CN103497175B - Prepare the method for Revlimid - Google Patents
Prepare the method for Revlimid Download PDFInfo
- Publication number
- CN103497175B CN103497175B CN201310472457.8A CN201310472457A CN103497175B CN 103497175 B CN103497175 B CN 103497175B CN 201310472457 A CN201310472457 A CN 201310472457A CN 103497175 B CN103497175 B CN 103497175B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- organic solvent
- methyl
- acid
- 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.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 52
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 title abstract description 38
- 229940120975 revlimid Drugs 0.000 title abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 103
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 239000003960 organic solvent Substances 0.000 claims description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 229960001701 chloroform Drugs 0.000 claims description 20
- 238000010511 deprotection reaction Methods 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 125000003368 amide group Chemical group 0.000 claims description 14
- 230000002140 halogenating effect Effects 0.000 claims description 14
- 239000003223 protective agent Substances 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 230000032050 esterification Effects 0.000 claims description 11
- 238000005886 esterification reaction Methods 0.000 claims description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000003999 initiator Substances 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 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 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003377 acid catalyst Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 6
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 5
- PZHIWRCQKBBTOW-UHFFFAOYSA-N 1-ethoxybutane Chemical compound CCCCOCC PZHIWRCQKBBTOW-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 5
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 5
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 claims description 5
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 150000008282 halocarbons Chemical class 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 235000010755 mineral Nutrition 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 5
- 150000003527 tetrahydropyrans Chemical class 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 3
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- WYGWHHGCAGTUCH-UHFFFAOYSA-N 2-[(2-cyano-4-methylpentan-2-yl)diazenyl]-2,4-dimethylpentanenitrile Chemical compound CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C WYGWHHGCAGTUCH-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- UNGVHYYDHXGTTP-UHFFFAOYSA-N C[S](C)Br Chemical compound C[S](C)Br UNGVHYYDHXGTTP-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- BWJUFXUULUEGMA-UHFFFAOYSA-N propan-2-yl propan-2-yloxycarbonyloxy carbonate Chemical compound CC(C)OC(=O)OOC(=O)OC(C)C BWJUFXUULUEGMA-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- BYHMLZGICSEKIY-UHFFFAOYSA-N 3-amino-2-methylbenzoic acid Chemical compound CC1=C(N)C=CC=C1C(O)=O BYHMLZGICSEKIY-UHFFFAOYSA-N 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 11
- 229940125898 compound 5 Drugs 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000007259 addition reaction Methods 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- YCPULGHBTPQLRH-UHFFFAOYSA-N 3-aminopiperidine-2,6-dione;hydron;chloride Chemical class Cl.NC1CCC(=O)NC1=O YCPULGHBTPQLRH-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- 0 C[C@@](C1)*1OC(c1c(C*)c(N*)ccc1)=O Chemical compound C[C@@](C1)*1OC(c1c(C*)c(N*)ccc1)=O 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- -1 amine methyl benzoate Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229940095102 methyl benzoate Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- FPTXHPBEWHUDAV-YELSXNLMSA-N CC/C(/N)=C(/CN(C(CCC(N1)=O)C1=O)C1=O)\C1=C/C Chemical compound CC/C(/N)=C(/CN(C(CCC(N1)=O)C1=O)C1=O)\C1=C/C FPTXHPBEWHUDAV-YELSXNLMSA-N 0.000 description 1
- 208000009233 Morning Sickness Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000034850 Vomiting in pregnancy Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 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
Abstract
The invention discloses the method preparing Revlimid.Present method with 3-amino-2-methyl phenylformic acid for starting raw material synthesizes Revlimid.Utilize the method preparing Revlimid of the present invention effectively can prepare Revlimid, and technique is simple, combined coefficient is high, and the purity of prepared Revlimid is higher.In addition, this preparation method also has that starting raw material is easy to get, technological operation is simple, reaction conditions is gentle, without the need to special reaction equipment, in preparation process, be not difficult to the advantages such as the compound that is separated, thus is more suitable for extensive, suitability for industrialized production Revlimid.
Description
Technical field
The present invention relates to medical art.In particular to the method preparing Revlimid.
Background technology
Revlimid (Lenalidomide/Revlimid, compound 1), chemistry 3-(7-amino-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone by name, its chemical structure is as follows:
Revlimid is a kind of immunomodulator having angiogenesis inhibitor, immunomodulatory and directly kill the multiple actions such as tumour cell, it is developed by Celgene company of the U.S. and obtains U.S. FDA in December, 2005 and ratifies, be used for the treatment of multiple myeloma and myelodysplastic syndrome, be used for the treatment of the reinforcement version that morning sickness once caused thousands of baby due defect Thalidomides (thalidomide), there are anticancer potentiality, compared with Thalidomide, its less adverse effect, research proves that it can not cause baby due defect.Although the method preparing Revlimid is at present a lot, there is complicated process of preparation, combined coefficient is low, production cost is high, production security is low, pollute physical environment, be difficult to the shortcomings such as suitability for industrialized production.
Therefore, the method preparing Revlimid at present still haves much room for improvement.
Summary of the invention
The present invention is intended at least to solve one of technical problem existed in prior art.For this reason, the present invention proposes the method effectively can preparing Revlimid.
