CN115947675B - Rasagiline intermediate and preparation method and application thereof - Google Patents
Rasagiline intermediate and preparation method and application thereof Download PDFInfo
- Publication number
- CN115947675B CN115947675B CN202211648550.5A CN202211648550A CN115947675B CN 115947675 B CN115947675 B CN 115947675B CN 202211648550 A CN202211648550 A CN 202211648550A CN 115947675 B CN115947675 B CN 115947675B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- rasagiline
- preparation
- molar ratio
- 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.)
- Active
Links
- 229960000245 rasagiline Drugs 0.000 title claims abstract description 23
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 22
- KWRSKZMCJVFUGU-VIFPVBQESA-N (1s)-1h-inden-1-ol Chemical compound C1=CC=C2[C@@H](O)C=CC2=C1 KWRSKZMCJVFUGU-VIFPVBQESA-N 0.000 claims abstract description 14
- 229910000085 borane Inorganic materials 0.000 claims abstract description 11
- SNWQUNCRDLUDEX-UHFFFAOYSA-N inden-1-one Chemical compound C1=CC=C2C(=O)C=CC2=C1 SNWQUNCRDLUDEX-UHFFFAOYSA-N 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 18
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 9
- 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 claims description 9
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 9
- 229960001956 rasagiline mesylate Drugs 0.000 claims description 9
- 239000012190 activator Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical group [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 claims description 3
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 claims description 3
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 claims description 3
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 34
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 5
- 125000003277 amino group Chemical group 0.000 abstract description 4
- -1 nitro sulfonyl Chemical group 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 150000001412 amines Chemical class 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 239000012434 nucleophilic reagent Substances 0.000 abstract description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 4
- 239000002994 raw material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 16
- 238000002425 crystallisation Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012752 auxiliary agent Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- MHQIZLXEJZNBQI-UHFFFAOYSA-N 1h-inden-1-amine Chemical compound C1=CC=C2C(N)C=CC2=C1 MHQIZLXEJZNBQI-UHFFFAOYSA-N 0.000 description 1
- KWRSKZMCJVFUGU-UHFFFAOYSA-N 1h-inden-1-ol Chemical compound C1=CC=C2C(O)C=CC2=C1 KWRSKZMCJVFUGU-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- OBLHBIQJADNUED-UHFFFAOYSA-N n-prop-2-ynyl-1h-inden-1-amine Chemical compound C1=CC=C2C(NCC#C)C=CC2=C1 OBLHBIQJADNUED-UHFFFAOYSA-N 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a rasagiline intermediate, a preparation method and application thereof, wherein the intermediate has a structure shown in a formula 3. 1-indenone is used as a synthesis raw material, and (S) -1-indenol with high purity is obtained through asymmetric reduction of chiral auxiliary and borane; reacting (S) -1-indenol with a compound shown in a formula 2, wherein amino protected by sulfonyl is used as a nucleophilic reagent for a photo-delay reaction, so that chiral amine is simpler to construct and operation is simple; the amino group is protected by nitro sulfonyl to avoid the generation of polysubstituted byproducts, thereby generating rasagiline intermediates with higher yield. The intermediate can be used for asymmetrically synthesizing rasagiline. The invention solves the problems of low yield, more side reactions and more impurities of the chiral resolution route. The route has high total yield and product purity and certain market competitiveness;
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a rasagiline intermediate, a preparation method and application thereof.
Background
Rasagiline (RASAGILINE), i.e. N-propargyl-1-aminoindene, having the structural formula:
The salt of rasagiline, such as rasagiline mesylate, is an irreversible monoamine oxidase inhibitor, can reduce the decomposition of dopamine by selectively inhibiting monoamine oxidase, can promote the extracellular level of dopamine in the brain striatum, and can relieve the symptoms of parkinsonism. The composition can be used as monotherapy (without L-dopamine) or as adjuvant therapy (in combination with L-dopamine) for treating idiopathic Parkinson disease.
