CN107365295B - Improved method of pomalidomide synthesis process - Google Patents
Improved method of pomalidomide synthesis process Download PDFInfo
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- CN107365295B CN107365295B CN201610307145.5A CN201610307145A CN107365295B CN 107365295 B CN107365295 B CN 107365295B CN 201610307145 A CN201610307145 A CN 201610307145A CN 107365295 B CN107365295 B CN 107365295B
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- 229960000688 pomalidomide Drugs 0.000 title claims abstract description 27
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims description 19
- 230000015572 biosynthetic process Effects 0.000 title claims description 9
- 238000003786 synthesis reaction Methods 0.000 title claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- ROFZMKDROVBLNY-UHFFFAOYSA-N 4-nitro-2-benzofuran-1,3-dione Chemical compound [O-][N+](=O)C1=CC=CC2=C1C(=O)OC2=O ROFZMKDROVBLNY-UHFFFAOYSA-N 0.000 claims abstract description 9
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000013922 glutamic acid Nutrition 0.000 claims abstract description 7
- 239000004220 glutamic acid Substances 0.000 claims abstract description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000011085 pressure filtration Methods 0.000 claims description 4
- 238000005086 pumping Methods 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 229960002460 nitroprusside Drugs 0.000 claims description 2
- KVRCAGKHAZRSQX-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindole-1,3-dione Chemical compound O=C1C=2C([N+](=O)[O-])=CC=CC=2C(=O)N1C1CCC(=O)NC1=O KVRCAGKHAZRSQX-UHFFFAOYSA-N 0.000 abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 229960002989 glutamic acid Drugs 0.000 description 5
- 229960004942 lenalidomide Drugs 0.000 description 5
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical class O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- ZBZAVEORKXFUQB-UHFFFAOYSA-N 3-aminophthalic acid;hydron;chloride Chemical compound Cl.NC1=CC=CC(C(O)=O)=C1C(O)=O ZBZAVEORKXFUQB-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- BONIIQYTWOPUQI-UHFFFAOYSA-N 4-nitroisoindole-1,3-dione Chemical compound [O-][N+](=O)C1=CC=CC2=C1C(=O)NC2=O BONIIQYTWOPUQI-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- -1 (3-nitrophthalimide) -ethyl formate Chemical compound 0.000 description 1
- VNMYRXMKNMXTDZ-UHFFFAOYSA-N 4-aminopiperidine-2,6-dione;hydrochloride Chemical compound Cl.NC1CC(=O)NC(=O)C1 VNMYRXMKNMXTDZ-UHFFFAOYSA-N 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of high-purity pomalidomide, which is suitable for industrial production.A 3-nitrophthalic anhydride reacts with glutamic acid to obtain an intermediate, the intermediate is obtained by reaction under the condition of acetic anhydride, 3-nitro-N- (2, 6-dioxo-3-piperidyl) phthalimide is obtained by ammoniation reaction under the condition of DMSO, and pomalidomide is obtained by palladium carbon hydrogenation.
Description
Technical Field
The invention relates to a preparation method of pomalidomide (shown as a formula I) with optimized synthesis conditions.
Background
Pomalidomide (pomalidomide) is a thalidomide analogue, has antitumor activity, and can inhibit the proliferation of hematopoietic tumor cells and induce apoptosis. In addition, pomalidomide can inhibit the proliferation of lenalidomide-resistant multiple myeloma cell strains, can cooperate with dexamethasone to induce tumor cell apoptosis, enhance T cell and natural killer cell mediated immune reaction, and inhibit monocytes from generating proinflammatory cytokines. Pomalidomide was developed by american seille gene (Celgene) and approved by the FDA in 2013 for marketing in the treatment of Multiple Myeloma (Multiple myelomas) that are ineffective with other drugs (e.g., lenalidomide, bortezomib).
Pomalidomide (pomalidomide) is the third-degree amine drug after Thalidomide (Thalidomide) and Lenalidomide (Lenalidomide), is mainly used for patients resistant to Lenalidomide and bortezomib, and is expected to sell for $ 10 billion in 2017.
Route 1: in patent CN101253163 (EP 1907373), 3-nitrophthalic anhydride and L-glutamic acid are reacted in DMF, and then are subjected to reduction and cyclization to prepare pomalidomide.
Route 2: WO2012149299A2 (family CN103688176A) has short route, but 3-amino-2, 6-piperidedione hydrochloride has smaller market yield and higher price at present.
Route 3: patent US2007004920, 3-nitro phthalimide reacts with ethyl chloroformate, is condensed with glutamine butyl ester, and finally, the product is obtained through hydrolysis, reduction and intramolecular condensation cyclization. This route is long and the manufacturing cost of 3-nitrophthalimide is higher than that of 3-nitrophthalic anhydride.