The present invention proposes a kind of method preparing Revlimid.According to embodiments of the invention, the method comprises:
1) with reference to following formula, the esterification of compound generation shown in formula 2 is made, to obtain compound shown in formula 3,
2) with reference to following formula, compound shown in described formula 3 is contacted with amino protecting agent, to obtain compound shown in formula 4,
3) with reference to following formula, compound generation halogenating reaction shown in described formula 4 is made, to obtain compound shown in formula 5,
4) with reference to following formula, compound shown in compound with formula 6 shown in described formula 5 is contacted, to obtain compound shown in formula 7,
and
5) with reference to following formula, by compound generation deprotection reaction shown in described formula 7, to obtain compound shown in described formula 1,
Term " contact " used in this article should be interpreted broadly, and it can be any mode that can make at least two kinds of reactant generation chemical reactions, such as, can be mixed under suitable condition by two kinds of reactants.In this article, " compound N ", in this article sometimes also referred to as " shown in formula N compound ", N is the arbitrary integer of 1-13 in this article, and such as " compound 2 " also can be called " shown in formula 2 compound " in this article.
The similar description such as term " first ", " second " used in this article only for describing object, and can not be interpreted as instruction or hint relative importance or imply the quantity indicating indicated technical characteristic.Thus, be limited with " first ", the feature of " second " can express or impliedly comprise one or more these features.In describing the invention, except as otherwise noted, the implication of " multiple " is two or more, unless otherwise clear and definite restriction.
Utilize and effectively can prepare Revlimid according to the method preparing Revlimid of the embodiment of the present invention, and preparation technology is simple, combined coefficient is high, and the purity of prepared Revlimid is higher, and this preparation method has no bibliographical information.In addition, this preparation method also has that starting raw material is easy to get, reaction conditions is gentle, without the need to special reaction equipment, in preparation process, be not difficult to the advantages such as the compound that is separated, thus is more suitable for extensive, suitability for industrialized production Revlimid.
In addition, following additional technical characteristic can also be had according to the method preparing Revlimid of the embodiment of the present invention:
According to embodiments of the invention, R1 to be carbon atom number be 1 ~ 10 alkyl, preferred R1 is methyl, and R2 is Br or Cl, and preferred R2 is Br.
According to embodiments of the invention, make the means of the esterification of compound generation shown in formula 2, and be not particularly limited.Such as according to some embodiments of the present invention, in step 1), when there is acid catalyst, compound shown in described formula 2 being contacted with monohydroxy-alcohol, there is described esterification, thus obtains compound shown in described formula 3.According to other embodiment of the present invention, at the temperature of 50 ~ 80 degrees Celsius, carry out described esterification 8 ~ 15 hours.
According to embodiments of the invention, kind and the usage quantity thereof of described acid catalyst and monohydroxy-alcohol are not particularly limited.Such as according to some embodiments of the present invention, described acid catalyst is at least one being selected from tosic acid and sulfuric acid, described monohydroxy-alcohol to be carbon atom number be 1 ~ 10 monohydroxy-alcohol, particular methanol.According to other embodiment of the present invention, shown in shown formula 2, the mol ratio of compound and described acid catalyst is 1:1.2 ~ 3.0.
According to embodiments of the invention, by the means that compound shown in described formula 3 contacts with amino protecting agent, and be not particularly limited.Such as according to some embodiments of the present invention; described amino protecting agent is be selected from least one in tert-Butyl dicarbonate, chloroformic acid benzyl ester, bromobenzyl and Tosyl chloride; preferred described amido protecting agent is be selected from least one in tert-Butyl dicarbonate and chloroformic acid benzyl ester, and most preferably described amido protecting agent is tert-Butyl dicarbonate.
According to some embodiments of the present invention; in step 2) in; in the first organic solvent; when there is alkaline catalysts, compound shown in described formula 3 is contacted with described amino protecting agent, to carry out amido protecting reaction; thus obtain compound shown in formula 4; wherein, described first organic solvent is at least one being selected from halogenated hydrocarbon organic solvent and ether organic solvent, and described alkaline catalysts is at least one being selected from organic bases and mineral alkali.
According to some embodiments of the present invention, described halogenated hydrocarbon organic solvent is for being selected from methyl chloride, methylene dichloride, trichloromethane, monochloroethane, the at least one of ethylene dichloride and trichloroethane, preferred described halogenated hydrocarbon organic solvent is at least one being selected from methylene dichloride and trichloromethane, described ether organic solvent is for being selected from methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, the at least one of dioxane and methyl-phenoxide, preferred described ether organic solvent is for being selected from sherwood oil, tetrahydrofuran (THF), the at least one of methyl tertiary butyl ether and dioxane, described alkaline catalysts is at least one being selected from DMAP and triethylamine.
According to some embodiments of the present invention; shown in described formula 3, the mol ratio of compound and described amido protecting agent is 1:1.1 ~ 2.0; shown in described formula 3, the mol ratio of compound and alkaline catalysts is 1:1.5 ~ 3.0, and described amido protecting reaction carries out 3 ~ 8 hours at the temperature of 0 ~ 45 degree Celsius.