The existing mode for synthesizing rasagiline mainly comprises the steps of introducing racemic 1-aminoindene or 1-hydroxy indene into propargyl through chiral resolution, and then separating through chiral resolving agent to obtain a target chiral product. The method has the defects of large loss, high cost and environmental protection; the amino has a plurality of reaction sites, has polysubstituted side reactions, and is difficult to control the product quality. Therefore, the improvement of the prior art conditions is urgent, and a method with simple operation steps and higher yield is found to be used for preparing rasagiline so as to meet the requirement of industrial production.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides the rasagiline intermediate, the preparation method and the application thereof, and the rasagiline intermediate can be used for preparing the rasagiline mesylate with high purity (more than or equal to 99.5%) and high yield, and the preparation process is simple and is suitable for industrial production.
In a first aspect of the present invention, there is provided a rasagiline intermediate having a structure represented by formula 3:
In a second aspect of the present invention, there is provided a process for preparing a compound of formula 3 as described above, comprising the steps of:
Reacting (S) -1-indenol with a compound of formula 2 in the presence of an activator and a first organic solvent to produce a compound of formula 3;
The invention adopts the compound of the formula 2 to react with (S) -1-indenol to obtain the compound of the formula 3. In the structure of the compound of the formula 2, the ortho-position nitro has an electron withdrawing effect, and the ortho-position nitro can form a hydrogen bond with the amino group of the sulfonamide, so that the nucleophilicity of the amino group is enhanced, and the yield and the purity of the compound of the formula 3 are improved.
According to some embodiments of the invention, the first organic solvent is tetrahydrofuran.
According to some embodiments of the invention, the molar ratio of the activator to (S) -1-indenol is from 2.0 to 3.0:1.
According to some embodiments of the invention, the molar ratio of the activator to the compound of formula 2 is from 1.0 to 3.0:1.
According to some embodiments of the invention, the molar ratio of (S) -1-indenol to the compound of formula 2 is 1:1.0 to 2.5.
According to some embodiments of the invention, the activator comprises triphenylphosphine and an azo condensing agent.
According to some embodiments of the invention, the azo condensing agent is at least one of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DTAD), dipropyl azodicarboxylate (DPAD), dimethyl azodicarboxylate (DMAD).
According to some embodiments of the invention, the molar ratio of triphenylphosphine to the azo condensing agent is between 0.5 and 1.5:1.
According to some embodiments of the present invention, triphenylphosphine, (S) -1-indenol is mixed with a compound of formula 2, and then an azo condensing agent is added to react.
According to some embodiments of the invention, the temperature of the reaction is 10 ℃ to 40 ℃ and the time of the reaction is 15 to 30 hours.
According to some embodiments of the invention, purifying the compound of formula 3 is also included.
Further, the purifying includes crystallization.
Further, the crystallization is performed by a solvent-based crystallization method, wherein the solvent is selected from n-heptane.
Further, the crystallization temperature is 20-30 ℃, and the crystallization time is 1-3 hours.
According to some embodiments of the invention, the crystallization is followed by solid-liquid separation in at least one of centrifugation, filtration, or sedimentation.
According to some embodiments of the invention, the method for preparing a compound of formula 3 further comprises the steps of:
reacting the 1-indenone with borane in the presence of a chiral auxiliary and a second organic solvent to form (S) -1-indenol.
According to some embodiments of the invention, the chiral auxiliary is at least one of (1R, 2 s) -1-amino-indenol, (R) -CBS; wherein the structure of (R) -CBS is
According to some embodiments of the invention, the borane is at least one of borane dimethyl sulfide, N-diethylaniline borane.
According to some preferred embodiments of the invention, the borane is N, N-diethylaniline borane.
According to the invention, the (1R, 2S) -1-amino-indenol or (R) -CBS is adopted as a chiral auxiliary agent, and N, N-diethylaniline borane is adopted as borane, and because N atoms in the chiral auxiliary agent have certain nucleophilicity, the N atoms are easily complexed with borane in a reaction system to enable B atoms to have Lewis acidity, the B atoms react with oxygen atoms on a ketone carbonyl to obtain an unstable intermediate, the unstable intermediate is easily cracked into chiral alcohol and the chiral auxiliary agent after undergoing a reduction reaction, then the chiral auxiliary agent enters into circulation again, the reaction is promoted, the chiral purity of the generated (S) -1-indenol is improved, and the ee value is more than 95%, so that the post-treatment step is greatly simplified.
According to some embodiments of the invention, the second organic solvent is at least one of tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, 1, 4-dioxane.
