Gusperimus hydrochloride, Deoxyspergualin hydrochloride, BMY-42215-1, BMS-181173, NSC-356894, NKT-01, DSG, Spanidin, -Drug Synthesis Database

【结构式】

【药物名称】Gusperimus hydrochloride, Deoxyspergualin hydrochloride, BMY-42215-1, BMS-181173, NSC-356894, NKT-01, DSG, Spanidin

【化学名称】(±)-7-Guanidino-N-[2-[4-(3-aminopropylamino)butylamino]-1-hydroxy-2-oxoethyl]heptanamide trihydrochloride
　　　　　　(±)-1-Amino-19-guanidino-11-hydroxy-4,9,12-triazanonadecane-10,13-dione trihydrochloride
　　　　　　(±)-15-Deoxyspergualin trihydrochloride
　　　　　　(±)-N-[[[4-[(3-Aminopropyl)amino]butyl]carbamoyl]hydroxymethyl]-7-guanidinoheptanamide trihydrochloride

【CA登记号】84937-45-1 ((-)-enantiomer), 104317-84-2 (free base), 85468-01-5 (undefined isomer), 98629-43-7 (undefined isomer;free base)

【分子式】C₁₇H₄₀Cl₃N₇O₃

【分子量】496.91245

【开发单位】Nippon Kayaku (Orphan Drug), Nippon Kayaku (Originator), Bristol-Myers Squibb (Licensee), Dade Behring Marburg (Licensee), TaKaRa Shuzo (Bulk Supplier)

【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants, Nephritis, Agents for, Oncolytic Drugs, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Treatment of Transplant Rejection, Angiogenesis Inhibitors

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

The synthesis of racemic 15-deoxyspergualin and tritium-labeled compound has been described: The oxidation of N-(3-hydroxypropyl)carbamic acid tert-butyl ester (I) with pyridinium chlorochromate in dichloromethane gives N-(3-oxopropyl)carbamic acid tert-butyl ester (II), which is condensed with 4-(triphenylphosphonium)butyrate (III) by means of lithium bis(trimethylsilyl)amide in THF yielding 7-(tert-butoxycarbonylamino)-4-heptenoic acid (IV). The esterification of (IV) with N-hydroxysuccinimide (V) by means of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole affords the corresponding ester (VI), which is treated with ammonia in methanol giving the corresponding amide (VII). The hydrolysis of (VII) with HCl in ethyl acetate yields 7-amino-4-heptenamide (VIII), which is treated with 3,5-dimethylpyrazole-1-carboxamidine (IX) and K2CO3 in methanol affording 7-guanidino-4-heptenamide (X). The reduction of (X) gives 7-guanidinoheptanamide (XI), which is finally condensed with glyoxylspermidine (XII) by means of glutaric acid in hot water. The tritium-labeled compound can also be obtained in the same way by performing the reduction of heptenamide (X) with tritium gas.

参考文献中间体

【1】 Cook, D.J.; Tepper, M.A.; Saulnier, M.G.; Dischino, D.D.; Synthesis of tritium labeled (±) 15-deoxyspergualin trihydrochloride. J Label Compd Radiopharm 1993, 33, 2, 137.

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)	10260	tert-butyl N-(3-hydroxypropyl)carbamate	58885-58-8	C₈H₁₇NO₃	详情	详情
(II)	10261	tert-butyl N-(3-oxopropyl)carbamate		C₈H₁₅NO₃	详情	详情
(III)	10262	4-(triphenylphosphonio)butanoate		C₂₂H₂₂O₂P	详情	详情
(IV)	10263	(E)-7-[(tert-Butoxycarbonyl)amino]-4-heptenoic acid		C₁₂H₂₁NO₄	详情	详情
(V)	10264	1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione	6066-82-6	C₄H₅NO₃	详情	详情
(VI)	10265	tert-butyl N-[(E)-7-[(2,5-dioxo-1-pyrrolidinyl)oxy]-7-oxo-3-heptenyl]carbamate		C₁₆H₂₄N₂O₆	详情	详情
(VII)	10266	tert-butyl N-[(E)-7-amino-7-oxo-3-heptenyl]carbamate		C₁₂H₂₂N₂O₃	详情	详情
(VIII)	10267	(E)-7-Amino-4-heptenamide		C₇H₁₄N₂O	详情	详情
(IX)	10268	3,5-Dimethyl-1H-pyrazole-1-carboximidamide		C₆H₁₀N₄	详情	详情
(X)	10269	(E)-7-[[Amino(imino)methyl]amino]-4-heptenamide		C₈H₁₆N₄O	详情	详情
(XI)	10270	7-[[Amino(imino)methyl]amino]heptanamide		C₈H₁₈N₄O	详情	详情
(XI)	44635	7-[[amino(imino)methyl]amino]heptanamide		C₈H₁₈N₄O	详情	详情
(XII)	10271	N-[4-[(3-Aminopropyl)amino]butyl]-2,2-dihydroxyacetamide		C₉H₂₁N₃O₃	详情	详情

