Cilengitide, NSC-707544, EMD-85189, EMD-121974, -Drug Synthesis Database

【结构式】

【药物名称】Cilengitide, NSC-707544, EMD-85189, EMD-121974

【化学名称】Cyclo(L-arginyl-glycyl-L-aspartyl-D-phenylalanyl-N-methyl-L-valyl)

【CA登记号】188968-51-6, 188969-00-8 (monoHCl), 199807-38-0 (monomethanesulfonate), 199807-35-7 (monotrifluoroacetate)

【分子式】C₂₇H₄₀N₈O₇

【分子量】588.66925

【开发单位】Merck KGaA (Originator), National Cancer Institute (Codevelopment)

【药理作用】Antiarthritic Drugs, Brain Cancer Therapy, Kaposi's Sarcoma Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Solid Tumors Therapy, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Angiogenesis Inhibitors, Integrin alphavbeta3 (Vitronectin) Antagonists, Integrin alphavbeta5 Antagonists

合成路线1 合成路线2

合成路线1

Cilengitide is synthesized using solid-phase Merrifield-type methods by sequentially adding N-Boc-N-Me-L-Val (I), N-Boc-D-Phe (III), N-Boc-4-O-t-Bu-L-Asp (V), N-Boc-Gly (VII) and Nalpha-Fmoc-Nomega-Mtr-L-Arg (IX) in a stepwise manner to a 4-hydroxymethylphenoxymethyl-polystyrene resin (Wang type resin), yielding peptide-resin intermediates (II), (IV), (VI), (VIII) and (X), respectively. Elimination of the resin from the peptide chain with a 1:1 mixture of TFA/dichloromethane results in the linear peptide (XI), which is then deprotected at the amino-terminal group by removing the Fmoc group with a 1:1 mixture of piperidine/DMF, to give peptide (XII).

参考文献中间体

【1】 Graul, A.; Sorbera, L.A.; Castañer, J.; Cilengitide. Drugs Fut 2000, 25, 7, 674.
【2】 Jonczyk, A.; Goodman, S.; Diefenbach, B.; Sutter, A.; Holzmann, G.; Kessler, H.; Dechantsreiter, M. (Merck Patent GmbH); Cyclic adhesion inhibitors. DE 19534177; EP 0770622; JP 1997132593; US 6001961 .

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),(II)	27154	(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid	45170-31-8	C₁₁H₂₁NO₄	详情	详情
(X),(XI)	37627	(8S,14S,17R,20S)-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid		C₆₆H₇₆N₈O₁₁	详情	详情
(III)	22184	(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid		C₁₄H₁₉NO₄	详情	详情
(IV)	37622	(2S)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl](methyl)amino]-3-methylbutyric acid		C₂₀H₃₀N₂O₅	详情	详情
(V)	37623	(2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid		C₁₃H₂₃NO₆	详情	详情
(VI)	37624	(6S,9R,12S)-9-benzyl-6-[2-(tert-butoxy)-2-oxoethyl]-12-isopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid		C₂₈H₄₃N₃O₈	详情	详情
(VII)	18066	N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid	4530-20-5	C₇H₁₃NO₄	详情	详情
(VIII)	37625	(9S,12R,15S)-12-benzyl-9-[2-(tert-butoxy)-2-oxoethyl]-15-isopropyl-2,2,14-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid		C₃₀H₄₆N₄O₉	详情	详情
(IX)	37626	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]pentanoic acid		C₄₁H₄₀N₄O₅	详情	详情
(XII)	37628	(8S,14S,17R,20S)-8-amino-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid		C₅₁H₆₆N₈O₉	详情	详情

合成路线2

Cyclization of (XII) by means of DPPA in DMF/dichloromethane affords the cyclic peptide (XIII), which is finally deprotected by treatment with TFA/water 98:2.

参考文献中间体

【1】 Graul, A.; Sorbera, L.A.; Castañer, J.; Cilengitide. Drugs Fut 2000, 25, 7, 674.
【2】 Jonczyk, A.; Goodman, S.; Diefenbach, B.; Sutter, A.; Holzmann, G.; Kessler, H.; Dechantsreiter, M. (Merck Patent GmbH); Cyclic adhesion inhibitors. DE 19534177; EP 0770622; JP 1997132593; US 6001961 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	37628	(8S,14S,17R,20S)-8-amino-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid		C₅₁H₆₆N₈O₉	详情	详情
(XIII)	37629	tert-butyl 2-[(2S,5R,8S,11S)-11-(3-[[amino(imino)methyl]amino]propyl)-5-benzyl-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl]acetate		C₃₁H₄₈N₈O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)