3) Synthesis of 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole (Compound d)
Under the protection of nitrogen, the compound c (4.8 g,28.54 mmol) is dissolved in 120mL of anhydrous 1, 2-dichloroethane, cooled in an ice bath for 10min, n-propylamine (4.97 mL,42.80 mmol) and glacial acetic acid are sequentially added, stirring reaction is continued in the ice bath for 40min, and then NaCNBH is slowly added in batches 3 (5.37 g,85.61 mmol). After the addition, the reaction was carried out at room temperature for 6 hours. Adding 40mL of hydrochloric acid with the mass fraction of 10% for quenching reaction, adding saturated sodium bicarbonate for regulating the system to pH=8-9, extracting with dichloromethane (3X 80 mL), combining organic phases, and sequentially washing the organic phases with supersaturated salt water (3X 50 mL), drying with anhydrous sodium sulfate and concentrating under reduced pressure to obtain crude solid.
The crude product is dissolved in 40mL of dichloromethane, 9mL of saturated hydrogen chloride ethyl acetate solution is added dropwise under stirring, suction filtration is carried out, a filter cake is washed by dichloromethane, and a white solid is obtained after drying.
The white solid was added to 30mL of an aqueous solution of 20% by mass of potassium carbonate, stirred at room temperature for 30min, filtered, and the cake was washed with ice water and dried under vacuum to give compound d (5.07 g, purity 98.7%, yield 84.1%).
(4) Synthesis of pramipexole dihydrochloride (Compound e)
Compound d (5.0 g,23.66 mmol) was dissolved in 25mL of methanol, heated to complete dissolution, then concentrated hydrochloric acid (1.96 mL,23.66 mmol) was added dropwise, stirring was continued for 20min, filtration, washing of the filter cake with cold methanol, and drying to give a white solid, 5.72g.
The white solid is fully dissolved in 60mL of methanol, heated to be dissolved, then L- (+) -tartaric acid (3.48 g,23.09 mmol) is added, stirring is continued until the white solid appears, cooling is carried out, crystallization is carried out at 0 ℃ for 12h, filtering, washing with cold methanol, infrared drying is carried out, and the obtained solid methanol is recrystallized once, thus obtaining 4.05g of white solid.
The solid was dissolved in 25mL of water, cooled to 5℃and 10mL of 30% KOH aqueous solution was added, followed by stirring for 20min, filtration, washing of the cake with cold water and vacuum drying to give 2.10g of a white solid.
The above solid was dissolved in 15mL of ethyl acetate, 6mL of ethyl acetate solution of saturated hydrogen chloride was added dropwise with stirring at room temperature, and after stirring for 30min, filtration, washing with ethyl acetate, and vacuum drying, to give compound e (2.82 g, total yield of compound e from compound D: 41.9%) with a purity of 99.1% and an optical rotation [ αd= -63.8 ° (c=1 in methanol).
Example 3
(1) Synthesis of Compound b
1, 4-cyclohexanedione monoethylene ketal (10.0 g,64.03 mmol) was dissolved in 170mL of chloroform under nitrogen protection in a 250mL three-necked flask, triethylamine (35.60 mL,256.11 mmol) was added, and TMSOTF (15.06 mL,83.24 mmol) was slowly added dropwise with stirring and cooling in a low temperature reactor at-10℃for 20 min. After the completion of the dropwise addition, the reaction was continued with stirring for 40min under heat preservation, and the reaction was monitored by tlc (petroleum ether: ethyl acetate=9:1 as developing agent, and phosphomolybdic acid in ethanol as color developing agent) until the reaction of the starting materials was complete. To the reaction was added 70mL of saturated sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane (2X 120 mL), and the organic phases were combined. The organic phase was washed successively with water (3X 60 mL), saturated brine (3X 60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound b (14.37 g as pale yellow oil, crude yield 98.3%) which was directly carried out in the next step without further purification.