合成路线2

The synthesis of [14C]-labeled 15-deoxyspergualin trihydrochloride has been reported: The condensation of [14C]-labeled S-methylisothiourea (I) with 7-aminoheptanoic acid (II) by means of NaOH in water gives 7-guanidinoheptanoic acid (III), which is treated with Dowex 50W resin (H+ form) in refluxing methanol yielding the corresponding methyl ester (IV). The reaction of (IV) with concentrated NH4OH affords the amide (V), which is finally condensed with glyoxyloxyspermidine (VI) by means of glutaric acid in hot water (60 C), and purified by chromatography over Sephadex CM-25 (Na+ form).

参考文献中间体

【1】 Dischino, D.D.; Synthesis of carbon-14 labeled (±) 15-deoxyspergualin trihydrochloride. J Label Compd Radiopharm 1995, 36, 11, 1097.

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)	10272	[[Amino(imino)methyl]sulfanyl]methane	2986-19-8	C₂H₆N₂S	详情	详情
(I)	44636	[[amino(imino)methyl]sulfanyl]methane		C₂H₆N₂S	详情	详情
(II)	10273	7-Aminoheptanoic acid	929-17-9	C₇H₁₅NO₂	详情	详情
(III)	10274	7-[[Amino(imino)methyl]amino]heptanoic acid		C₈H₁₇N₃O₂	详情	详情
(III)	44637	7-[[amino(imino)methyl]amino]heptanoic acid		C₈H₁₇N₃O₂	详情	详情
(IV)	10275	methyl 7-[[amino(imino)methyl]amino]heptanoate		C₉H₁₉N₃O₂	详情	详情
(IV)	44638	methyl 7-[[amino(imino)methyl]amino]heptanoate		C₉H₁₉N₃O₂	详情	详情
(V)	10270	7-[[Amino(imino)methyl]amino]heptanamide		C₈H₁₈N₄O	详情	详情
(V)	44639	7-[[amino(imino)methyl]amino]heptanamide		C₈H₁₈N₄O	详情	详情
(VI)	10271	N-[4-[(3-Aminopropyl)amino]butyl]-2,2-dihydroxyacetamide		C₉H₂₁N₃O₃	详情	详情

合成路线3

1) By a stepwise conversion of spergualin to DSG in the following sequence: a) Protecting the primary and secondary amines of spergualin with N-(benzyloxycarbonyloxy)suc cinimide to form the N,N'-benzyloxycarbonyl derivative (I); b) protecting the 11-hydroxy group with 3,4-dihydro-2H-pyran to the 11-O tetrahydropyranyl derivative (II); c) converting the 1,5-hydroxy function of (II) to a 1,5-mesylate (III); d) halogenation of (III) with sodium iodide, followed by catalytic hydrogenation, to give 15-deoxy-1-O-tetrahydropyranylspergualin (IV); e) hydrolysis of (IV) with p-toluenesulfonic acid in water to yield 1,5-deoxyspergualin. The overall yield of DSG is 1.8%, based on the amount of spergualin used.