According to some embodiments of the invention, the molar ratio of the chiral auxiliary to 1-indenone is from 0.1 to 0.4:1.
According to some embodiments of the invention, the molar ratio of 1-indenone to the borane is 1:1.0 to 4.0.
According to some embodiments of the invention, the chiral auxiliary is mixed with the borane and then the 1-indenone is added to react.
Further, in order to maintain the uniformity of the reaction system, the mixing may be performed by stirring for a period of 0.5 to 1 hour.
According to some embodiments of the invention, the temperature of the reaction is between 0 ℃ and 25 ℃ and the time of the reaction is between 1 and 3 hours.
According to some embodiments of the invention, the purification of the (S) -1-indenol obtained is also included.
Further, the purifying includes crystallization.
Further, the crystallization adopts a solution crystallization method; the solvent of the solvent-out crystallization method is selected from n-heptane.
Further, the crystallization temperature is 20-30 ℃, and the crystallization time is 1-3 hours.
According to some embodiments of the invention, the crystallization is preceded by a quenching reaction and an acid wash. Wherein the quenching reaction is achieved by adding acetone; the acid washing adopts sulfuric acid solution with the mass concentration of 5% -15%, preferably 10%.
According to some embodiments of the invention, the crystallization is followed by solid-liquid separation in at least one of centrifugation, filtration, or sedimentation.
In a third aspect of the invention there is provided the use of a compound of formula 3 as hereinbefore described for the preparation of rasagiline mesylate.
In a fourth aspect of the present invention, there is provided a process for the preparation of rasagiline mesylate comprising the steps of:
Reacting a compound of formula 3 with a mercaptoacid compound in the presence of a base and a third organic solvent to obtain rasagiline; salifying rasagiline with methanesulfonic acid to obtain the product.
According to some embodiments of the invention, the base is lithium hydroxide and/or lithium bis trimethylsilylamide.
According to some embodiments of the invention, the mercaptoacid compound is mercaptoacetic acid and/or mercaptopropionic acid.
According to some embodiments of the invention, the third organic solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.
According to some embodiments of the invention, the molar ratio of the compound of formula 3 to the base is 1:3.8 to 9.0.
According to some embodiments of the invention, the molar ratio of the compound of formula 3 to the mercaptoacid compound is 1:1 to 1.5.
According to some embodiments of the invention, the molar ratio of the base to the mercaptoacid compound is from 3.0 to 8.0:1.
According to some embodiments of the invention, the base is mixed with the compound of formula 3 prior to the addition of the mercaptoacid compound for reaction.
Further, the reaction temperature is 10-25 ℃, and the reaction time is 5-15 h.
According to some embodiments of the invention, purifying the rasagiline obtained is further included.
The purification comprises the following steps:
Adding water into the reaction system, adjusting the pH to 2-3, adding ethyl acetate for extraction, collecting water phase, adjusting the pH to 11-12, adding ethyl acetate for extraction, collecting organic phase, and concentrating to dryness.
According to some embodiments of the invention, the salt forming reaction is carried out at a temperature of 20-30 ℃ for a time of 2-4 hours.
According to some embodiments of the invention, the salifying reaction is carried out in a fourth organic solvent, which is ethyl acetate, isopropyl ether or a mixed solvent of isopropyl alcohol and isopropyl ether.
According to some embodiments of the invention, the salifying is followed by solid-liquid separation in at least one of centrifugation, filtration or sedimentation.
The beneficial effects are that:
The invention develops a brand new process route for asymmetrically synthesizing rasagiline, and the amino protected by sulfonyl is used as a nucleophilic reagent for the photo-delay reaction, so that chiral amine is constructed more simply, and the operation is simple; the amino group is protected by nitro sulfonyl, and the generation of polysubstituted byproducts is avoided. Solves the problems of low yield and more side reactions and impurities of chiral resolution routes. The route has higher total yield, high product purity and high chiral purity, and has market competitiveness.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values for the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
Examples
EXAMPLE 1 Synthesis of Compound 1
Mixing 100g (0.76 mol) of 1-indanone with 800mL of anhydrous THF at room temperature of 25 ℃ to obtain a solution for later use; (1R, 2S) -1-amino-indanol (17 g,0.11mol,0.15 eq) was mixed with THF 1000mL, nitrogen was purged to reduce the temperature to 0 ℃, DEANB (185 g,1.14mol,1.5 eq) was added dropwise, stirring was continued for 30min at a constant temperature, 1-indanone in THF was added dropwise, stirring was continued for 1-3h at a constant temperature, acetone 800mL was added dropwise to quench the reaction, concentrated to dryness, 1000mL of ethyl propyl acetate was added, 600mL of 10% sulfuric acid solution was washed twice the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was added with about 200mL of n-heptane, crystallized at room temperature for 2 hours, filtered, and the cake was dried under reduced pressure to give 181g (80%, purity: 98.6%, EE=96.2%) of the compound.