According to embodiments of the invention, make the means of compound generation halogenating reaction shown in described formula 4, and be not particularly limited.Such as according to some embodiments of the present invention, in step 3), in a second organic solvent, when there is initiator, by compound and halogenating agent shown in described formula 4, to carry out halogenating reaction, thus generate compound shown in described formula 5, wherein, described second organic solvent is for being selected from methyl chloride, methylene dichloride, trichloromethane, monochloroethane, the at least one of ethylene dichloride and trichloroethane, be preferably at least one be selected from methylene dichloride and trichloromethane, described halogenating agent is for being selected from cupric bromide, hydrogen bromide, N-bromo-succinimide (NBS), bromination dimethyl bromo sulphur (DMBS), Sodium Bromide, Potassium Bromide, at least one in brometo de amonio and bromine chloride, preferred described bromizating agent is N-bromo-succinimide, described initiator is for being selected from Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile), the at least one of benzoyl peroxide and di-isopropyl peroxydicarbonate, preferred described initiator is Diisopropyl azodicarboxylate.
According to some embodiments of the present invention, shown in described formula 4, the mol ratio of compound and described bromizating agent is 1:1.05 ~ 2.0, shown in described formula 4, the mol ratio of compound and described initiator is 1:0.1 ~ 0.5, and described halogenating reaction carries out 3 ~ 8 hours at the temperature of 30 ~ 80 degrees Celsius.
According to embodiments of the invention, by the means that compound shown in compound with formula 6 shown in described formula 5 contacts, and be not particularly limited.Such as according to some embodiments of the present invention, in step 4), in the 3rd organic solvent, when there is basic cpd, compound shown in compound with formula 6 shown in formula 5 is contacted, there is ring-closure reaction, thus compound shown in production 7, wherein, described 3rd organic solvent is for being selected from N, dinethylformamide (DMF) and N, at least one in N-N,N-DIMETHYLACETAMIDE, preferred N, dinethylformamide, described basic cpd is at least one being selected from organic bases and mineral alkali, preferred described basic cpd is at least one being selected from salt of wormwood and triethylamine.
According to some embodiments of the present invention, in step 4), shown in described formula 5, shown in compound and described formula 6, the mol ratio of compound is 1:1.0 ~ 1.5, shown in described formula 5, the mol ratio of compound and described basic cpd is 1:1.5 ~ 3.5, and described ring-closure reaction carries out 8 ~ 16 hours at the temperature of 50 ~ 100 degrees Celsius.
According to embodiments of the invention, by the means of compound generation deprotection reaction shown in described formula 7, and be not particularly limited.Such as according to some embodiments of the present invention, in step 5), in the 3rd organic solvent, when there is acid, make compound generation deprotection reaction shown in described formula 7, so that compound shown in production 1, wherein, described 3rd organic solvent is methyl chloride, methylene dichloride, trichloromethane, monochloroethane, ethylene dichloride and trichloroethane, methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, the at least one of dioxane and methyl-phenoxide, preferably described 3rd organic solvent is for being selected from methylene dichloride and trichloromethane, sherwood oil, tetrahydrofuran (THF), at least one in methyl tertiary butyl ether and dioxane, described acid is for being selected from least one in organic acid and mineral acid, preferred described acid is for being selected from trifluoracetic acid, hydrochloric acid, the at least one of trifluoromethanesulfonic acid and p-methyl benzenesulfonic acid.
According to some embodiments of the present invention, shown in described formula 7, the mol ratio of compound and described acid is 1:0.5 ~ 2.5, and described deprotection reaction carries out 5 ~ 10 hours under 0 ~ 35 degree Celsius.
According to embodiments of the invention, in step 5), in the 4th organic solvent, when there is palladium and ammonium formiate, make compound generation deprotection reaction shown in described formula 7, so that compound shown in production 1, wherein, described 4th organic solvent is for being selected from methyl alcohol, ethanol, propyl alcohol, butanols and ethylene glycol, methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, the at least one of dioxane and methyl-phenoxide, preferably described 4th organic solvent is for being selected from methyl alcohol, sherwood oil, tetrahydrofuran (THF), at least one in methyl tertiary butyl ether and dioxane.Again according to some embodiments of the present invention, described palladium provides with palladium charcoal form, and described deprotection reaction carries out 2 ~ 6 hours at the temperature of 20 ~ 60 degrees Celsius.
According to embodiments of the invention, described deprotection reaction carries out in an inert atmosphere, use the kind of rare gas element to be not particularly limited, preferred described inert atmosphere is made up of at least one be selected from nitrogen and argon gas.
Following advantages can be realized one of at least according to the method preparing Revlimid of the embodiment of the present invention:
1) according to the method preparing Revlimid of the embodiment of the present invention, the route of this synthesis Revlimid has no bibliographical information, and combined coefficient is high, and the purity of prepared Revlimid is also higher;
2) according to the method preparing Revlimid of the embodiment of the present invention, reaction conditions is gentle, without the need to the equipment of special reaction, also without the need to using danger, severe toxicity and special reagent;
3) according to the method preparing Revlimid of the embodiment of the present invention, the compound be separated is not difficult in preparation process, gained intermediate and finished product can be obtained by recrystallization, and some intermediate can not need separation and purification, and whole process does not need the complicated separation and purification such as column chromatography to operate yet;
4) according to the method preparing Revlimid of the embodiment of the present invention, starting raw material used and reagent are easily buied from market, thus are conducive to reducing production cost;
5) prepare the method for Revlimid according to an embodiment of the invention, technological operation is simple, and with short production cycle, production security is high, thus is more suitable for extensive, suitability for industrialized production Revlimid.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.