参考文献中间体

【1】 Takeuchi, T.; Umezawa, H.; Iwasawa, H.; Ikeda, D.; Kondo, S.; Synthesis of (-)-15-deoxyspergualin and (-)-spergualin-15-phosphate. J Antibiot 1982, 35, 12, 1665-1669.
【2】 Kondo, S.; Takeuchi, T.; Umezawa, H. (Microbial Chemistry Research Foundation); (-)-15-Deoxyspergualin, a process for the preparation of the same, an intermediate of the same, and its use as medicament. EP 0094632 .
【3】 Cheng, C.C.; Zee-Cheng, R.K.-Y.; Deoxyspergualin. Drugs Fut 1987, 12, 2, 113.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	详情	详情
	62979	benzyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate		C₁₂H₉NO₄	详情	详情
Spergualin	62980	7-{[amino(imino)methyl]amino}-N-[2-({4-[(3-aminopropyl)amino]butyl}amino)-1-hydroxy-2-oxoethyl]-3-hydroxyheptanamide		C₁₇H₃₇N₇O₄	详情	详情
(I)	22886	benzyl 21-amino-4-[(benzyloxy)carbonyl]-11,15-dihydroxy-21-imino-10,13-dioxo-4,9,12,20-tetraazahenicos-1-ylcarbamate		C₃₃H₄₉N₇O₈	详情	详情
(II)	22887	benzyl 21-amino-4-[(benzyloxy)carbonyl]-15-hydroxy-21-imino-10,13-dioxo-11-(tetrahydro-2H-pyran-2-yloxy)-4,9,12,20-tetraazahenicos-1-ylcarbamate		C₃₈H₅₇N₇O₉	详情	详情
(III)	22888	benzyl 15-(4-[[amino(imino)methyl]amino]butyl)-4-[(benzyloxy)carbonyl]-10,13,17-trioxo-11-(tetrahydro-2H-pyran-2-yloxy)-16,18-dioxa-17lambda(4)-thia-4,9,12-triazanonadec-1-ylcarbamate		C₃₉H₅₉N₇O₁₁S	详情	详情
(IV)	22889	7-[[amino(imino)methyl]amino]-N-[2-([4-[(3-aminopropyl)amino]butyl]amino)-2-oxo-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]heptanamide		C₂₂H₄₅N₇O₄	详情	详情

合成路线4

2) By an acid catalyzed condensation of 7-guanidinoheptanamide (IX) with an equivalent amount of glyoxylspermidine (X) in the presence of glutaric acid at 60 C for 8 h. Purification of the reaction mixture gives DSG in 39% yield.

参考文献中间体

【1】 Umezawa, H.; Kuroda, H.; Nakamura, T.; Umeda, Y.; Iinuma, H.; Moriguchi, M.; Takeuchi, T.; Synthesis and antitumor activity of spergualin analogues. I. Chemical modification of 7-guanidino-3-hydroxyacyl moiety. J Antibiot 1985, 38, 7, 886-898.
【2】 Kondo, S.; Ikeda, Y.; Ikeda, D.; Iwasawa, H.; Umezawa, H.; Iinuma, H.; Umeda, Y.; The total synthesis of spergualin, an antitumor antibiotic. J Antibiot 1981, 34, 12, 1625-1627.
【3】 Umezawa, H.; Takeuchi, T.; Kondo, S. (Microbial Chemistry Research Foundation); (-)-15-Deoxyspergualin, process for the preparation thereof, and intermediate of the same. US 4525299 .
【4】 Fujii, A.; Iinuma, H.; Ikeda, D.; Kondo, S.; Nakamura, T.; Takeuchi, T.; Umezawa, H. (Microbial Chemistry Research Foundation); N-[4-(3-Aminopropyl)-aminobutyl]-2-(omega-guanidino-fatty-acid-amido)-2-substd.-ethanamide and salt thereof. BE 0894651; US 4518532; US 4658058 .
【5】 Inokai, K.; Fujii, A.; Takeuchi, T.; Umeda, Y.; Moriguchi, M.; Nakamura, T.; Umezawa, H. (Nippon Kayaku Co., Ltd.; Takara Shuzo Co., Ltd.); Spegualin-related nitrile cpds. and their preparation method. JP 1985178853 .
【6】 Suzuki, M.; Nishizawa, R.; Takei, M.; Yoshida, M. (Nippon Kayaku Co., Ltd.); Purification method of spergualin or its derivs.. JP 1984029652 .
【7】 Nakamura, T.; Moriguchi, M.; Inokai, K.; Umeda, Y.; Umezawa, H.; Takeuchi, T.; Fujii, A. (Nippon Kayaku Co., Ltd.; Takara Shuzo Co., Ltd.); Adduct of omega-guanidino fatty acid amide and glyoxylic acid, and its preparation method. JP 1985178852 .
【8】 Takeuchi, T.; Umezawa, H.; Kondo, S.; Nakamura, T.; Iinuma, H.; Ikeda, T.; Fujii, A. (Microbial Chemistry Research Foundation); (S)-7-Guanidino-3-hydroxyheptanamide and its synthesis method. JP 1982188562 .
【9】 Ikeda, D.; Nakamura, T.; Fujii, A.; Umezawa, H.; Kondo, S.; Iinuma, H.; Takeuchi, T. (Microbial Chemistry Research Foundation); N-[4-(3-Aminopropyl)aminobutyl]-2,2-dihydroxyethanamide and process for its synthesis. DE 3217693; GB 2100253 .
【10】 Takeuchi, T.; Fujii, A.; Nakamura, T.; Umeda, Y.; Moriguchi, M.; Umezawa, H. (Nippon Kayaku Co., Ltd.; Takara Shuzo Co., Ltd.); Method for producing glyoxylspermidine and the use thereof for the production of 15-deoxy spergualin-related cpds.. DE 3506330; US 4603015 .
【11】 Cheng, C.C.; Zee-Cheng, R.K.-Y.; Deoxyspergualin. Drugs Fut 1987, 12, 2, 113.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	10274	7-[[Amino(imino)methyl]amino]heptanoic acid		C₈H₁₇N₃O₂	详情	详情
(VI)	10273	7-Aminoheptanoic acid	929-17-9	C₇H₁₅NO₂	详情	详情
(VII)	22892	N-(4-aminobutyl)-N-(3-aminopropyl)amine; N(1)-(3-aminopropyl)-1,4-butanediamine	124-20-9	C₇H₁₉N₃	详情	详情
(VIII)	22893	2,2-diethoxyacetic acid		C₆H₁₂O₄	详情	详情
(IX)	10270	7-[[Amino(imino)methyl]amino]heptanamide		C₈H₁₈N₄O	详情	详情
(X)	10271	N-[4-[(3-Aminopropyl)amino]butyl]-2,2-dihydroxyacetamide		C₉H₂₁N₃O₃	详情	详情