EXAMPLE 2 Synthesis of Compound 1
Mixing 100g (0.76 mol) of 1-indanone with 800mL of anhydrous MTBE at room temperature of 25 ℃ for later use; (1R, 2S) -1-amino-indanol (34 g,0.23mol,0.30 eq) was mixed with 1000mL of MTBE, nitrogen was purged to reduce the temperature to 0 ℃, DEANB (247 g,1.52mol,2.0 eq) was added dropwise, stirring was continued for 30min at the temperature, MTBE solution of 1-indanone was added dropwise, stirring was continued overnight at 25 ℃, 800mL of acetone was added dropwise to quench the reaction, 600mL of 10% sulfuric acid solution was used to wash the organic phase twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was added with about 200mL of n-heptane, crystallized at room temperature for 2 hours, filtered, and the cake was dried under reduced pressure to give 176.5g (75.6%, purity: 98.3%, EE=95.3%).
EXAMPLE 3 Synthesis of Compound 1
Mixing 100g (0.76 mol) of 1-indanone with 800mL of THF at room temperature of 25 ℃ for later use; (R) -CBS (63 g,0.23mol,0.30 eq) was mixed with 1000mL of THF, nitrogen was purged to reduce the temperature to 0 ℃, DEANB (247 g,1.52mol,2.0 eq) was added dropwise, stirring was continued for 30min, 1-indanone in THF was added dropwise, stirring was continued overnight at 25 ℃, acetone was added dropwise to quench the reaction, 10% sulfuric acid solution 600mL was used to wash the organic phase twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was added with about 200mL of n-heptane, crystallized at room temperature for 2 hours, filtered, and the filter cake was dried under reduced pressure to give 183.2g (82% purity: 98.6%, EE=95.4%).
EXAMPLE 4 Synthesis of Compound 3
50G of Compound 1 (0.37 mol), 90g of Compound 2 (0.37 mol) and 127g of triphenylphosphine (0.48 mol) were taken, dissolved in 1500mL of THF, nitrogen-protected, and cooled to 0 ℃. 98g of diisopropyl azodicarboxylate (DIAD) (0.48 mol) was dissolved in 500mL of THF under nitrogen protection, and the system was dropped dropwise, followed by reaction at 25℃for 20 hours. After the reaction, 150mL of n-heptane was added, and the mixture was slurried at room temperature for 2 hours, filtered, and the cake was dried under vacuum at 45℃to a constant weight to give 107g (85%, purity: 98.8%) of compound 3.
1H NMR(500MHz,Chloroform-d)δ8.25(d,J＝7.4Hz,1H),7.70(d,J＝10.4Hz,3H),7.33–7.22(m,3H),5.64(t,J＝7.7Hz,1H),4.23(dd,J＝18.7,2.0Hz,1H),3.63(dd,J＝18.7,2.4Hz,1H),3.08(ddd,J＝13.4,9.2,4.0Hz,1H),2.94–2.80(m,1H),2.55(dtd,J＝12.8,8.5,4.1Hz,1H),2.40(dq,J＝16.2,7.4Hz,1H).
EXAMPLE 5 Synthesis of Compound 3
50G of Compound 1 (0.37 mol), 180g of Compound 2 (0.75 mol), 127g of triphenylphosphine (0.48 mol), dissolved in 1500mL of THF, nitrogen-protected, and cooled to 0 ℃.85g of diethyl azodicarboxylate (DEAD) (0.42 mol) was dissolved in 500mL of THF, the system was dropwise added under nitrogen protection, and the temperature was raised to 35℃for 15 hours. After the reaction, 300mL of n-heptane was added and pulped at room temperature for 2 hours, and the mixture was filtered, and the filter cake was dried under vacuum at 45℃to a constant weight, to give 104.3g (82.9%, purity: 98%) of the compound. 1 H NMR data were substantially the same as in scheme example 4.
