CN109180499B - Preparation method of rasagiline mesylate and intermediate thereof - Google Patents
Preparation method of rasagiline mesylate and intermediate thereof Download PDFInfo
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- CN109180499B CN109180499B CN201810856618.6A CN201810856618A CN109180499B CN 109180499 B CN109180499 B CN 109180499B CN 201810856618 A CN201810856618 A CN 201810856618A CN 109180499 B CN109180499 B CN 109180499B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 69
- JDBJJCWRXSVHOQ-UTONKHPSSA-N methanesulfonic acid;(1r)-n-prop-2-ynyl-2,3-dihydro-1h-inden-1-amine Chemical compound CS(O)(=O)=O.C1=CC=C2[C@H](NCC#C)CCC2=C1 JDBJJCWRXSVHOQ-UTONKHPSSA-N 0.000 title claims abstract description 40
- 229960001956 rasagiline mesylate Drugs 0.000 title claims abstract description 40
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 claims abstract description 96
- 229960000245 rasagiline Drugs 0.000 claims abstract description 94
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000003960 organic solvent Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 238000006722 reduction reaction Methods 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 14
- 239000007789 gas Substances 0.000 claims description 103
- 239000002904 solvent Substances 0.000 claims description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- 238000005406 washing Methods 0.000 claims description 28
- XJEVHMGJSYVQBQ-SECBINFHSA-N (1r)-2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2[C@H](N)CCC2=C1 XJEVHMGJSYVQBQ-SECBINFHSA-N 0.000 claims description 25
- 238000001914 filtration Methods 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 238000010791 quenching Methods 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- 238000001291 vacuum drying Methods 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 230000000171 quenching effect Effects 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000008282 halocarbons Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 claims description 9
- 230000001681 protective effect Effects 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical group 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 claims description 4
- OKHRRIGNGQFVEE-UHFFFAOYSA-N methyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C)C1=CC=CC=C1 OKHRRIGNGQFVEE-UHFFFAOYSA-N 0.000 claims description 4
- AKQNYQDSIDKVJZ-UHFFFAOYSA-N triphenylsilane Chemical compound C1=CC=CC=C1[SiH](C=1C=CC=CC=1)C1=CC=CC=C1 AKQNYQDSIDKVJZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000007086 side reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000007281 aminoalkylation reaction Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 108
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 106
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 53
- 235000017557 sodium bicarbonate Nutrition 0.000 description 53
- 239000007864 aqueous solution Substances 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 32
- 238000003756 stirring Methods 0.000 description 22
- 239000011780 sodium chloride Substances 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 description 6
- 239000002274 desiccant Substances 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- -1 seguinine Substances 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- OWAHJGWVERXJMI-UHFFFAOYSA-N prop-2-ynyl methanesulfonate Chemical compound CS(=O)(=O)OCC#C OWAHJGWVERXJMI-UHFFFAOYSA-N 0.000 description 2
- LJZPPWWHKPGCHS-UHFFFAOYSA-N propargyl chloride Chemical compound ClCC#C LJZPPWWHKPGCHS-UHFFFAOYSA-N 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 229940031774 azilect Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/50—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a preparation method of rasagiline mesylate and an intermediate thereof. The invention provides a preparation method of rasagiline mesylate I, which comprises the following steps: step 1: in an organic solvent, carrying out reduction reaction on the rasagiline intermediate II and a reducing agent in the presence of the reducing agent and a catalyst to obtain a rasagiline intermediate III; step 2: and (3) in an organic solvent, carrying out a salt forming reaction on the rasagiline intermediate III obtained in the step (1) and methanesulfonic acid to obtain rasagiline mesylate I. The preparation method does not use amino alkylation reaction with more side reactions, and the prepared rasagiline mesylate I has high purity which meets the requirements of raw material medicaments, the purity is more than 99.5%, the maximum single impurity is less than 0.10%, the yield is high, the production cost is low, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of rasagiline mesylate and an intermediate thereof.
Background
Rasagiline mesylate (I) was developed by the pharmaceutical industry corporation of israel terra watt (Teva), first approved by the European Medicines Agency (EMA) to be marketed at 21/2/2005 and approved by the U.S. Food and Drug Administration (FDA) to be marketed at 16/5/2006, and marketed by terra watt under the trade name Azilect, respectively. Rasagiline mesylate is an irreversible monoamine oxidase inhibitor, can reduce decomposition of dopamine by selectively inhibiting monoamine oxidase, improves the extracellular level of dopamine in high striatum of the brain, and can relieve symptoms of Parkinson's disease by the increased dopamine level. The medicine is used as monotherapy (without levodopamine) or as adjuvant therapy (in combination with levodopamine) for treating idiopathic Parkinson disease.
Compared with selegiline (the first generation monoamine oxidase inhibitor, including seguinine, pyridoxine, cispine, etc.), rasagiline mesylate has the inhibition effect 5-10 times stronger, and also has the effect of improving patients who have declined drug effect after long-term application of the dopa preparation. In addition, the metabolite of rasagiline is an inactive non-amphetamine substance with small side effects, and more importantly, the drug has a certain symptom relieving effect, and more evidences prove that the drug has a certain neuroprotective effect.
The synthesis methods of rasagiline mesylate which have been publicly reported under the prior art conditions are reported in patent documents CN91100031.3, CN201410059002.8 and the like.