Embodiment
Be described below in detail embodiments of the invention, it should be noted that embodiment described below is exemplary, only for explaining the present invention, and can not limitation of the present invention be interpreted as.In addition, if do not clearly not stated, adopted in the following embodiments all reagent are, and market can be buied, or can according to herein or known method synthesis, for the reaction conditions do not listed, be also that those skilled in the art easily obtain.
General method
With reference to following formula, in the examples below that, the method preparing Revlimid method mainly comprises the following steps:
1) esterification: 3-amino-2-methyl phenylformic acid (compound 2), through acid, contacts with monohydroxy-alcohol and esterification occurs obtains 3-amino-2-methyl methyl benzoate (compound 3);
2) amido protecting reaction: compound 3 contacts with amino protecting agent, is obtained by reacting compound 4;
3) addition reaction: compound 4, through bromizating agent and initiator, halogenating reaction occurs and obtains compound 5;
4) ring-closure reaction: compound 5, through alkali, with 3-amino-2,6-dioxopiperidine hydrochlorides (compound 6), cyclization occurs and is obtained by reacting compound 7;
5) deprotection reaction: deprotection reaction occurs compound 7, finally obtains Revlimid (compound 1).
According to embodiments of the invention, above-mentionedly prepare Revlimid method, the synthetic route that can preferably adopt is as follows:
Embodiment 1: esterification
(100 grams, 3-amino-2-methyl phenylformic acid, 0.662 mole) and tosic acid (200 grams, 1.162 mole), add methyl alcohol 3000 milliliters, stir, back flow reaction 10 hours, ethyl acetate 3000 milliliters and 1M wet chemical 3000 milliliters stirring is added after being chilled to room temperature, filter, filtrate is extracted with ethyl acetate, with wet chemical and the saturated common salt water washing of 1M, after organic layer drying, concentrating under reduced pressure obtains 3-amino-2-methyl methyl benzoate (compound 3,93.0 grams, 0.564 mole), yield 85%.
1H NMR(CDCl
3):δ2.36(s,3H),3.82(s,3H),6.71-6.77(m,1H),6.99-7.01(m,1H),7.16-7.20(m,1H).MS(m/z):165[M+H]
+。
Embodiment 2: esterification
(100 grams, 3-amino-2-methyl phenylformic acid, 0.662 mole) and (63 milliliters, sulfuric acid, 1.162 mole), add methyl alcohol 3000 milliliters, stir, back flow reaction 10 hours, ethyl acetate 3000 milliliters and 1M wet chemical 3000 milliliters stirring is added after being chilled to room temperature, filter, filtrate is extracted with ethyl acetate, with wet chemical and the saturated common salt water washing of 1M, after organic layer drying, concentrating under reduced pressure obtains 3-amino-2-methyl methyl benzoate (compound 3,79.0 grams, 0.483 mole), yield 73%.MS(m/z):165[M+H]
+。
Embodiment 3: amido protecting reacts
By compound 3(93.0 gram, 0.564 mole) be dissolved in methylene dichloride 1000 milliliters, add tert-Butyl dicarbonate (147.5 grams, 0.677 mole), temperature control 25 degrees Celsius, stirring reaction is after 5 hours, and dichloromethane extraction, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing, obtain 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 143.5 grams, 0.541 mole), yield 96%.
1H NMR(CDCl
3):δ1.41(s,9H),2.35(s,3H),3.87(s,3H),6.92-6.97(m,1H),7.05-7.11(m,1H),7.56-7.59(m,1H).MS(m/z):265[M+H]
+。
Embodiment 4: amido protecting reacts
By compound 3(93.0 gram, 0.564 mole) be dissolved in tetrahydrofuran (THF) 800 milliliters, add triethylamine (118 milliliters, 0.846 mole), temperature control 0 degree Celsius, drips chloroformic acid benzyl ester (another name CbzCl, 93 milliliters, 0.677 mole), after stirring at room temperature reacts 3 hours, dichloromethane extraction, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing, obtain 3-benzyloxy-formyl amine-2-methyl-toluate (compound 4 (b), 146.7 grams, 0.491 mole), yield 87%.