EXAMPLE 6 Synthesis of Compound 3
50G of Compound 1 (0.37 mol), 90g of Compound 2 (0.37 mol), 127g of triphenylphosphine (0.48 mol), dissolved in 1500mL of THF, nitrogen-protected, and cooled to 0 ℃.98g of diisopropyl azodicarboxylate (DIAD) (0.48 mol) was dissolved in 500mL of THF under nitrogen protection, and the system was dropped, and the temperature was raised to 15℃for 24 hours. After the reaction, 150mL of n-heptane was added, and the mixture was slurried at room temperature for 2 hours, filtered, and the cake was dried under vacuum at 45℃to a constant weight to give 102.5g (81.5% purity: 98.3%) of a compound. 1 The H NMR data were essentially the same as in example 4.
EXAMPLE 7 Synthesis of Compound 4
50G of Compound 3 (0.14 mol), 28g of lithium hydroxide (1.17 mol,8.4 eq) are dissolved in 500mL of DMF.17g of mercaptopropionic acid (0.16 mol,1.1 eq) was dissolved in 500mL of DMF and the system was added dropwise. After the addition, the mixture was reacted at 25℃for 5 hours. After the reaction, 1000mL of water was added and mixed, the pH was adjusted to 2-3 with hydrochloric acid, washing twice with 1000mL of ethyl acetate, merging the aqueous phases, adjusting the pH to 11-12 with NaOH, extracting twice with 1000mL of ethyl acetate, merging the organic phases, washing once with 500mL of saturated aqueous NaCl solution, drying over 150g of anhydrous sodium sulfate for 0.5h, after the drying, filtering, concentrating the filtrate under reduced pressure until no fraction was obtained, and obtaining compound 4.6 g (92%, purity: 97.5%).
1H NMR(500MHz,Chloroform-d)δ7.32–7.24(m,1H),7.20–7.07(m,3H),4.34(t,J＝6.1Hz,1H),3.54–3.38(m,2H),2.96(ddd,J＝14.8,8.2,5.8Hz,1H),2.75(ddd,J＝15.4,8.3,6.2Hz,1H),2.32(ddt,J＝12.8,8.3,6.3Hz,1H),2.17(t,J＝2.4Hz,1H),1.79(ddt,J＝13.3,8.3,5.7Hz,1H),1.63(s,1H),1.41–1.04(m,4H),0.85–0.73(m,1H).
EXAMPLE 8 Synthesis of Compound 4
50G of Compound 3 (0.14 mol), 14g of lithium hydroxide (0.58 mol,4.2 eq) are dissolved in 500mL of DMAc.14.7g of thioglycollic acid (0.16 mol,1.1 eq) was dissolved in 500mL of DMAc, and the system was dropped. After the addition, the mixture was reacted at 10℃for 11 hours. After the reaction, 1000mL of water was added and mixed, the pH was adjusted to 2-3 by hydrochloric acid, washing twice by 1000mL of ethyl acetate, merging the aqueous phases, adjusting the pH to 11-12 by NaOH, extracting twice by 1000mL of ethyl acetate, merging the organic phases, washing once by 500mL of saturated NaCl aqueous solution, drying 150g of anhydrous sodium sulfate for 0.5h, after the drying, filtering, concentrating the filtrate under reduced pressure until no fraction was obtained, and obtaining 21.7g (84.4% purity 97.1%) of the compound. 1 The H NMR data were essentially the same as in example 7.
EXAMPLE 9 Synthesis of Compound 4
50G of Compound 3 (0.14 mol), 88g of lithium bistrimethylsilylamino (0.53 mol,3.8 eq) are dissolved in 500mL of NMP.14.7g of thioglycollic acid (0.16 mol,1.1 eq) was dissolved in 500mL of NMP and the system was added dropwise. After the addition, the mixture was reacted at 10℃for 11 hours. After the reaction, 1000mL of water was added and mixed, the pH was adjusted to 2-3 by hydrochloric acid, washing twice by 1000mL of ethyl acetate, merging the aqueous phases, adjusting the pH to 11-12 by NaOH, extracting twice by 1000mL of ethyl acetate, merging the organic phases, washing once by 500mL of saturated NaCl aqueous solution, drying 150g of anhydrous sodium sulfate for 0.5h, after the drying, filtering, concentrating the filtrate under reduced pressure until no fraction was obtained, and obtaining 4.7g (77.0% purity 95.8%) of the compound. 1 The H NMR data were essentially the same as in example 7.