Route 4: in patent CN101253163 (EP 1907373), 3-aminophthalic acid hydrochloride and 3-aminoglutarimide hydrochloride are reported to be condensed, the yield is 84%, the market supply of the 3-aminophthalic acid hydrochloride is less, two raw material active groups are more, and the probability of side reaction is higher.
In the route, 5 (3-nitrophthalimide) -ethyl formate and 5-carbamoyl-4-amino-butyl valerate are condensed, hydrolyzed, reduced and subjected to intramolecular condensation to obtain pomalidomide.
The methods have the characteristics of difficult obtainment of intermediates, high cost, poor quality and the like.
Disclosure of Invention
The invention aims to provide a novel synthesis process of pomalidomide, which is more suitable for industrial production. The inventor provides a simple and effective method for improving the synthesis process of pomalidomide by deeply researching the synthesis process of pomalidomide. The improved process overcomes the defects of low yield, long process route and great environmental pollution in the prior art, and simultaneously solves the problem of solvent residue in the refining process.
The invention is realized by the following technical scheme:
1. the method comprises the steps of synthesizing a pomalidomide crude product by using 3-nitrophthalic anhydride and glutamic acid as raw materials through condensation, cyclization, ammoniation and hydrogenation, and then refining to obtain a pomalidomide finished product.
2. An improved method for a pomalidomide synthesis process comprises the following aspects:
3-nitro-N- (2, 6-dioxo-3-piperidyl) phthalimide is directly synthesized by taking 3-nitrophthalic anhydride and glutamic acid as raw materials through condensation, cyclization and ammoniation;
the condensation is characterized in that the solvent adopted in the condensation is alkaline solvents such as pyridine, 4-methylpyridine, N-dimethylformamide, N-methylpyrrolidone and the like, wherein the effect of the N, N-dimethylformamide is optimal;
the ammoniation is characterized in that ammonia gas is introduced at the temperature of 150 ℃ and 250 ℃ and 0.2Mp is added for ammoniation for 3-5 h;
the crystallization solvent of the 3-nitro-N- (2, 6-dioxo-3-piperidyl) phthalimide in the DMSO is methanol, ethanol, acetonitrile, acetone or isopropyl ether.
3. Hydrogenating and refining the 3-nitro-N- (2, 6-dioxo-3-piperidyl) phthalimide in a 1, 4-dioxane/methanol mixed solvent to obtain pomalidomide;
hydrogenation is carried out under the conditions that the volume ratio of the hydrogenation characteristic solvent is 1:0.5-1:10, the temperature is 15-50 ℃, the hydrogen pressure is 0.2-0.4Mp and 10 percent of palladium carbon is used;
DMSO, acetonitrile, ethyl acetate, DMF, ethanol, methanol, isopropyl ether, acetone and their mixed solvent.
Detailed description of the preferred embodiments
Examples 1
Pumping N, N-dimethylformamide (50 kg) into a reaction kettle, adding glutamic acid (32 kg) and 3-nitrophthalic anhydride (40 kg) under stirring, heating, reacting at 95-100 ℃ for 3 hours, then distilling out N, N-dimethylformamide under reduced pressure, cooling, adding acetic anhydride (50 kg), heating to 100-phase reaction at 110 ℃ for 1 hour, distilling out excessive anhydride under reduced pressure, adding DMSO (400L), heating the reaction to 200 ℃, slowly introducing ammonia gas under stirring, cooling to room temperature after the reaction is finished, adding methanol (800L), crystallizing, centrifuging, and drying to obtain 3-nitroparaffin (62.76 kg) with the yield of 71%. The purity is 99.99%.
Dissolving 3-nitroprusside (30 kg) in 1, 4-dioxane \ methanol =300L \300L, adding 10% palladium carbon, 35 ℃, 0.4M, hydrogenating until the reaction is finished, performing pressure filtration, concentrating under reduced pressure to dryness, adding DMF (300L) for dissolving, crystallizing by isopropyl ether (600L), centrifuging to obtain a yellow product, recrystallizing by using ethanol to obtain high-purity pomalidomide, and performing HPLC: 99.84 percent.
EXAMPLES example 2
Pumping pyridine (50 kg) into a reaction kettle, adding glutamic acid (32 kg) and 3-nitrophthalic anhydride (40 kg) under stirring, heating, reacting at 95-100 ℃ for 5 hours, then distilling out the pyridine under reduced pressure, cooling, adding acetic anhydride (50 kg), heating to 100 ℃ and 110 ℃ for reaction for 2 hours, distilling off excessive anhydride under reduced pressure, adding DMSO (400L), heating the reaction to 180 ℃, slowly introducing ammonia gas under stirring, cooling to room temperature after the reaction is finished, adding ethanol (800L) for crystallization and centrifugation, and drying to obtain the 3-nitroparaffin amine (62.76 kg), wherein the yield is 71%, and the purity is 99.2%.