1H NMR(CDCl
3):δ2.33(s,3H),3.86(s,3H),5.22(s,2H),6.94-7.00(m,1H),7.05-7.15(m,3H),7.18-7.22(m,3H),7.52-7.57(m,1H).MS(m/z):300[M+H]
+。
Embodiment 5: addition reaction
By 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 150 grams, 0.566 mole) be dissolved in trichloromethane 1200 milliliters, add N-bromo-succinimide (110 grams, 0.618 mole), Diisopropyl azodicarboxylate (16.4 grams, 0.100 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 142 grams, 0.414 mole), yield 73%.MS(m/z):345[M+H]
+。
Embodiment 6: addition reaction
By 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 150 grams, 0.566 mole) be dissolved in trichloromethane 1200 milliliters, add cupric bromide (138 grams, 0.618 mole), Diisopropyl azodicarboxylate (16.4 grams, 0.100 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 88 grams, 0.255 mole), yield 45%.MS(m/z):345[M+H]
+。
Embodiment 7: addition reaction
By 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 150 grams, 0.566 mole) be dissolved in trichloromethane 1200 milliliters, add N-bromo-succinimide (110 grams, 0.618 mole), benzoyl peroxide (24.2 grams, 0.100 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 101 grams, 0.294 mole), yield 52%.MS(m/z):345[M+H]
+。
Embodiment 8: addition reaction
By 3-tert.-butoxy methane amide-2-methyl-toluate (compound 4 (a), 150 grams, 0.566 mole) be dissolved in 1200 milliliters, tetracol phenixin, add N-bromo-succinimide (110 grams, 0.618 mole), Diisopropyl azodicarboxylate (16.4 grams, 0.100 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 150 grams, 0.436 mole), yield 77%.MS(m/z):345[M+H]
+。
Embodiment 9: addition reaction
By 3-benzyloxy-formyl amine-2-methyl-toluate (compound 4 (a), 150 grams, 0.500 mole) be dissolved in trichloromethane 1200 milliliters, add N-bromo-succinimide (97 grams, 0.546 mole), Diisopropyl azodicarboxylate (14.5 grams, 0.088 mole), back flow reaction 6 hours, filters after being cooled to room temperature, filtrate chloroform extraction, with water, saturated common salt water washing, organic layer drying is concentrated, obtains 2-brooethyl-3-benzyloxy-formyl amine methyl benzoate (compound 5 (b), 132 grams, 0.350 mole), yield 70%.MS(m/z):379[M+H]
+。
Embodiment 10: ring-closure reaction
By obtained 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 142 grams, 0.414 mole) and 3-amino-2, 6-dioxopiperidine hydrochloride (compound 6, 75 grams, 0.455 mole) be dissolved in N, dinethylformamide 800 milliliters, add (170 grams, salt of wormwood, 1.242 mole), temperature control 60 degrees Celsius, stirring reaction 10 hours, be cooled to room temperature, pour in frozen water and stir 1 hour, filter, wash with water, dry, obtain 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 102 grams, 0.286 mole), yield 69%.
1H NMR(DMSO-d
6):δ1.40(s,9H),2.11-2.26(m,2H),2.69-2.84(m,2H),4.69-4.76(m,2H),5.11-5.15(m,1H),6.90-6.95(m,1H),7.65-7.71(m,1H),7.71-7.77(m,1H),10.95(br,1H).MS(m/z):360[M+H]
+。
Embodiment 11: ring-closure reaction
By obtained 2-brooethyl-3-tert.-butoxy formamide benzene methyl-formiate (compound 5 (a), 142 grams, 0.414 mole) and 3-amino-2, 6-dioxopiperidine hydrochloride (compound 6, 75 grams, 0.455 mole) be dissolved in N, dinethylformamide 800 milliliters, add triethylamine (173 milliliters, 1.242 mole), temperature control 60 degrees Celsius, stirring reaction 10 hours, be cooled to room temperature, pour in frozen water and stir 1 hour, filter, wash with water, dry, obtain 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 76 grams, 0.211 mole), yield 51%.MS(m/z):360[M+H]
+。
Embodiment 12: ring-closure reaction
By obtained 2-brooethyl-3-benzyloxy-formyl amine methyl benzoate (compound 5 (b), 132 grams, 0.350 mole) and 3-amino-2, 6-dioxopiperidine hydrochloride (compound 6, 63 grams, 0.385 mole) be dissolved in N, dinethylformamide 800 milliliters, add (144 grams, salt of wormwood, 1.050 mole), temperature control 60 degrees Celsius, stirring reaction 10 hours, be cooled to room temperature, pour in frozen water and stir 1 hour, filter, wash with water, dry, obtain 3-(7-benzyloxyformamido-3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (b), 92 grams, 0.235 mole), yield 67%.
1H NMR(DMSO-d
6):δ2.13-2.20(m,2H),2.34-2.44(m,2H),4.29-4.35(m,2H),5.02-5.06(m,1H),5.21(s,2H),6.92-6.98(m,1H),7.17-7.29(m,5H),7.58-7.64(m,1H),7.71-7.76(m,1H),10.26(br,1H).MS(m/z):394[M+H]
+。
Embodiment 13: deprotection reaction
By 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 100 grams, 0.278 mole) be dissolved in tetrahydrofuran (THF) 1000 milliliters, temperature control less than 10 degrees Celsius slowly adds trifluoracetic acid 50 milliliters, temperature control 25 degrees Celsius, stirring reaction is after 6 hours, concentrating under reduced pressure removes most solvent, add saturated sodium bicarbonate aqueous solution 2000 milliliters, with dichloromethane extraction, with water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing, dry, after concentrating under reduced pressure, available isopropyl alcohol and water recrystallization obtains Revlimid (63 grams, 0.245 mole), yield 88%.