Example 10 Synthesis of RSG
20G of Compound 4 are dissolved in 100mL of isopropyl alcohol/isopropyl ether=1:2 solvent mixture under nitrogen. 12g of methanesulfonic acid, dissolved in 100mL of isopropyl alcohol/isopropyl ether=1:2 mixed solvent, nitrogen-protected, and the system was dropped. After the addition, the mixture was reacted at 25℃for 3 hours. After the reaction, the mixture was filtered, and the filter cake was dried under vacuum at 45℃to a constant weight to give 28.1g (90.1%, 99.8%) of rasagiline mesylate.
1H NMR(500MHz,Chloroform-d)δ9.30(s,2H),7.62(d,J＝7.6Hz,1H),7.33–7.16(m,3H),4.90(p,J＝5.6Hz,1H),3.81(dq,J＝7.2,4.1Hz,2H),3.25(dt,J＝16.0,7.9Hz,1H),2.86(ddd,J＝16.3,7.9,4.8Hz,1H),2.53(d,J＝2.6Hz,1H),2.52(s,3H),2.47–2.36(m,2H).
EXAMPLE 11 Synthesis of RSG
20G of Compound 4 are dissolved in 500mL of ethyl acetate under nitrogen. 12g of methanesulfonic acid is added dropwise at 25 ℃, and the reaction is carried out for 3 hours after the addition of methanesulfonic acid. The mixture was filtered and the filter cake was dried under vacuum at 45℃to a constant weight to give 26.7g (85.5%, 99.5%) of rasagiline mesylate. 1 HNMR data are substantially as in example 10.
EXAMPLE 12 Synthesis of RSG
20G of Compound 4 are dissolved in 100mL of isopropyl ether under nitrogen. 12g of methanesulfonic acid is added dropwise at 5 ℃, and the reaction is carried out for 3 hours after the addition of methanesulfonic acid. The mixture was filtered and the filter cake was dried under vacuum at 45℃to a constant weight to give rasagiline mesylate (19.3 g, 61.7%, 99.5%). 1 The H NMR data were essentially the same as in example 10.
Comparative example 1
100G (0.76 mol) of 1-indanone is mixed with 800mL of dioxane at room temperature of 25 ℃ to dissolve for later use; (1R, 2S) -1-amino-indanol (17 g,0.11mol,0.15 eq) was mixed with 1000mL of dioxane, nitrogen was purged to reduce the temperature to 0 ℃, borane-tetrahydrofuran (98 g,1.14mol,1.5 eq) was added dropwise, stirring was continued for 30min, 1-indanone in THF was added dropwise, stirring was continued for 1-3h, 600mL of methanol was added dropwise to quench the reaction, concentrated to dryness, 1000mL of ethyl acetate was added 1000mL, 600mL of 10% hydrochloric acid solution was added to wash the organic phase twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was added with about 200mL of n-heptane, crystallized at room temperature for 2 hours, filtered, and the filter cake was dried under reduced pressure to give 64.3g (63.5% purity: 98.2% EE=94.7%) of the compound 1.
Comparative example 2
50G of compound 1, 90g of compound 2b,127g of triphenylphosphine were dissolved in 1500mL of THF, nitrogen protection and cooled to 0 ℃.98g of diisopropyl azodicarboxylate (DIAD) was dissolved in 500mL of THF, nitrogen was used to protect the system, and the system was dropped, and the temperature was raised to 15℃for 24 hours. After the reaction, 150mL of n-heptane was added, and the mixture was slurried at room temperature for 2 hours, filtered, and the cake was dried under vacuum at 45℃to a constant weight to give 66.2g (52.6% purity: 96.8%) of Compound 3 b.