合成路线5

A new synthesis of (-)-15-deoxyspergualin has been reported: The hydrolysis of 7-bromoheptanenitrile (I) with HCl gives the corresponding amide (II), which by reaction with sodium azide yields 7-azidoheptanamide (III). The condensation of (III) with 2-hydroxy-2-methoxyacetic acid methyl ester (IV) affords the alpha-hydroxyglycine derivative (V), which is condensed with 1(S)-(2-naphthyl)ethanol (VI) by means of SO2Cl2 and triethylamine in dichloromethane providing the diastereomeric mixture (VII). Hydrolysis of the ester group of (VII) with NaOH yields the corresponding free acid (VIII), which is condensed with the diprotected triamine (IX) by means of DCC and HOBt in dichloromethane affording a diastereomeric mixture of diamides. This mixture is separated by flash chromatography giving the desired diastereomer (X). The condensation of (X) with the protected isothiourea (XI) by means of triphenylphosphine in THF/water provides the proteted guanidino derivative (XII), which is finally deprotected by hydrogenation with H2 over Pd/C in methanol/acetic acid.

参考文献中间体

【1】 Durand, P.; et al.; (-)-15-Deoxyspergualin: A new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration. J Org Chem 1998, 63, 26, 9723.

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)	32852	7-bromoheptanenitrile	20965-27-9	C₇H₁₂BrN	详情	详情
(II)	32853	7-bromoheptanamide		C₇H₁₄BrNO	详情	详情
(III)	32854	7-azidoheptanamide		C₇H₁₄N₄O	详情	详情
(IV)	22764	methyl 2-hydroxy-2-methoxyacetate	19757-97-2	C₄H₈O₄	详情	详情
(V)	32855	methyl 2-[(7-azidoheptanoyl)amino]-2-hydroxyacetate		C₁₀H₁₈N₄O₄	详情	详情
(VI)	32856	(1S)-1-(2-naphthyl)-1-ethanol; 1(S)-(2-naphthyl)ethanol	7228-47-9	C₁₂H₁₂O	详情	详情
(VII)	32857	methyl 2-[(7-azidoheptanoyl)amino]-2-[[(1S)-1-(2-naphthyl)ethyl]oxy]acetate		C₂₂H₂₈N₄O₄	详情	详情
(VIII)	32858	2-[(7-azidoheptanoyl)amino]-2-[[(1S)-1-(2-naphthyl)ethyl]oxy]acetic acid		C₂₁H₂₆N₄O₄	详情	详情
(IX)	32859	benzyl 4-aminobutyl(3-[[(benzyloxy)carbonyl]amino]propyl)carbamate		C₂₃H₃₁N₃O₄	详情	详情
(X)	32860	benzyl 4-[((2S)-2-[(7-azidoheptanoyl)amino]-2-[[(1S)-1-(2-naphthyl)ethyl]oxy]ethanoyl)amino]butyl(3-[[(benzyloxy)carbonyl]amino]propyl)carbamate		C₄₄H₅₅N₇O₇	详情	详情
(XI)	32861	benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate		C₁₈H₁₈N₂O₄S	详情	详情
(XII)	32862	benzyl (7S,17Z)-17-[[(benzyloxy)carbonyl]amino]-7-[[(1S)-1-(2-naphthyl)ethyl]oxy]-6,9,19-trioxo-21-phenyl-20-oxa-5,8,16,18-tetraaza-17-henicosen-1-yl(3-[[(benzyloxy)carbonyl]amino]propyl)carbamate		C₆₁H₇₁N₇O₁₁	详情	详情