1H NMR(DMSO-d
6):δ2.12-2.23(m,2H),2.72-2.95(m,2H),4.38-4.46(m,2H),5.12-5.15(m,1H),6.88-6.92(m,1H),7.00-7.07(m,1H),7.17-7.25(m,1H),10.93(br,1H).MS(m/z):260[M+H]
+。
Embodiment 14: deprotection reaction
By 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 100 grams, 0.278 mole) be dissolved in tetrahydrofuran (THF) 1000 milliliters, temperature control less than 10 degrees Celsius slowly adds the hydrochloric acid 80 milliliters of 2M, temperature control 25 degrees Celsius, stirring reaction is after 6 hours, concentrating under reduced pressure removes most solvent, add saturated sodium bicarbonate aqueous solution 2000 milliliters, with dichloromethane extraction, with water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing, dry, after concentrating under reduced pressure, available isopropyl alcohol and water recrystallization obtains Revlimid (53 grams, 0.206 mole), yield 74%.MS(m/z):260[M+H]
+。
Embodiment 15: deprotection reaction
By 3-(7-tert.-butoxy formamido--3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (a), 100 grams, 0.278 mole) be dissolved in tetrahydrofuran (THF) 1000 milliliters, temperature control less than 10 degrees Celsius slowly adds trifluoracetic acid 50 milliliters, temperature control 25 degrees Celsius, stirring reaction is after 6 hours, concentrating under reduced pressure removes most solvent, add saturated sodium bicarbonate aqueous solution 2000 milliliters, with dichloromethane extraction, with water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing, dry, after concentrating under reduced pressure, available second alcohol and water recrystallization obtains Revlimid (55 grams, 0.214 mole), yield 77%.MS(m/z):260 [M+H]
+。
Embodiment 16: deprotection reaction
By 3-(7-benzyloxyformamido-3-oxo-1H-isoindole-2-base) piperidines-2, 6-diketone (compound 7 (b), 100 grams, 0.254 mole) be dissolved in methyl alcohol 1000 milliliters, add 10% palladium charcoal (Pd/C, 10g) with ammonium formiate (158g, 2.500 mole), nitrogen protection can be added, temperature control 25 ~ 35 degrees Celsius, stirring reaction 3 hours, suction filtration removing palladium charcoal, filtrate reduced in volume, with dichloromethane extraction, with water, saturated common salt water washing, dry, after concentrating under reduced pressure, available isopropyl alcohol and water recrystallization obtains Revlimid (56 grams, 0.216 mole), yield 85%.MS(m/z):260[M+H]
+。
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " illustrative examples ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above; be understandable that; above-described embodiment is exemplary; limitation of the present invention can not be interpreted as; those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification, and these all drop on the scope of the present invention.
Claims (26)
1. a method for compound shown in preparation formula 1, is characterized in that, comprising:
1) esterification of compound generation shown in formula 2 is made, to obtain compound shown in formula 3;
2) compound shown in described formula 3 is contacted with amino protecting agent, to obtain compound shown in formula 4;
3) compound generation halogenating reaction shown in described formula 4 is made, to obtain compound shown in formula 5;
4) compound shown in compound with formula 6 shown in described formula 5 is contacted, to obtain compound shown in formula 7; And
5) by compound generation deprotection reaction shown in described formula 7, to obtain compound shown in described formula 1,
Wherein, R1 is alkyl, and R2 is halogen, and PG represents amido protecting group,
In step 2) in, in the first organic solvent, when there is alkaline catalysts, compound shown in described formula 3 being contacted with described amino protecting agent, to carry out amido protecting reaction, thus obtaining compound shown in formula 4,
Wherein,
Described first organic solvent is at least one being selected from halogenated hydrocarbon organic solvent and ether organic solvent,
Wherein,
Described halogenated hydrocarbon organic solvent is at least one being selected from methylene dichloride and trichloromethane,
Described ether organic solvent is at least one being selected from tetrahydrofuran (THF), methyl tertiary butyl ether and dioxane,
Described alkaline catalysts is at least one being selected from DMAP and triethylamine,
Shown in described formula 3, the mol ratio of compound and described amido protecting agent is 1:1.1 ~ 2.0,
Shown in described formula 3, the mol ratio of compound and alkaline catalysts is 1:1.5 ~ 3.0,
Described amido protecting reaction carries out 3 ~ 8 hours at the temperature of 0 ~ 45 degree Celsius.
2. method according to claim 1, is characterized in that, R1 to be carbon atom number be 1 ~ 10 alkyl.
3. method according to claim 2, is characterized in that, R1 is methyl, and R2 is Br or Cl.
4. method according to claim 3, is characterized in that, R2 is Br.
5. method according to claim 1, is characterized in that, in step 1) in, when there is acid catalyst, compound shown in described formula 2 being contacted with monohydroxy-alcohol, there is described esterification, thus obtains compound shown in described formula 3.
6. method according to claim 5, is characterized in that, described acid catalyst is at least one being selected from tosic acid and sulfuric acid, described monohydroxy-alcohol to be carbon atom number be 1 ~ 10 monohydroxy-alcohol.
7. method according to claim 6, is characterized in that, described monohydroxy-alcohol is methyl alcohol.
8. method according to claim 5, is characterized in that, shown in described formula 2, the mol ratio of compound and described acid catalyst is 1:1.2 ~ 3.0.
9. method according to claim 5, is characterized in that, at the temperature of 50 ~ 80 degrees Celsius, carries out described esterification 8 ~ 15 hours.