Patent document CN91100031.3 reports a method of coupling (R) - (-) -1-aminoindan with 3-chloropropyne to form a salt:
patent document CN201410059002.8 reports a method of coupling (R) - (-) -1-aminoindan with propargyl methanesulfonate to form a salt:
the above preparation routes all use alkylation reaction of amino indane, and since the alkylation of amino usually generates polysubstituted side reaction, the impurity content of the product is large, not only the yield is low (about 35%) but also the product quality is difficult to control (maximum impurity is 0.50%). Therefore, the prior art conditions need to be changed urgently, and a preparation method which is simple and convenient to operate is required to be found for preparing the rasagiline mesylate, has shorter steps and safe operation and is suitable for the requirement of industrial production.
Disclosure of Invention
The invention aims to solve the technical problems that the preparation method of rasagiline mesylate in the prior art is harsh in reaction conditions, multiple in side reactions, high in impurity content, low in reaction yield, low in purity of the prepared product, incapable of reaching the standard of raw material medicines, not suitable for industrial production and the like, and provides a preparation method of rasagiline mesylate and an intermediate thereof. The preparation method does not use an amino alkylation reaction with more side reactions, and the prepared rasagiline mesylate I has high purity, high yield (about 56-58 percent) and low production cost, meets the requirements of raw material medicaments (the purity is more than 99.5 percent, and the maximum single impurity is less than 0.10 percent), and is suitable for industrial production.
The invention provides a preparation method of rasagiline mesylate I, which comprises the following steps:
step 1: in an organic solvent, carrying out reduction reaction on the rasagiline intermediate II and a reducing agent in the presence of the reducing agent and a catalyst to obtain a rasagiline intermediate III;
step 2: in an organic solvent, carrying out a salt forming reaction on the rasagiline intermediate III obtained in the step 1 and methanesulfonic acid to obtain rasagiline mesylate I;
in the step 1, the organic solvent is preferably an aromatic hydrocarbon solvent, and the aromatic hydrocarbon solvent is preferably one or more of toluene, benzene, ethylbenzene and xylene.
In step 1, the volume-to-mass ratio of the organic solvent to the rasagiline intermediate II is preferably 3mL/g to 20mL/g, more preferably 5mL/g to 10mL/g, such as 5mL/g, 7.5mL/g, or 10 mL/g.
In step 1, the reducing agent is preferably one or more of triphenylsilane, diphenylsilane and diphenylmethylsilane.
In the step 1, the molar ratio of the reducing agent to the rasagiline intermediate II is preferably 1.5 to 10, and more preferably 2 to 4, for example, 2.5, 3.2 or 4.
In the step 1, the catalyst is preferably bis-o-chlorophenyl boronic acid and/or bis-o-fluorophenyl boronic acid.
In step 1, the molar ratio of the catalyst to the rasagiline intermediate II is preferably 0.01 to 1.0, more preferably 0.03 to 0.2, such as 0.05, 0.10 or 0.07.
In step 1, the temperature of the reduction reaction is preferably 0 to 40 ℃, more preferably 10 to 25 ℃, for example 10 to 15 ℃, 20 to 25 ℃ or 15 to 20 ℃.
In step 1, the progress of the reduction reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), and is generally at the end of the reaction when the rasagiline intermediate II disappears, and the time of the reduction reaction is preferably 12 hours to 48 hours, more preferably 18 hours to 36 hours, such as 24 hours or 18 hours.
Step 1 is preferably carried out under the protection of a protective gas, preferably nitrogen and/or argon.
Step 1 preferably employs the following post-treatment steps: and after the reaction is finished, removing the solvent, quenching the reaction, extracting, washing, adjusting the pH value to 10-12, extracting, washing, drying, filtering and removing the solvent to obtain the rasagiline intermediate III. The rasagiline intermediate III was used in the next reaction without further purification.
The solvent removal is preferably concentrated in vacuo; the temperature of the vacuum concentration is preferably 45 ℃ to 75 ℃, for example 45 ℃ to 65 ℃. The pressure of the vacuum concentration is preferably-0.085 MPa to-0.1 MPa. The quenching reaction preferably adopts a sodium bicarbonate aqueous solution, the mass concentration of the sodium bicarbonate aqueous solution is preferably 1-30%, for example 10%, and the mass concentration refers to the mass percentage of the sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution. The solvent used for extraction is preferably halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The pH is preferably adjusted by using an aqueous solution of sodium hydroxide; the mass concentration of the sodium hydroxide aqueous solution is preferably 10-40%, for example 20%, and the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution. The washing is preferably performed with an aqueous sodium bicarbonate solution and brine. The mass concentration of the sodium bicarbonate aqueous solution is preferably 1-20%, for example 10%, and the mass concentration refers to the mass percentage of sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution. The salt solution preferably has a mass concentration of 1% to 20%, for example 15%, wherein the mass concentration is the mass percentage of sodium chloride to the total mass of the salt solution. The drying is preferably carried out by adopting a drying agent; the drying agent is preferably anhydrous sodium sulfate. The filtration is preferably carried out by silica gel pad filtration.
In the step 2, the organic solvent is preferably an alcohol solvent; the alcohol solvent is preferably isopropanol.
In the step 2, the molar ratio of the methanesulfonic acid to the rasagiline intermediate II is preferably 0.8 to 1.5, more preferably 0.9 to 1.2, for example 1.0.