Dissolving 3-nitro-pomalidomide (30 kg) in 1, 4-dioxane \ methanol =150L \150L, adding 10% palladium carbon, 35 ℃, 0.4Mp, hydrogenating until the reaction is finished, performing pressure filtration, concentrating under reduced pressure to dryness, adding DMF (300L) for dissolving, crystallizing by isopropyl ether (600L), centrifuging to obtain a yellow product, and recrystallizing by using ethanol to obtain high-purity pomalidomide 99.9%.
Claims (2)
1. An improved method for a pomalidomide synthesis process comprises the following aspects:
pumping 50kg of N, N-dimethylformamide into a reaction kettle, adding 32kg of glutamic acid and 40kg of 3-nitrophthalic anhydride under stirring, heating, reacting at 95-100 ℃ for 3 hours, then distilling out the N, N-dimethylformamide under reduced pressure, cooling, adding 50kg of acetic anhydride, heating to 100 ℃ for 110 ℃ to react for 1 hour, distilling out excessive anhydride under reduced pressure, adding 400L of DMSO, heating the reaction to 200 ℃, slowly introducing ammonia gas under stirring, cooling to room temperature after the reaction is finished, adding 800L of methanol, crystallizing, centrifuging, and drying to obtain 62.76kg of 3-nitroparaffin amine, wherein the yield is 71%, and the purity is 99.99%;
dissolving 30kg of 3-nitroprusside in 1, 4-dioxane \ methanol =300L \300L, adding 10% palladium carbon, 35 ℃, 0.4Mp, hydrogenating until the reaction is finished, performing pressure filtration, concentrating under reduced pressure to dryness, adding 300L of DMF for dissolving, crystallizing by 600L of isopropyl ether, centrifuging to obtain a yellow product, recrystallizing by using ethanol to obtain high-purity pomalidomide, and performing HPLC: 99.84 percent.
2. An improved method for a pomalidomide synthesis process comprises the following aspects:
pumping 50kg of pyridine into a reaction kettle, adding 32kg of glutamic acid and 40kg of 3-nitrophthalic anhydride under stirring, heating, reacting at 95-100 ℃ for 5 hours, then distilling out the pyridine under reduced pressure, cooling, adding 50kg of acetic anhydride, heating to 100 ℃ and 110 ℃ for reaction for 2 hours, distilling out excessive anhydride under reduced pressure, adding 400L of DMSO, heating the reaction to 180 ℃, slowly introducing ammonia gas under stirring, cooling to room temperature after the reaction is finished, adding 800L of ethanol, crystallizing, centrifuging, and drying to obtain 62.76kg of 3-nitroparaffin amine, wherein the yield is 71%, and the purity is 99.2%;
dissolving 3-nitroparaffin in 1, 4-dioxane \ methanol =150L \150L, adding 10% palladium carbon, 35 ℃, 0.4Mp, hydrogenating until the reaction is completed, performing pressure filtration, concentrating under reduced pressure to dryness, adding 300L of DMF to dissolve, crystallizing by 600L of isopropyl ether, centrifuging to obtain a yellow product, and recrystallizing by using ethanol to obtain the high-purity pomalidomide 99.9%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1342146A (en) * | 1999-03-18 | 2002-03-27 | 塞尔基因公司 | Substituted 1-oxo-and 1,3-dioxoisoindolines and their use in pharmaceutical compositions for reducing inflammatory cytokine levels |
| CN102863424A (en) * | 2012-03-20 | 2013-01-09 | 常州制药厂有限公司 | Synthetic method of medicine for treating leprosy |
| WO2012177678A3 (en) * | 2011-06-22 | 2013-03-07 | Celgene Corporation | Isotopologues of pomalidomide |
| CN103232380A (en) * | 2013-05-08 | 2013-08-07 | 中国药科大学 | Method for preparing pomalidomide key intermediate |
-
2016
- 2016-05-11 CN CN201610307145.5A patent/CN107365295B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1342146A (en) * | 1999-03-18 | 2002-03-27 | 塞尔基因公司 | Substituted 1-oxo-and 1,3-dioxoisoindolines and their use in pharmaceutical compositions for reducing inflammatory cytokine levels |
| WO2012177678A3 (en) * | 2011-06-22 | 2013-03-07 | Celgene Corporation | Isotopologues of pomalidomide |
| CN102863424A (en) * | 2012-03-20 | 2013-01-09 | 常州制药厂有限公司 | Synthetic method of medicine for treating leprosy |
| CN103232380A (en) * | 2013-05-08 | 2013-08-07 | 中国药科大学 | Method for preparing pomalidomide key intermediate |
Non-Patent Citations (1)
| Title |
|---|
| Possible Antineoplastic Agents I;A. U. DE et al.;《Journal of Pharmaceutical Sciences》;19750228;262-266 * |
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