(2) Synthesis of 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole (Compound c)
Compound b (14.37 g,62.93 mmol) was dissolved in THF: H in a 250mL three-necked flask 2 To a mixed solvent of O volume ratio=1:1 (200 mL), NBS (12.32 g,69.22 mmol) and AcONa (0.52 g,6.29 mmol) were added in this order, the reaction was stirred at 40 ℃ for 1h, and tlc monitored (petroleum ether: ethyl acetate=7:1 as developing agent, phosphomolybdic acid in ethanol as color developer) until the starting material was completely reacted. Thiourea (6.23 g,81.81 mmol) was added in portions to the reaction system,heating to 60 ℃ for continuous reaction for 5 hours, cooling to room temperature, and dropwise adding concentrated hydrochloric acid under stirring to ensure the pH of the reaction system<1, the reaction was continued at 50℃for 2h. After the reaction, cooling to room temperature, dropwise adding a saturated sodium bicarbonate solution into an ice bath, adjusting the pH=9 of the system, adding sodium chloride solid to saturate the water phase, extracting with THF (3×120 mL), combining the organic phases, drying the organic phase with saturated brine (3×60 mL), drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, dissolving the obtained reddish brown oily substance into 60mL of methanol, stirring uniformly, filtering with diatomite, distilling the filtrate under reduced pressure, and obtaining the reddish brown oily substance.
The above reddish brown oily substance was dissolved in 80mL of a mixed solvent of dichloromethane/methanol (volume ratio=5:1), 30mL of a saturated hydrogen chloride ethyl acetate solution was added dropwise under stirring, suction filtration was performed, and the filter cake was washed with dichloromethane and dried to obtain a pale yellow solid.
The solid was added to 40mL of 15% by mass aqueous sodium hydroxide solution, stirred at room temperature for 30min, filtered, and the cake was washed with ice water and dried under vacuum to give compound c (7.79 g, purity 98.8%, yield 73.6%).
(3) Synthesis of 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole (Compound d)
Under the protection of nitrogen, the compound c (7.79 g,46.31 mmol) is dissolved in 180mL of anhydrous THF, cooled in an ice bath for 10min, n-propylamine (10.76 mL,92.62 mmol) and glacial acetic acid are added in sequence, the stirring reaction is continued in the ice bath for 40min, and then NaCNBH is added slowly in batches 3 (6.06 g,96.62 mmol). After the addition, the reaction was carried out at room temperature for 6 hours. Adding 60mL of hydrochloric acid with the mass fraction of 10% for quenching reaction, adding saturated sodium bicarbonate to adjust the system to pH=8-9, removing THF under reduced pressure, extracting dichloromethane (3X 120 mL), combining organic phases, washing the organic phases with supersaturated salt water (3X 60 mL), drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude solid.
The crude product is dissolved in 60mL of dichloromethane, 20mL of saturated hydrogen chloride ethyl acetate solution is added dropwise under stirring, suction filtration is carried out, a filter cake is washed by dichloromethane, and a white solid is obtained after drying.
The white solid was added to 40mL of an aqueous solution of 20% by mass of potassium carbonate, stirred at room temperature for 30min, filtered, and the cake was washed with ice water and dried under vacuum to give compound d (8.24 g, purity 98.5%, yield 84.2%).
(4) Synthesis of pramipexole dihydrochloride (Compound e)
Compound d (8.24 g,38.99 mmol) was dissolved in 40mL of methanol, heated to complete dissolution, then concentrated hydrochloric acid (3.23 mL,38.99 mmol) was added dropwise, stirring was continued for 20min, filtration, washing of the filter cake with cold methanol, and drying to give 9.44g of a white solid.
The white solid is fully dissolved in 90mL of methanol, heated to be dissolved, then L- (+) -tartaric acid (5.75 g,38.21 mmol) is added, stirring is continued until the white solid appears, cooling is carried out, crystallization is carried out at 0 ℃ for 12h, filtering, washing with cold methanol, infrared drying is carried out, and the obtained solid methanol is recrystallized once, thus obtaining 6.70g of white solid.
The solid was dissolved in 40mL of water, cooled to 5℃and 30mL of 30% KOH aqueous solution was added, followed by stirring for 20min, filtration, washing of the cake with cold water and vacuum drying to give 3.56g of a white solid.