In step 2, the temperature of the salt forming reaction is preferably 50 ℃ to 90 ℃, more preferably 60 ℃ to 80 ℃, for example 70 ℃ to 75 ℃.
In step 2, the time of the salt formation reaction is preferably 30 minutes to 10 hours, more preferably 1 hour to 5 hours, for example, 1 hour or 3 hours.
Step 2 preferably comprises the following steps: and adding methanesulfonic acid into a mixture formed by the rasagiline intermediate III and an organic solvent, and carrying out salt forming reaction to obtain the rasagiline mesylate I. The addition is preferably dropwise.
Step 2 preferably employs the following post-treatment steps: and after the reaction is finished, cooling, filtering, washing and drying to obtain the rasagiline mesylate I. The cooling temperature is preferably 15 ℃ to 25 ℃. The cooling time is preferably 1 hour to 5 hours, for example 2 hours. The washing is preferably performed by using an alcohol solvent, and the alcohol solvent is preferably isopropanol. The washing temperature is preferably 15 to 25 ℃. The drying is preferably vacuum drying, the temperature of the vacuum drying is preferably 45-55 ℃, and the pressure of the vacuum drying is preferably-0.01 MPa-0.1 MPa. The time for vacuum drying is preferably 12 to 16 hours.
In the present invention, the preparation method of rasagiline mesylate I preferably further comprises a preparation method of rasagiline mesylate intermediate II, which comprises the following steps: in an organic solvent, in the presence of a condensing agent, carrying out condensation reaction on (R) - (-) -1-aminoindane and propiolic acid to obtain the rasagiline mesylate intermediate II;
the preparation method of the rasagiline intermediate II can be a conventional method in the field of condensation reactions of the type, and the following reaction methods and conditions are particularly preferred in the invention:
in the preparation method of rasagiline intermediate II, the organic solvent is preferably a halogenated hydrocarbon solvent and/or an ether solvent. The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, trichloromethane, 1, 2-dichloroethane and 1,1,2, 2-tetrachloroethane; the ether solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether and dioxane.
In the preparation method of rasagiline intermediate II, the volume-to-mass ratio of the organic solvent to the (R) - (-) -1-aminoindane is preferably 5mL/g to 50mL/g, more preferably 10mL/g to 20mL/g, such as 15mL/g, 20mL/g or 10 mL/g.
In the process for the preparation of rasagiline intermediate II, the condensing agent is preferably dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate. When dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is used as the condensing agent, the reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably 4-dimethylaminopyridine or 1-hydroxybenzotriazole. Further preferably, dicyclohexylcarbodiimide is used together with 4-dimethylaminopyridine, or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is used together with 1-hydroxybenzotriazole. The molar ratio of the catalyst to the (R) - (-) -1-aminoindane is preferably 1 to 10, more preferably 1.1 to 3, such as 1.1, 1.8 or 1.3. When 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate is used as a condensing agent, the reaction is preferably carried out in the presence of a base. The base is preferably an organic base; the organic base is preferably triethylamine and/or diisopropylethylamine. The molar ratio of the base to the (R) - (-) -1-aminoindane is preferably 1 to 10, more preferably 1.1 to 3, for example 2.5 or 1.5.
In the preparation method of rasagiline intermediate II, the molar ratio of the condensing agent to the (R) - (-) -1-aminoindane is preferably 1 to 10, more preferably 1.1 to 1.8, such as 1.7, 1.3 or 1.1.
In the preparation method of rasagiline intermediate II, the equivalent ratio of propiolic acid to (R) - (-) -1-aminoindane is preferably 1 to 10, more preferably 1.1 to 1.5, such as 1.1, 1.4 or 1.3.
In the preparation method of rasagiline intermediate II, the condensation reaction temperature is preferably 0 ℃ to 40 ℃, more preferably 15 ℃ to 25 ℃, for example 15 ℃ to 20 ℃, 20 ℃ to 25 ℃, or 10 ℃ to 15 ℃.
In the preparation method of rasagiline intermediate II, the progress of the condensation reaction can be monitored by a conventional monitoring method in the art (e.g. TLC, HPLC or NMR), and is generally the end point of the reaction when the (R) - (-) -1-aminoindane disappears, and the time of the condensation reaction is preferably 1 hour to 24 hours, more preferably 1 hour to 5 hours, such as 3 hours to 4 hours, 2 hours to 3 hours, or 1 hour to 2 hours.
The preparation method of the rasagiline intermediate II is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
The preparation method of the rasagiline intermediate II preferably comprises the following steps: adding a condensing agent (which can also further comprise a catalyst) into a mixture of an organic solvent, the (R) - (-) -1-aminoindane and propiolic acid for condensation reaction to obtain the rasagiline intermediate II.