10. method according to claim 1, is characterized in that, described amino protecting agent is be selected from least one in tert-Butyl dicarbonate, chloroformic acid benzyl ester, bromobenzyl and Tosyl chloride.
11. methods according to claim 10, is characterized in that, described amido protecting agent is be selected from least one in tert-Butyl dicarbonate and chloroformic acid benzyl ester.
12. methods according to claim 11, is characterized in that, described amido protecting agent is tert-Butyl dicarbonate.
13. methods according to claim 1, is characterized in that, in step 3) in, in a second organic solvent, when there is initiator, by compound and halogenating agent shown in described formula 4, to carry out halogenating reaction, thus generate compound shown in described formula 5
Wherein,
Described second organic solvent is at least one being selected from methyl chloride, methylene dichloride, trichloromethane, monochloroethane, ethylene dichloride and trichloroethane,
Described halogenating agent for being selected from least one in cupric bromide, hydrogen bromide, N-bromo-succinimide (NBS), bromination dimethyl bromo sulphur (DMBS), Sodium Bromide, Potassium Bromide, brometo de amonio and bromine chloride,
Described initiator is at least one being selected from Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile), benzoyl peroxide and di-isopropyl peroxydicarbonate.
14. methods according to claim 13, is characterized in that, described second organic solvent is be selected from least one in methylene dichloride and trichloromethane, and described halogenating agent is N-bromo-succinimide, and described initiator is Diisopropyl azodicarboxylate.
15. methods according to claim 14, it is characterized in that, shown in described formula 4, the mol ratio of compound and described halogenating agent is 1:1.05 ~ 2.0, shown in described formula 4, the mol ratio of compound and described initiator is 1:0.1 ~ 0.5, and described halogenating reaction carries out 3 ~ 8 hours at the temperature of 30 ~ 80 degrees Celsius.
16. methods according to claim 1, is characterized in that, in step 4) in, in the 3rd organic solvent, when there is basic cpd, compound shown in compound with formula 6 shown in formula 5 is contacted, there is ring-closure reaction, thus compound shown in production 7
Wherein,
Described 3rd organic solvent is for being selected from least one in DMF (DMF) and N,N-dimethylacetamide, and described basic cpd is at least one being selected from organic bases and mineral alkali.
17. methods according to claim 16, is characterized in that, described 3rd organic solvent is DMF, and described basic cpd is at least one being selected from salt of wormwood and triethylamine.
18. methods according to claim 17, it is characterized in that, in step 4) in, shown in described formula 5, shown in compound and described formula 6, the mol ratio of compound is 1:1.0 ~ 1.5, shown in described formula 5, the mol ratio of compound and described basic cpd is 1:1.5 ~ 3.5, and described ring-closure reaction carries out 8 ~ 16 hours at the temperature of 50 ~ 100 degrees Celsius.
19. methods according to claim 1, is characterized in that, in step 5) in, in the 3rd organic solvent, when there is acid, make compound generation deprotection reaction shown in described formula 7, so that compound shown in production 1,
Wherein, described 3rd organic solvent is at least one of methyl chloride, methylene dichloride, trichloromethane, monochloroethane, ethylene dichloride and trichloroethane, methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, dioxane and methyl-phenoxide, and described acid is for being selected from least one in organic acid and mineral acid.
20. methods according to claim 19, is characterized in that, described 3rd organic solvent is be selected from least one in methylene dichloride and trichloromethane, sherwood oil, tetrahydrofuran (THF), methyl tertiary butyl ether and dioxane,
Described acid is for being selected from least one of trifluoracetic acid, hydrochloric acid, trifluoromethanesulfonic acid and p-methyl benzenesulfonic acid.
21. methods according to claim 20, is characterized in that, shown in described formula 7, the mol ratio of compound and described acid is 1:0.5 ~ 2.5, and described deprotection reaction carries out 5 ~ 10 hours under 0 ~ 35 degree Celsius.
22. methods according to claim 1, is characterized in that, in step 5) in, in the 4th organic solvent, when there is palladium and ammonium formiate, make compound generation deprotection reaction shown in described formula 7, so that compound shown in production 1,
Wherein, described 4th organic solvent is at least one being selected from methyl alcohol, ethanol, propyl alcohol, butanols and ethylene glycol, methyl ether, ether, sherwood oil, isopropyl ether, methyl tertiary butyl ether, ethyl-butyl ether, Ethyl Tertisry Butyl Ether, tetrahydrofuran (THF), tetrahydropyrans, dioxane and methyl-phenoxide.
23. methods according to claim 22, is characterized in that, described 4th organic solvent is be selected from least one in methyl alcohol, sherwood oil, tetrahydrofuran (THF), methyl tertiary butyl ether and dioxane.
24. methods according to claim 23, is characterized in that, described palladium provides with palladium charcoal form, and described deprotection reaction carries out 2 ~ 6 hours at the temperature of 20 ~ 60 degrees Celsius.
25. methods according to claim 1, is characterized in that, described deprotection reaction carries out in an inert atmosphere.