The above solid was dissolved in 25mL of ethyl acetate, 12mL of ethyl acetate solution of saturated hydrogen chloride was added dropwise with stirring at room temperature, and after stirring for 30min, filtration, washing with ethyl acetate, and vacuum drying, to give compound e (4.87 g, total yield of compound e from compound D: 43.9%) with a purity of 99.3% and an optical rotation [ αd = -63.5 ° (c=1 in methanol).
Example 4
(1) Synthesis of Compound b
1, 4-cyclohexanedione monoethylene ketal (8.0 g,51.22 mmol) was dissolved in 140mL1, 2-dichloroethane under nitrogen protection in a 250mL three-necked flask, triethylamine (28.48 mL,204.89 mmol) was added, and TMSOTF (13.90 mL,76.83 mmol) was slowly added dropwise with stirring and cooling in a reactor at 5℃for 20 min. After the completion of the dropwise addition, the reaction was continued with stirring for 30min under heat preservation, and the TLC monitored the reaction (petroleum ether: ethyl acetate=9:1 as developing agent, phosphomolybdic acid in ethanol as color developing agent) until the raw material reaction was completed. To the reaction was added 60mL of saturated sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane (2X 100 mL), and the organic phases were combined. The organic phase was washed successively with water (3X 50 mL), saturated brine (3X 50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound b (pale yellow oil, 11.45g, crude yield 97.9%) which was directly subjected to the next step without further purification.
(2) Synthesis of 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole (Compound c)
Compound b (10.0 g,43.79 mmol) was dissolved in THF: H in a 250mL three-necked flask 2 To a mixed solvent of O volume ratio=1:3 (160 mL), NBS (10.13 g,56.93 mmol) and AcONa (0.57 g,7.0 mmol) were added in this order, the reaction was stirred at 20 ℃ for 1.5h, and tlc was monitored for reaction (petroleum ether: ethyl acetate=7:1 as developing agent, and phosphomolybdic acid in ethanol as color developer) until the starting material was completely reacted. Thiourea (5.0 g,65.69 mmol) was added to the reaction system in portions, the temperature was raised to 80℃and the reaction was continued for 3 hours, cooled to room temperature, and concentrated hydrochloric acid was added dropwise with stirring to adjust the pH of the reaction system<1, continuing the heating reaction at 80 ℃ for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, THF was removed under reduced pressure, saturated sodium bicarbonate solution was added dropwise to the ice bath, ph=9 of the system was adjusted, a mixed solvent of dcm: meoh (volume ratio=20:1) was extracted (3×100 mL), the organic phases were combined, and the organic phase was successively washed with water (3×30 mL), saturated brine (3×60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a reddish brown oily substance.
The above reddish brown oily substance was dissolved in 60mL of a mixed solvent of dichloromethane/methanol (volume ratio=5:1), 20mL of 4m hydrogen chloride-1, 4-dioxane solution was added dropwise under stirring, suction filtration was performed, and the filter cake was washed with dichloromethane and dried to obtain a pale yellow solid.
The solid was added to 40mL of 15% by mass aqueous sodium hydroxide solution, stirred at room temperature for 30min, filtered, and the cake was washed with ice water and dried under vacuum to give compound c (5.46 g, purity 98.9%, yield 74.1%).
(3) Synthesis of 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole (Compound d)
Compound c (5.0 g,29.72 mmol) was dissolved in 130mL of anhydrous dichloromethane under nitrogen protection, cooled in an ice bath for 10min, n-propylamine (5.18 mL,44.59 mmol) and glacial acetic acid were added in sequence, stirring reaction was continued in an ice bath for 40min, and then NaCNBH was added slowly in portions 3 (4.66 g,74.31 mmol). After the addition, the reaction was carried out at room temperature for 6 hours. Adding 30mL of hydrochloric acid with the mass fraction of 10% for quenching reaction, adding saturated sodium bicarbonate for regulating the system to pH=8-9, extracting with dichloromethane (3X 80 mL), combining organic phases, and sequentially washing the organic phases with supersaturated salt water (3X 60 mL), drying with anhydrous sodium sulfate and concentrating under reduced pressure to obtain crude solid.
The crude product is dissolved in 40mL of dichloromethane, 10mL of saturated hydrogen chloride ethyl acetate solution is added dropwise under stirring, suction filtration is carried out, a filter cake is washed by dichloromethane, and a white solid is obtained after drying.