The preparation method of the rasagiline intermediate II preferably adopts the following post-treatment steps: and after the reaction is finished, quenching the reaction, extracting, washing, drying, filtering and concentrating to obtain the rasagiline intermediate II. The extraction, washing, drying, filtration and concentration can be carried out by methods conventional in the art for such procedures. The concentration is preferably vacuum concentration; the temperature of the vacuum concentration is preferably 45-55 ℃, and the pressure of the vacuum concentration is preferably-0.085 MPa-0.1 MPa. The quenching reaction preferably adopts hydrochloric acid aqueous solution, the mass concentration of the hydrochloric acid aqueous solution is preferably 1-30%, for example 12%, and the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution. The solvent used for extraction is preferably halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The washing is preferably carried out by washing with an aqueous sodium hydroxide solution, an aqueous sodium bicarbonate solution and brine in this order. The mass concentration of the sodium hydroxide aqueous solution is preferably 1 to 30 percent, for example 10 percent, and the mass concentration refers to the percentage of the mass of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution. The mass concentration of the sodium bicarbonate aqueous solution is preferably 1-20%, for example 10%, and the mass concentration refers to the mass percentage of sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution. The salt solution preferably has a mass concentration of 1% to 20%, for example 15%, wherein the mass concentration is the mass percentage of sodium chloride to the total mass of the salt solution. The drying is preferably carried out by adopting a drying agent; the drying agent is preferably anhydrous sodium sulfate. The filtration is preferably carried out by silica gel pad filtration.
In the invention, the preparation method of rasagiline mesylate I preferably adopts the following route:
the invention also provides a preparation method of the rasagiline intermediate III, which comprises the following steps: in an organic solvent, in the presence of a reducing agent and a catalyst, carrying out a reduction reaction on the rasagiline intermediate II and the reducing agent to obtain a rasagiline intermediate III;
in the preparation method of rasagiline intermediate III, the organic solvent is preferably an aromatic hydrocarbon solvent, and the aromatic hydrocarbon solvent is preferably one or more of toluene, benzene, ethylbenzene and xylene.
In the preparation method of rasagiline intermediate III, the volume-to-mass ratio of the organic solvent to rasagiline intermediate II is preferably 3mL/g to 20mL/g, more preferably 5mL/g to 10mL/g, such as 5mL/g, 7.5mL/g or 10 mL/g.
In the preparation method of rasagiline intermediate III, the reducing agent is preferably one or more of triphenylsilane, diphenylsilane and diphenylmethylsilane.
In the preparation method of rasagiline intermediate III, the molar ratio of the reducing agent to rasagiline intermediate II is preferably 1.5-10, more preferably 2-4, such as 2.5, 3.2 or 4.
In the preparation method of rasagiline intermediate III, the catalyst is preferably bis-o-chlorophenyl boronic acid and/or bis-o-fluorophenyl boronic acid.
In the preparation method of rasagiline intermediate III, the molar ratio of the catalyst to rasagiline intermediate II is preferably 0.01-1.0, more preferably 0.03-0.2, such as 0.05, 0.10 or 0.07.
In the process for the preparation of rasagiline intermediate III, the temperature of the reduction reaction is preferably between 0 ℃ and 40 ℃, more preferably between 10 ℃ and 25 ℃, e.g. between 10 ℃ and 15 ℃, between 20 ℃ and 25 ℃ or between 15 ℃ and 20 ℃.
In the preparation of rasagiline intermediate III, the progress of the reduction reaction may be monitored by monitoring methods conventional in the art (e.g. TLC, HPLC or NMR), typically with the end of the reaction at the time when rasagiline intermediate II disappears, preferably for a period of 12 hours to 48 hours, more preferably for a period of 18 hours to 36 hours, such as 24 hours or 18 hours.
The preparation method of rasagiline intermediate III is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
The preparation method of the rasagiline intermediate III preferably adopts the following post-treatment steps: and after the reaction is finished, removing the solvent, quenching the reaction, extracting, washing, adjusting the pH value to 10-12, extracting, washing, drying, filtering and removing the solvent to obtain the rasagiline intermediate III. The rasagiline intermediate III was used in the next reaction without further purification. The solvent removal is preferably concentrated in vacuo; the temperature of the vacuum concentration is preferably 45 ℃ to 75 ℃, for example 45 ℃ to 65 ℃. The pressure of the vacuum concentration is preferably-0.085 MPa to-0.1 MPa. The quenching reaction preferably adopts a sodium bicarbonate aqueous solution, the mass concentration of the sodium bicarbonate aqueous solution is preferably 1-30%, for example 10%, and the mass concentration refers to the mass percentage of the sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution. The solvent used for extraction is preferably halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The pH is preferably adjusted by using an aqueous solution of sodium hydroxide; the mass concentration of the sodium hydroxide aqueous solution is preferably 10-40%, for example 20%, and the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution. The washing is preferably performed with an aqueous sodium bicarbonate solution and brine. The mass concentration of the sodium bicarbonate aqueous solution is preferably 1-20%, for example 10%, and the mass concentration refers to the mass percentage of sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution. The salt solution preferably has a mass concentration of 1% to 20%, for example 15%, wherein the mass concentration is the mass percentage of sodium chloride to the total mass of the salt solution. The drying is preferably carried out by adopting a drying agent; the drying agent is preferably anhydrous sodium sulfate. The filtration is preferably carried out by silica gel pad filtration.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: compared with the original method, the preparation method avoids the amino alkylation reaction with more side reactions, and the prepared rasagiline mesylate I has high purity, meets the requirement of raw material medicaments (the purity is more than 99.5 percent, and the maximum single impurity is less than 0.10 percent), has high yield (about 56 to 58 percent), has low production cost, and is suitable for industrial production.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Detailed Description
Example 1: preparation of rasagiline intermediate II
Under the protection of nitrogen, 22g (0.165mol) of (R) - (-) -1-aminoindane and 16.2g (0.231mol) of propiolic acid are added to 440mL of dichloromethane, 57.8g (0.280mol) of dicyclohexylcarbodiimide and 36.3g (0.297mol) of 4-dimethylaminopyridine are added with stirring, and the mixture is stirred at 15 to 20 ℃ for 3 to 4 hours. Adding a hydrochloric acid aqueous solution with the mass concentration of 12% to quench (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the hydrochloric acid aqueous solution), and then extracting with dichloromethane. The organic phase was washed with a 10% by mass aqueous sodium hydroxide solution (the mass concentration is the mass percentage of sodium hydroxide to the total mass of the aqueous sodium hydroxide solution), a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution), and a 15% by mass brine (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtration through a funnel lined with 100g of silica gel, washing and concentration gave 29.9g of a pale yellow liquid in 97.7% yield with an HPLC purity of 96.76%.