Comparative example 3
50G of Compound 3b (0.14 mol), 85.3g of DBU (0.56 mol,4.0 eq) were dissolved in 500mL of DMF,14.7g of thioglycolic acid (0.16 mol,1.1 eq) were dissolved in 500mL of DMF, and the system was dropped. After the addition, the mixture was reacted at 25℃for 6 hours. After the reaction, 1000mL of water was added and mixed, the pH was adjusted to 2-3 by hydrochloric acid, washing twice by 1000mL of ethyl acetate, merging the aqueous phases, adjusting the pH to 11-12 by NaOH, extracting twice by 1000mL of ethyl acetate, merging the organic phases, washing once by 500mL of saturated NaCl aqueous solution, drying 150g of anhydrous sodium sulfate for 0.5h, after the drying, filtering, concentrating the filtrate under reduced pressure until no fraction was obtained, and obtaining 11.5g (48% purity: 95.4%) of the compound.
Comparative example 4
20G of Compound 4 are dissolved in 100mnL isopropanol under nitrogen. 12g of methanesulfonic acid is added dropwise at 5 ℃, and the reaction is carried out for 3 hours after the addition of methanesulfonic acid. The mixture was filtered and the filter cake was dried under vacuum at 45℃to a constant weight to give 16.9g (54%, 99.2%) of rasagiline mesylate.
The above description has been given of the embodiments of the present invention, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (13)
1. A method for preparing rasagiline intermediate, which is characterized in that the rasagiline intermediate has a structure shown in a formula 3:
3；
the preparation method comprises the following steps:
Reacting 1-indenone with borane in the presence of a chiral auxiliary and a second organic solvent to form (S) -1-indenol; reacting (S) -1-indenol with a compound of formula 2 in the presence of an activator and a first organic solvent to produce a compound of formula 3;
2；
the chiral auxiliary is at least one of (1R, 2S) -1-amino-indenol and (R) -CBS;
The borane is N, N-diethyl aniline borane;
the activator is triphenylphosphine and an azo condensing agent;
Wherein the azo condensing agent is at least one of diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, dipropyl azodicarboxylate and dimethyl azodicarboxylate.
2. The preparation method according to claim 1, wherein the molar ratio of the activator to (S) -1-indenol is 2.0 to 3.0:1.
3. The method of claim 1, wherein the molar ratio of the activator to the compound of formula 2 is 1.0 to 3.0:1.
4. The process according to claim 1, wherein the molar ratio of (S) -1-indenol to the compound of formula 2 is 1:1.0 to 2.5.
5. The preparation method according to claim 1, wherein the molar ratio of triphenylphosphine to the azo condensing agent is 0.5-1.5: 1.
6. The preparation method of claim 1, wherein the molar ratio of the chiral auxiliary to the 1-indenone is 0.1-0.4: 1.
7. The preparation method according to claim 1, wherein the molar ratio of 1-indenone to borane is 1:1.0 to 4.0.
8. The method according to any one of claims 1 to 7, wherein the first organic solvent is tetrahydrofuran;
And/or the second organic solvent is at least one of tetrahydrofuran, methyl tertiary butyl ether, methyl tetrahydrofuran and 1, 4-dioxane.
9. A preparation method of rasagiline mesylate, which is characterized in that a compound of formula 3 is reacted with a mercapto acid compound in the presence of alkali and a third organic solvent to obtain rasagiline; salifying rasagiline with methanesulfonic acid to obtain the rasagiline;
Wherein the compound of formula 3 is prepared by the preparation method of any one of claims 1 to 8.
10. The method of claim 9, wherein the base is lithium hydroxide and/or lithium bis trimethylsilylamide.
11. The process of claim 9, wherein the molar ratio of the compound of formula 3 to the base is 1:3.8 to 9.0.
12. The method of claim 9, wherein the molar ratio of the compound of formula 3 to the mercaptoacid compound is 1:1 to 1.5.