The white solid was added to 30mL of an aqueous solution of 20% by mass of potassium carbonate, stirred at room temperature for 30min, filtered, and the cake was washed with ice water and dried in vacuo to give compound d (5.27 g, purity 98.4%, yield 83.9%).
(4) Synthesis of pramipexole dihydrochloride (Compound e)
Compound d (5.0 g,23.66 mmol) was dissolved in 20mL of methanol, heated to complete dissolution, then concentrated hydrochloric acid (1.95 mL,23.66 mmol) was added dropwise, stirring was continued for 20min, filtration, washing of the filter cake with cold methanol, and drying to give a white solid, 5.75g.
The white solid was dissolved in 60mL of methanol, heated to dissolve, then L- (+) -tartaric acid (3.49 g,23.19 mmol) was added, stirring was continued until a white solid appeared, cooling, crystallization at 0℃for 12h, filtration, washing with cold methanol, infrared drying, and recrystallization of the resulting solid methanol once gave a white solid of 4.07g.
The solid was dissolved in 25mL of water, cooled to 5℃and 10mL of 30% by mass KOH aqueous solution was added, followed by stirring for 20min, filtration, washing of the cake with cold water and vacuum drying to give 2.16g of a white solid.
The above solid was dissolved in 15mL of ethyl acetate, 7mL of ethyl acetate solution of saturated hydrogen chloride was added dropwise with stirring at room temperature, and after stirring for 30min, filtration, washing with ethyl acetate, and vacuum drying, to give compound e (2.81 g, total yield of compound e from compound D: 41.8%) with a purity of 99.0% and an optical rotation [ αd= -63.6 ° (c=1 in methanol).
As described above, although the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limiting the invention itself. Various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. The synthesis method of pramipexole dihydrochloride is characterized by comprising the following steps of:
(1) Taking 1, 4-cyclohexanedione monoethylene glycol ketal a as a raw material, and generating a compound b through trimethylsilylation reaction;
(2) In an organic solvent, sequentially carrying out carbonyl alpha-position bromination, hantzsch condensation and ketal protecting group removal on a compound b to obtain an intermediate 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole c;
(3) The intermediate c is subjected to reductive amination to generate 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole d;
(4) And resolving the compound d to form salt to obtain pramipexole dihydrochloride.
2. The method for synthesizing pramipexole dihydrochloride according to claim 1, comprising the steps of:
(1) Under the existence of TMSOTF and triethylamine, carrying out trimethylsilylation reaction on 1, 4-cyclohexanedione monoethylene ketal a in chlorinated hydrocarbon solvent to generate a silicon etherification product b of carbonyl;
(2) In an organic solvent, the compound b is subjected to one-pot boiling method to sequentially generate NBS bromination, condensation with thiourea Hantzsch and removal of ketal protecting group by HCl in the presence of Acona, so as to obtain an intermediate 2-amino-6-oxo-4, 5,6, 7-tetrahydrobenzothiazole c;
(3) The intermediate c and n-propylamine are subjected to reductive amination in the presence of sodium cyanoborohydride to generate 2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole d;
(4) The compound d is resolved by L- (+) -tartaric acid and salified to obtain pramipexole dihydrochloride.
3. The method of claim 2, wherein in step (1), the chlorinated hydrocarbon solvent is one of dichloromethane, chloroform or 1, 2-dichloroethane.
4. The method for synthesizing pramipexole dihydrochloride according to claim 2, wherein in the step (1), the molar ratio of 1, 4-cyclohexanedione monoethylene glycol ketal a, TMSOTf and triethylamine is 1:1.1 to 1.5:3 to 4.
5. The method for synthesizing pramipexole dihydrochloride according to claim 2, wherein in the step (1), the reaction temperature is-30 to 5 ℃ and the reaction time is 0.5 to 1h.
6. The method for synthesizing pramipexole dihydrochloride according to claim 2, wherein in the step (2), the organic solvent is a mixed solvent of water and THF, and the volume ratio of the two solvents is 0-3:1.