Example 2: preparation of rasagiline intermediate II
To 495mL of tetrahydrofuran were added 33g (0.248mol) of (R) - (-) -1-aminoindan and 22.1g (0.315mol) of propiolic acid under nitrogen atmosphere, and to 495mL of 1-hydroxybenzotriazole was added with stirring 42.7g (0.316mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 62.7g (0.327mol), and triethylamine was added thereto 37.6g (0.621 mol). Stirring for 2-3 hours at 20-25 ℃. Adding a hydrochloric acid aqueous solution with the mass concentration of 12% to quench (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the hydrochloric acid aqueous solution), and then extracting with dichloromethane. The organic phase was washed with a 10% by mass aqueous sodium hydroxide solution (the mass concentration is the mass percentage of sodium hydroxide to the total mass of the aqueous sodium hydroxide solution), a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution), and a 15% by mass brine (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtration through a funnel lined with 150g of silica gel, washing and concentration gave 43.7g of a pale yellow liquid in 95.2% yield with an HPLC purity of 96.59%.
Example 3: preparation of rasagiline intermediate II
To 220mL of 2-methyltetrahydrofuran were added 22g (0.165mol) of (R) - (-) -1-aminoindan and 12.7g (0.181mol) of propiolic acid under nitrogen atmosphere, followed by 68.9g (0.181mol) of O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 31.9g (0.247mol) of diisopropylethylamine with stirring. Stirring for 1-2 hours at 10-15 ℃. Adding a hydrochloric acid aqueous solution with the mass concentration of 12% to quench (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the hydrochloric acid aqueous solution), and then extracting with dichloromethane. The organic phase was washed with a 10% by mass aqueous sodium hydroxide solution (the mass concentration is the mass percentage of sodium hydroxide to the total mass of the aqueous sodium hydroxide solution), a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution), and a 15% by mass brine (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtration through a funnel lined with 100g of silica gel, washing and concentration gave 29.6g of a pale yellow liquid in 96.8% yield with an HPLC purity of 96.84%.
Example 4: preparation of rasagiline mesylate I
20.0g (0.108mol, 96.76% purity by HPLC) of rasagiline intermediate II was added to 100mL of toluene under nitrogen, 70.3g (0.270mol) of triphenylsilane and 1.36g (0.00542mol) of bis-o-chlorophenyl boronic acid were added with stirring, and the mixture was stirred at 10 to 15 ℃ for 24 hours. Vacuum concentrating (the temperature is preferably 45-65 ℃, the vacuum pressure is preferably-0.085 MPa-0.1 MPa) to remove the solvent, adding a sodium bicarbonate aqueous solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate aqueous solution) for quenching, and then extracting with dichloromethane. And (2) combining the organic phases, adding a hydrochloric acid aqueous solution with the mass concentration of 12% (the mass concentration refers to the mass percentage of hydrogen chloride to the total mass of the hydrochloric acid aqueous solution) for extraction for three times, combining the aqueous phases, adjusting the pH to 10-12 by using a sodium hydroxide aqueous solution with the mass concentration of 20% (the mass concentration refers to the mass percentage of sodium hydroxide to the total mass of the sodium hydroxide aqueous solution), and then extracting by using dichloromethane. The organic phases were combined, washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass brine (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. The mixture was filtered through a funnel lined with 100g of silica gel, washed and concentrated to give a pale yellow liquid, dissolved in isopropanol, and 10.4g (0.108mol) of methanesulfonic acid was added dropwise, followed by heating to 70-75 ℃ and stirring for 1 hour. Cooling to 15-25 ℃, stirring for 2 hours, filtering, washing with cold isopropanol, and vacuum drying (temperature 45-55 ℃, pressure-0.01 MPa-0.1 MPa) for 12-16 hours to obtain a white-like solid, namely rasagiline mesylate I, with a yield of 17.1g (total yield 58.0% in terms of (R) - (-) -1-aminoindane), an HPLC purity of 99.87% and a maximum single impurity of 0.04%.
Example 5: preparation of rasagiline mesylate I.