合成路线6

The hydrolysis of 7-bromoheptanenitrile (I) with HCl gives the corresponding amide (II), which is treated with Na-N3 in hot DMSO to yield 7-azidoheptanamide (III) (1). The condensation of (III) with 2-hydroxy-2-methoxyacetic acid methyl ester (IV) in hot dichloromethane affords the alpha-hydroxyglycine (V), which is treated with SOCl2 in the same solvent to provide the alpha-chloroglycine (VI). The reaction of (VI) with benzyl alcohol and TEA in dichloromethane furnishes the benzyloxy derivative (VII), which is hydrolyzed at the ester group by means of NaOH in DME to give the carboxylic acid (VIII). The condensation of (VIII) with N1,N4-bis(benzyloxycarbonyl)spermidine (IX) by means of DCC and HOBt in dichloromethane yields the corresponding amide (X), which is reduced at the terminal azido group by means of PPh3 in THF/water, affording the expected primary amine (XI). The condensation of (XI) with the protected isothiourea (XII) in THF affords the protected guanidine derivative (XIII), which is finally deprotected by hydrogenolysis with H2 over Pd(OH)2 in methanol/acetic acid to provide the target compound.

参考文献中间体

【1】 Durand, P.; et al.; A new efficient synthesis of the immunosuppressive agent (±)-15-deoxyspergualin. Tetrahedron 2001, 57, 14, 2757.
【2】 Durand, P.; et al.; (-)-15-Deoxyspergualin: A new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration. J Org Chem 1998, 63, 26, 9723.

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)	32852	7-bromoheptanenitrile	20965-27-9	C₇H₁₂BrN	详情	详情
(II)	32853	7-bromoheptanamide		C₇H₁₄BrNO	详情	详情
(III)	32854	7-azidoheptanamide		C₇H₁₄N₄O	详情	详情
(IV)	22764	methyl 2-hydroxy-2-methoxyacetate	19757-97-2	C₄H₈O₄	详情	详情
(V)	32855	methyl 2-[(7-azidoheptanoyl)amino]-2-hydroxyacetate		C₁₀H₁₈N₄O₄	详情	详情
(VI)	55499	methyl 2-[(7-azidoheptanoyl)amino]-2-chloroacetate		C₁₀H₁₇ClN₄O₃	详情	详情
(VII)	55500	methyl 2-[(7-azidoheptanoyl)amino]-2-(benzyloxy)acetate		C₁₇H₂₄N₄O₄	详情	详情
(VIII)	55501	2-[(7-azidoheptanoyl)amino]-2-(benzyloxy)acetic acid		C₁₆H₂₂N₄O₄	详情	详情
(IX)	32859	benzyl 4-aminobutyl(3-[[(benzyloxy)carbonyl]amino]propyl)carbamate		C₂₃H₃₁N₃O₄	详情	详情
(X)	55502	benzyl 4-{[2-[(7-azidoheptanoyl)amino]-2-(benzyloxy)acetyl]amino}butyl(3-{[(benzyloxy)carbonyl]amino}propyl)carbamate		C₃₉H₅₁N₇O₇	详情	详情
(XI)	55503	benzyl 4-{[2-[(7-aminoheptanoyl)amino]-2-(benzyloxy)acetyl]amino}butyl(3-{[(benzyloxy)carbonyl]amino}propyl)carbamate		C₃₉H₅₃N₅O₇	详情	详情
(XII)	32861	benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate		C₁₈H₁₈N₂O₄S	详情	详情
(XIII)	55504	benzyl (Z)-7-(benzyloxy)-17-{[(benzyloxy)carbonyl]amino}-6,9,19-trioxo-21-phenyl-20-oxa-5,8,16,18-tetraaza-17-henicosen-1-yl(3-{[(benzyloxy)carbonyl]amino}propyl)carbamate		C₅₆H₆₇N₇O₁₁	详情	详情

Extended Information