13. The preparation method according to claim 9, wherein the molar ratio of the base to the mercapto acid compound is 3.0 to 8.0:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211648550.5A CN115947675B (en) | 2022-12-21 | 2022-12-21 | Rasagiline intermediate and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211648550.5A CN115947675B (en) | 2022-12-21 | 2022-12-21 | Rasagiline intermediate and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115947675A CN115947675A (en) | 2023-04-11 |
| CN115947675B true CN115947675B (en) | 2024-05-31 |
Family
ID=87288402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211648550.5A Active CN115947675B (en) | 2022-12-21 | 2022-12-21 | Rasagiline intermediate and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115947675B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7385064B1 (en) * | 2005-11-30 | 2008-06-10 | The Research Foundation Of State University Of New York | Catalysts for use in enantioselective synthesis |
| CN101381314A (en) * | 2007-09-05 | 2009-03-11 | 成都和康药业有限责任公司 | Preparation method of (R)-(+)-N-propargyl-1-indan amines |
| CN102010353A (en) * | 2010-10-22 | 2011-04-13 | 湖北能特科技股份有限公司 | New method for preparing rasagiline mesylate |
| CN103188933A (en) * | 2010-10-26 | 2013-07-03 | 泰华制药工业有限公司 | Deuterium enriched rasagiline |
-
2022
- 2022-12-21 CN CN202211648550.5A patent/CN115947675B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7385064B1 (en) * | 2005-11-30 | 2008-06-10 | The Research Foundation Of State University Of New York | Catalysts for use in enantioselective synthesis |
| CN101381314A (en) * | 2007-09-05 | 2009-03-11 | 成都和康药业有限责任公司 | Preparation method of (R)-(+)-N-propargyl-1-indan amines |
| CN102010353A (en) * | 2010-10-22 | 2011-04-13 | 湖北能特科技股份有限公司 | New method for preparing rasagiline mesylate |
| CN103188933A (en) * | 2010-10-26 | 2013-07-03 | 泰华制药工业有限公司 | Deuterium enriched rasagiline |
Non-Patent Citations (3)
| Title |
|---|
| A convenient enantioselective CBS-reduction of arylketones in flow-microreactor systems;Sonia De Angelis et al;《Organic & Biomolecular Chemistry》;第14卷;4304-4311 * |
| Xavier Lyndon C. et al.(S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo- [1,2-c][1,3,2]oxazaborole-borane complex.《Organic Syntheses》.1997,第74卷50-71. * |
| 雷沙吉兰合成研究进展;郑欣等;《中国医药导报》;第9卷(第19期);13-15 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115947675A (en) | 2023-04-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2014268009B2 (en) | Preparation method of azoxystrobin | |
| CN107857743B (en) | Method for preparing roxatidine acetate hydrochloride and intermediate | |
| TWI703163B (en) | Method for preparing sugammadex sodium and crystalline form thereof | |
| CA2857230A1 (en) | Process for preparing and purifying salts of acrylamido-2-methylpropanesulfonic acid | |
| CN109096122B (en) | Process for preparing spermidine | |
| TW202030177A (en) | Processes to produce elagolix | |
| CN105452228B (en) | Prepare the novel method of Febuxostat | |
| CN115947675B (en) | Rasagiline intermediate and preparation method and application thereof | |
| KR101595747B1 (en) | Method for preparing of nafamostat mesilate | |
| CN107935892B (en) | Method for preparing ethylenediamine ethanesulfonic acid sodium salt | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| CN107001250B (en) | A method of Ao Dangka is prepared for intermediate | |
| CN105745191A (en) | Method for preparing silodosin and intermediate thereof | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN113651772A (en) | Preparation method of cloperastine hydrochloride | |
| CN109810059A (en) | A kind of preparation method of left-handed hydrochloric acid demethyl benzene ring pelargonate | |
| CN111018782B (en) | Preparation method of 9-aminoacridine and derivatives thereof | |
| CN113735693B (en) | Synthesis method of resveratrol dimethyl ether | |
| CN108658961A (en) | A kind of preparation method of Azilsartan | |
| TWI844663B (en) | Process for the production of substituted 2-[2-(phenyl)ethylamino]alkaneamide derivatives | |
| CN112624968B (en) | Synthetic method of 5-amino-3-cyanopyridine methyl formate hydrochloride | |
| JP2001158777A (en) | Method for producing 2-cyanopiperazine | |
| CN116574059A (en) | Synthesis method of 10-methoxyiminostilbene | |
| CN116041327A (en) | Preparation method of vonoprazan fumarate impurity | |
| CN114933562A (en) | Efficient preparation method of chloroquine based on catalysis of (2-hydroxybenzyl) disubstituted phosphine oxide |
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 | ||
| GR01 | Patent grant |