30.0g (0.162mol, HPLC purity 96.59%) of rasagiline intermediate II was added to 300mL of xylene under nitrogen, and 95.5g (0.518mol) of diphenylsilane and 3.53g (0.016mol) of bis-o-fluorophenylboronic acid were added with stirring, followed by stirring at 20-25 ℃ for 18 hours. Vacuum concentrating (the temperature is preferably 45-75 ℃, the vacuum pressure is preferably-0.085 MPa-0.1 MPa) to remove the solvent, adding a sodium bicarbonate aqueous solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate aqueous solution) for quenching, and then extracting with dichloromethane. And (2) combining the organic phases, adding a hydrochloric acid aqueous solution with the mass concentration of 12% (the mass concentration refers to the mass percentage of hydrogen chloride to the total mass of the hydrochloric acid aqueous solution) for extraction for three times, combining the aqueous phases, adjusting the pH to 10-12 by using a sodium hydroxide aqueous solution with the mass concentration of 20% (the mass concentration refers to the mass percentage of sodium hydroxide to the total mass of the sodium hydroxide aqueous solution), and then extracting by using dichloromethane. The organic phases were combined, washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass brine (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtered through a funnel lined with 150g of silica gel, washed and concentrated to give a pale yellow liquid, dissolved in isopropanol, 15.9g (0.165mol) of methanesulfonic acid was added dropwise, then heated to 70-75 ℃ and stirred for 1 hour. Cooling to 15-25 ℃, stirring for 2 hours, filtering, washing with cold isopropanol, and vacuum drying (temperature 45-55 ℃, pressure-0.01 MPa-0.1 MPa) for 12-16 hours to obtain a white-like solid, namely rasagiline mesylate I, with a yield of 60.7% (total yield 57.8%, calculated as (R) - (-) -1-aminoindan), an HPLC purity of 99.72%, and a maximum single impurity of 0.07%.
Example 6: preparation of rasagiline mesylate I
Under nitrogen protection, 20.0g (0.108mol, HPLC purity 96.76%) of rasagiline intermediate II was added to 150mL of benzene, and 85.7g (0.432mol) of diphenylmethylsilane and 2.03g (0.00809mol) of bis-o-chlorophenylboronic acid were added with stirring, and the mixture was stirred at 15-20 ℃ for 18 hours. Vacuum concentrating (the temperature is preferably 45-65 ℃, the vacuum pressure is preferably-0.085 MPa-0.1 MPa) to remove the solvent, adding a sodium bicarbonate aqueous solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate aqueous solution) for quenching, and then extracting with dichloromethane. And (2) combining the organic phases, adding a hydrochloric acid aqueous solution with the mass concentration of 12% (the mass concentration refers to the mass percentage of hydrogen chloride to the total mass of the hydrochloric acid aqueous solution) for extraction for three times, combining the aqueous phases, adjusting the pH to 10-12 by using a sodium hydroxide aqueous solution with the mass concentration of 20% (the mass concentration refers to the mass percentage of sodium hydroxide to the total mass of the sodium hydroxide aqueous solution), and then extracting by using dichloromethane. The organic phases were combined, washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass brine (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. The mixture was filtered through a funnel lined with 100g of silica gel, washed and concentrated to give a pale yellow liquid, dissolved in isopropanol, and 10.4g (0.108mol) of methanesulfonic acid was added dropwise, followed by heating to 70-75 ℃ and stirring for 1 hour. Cooling to 15-25 ℃, stirring for 2 hours, filtering, washing with cold isopropanol, and vacuum drying (temperature 45-55 ℃, pressure-0.01 MPa-0.1 MPa) for 12-16 hours to obtain a white-like solid, namely rasagiline mesylate I, 16.9g, 58.5% of yield (total yield 56.7% calculated by (R) - (-) -1-aminoindane), 99.89% of HPLC purity and 0.03% of maximum single impurity.
Comparative example 1: preparation of rasagiline I mesylate (cf. patent CN91100031.3, example 4).
Adding 12.4g (0.093mol) of (R) - (-) -1-aminoindane and 12.9g (0.093mol) of potassium carbonate into 95mL of acetonitrile, heating to 60 ℃, stirring and dropwise adding 7.45g (0.1mol) of propargyl chloride, stirring for 16 hours at 60 ℃, vacuum concentrating (the temperature is 45-55 ℃, and the pressure is-0.085 MPa-0.1 MPa) to remove most of the solvent, adding a sodium hydroxide aqueous solution with the mass concentration of 20% (the mass concentration refers to the mass percentage of sodium hydroxide to the total mass of the sodium hydroxide aqueous solution), and then extracting with dichloromethane. The organic phases were combined, washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass saline solution (the mass concentration is the mass percentage of sodium chloride to the total mass of the saline solution), and dried over anhydrous sodium sulfate. Filtering and concentrating to obtain light yellow liquid, dissolving in isopropanol, dropwise adding 5.4g of methanesulfonic acid, heating to 70-75 ℃ and stirring for 1 hour. Cooling to 15-25 ℃, stirring for 2 hours, filtering, washing with cold isopropanol, and vacuum drying (temperature 45-55 ℃, pressure-0.01 MPa-0.1 MPa) for 12-16 hours to obtain a white-like solid, namely rasagiline mesylate I, 8.71g, 35.0% of yield (calculated by (R) - (-) -1-aminoindane), 99.27% of HPLC purity and 0.50% of maximum single impurity.