7. The method for synthesizing pramipexole dihydrochloride according to claim 2, wherein in the step (2), the reaction temperature of the NBS bromination is 10-40 ℃ and the reaction time is 1-2 h; the reaction temperature of the Hantzsch condensation is 50-80 ℃ and the reaction time is 3-5 h; the reaction temperature for removing ketal protecting group from HCl is 50-80 ℃ and the reaction time is 1-2 h.
8. The method for synthesizing pramipexole dihydrochloride according to claim 2, wherein in the step (2), the reaction system for removing ketal protecting group by HCl has a pH of <1.
9. The method for synthesizing pramipexole dihydrochloride according to claim 2, wherein in the step (2), the molar ratio of the compound b, NBS, acONa to thiourea is 1:1.05 to 1.3:0.1 to 0.2:1.1 to 1.5.
10. The method for synthesizing pramipexole dihydrochloride according to claim 2, wherein in the step (3), the reaction solvent for reductive amination is one of methanol, 1, 2-dichloroethane, tetrahydrofuran, or dichloromethane; the molar ratio of the compound c to the n-propylamine to the sodium cyanoborohydride is 1:1.5-2:2-3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310228213.9A CN116178304B (en) | 2023-03-10 | Synthesis method of pramipexole dihydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310228213.9A CN116178304B (en) | 2023-03-10 | Synthesis method of pramipexole dihydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116178304A true CN116178304A (en) | 2023-05-30 |
| CN116178304B CN116178304B (en) | 2024-10-25 |
Family
ID=
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020103240A1 (en) * | 2000-09-18 | 2002-08-01 | Karel Pospisilik | Process for resolution of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole and compounds therefor |
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020103240A1 (en) * | 2000-09-18 | 2002-08-01 | Karel Pospisilik | Process for resolution of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole and compounds therefor |
Non-Patent Citations (1)
| Title |
|---|
| P. FERRABOSCHI ET AL.: "Baker’s yeast catalyzed preparation of a new enantiomerically pure synthon of (S)-pramipexole and its enantiomer (dexpramipexole)", 《TETRAHEDRON: ASYMMETRY》, vol. 25, 31 December 2014 (2014-12-31), pages 1239 - 1245 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS6328438B2 (en) | ||
| CN107857743B (en) | Method for preparing roxatidine acetate hydrochloride and intermediate | |
| CN103880903A (en) | Method for preparing tylosin macrolide and derivatives thereof | |
| CN107365275A (en) | The Sai Lexipa of high-purity | |
| CN106256825A (en) | The synthetic method of his Wei of Dacca | |
| CN116178304B (en) | Synthesis method of pramipexole dihydrochloride | |
| CN117603081A (en) | Preparation method of N- (2- ((2- (3-methoxyphenoxy) phenyl) amino) -2-acetoxy) -1-naphthylamine | |
| CN116178304A (en) | Synthesis method of pramipexole dihydrochloride | |
| CN111072660B (en) | Simple preparation method of rilibatan | |
| CN111793016A (en) | Preparation method of larotinib intermediate and intermediate compound | |
| CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
| JPS6391352A (en) | Production of optically active phenylpropanolamines | |
| CN109574860B (en) | Method for preparing vilanterol | |
| CN109678701B (en) | Preparation method of vilanterol intermediate | |
| CN111675660A (en) | Preparation method for synthesizing palbociclib intermediate and method for synthesizing palbociclib | |
| CN111848423A (en) | Preparation method of tert-butyl 3-oxocyclobutylcarbamate | |
| CN108239040B (en) | Preparation method of nitric acid 2- (4-methylthiazol-5-yl) ethyl ester hydrochloride | |
| CN113801082B (en) | Preparation method of ranimivir octoate | |
| CN111100112A (en) | Benzothiophene derivative and process for producing the same | |
| CN111574540B (en) | Preparation method of Degatinib | |
| CN111171094B (en) | Vanillin intermediate and preparation method and application thereof | |
| TWI845992B (en) | A method for preparing a hepatitis B virus nucleocapsid inhibitor | |
| WO2021232694A1 (en) | Method for nickel-based catalytic synthesis of 3-decarbamoyl cefuroxime acid | |
| CN108101881B (en) | Process for the preparation of trabectedin and intermediates thereof | |
| CN110878097B (en) | Preparation method of feigninib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |