Thalidomide, NSC-66847, K-17, Talizer, Thalomid, Synovir, -Drug Synthesis Database

【结构式】

【药物名称】Thalidomide, NSC-66847, K-17, Talizer, Thalomid, Synovir

【化学名称】(±)-2-(2,6-Dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione
　　　　　　(±)-N-(2,6-Dioxopiperidin-3-yl)phthalimide
　　　　　　(±)-alpha-(N-Phthalimido)glutarimide

【CA登记号】50-35-1

【分子式】C₁₃H₁₀N₂O₄

【分子量】258.23565

【开发单位】Celgene (Orphan Drug), Andrulis (Originator), EntreMed (Originator), University of Minnesota (Not Determined), Celgene (Licensee), Penn (Licensee), Pharmion (Licensee), National Cancer Institute (Codevelopment), Pfizer (Codevelopment)

【药理作用】AIDS Medicines, Antiarthritic Drugs, ANTIINFECTIVE THERAPY, Antimycobacterial Agents, Brain Cancer Therapy, Breast Cancer Therapy, Cognition Disorders, Treatment of, Colorectal Cancer Therapy, GASTROINTESTINAL DRUGS, Glioblastoma MultiformeTherapy, Immunologic Neuromuscular Disorders, Treatment of, Inflammatory Bowel Disease, Agents for, Kaposi's Sarcoma Therapy, Leukemia Therapy, Liver Cancer Therapy, Lung Cancer Therapy, Multiple Myeloma Therapy, Multiple Sclerosis, Agents for, Myelodysplastic Syndrome Therapy, NEUROLOGIC DRUGS, Non-Small Cell Lung Cancer Therapy, OCULAR MEDICATIONS, Oncolytic Drugs, Ophthalmic Drugs, Prostate Cancer Therapy, Renal Cancer Therapy, Scleroderma, Agents for, Treatment of Age-Related Macular Degeneration, Treatment of AIDS-Associated Malignancies, Treatment of Cachexia, Treatment of Leprosy, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Other Autoimmune Disorders, Angiogenesis Inhibitors, TNF-alpha Production Inhibitors, TNF-alp

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6

合成路线1

A new scaleable two-step synthesis of thalidomide was reported: The reaction of L-glutamine (I) with N-(ethoxycarbonyl)phthalimide (II) gives the N-phthaloyl-L-glutamine (III), which is finally cyclized by means of carbonyldimidazole (CDI) and dimethylaminopyridine.

参考文献中间体

【1】 Muller, G.W.; et al.; A two step synthesis of thalidomide. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst ORGN 079.
【2】 Muller, G.W.; et al.; A concise two-step synthesis of thalidomide. Org Process Res Dev 1999, 3, 2, 139.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	24948	L-glutamine	56-85-9	C₅H₁₀N₂O₃	详情	详情
(II)	10283	ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide	22509-74-6	C₁₁H₉NO₄	详情	详情
(III)	32017	(2S)-5-amino-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acid		C₁₃H₁₂N₂O₅	详情	详情

合成路线2

A new direct synthesis of thalidomide has been reported: Reaction of the commercially available N-phthaloyl-L-glutamic acid (I) with either urea (II) or thiourea (III) under microwave irradiation (1000 W output) provides thalidomide in 63 or 85% yield, respectively.

参考文献中间体

【1】 Vazquez-Tato, M.P.; Pacios-Lopez, B.; Martinez, M.M.; Gonzalez-Bando, C.; Seijas, J.A.; Microwave promoted synthesis of a rehabilitated drug: Thalidomide. Synthesis (Stuttgart) 2001, 7, 999.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	54082	2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioic acid	2301-52-2	C₁₃H₁₁NO₆	详情	详情
(II)	19310	urea	57-13-6	CH₄N₂O	详情	详情
(III)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情

合成路线3

A novel solid-phase synthesis of thalidomide has been described: The coupling of phthalic anhydride (I) with hydroxymethyl polystyrene resin (II) by means of triethylamine and 4-dimethylaminopyridine (DMAP) in DMF affords the resin-linked acid (III), which is then condensed with alpha-aminoglutarimide (IV) by means of diisopropylcarbodiimide (DIC) and N-hydroxybenzotriazole (HOBt) in DMF to provide amide (V). Finally, thalidomide is obtained by treatment of resin (V) with TFA in refluxing toluene.

参考文献中间体

【1】 Schaefer, K.; Li, P.-K.; Xiao, Z.; Firestine, S.; Solid-phase synthesis of thalidomide and its analogues. J Comb Chem 2002, 4, 2, 149.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(III)	54083	2-(methoxycarbonyl)benzoic acid	n/a	C₉H₈O₄	详情	详情
(IV)	37576	3-amino-2,6-piperidinedione；3-aminopiperidine-2,6-dione；2-amino-Glutarimide；Glutamimide;a-Aminoglutarimide	2353-44-8	C₅H₈N₂O₂	详情	详情
(V)	54084	methyl 2-{[(2,6-dioxo-3-piperidinyl)amino]carbonyl}benzoate	n/a	C₁₄H₁₄N₂O₅	详情	详情

合成路线4

The reaction of 2-(phthalimido)glutaric acid (I) with acetic anhydride and SOCl2 gives 2-(phthalimido)glutaric anhydride (II), which is treated with urea at 180 C to yield the target thalidomide. Alternatively, anhydride (II) can also be treated with ammonia in dioxane at 180 C in a pressure vessel.

参考文献中间体

【1】 (Grunenthal GmbH); Novel products of the amino-piperidine-2,6-dione series. GB 0768821 .
【2】 Frankus, E.; Graudums, I.; Muckter, H. (Grunenthal GmbH); Derivs. of phthalimidines. GB 1185273 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	54082	2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioic acid	2301-52-2	C₁₃H₁₁NO₆	详情	详情
(II)	57860	N-Phthalyl-DL-glutamic anhydride; Phthalyl-Dl-Glutamic anhydride	3085-92-5	C₁₃H₉NO₅	详情	详情
(III)	57861	(+/-)-N-(2,6-Dioxo-3-piperidinyl)phthalimide; (+/-)-Thalidomide; (?-N-(2,6-Dioxo-3-piperidinyl)phthalimide; Thalidomide	50-35-1	C₁₃H₁₀N₂O₄	详情	详情

合成路线5

The esterification of N-(tert-butoxycarbonyl)-D-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-D-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(R)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(R)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(R)-(phthalimido)piperidine-2,6-dione (IX). Finally, the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (R)-thalidomide.

参考文献中间体

【1】 Robin, S.; et al.; A convenient asymmetric synthesis of thalidomide. Tetrahedron Asymmetry 1995, 6, 6, 1249.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	57869	(2R)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid		C₁₇H₂₃NO₆	详情	详情
(II)	57862	5-benzyl 1-phenyl (2R)-2-[(tert-butoxycarbonyl)amino]pentanedioate		C₂₃H₂₇NO₆	详情	详情
(III)	57863	(4R)-4-[(tert-butoxycarbonyl)amino]-5-oxo-5-phenoxypentanoic acid		C₁₆H₂₁NO₆	详情	详情
(IV)	14640	O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene	622-33-3	C₇H₉NO	详情	详情
(V)	57864	tert-butyl (3R)-1-(benzyloxy)-2,6-dioxopiperidinylcarbamate		C₁₇H₂₂N₂O₅	详情	详情
(VI)	57865	(3R)-3-amino-1-(benzyloxy)-2,6-piperidinedione		C₁₂H₁₄N₂O₃	详情	详情
(VII)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(VIII)	57866	2-[(3R)-1-(benzyloxy)-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione		C₂₀H₁₆N₂O₅	详情	详情
(IX)	57867	2-[(3R)-1-hydroxy-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione		C₁₃H₁₀N₂O₅	详情	详情
(X)	10315	2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone	70-11-1	C₈H₇BrO	详情	详情
(XI)	57868	2-[(3R)-2,6-dioxo-1-(2-oxo-2-phenylethoxy)piperidinyl]-1H-isoindole-1,3(2H)-dione		C₂₁H₁₆N₂O₆	详情	详情

合成路线6

The esterification of N-(tert-butoxycarbonyl)-L-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-L-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(S)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(S)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(S)-(phthalimido)piperidine-2,6-dione (IX). Finally the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (S)-thalidomide. Alternatively, the phthalimido derivative (VIII) can also be obtained by reaction of 2(S)-(phthalimido)glutaric anhydride (XII) with O-benzylhydroxylamine (IV) by means of DCC and pyridine in dichloromethane.

参考文献中间体

【1】 Robin, S.; et al.; A convenient asymmetric synthesis of thalidomide. Tetrahedron Asymmetry 1995, 6, 6, 1249.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	25141	(2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid	13574-13-5	C₁₇H₂₃NO₆	详情	详情
(II)	57870	5-benzyl 1-phenyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate		C₂₃H₂₇NO₆	详情	详情
(III)	57871	(4S)-4-[(tert-butoxycarbonyl)amino]-5-oxo-5-phenoxypentanoic acid		C₁₆H₂₁NO₆	详情	详情
(IV)	14640	O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene	622-33-3	C₇H₉NO	详情	详情
(V)	57872	tert-butyl (3S)-1-(benzyloxy)-2,6-dioxopiperidinylcarbamate		C₁₇H₂₂N₂O₅	详情	详情
(VI)	57873	(3S)-3-amino-1-(benzyloxy)-2,6-piperidinedione		C₁₂H₁₄N₂O₃	详情	详情
(VII)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(VIII)	57874	2-[(3S)-1-(benzyloxy)-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione		C₂₀H₁₆N₂O₅	详情	详情
(IX)	57875	2-[(3S)-1-hydroxy-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione		C₁₃H₁₀N₂O₅	详情	详情
(X)	10315	2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone	70-11-1	C₈H₇BrO	详情	详情
(XI)	57876	2-[(3S)-2,6-dioxo-1-(2-oxo-2-phenylethoxy)piperidinyl]-1H-isoindole-1,3(2H)-dione		C₂₁H₁₆N₂O₆	详情	详情
(XII)	57877	2-[(3S)-2,6-dioxotetrahydro-2H-pyran-3-yl]-1H-isoindole-1,3(2H)-dione		C₁₃H₉NO₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)