Comparative example 2: preparation of rasagiline mesylate I (see patent CN201410059002.8, example 1)
Adding 12.4g (0.093mol) of (R) - (-) -1-aminoindane and 12.9g (0.093mol) of potassium carbonate into 95mL of acetonitrile, heating to 35 ℃, stirring and dropwise adding 13.4g (0.1mol) of propargyl methanesulfonate, then stirring for 20 hours at 35 ℃, vacuum concentrating (the temperature is 45-55 ℃, and the pressure is-0.085 MPa-0.1 MPa) to remove most of the solvent, adding a sodium hydroxide aqueous solution with the mass concentration of 20% (the mass concentration refers to the mass percentage of sodium hydroxide to the total mass of the sodium hydroxide aqueous solution), and then extracting with dichloromethane. The organic phases were combined, washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass saline solution (the mass concentration is the mass percentage of sodium chloride to the total mass of the saline solution), and dried over anhydrous sodium sulfate. Filtering and concentrating to obtain light yellow liquid, dissolving in isopropanol, dropwise adding 5.4g of methanesulfonic acid, heating to 70-75 ℃ and stirring for 1 hour. Cooling to 15-25 ℃, stirring for 2 hours, filtering, washing with cold isopropanol, and vacuum drying (temperature 45-55 ℃, pressure-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 8.93g of a white-like solid, namely rasagiline mesylate I, wherein the yield is 35.9% (calculated by (R) - (-) -1-aminoindane), the HPLC purity is 99.34%, and the maximum single impurity is 0.46%.
Claims (10)
1. A preparation method of rasagiline mesylate I is characterized by comprising the following steps:
step 1: in an organic solvent, carrying out reduction reaction on the rasagiline intermediate II and a reducing agent in the presence of the reducing agent and a catalyst to obtain a rasagiline intermediate III; the reducing agent is one or more of triphenylsilane, diphenylsilane and diphenylmethylsilane; the catalyst is bis-o-chlorophenyl boronic acid and/or bis-o-fluorophenyl boronic acid;
step 2: in an organic solvent, carrying out a salt forming reaction on the rasagiline intermediate III obtained in the step 1 and methanesulfonic acid to obtain rasagiline mesylate I;
2. a process for the preparation of rasagiline I mesylate according to claim 1, wherein:
in the step 1, the organic solvent is an aromatic hydrocarbon solvent;
and/or the presence of a gas in the gas,
in the step 1, the volume-to-mass ratio of the organic solvent to the rasagiline intermediate II is 3 mL/g-20 mL/g;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the reducing agent to the rasagiline intermediate II is 1.5-10;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the catalyst to the rasagiline intermediate II is 0.01-1.0;
and/or the presence of a gas in the gas,
in the step 1, the temperature of the reduction reaction is 0-40 ℃;
and/or the presence of a gas in the gas,
in the step 1, the time of the reduction reaction is 12-48 hours;
and/or the presence of a gas in the gas,
step 1 is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
the step 1 adopts the following post-treatment steps: and after the reaction is finished, removing the solvent, quenching the reaction, extracting, washing, adjusting the pH value to 10-12, extracting, washing, drying, filtering and removing the solvent to obtain the rasagiline intermediate III.
3. The process for the preparation of rasagiline I mesylate according to claim 2, wherein:
in the step 1, the aromatic hydrocarbon solvent is one or more of toluene, benzene, ethylbenzene and xylene;
and/or the presence of a gas in the gas,
in the step 1, the volume-to-mass ratio of the organic solvent to the rasagiline intermediate II is 5 mL/g-10 mL/g;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the reducing agent to the rasagiline intermediate II is 2-4;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the catalyst to the rasagiline intermediate II is 0.03-0.2;
and/or the presence of a gas in the gas,
in the step 1, the temperature of the reduction reaction is 10-25 ℃;
and/or the presence of a gas in the gas,
in the step 1, the time of the reduction reaction is 18-36 hours;
and/or the presence of a gas in the gas,
when the step 1 is carried out under the protection of protective gas, the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
the rasagiline intermediate III was used in the next reaction without further purification.
4. A process for the preparation of rasagiline I mesylate according to claim 3, wherein:
in the step 1, the volume-to-mass ratio of the organic solvent to the rasagiline intermediate II is 5mL/g, 7.5mL/g or 10 mL/g;
and/or the presence of a gas in the gas,
in step 1, the molar ratio of the reducing agent to the rasagiline intermediate II is 2.5, 3.2 or 4;
and/or the presence of a gas in the gas,
in step 1, the molar ratio of the catalyst to the rasagiline intermediate II is 0.05, 0.10 or 0.07;
and/or the presence of a gas in the gas,
in the step 1, the temperature of the reduction reaction is 10-15 ℃, 20-25 ℃ or 15-20 ℃;
and/or the presence of a gas in the gas,
in step 1, the time of the reduction reaction is 18 hours or 24 hours.
5. A process for the preparation of rasagiline I mesylate according to claim 1, wherein:
in the step 2, the organic solvent is an alcohol solvent;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the methanesulfonic acid to the rasagiline intermediate II is 0.8-1.5;
and/or the presence of a gas in the gas,
in the step 2, the temperature of the salt forming reaction is 50-90 ℃;
and/or the presence of a gas in the gas,
in the step 2, the time of the salt forming reaction is 30 minutes to 10 hours;
and/or the presence of a gas in the gas,
the step 2 comprises the following steps: adding methanesulfonic acid into a mixture formed by the rasagiline intermediate III and an organic solvent, and carrying out a salt forming reaction to obtain rasagiline mesylate I;
and/or the presence of a gas in the gas,
the step 2 adopts the following post-treatment steps: and after the reaction is finished, cooling, filtering, washing and drying to obtain the rasagiline mesylate I.
6. The process for the preparation of rasagiline I mesylate according to claim 5, wherein:
in the step 2, the alcohol solvent is isopropanol;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the methanesulfonic acid to the rasagiline intermediate II is 0.9-1.2;
and/or the presence of a gas in the gas,
in the step 2, the temperature of the salt forming reaction is 60-80 ℃;
and/or the presence of a gas in the gas,
in the step 2, the time of the salt forming reaction is 1 to 5 hours;
and/or the presence of a gas in the gas,
in the step 2, the adding mode is dropwise adding;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, the cooling temperature is 15-25 ℃;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, the cooling time is 1-5 hours;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, an alcohol solvent is adopted for washing;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, the washing temperature is 15-25 ℃;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, the drying is vacuum drying.
7. The process for the preparation of rasagiline I mesylate according to claim 6, wherein:
in the step 2, the molar ratio of the methanesulfonic acid to the rasagiline intermediate II is 1.0;
and/or the presence of a gas in the gas,
in the step 2, the temperature of the salt forming reaction is 70-75 ℃;
and/or the presence of a gas in the gas,
in the step 2, the time of the salt forming reaction is 1 hour or 3 hours;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, the alcohol solvent adopted for washing is isopropanol;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, the temperature of the vacuum drying is 45-55 ℃;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, the pressure of the vacuum drying is-0.01 MPa to-0.1 MPa;
and/or the presence of a gas in the gas,
in the post-treatment step adopted in the step 2, the vacuum drying time is 12 to 16 hours.
8. A process for the preparation of rasagiline I mesylate according to claim 1, wherein:
the preparation method of the rasagiline mesylate I further comprises a preparation method of a rasagiline mesylate intermediate II, and is characterized by comprising the following steps: in an organic solvent, in the presence of a condensing agent, carrying out condensation reaction on (R) - (-) -1-aminoindane and propiolic acid to obtain the rasagiline mesylate intermediate II;
9. the process for the preparation of rasagiline I mesylate according to claim 8, wherein:
in the preparation method of the rasagiline intermediate II, the organic solvent is a halogenated hydrocarbon solvent and/or an ether solvent;
and/or the presence of a gas in the gas,
in the preparation method of the rasagiline intermediate II, the volume-mass ratio of the organic solvent to the (R) - (-) -1-aminoindane is 5 mL/g-50 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the rasagiline intermediate II, the condensing agent is dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate;
and/or the presence of a gas in the gas,
in the preparation method of the rasagiline intermediate II, the molar ratio of the condensing agent to the (R) - (-) -1-aminoindane is 1-10;
and/or the presence of a gas in the gas,
in the preparation method of the rasagiline intermediate II, the equivalent ratio of the propiolic acid to the (R) - (-) -1-aminoindane is 1-10;
and/or the presence of a gas in the gas,
in the preparation method of the rasagiline intermediate II, the condensation reaction temperature is 0-40 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the rasagiline intermediate II, the condensation reaction is carried out for 1 to 24 hours;
and/or the presence of a gas in the gas,
the preparation method of the rasagiline intermediate II is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
the preparation method of the rasagiline intermediate II comprises the following steps: adding a condensing agent into a mixture of an organic solvent, the (R) - (-) -1-aminoindane and propiolic acid, and carrying out condensation reaction to obtain the rasagiline intermediate II;
and/or the presence of a gas in the gas,
the preparation method of the rasagiline intermediate II comprises the following post-treatment steps: and after the reaction is finished, quenching the reaction, extracting, washing, drying, filtering and concentrating to obtain the rasagiline intermediate II.
10. A preparation method of rasagiline intermediate III is characterized by comprising the following steps:
in an organic solvent, in the presence of a reducing agent and a catalyst, carrying out a reduction reaction on the rasagiline intermediate II and the reducing agent to obtain a rasagiline intermediate III;
the reaction conditions are as described in step 1 of any one of claims 2 to 4.
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| WO2003093251A1 (en) * | 2002-05-01 | 2003-11-13 | Merck Sharp & Dohme Limited | Alkenyl-substituted spirocyclic sulfamides as inhibitors of gamma-secretase |
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| CN101260048A (en) * | 2008-04-15 | 2008-09-10 | 苏州凯达生物医药技术有限公司 | Method for preparing rasagiline |
| CN102464589A (en) * | 2010-11-17 | 2012-05-23 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of rasagiline, mesylate and intermediate thereof |
| CN102786422A (en) * | 2011-05-17 | 2012-11-21 | 上海特化医药科技有限公司 | Method for preparing rasagiline mesylate |
| CN106852143A (en) * | 2014-07-02 | 2017-06-13 | 埃斯蒂维实验室股份有限公司 | Tricyclic triazolic compounds |
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| WO2003093251A1 (en) * | 2002-05-01 | 2003-11-13 | Merck Sharp & Dohme Limited | Alkenyl-substituted spirocyclic sulfamides as inhibitors of gamma-secretase |
| CN101062897A (en) * | 2006-04-25 | 2007-10-31 | 重庆医药工业研究院有限责任公司 | Improved process for preparing 2,3-dihydro-1H-indenes-1-amine and derivative thereof |
| CN101260048A (en) * | 2008-04-15 | 2008-09-10 | 苏州凯达生物医药技术有限公司 | Method for preparing rasagiline |
| CN102464589A (en) * | 2010-11-17 | 2012-05-23 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of rasagiline, mesylate and intermediate thereof |
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