26. methods according to claim 25, is characterized in that, described inert atmosphere is made up of at least one be selected from nitrogen and argon gas.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310472457.8A CN103497175B (en) | 2013-03-14 | 2013-10-11 | Prepare the method for Revlimid |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100810682 | 2013-03-14 | ||
| CN201310081068 | 2013-03-14 | ||
| CN201310081068.2 | 2013-03-14 | ||
| CN201310472457.8A CN103497175B (en) | 2013-03-14 | 2013-10-11 | Prepare the method for Revlimid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103497175A CN103497175A (en) | 2014-01-08 |
| CN103497175B true CN103497175B (en) | 2015-08-05 |
Family
ID=49862462
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310472457.8A Expired - Fee Related CN103497175B (en) | 2013-03-14 | 2013-10-11 | Prepare the method for Revlimid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103497175B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA3017740A1 (en) | 2016-03-16 | 2017-09-21 | Pearlie BURNETTE | Small molecules against cereblon to enhance effector t cell function |
| CN107337666B (en) * | 2017-08-30 | 2019-06-04 | 上海万巷制药有限公司 | It is a kind of for treating the preparation method of the lenalidomide of Huppert's disease |
| CN107337667B (en) * | 2017-08-30 | 2020-10-09 | 湖南慧泽生物医药科技有限公司 | Preparation process of lenalidomide for treating multiple myeloma |
| EA202190248A1 (en) | 2018-07-11 | 2021-06-16 | Х. Ли Моффитт Кэнсер Сентер Энд Рисерч Инститьют, Инк. | DIMERIC IMMUNOMODULATING COMPOUNDS AGAINST MECHANISMS BASED ON CEREBLON |
| CN114933584B (en) * | 2021-08-09 | 2022-12-27 | 上海贵之言医药科技有限公司 | dihydro-2H-isoindole ester compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7153867B2 (en) * | 2001-08-06 | 2006-12-26 | Celgene Corporation | Use of nitrogen substituted thalidomide analogs for the treatment of macular degenerator |
| CN101959856A (en) * | 2008-03-11 | 2011-01-26 | 雷迪博士实验室有限公司 | Preparation of lenalidomide |
-
2013
- 2013-10-11 CN CN201310472457.8A patent/CN103497175B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7153867B2 (en) * | 2001-08-06 | 2006-12-26 | Celgene Corporation | Use of nitrogen substituted thalidomide analogs for the treatment of macular degenerator |
| CN101959856A (en) * | 2008-03-11 | 2011-01-26 | 雷迪博士实验室有限公司 | Preparation of lenalidomide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103497175A (en) | 2014-01-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103497175B (en) | Prepare the method for Revlimid | |
| CN102307866B (en) | Method for preparing linezolid and intermediates thereof | |
| EP3189053B1 (en) | An improved process for the preparation of apixaban and intermediates thereof | |
| CN110526859B (en) | Revinanexin intermediate, preparation method thereof and preparation method of Revinanexin | |
| CN101993407A (en) | Indoline compound for preparing silodosin and preparation method thereof | |
| CN103508899A (en) | Method for preparing ticagrelor key intermediate and racemate thereof and special intermediate for implementing method | |
| CN103880830B (en) | Synthesis method of azilsartan | |
| JP2007326784A (en) | Method for producing 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester | |
| CN104177331B (en) | The preparation method of bilastine | |
| CN102731491A (en) | Preparation method of azilsartan intermediate | |
| CN103864713B (en) | A kind of preparation method of Mirabegron | |
| CN105566260A (en) | Furosemide preparation method | |
| JP2009280521A (en) | Production method of 2,4-disubstituted pyridine | |
| CN102863371A (en) | Fluoro dihydropyrrole or fluoro pyrrole | |
| CN103396373B (en) | Preparation method of deferasirox and intermediate compound of deferasirox | |
| WO2015085827A1 (en) | Method for preparing silodosin and intermediate thereof | |
| CN106608853A (en) | Preparation method of dipeptidyl peptidase IV inhibitor | |
| KR101435741B1 (en) | Novel voriconazole intermediate and synthesis of voriconazole | |
| CN109020977B (en) | Preparation method of Acaraburtinib | |
| JP2023532362A (en) | Method for producing phenylisoxazoline compound | |
| CN102079720B (en) | Method for preparing 1-benzylpiperidine-4-carboxaldehyde | |
| KR101153713B1 (en) | Preparation method of itopride and intermediate compound | |
| CN104098556A (en) | Novel synthetic process for rivaroxaban | |
| ES2215120T3 (en) | PROCEDURE FOR OBTAINING HETEROCICLICAL COMPOUNDS. | |
| CN109456285A (en) | A kind of preparation method of ranolazine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: HUBEI BIOPHARMACEUTICAL INDUSTRY TECHNOLOGY RESEAR Free format text: FORMER OWNER: HUMANWELL HEALTHCARE GROUP CO., LTD. Effective date: 20150526 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20150526 Address after: The comprehensive office building of 430075 Hubei city of Wuhan province East Lake high tech Development Zone Road No. 666 humanwell Pharmaceutical Group Applicant after: HUBEI BIO-PHARMACEUTICAL INDUSTRIAL TECHNOLOGICAL INSTITUTE Inc. Address before: The comprehensive office building of 430075 Hubei city of Wuhan province East Lake high tech Development Zone Road No. 666, room 718, humanwell Pharmaceutical Group Applicant before: HUMANWELL HEALTHCARE (GROUP) Co.,Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150805 |