Capimorelin, Capromorelin, CP-424391-18(tartrate), CP-424391, -Drug Synthesis Database

【结构式】

【药物名称】Capimorelin, Capromorelin, CP-424391-18(tartrate), CP-424391

【化学名称】2-Amino-N-[2-[3a(R)-benzyl-2-methyl-3-oxo-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-5-yl]-1(R)-(benzyloxymethyl)-2-oxoethyl]isobutyramide

【CA登记号】193273-66-4, 193273-69-7 (L-tartrate(1:1)), 193270-49-4 (monoHCl), 193273-67-5 (monomesylate)

【分子式】C₂₈H₃₅N₅O₄

【分子量】505.62225

【开发单位】Pfizer (Originator)

【药理作用】Bone Diseases, Treatment of, CARDIOVASCULAR DRUGS, ENDOCRINE DRUGS, Heart Failure Therapy, METABOLIC DRUGS, Pituitary Disorder Therapy, Treatment of Growth Hormone Deficiency, Treatment of Growth Hormone Secretion Disorders, Treatment of Osteoporosis, Growth Hormone Secretagogues

合成路线1 合成路线2

合成路线1

The intermediate dipeptide (VI) was prepared by two similar ways. Treatment of N-Boc-O-benzyl-D-serine (I) with MeI and K2CO3 produced the methyl ester (II). Subsequent deprotection of the Boc group of (II) with trifluoroacetic acid gave aminoester (III), which was coupled with N-Boc-alpha-methylalanine (IV) using EDC and HOBt yielding (V). Hydrolysis of the resulting dipeptide ester (V) then provided intermediate (VI). In an alternative procedure, N-Boc-alpha-methyl alanine (IV) was activated as the N-hydroxysuccinimidyl ester (VII), which was condensed with O-benzyl-D-serine (VIII) to produce dipeptide (VI).

参考文献中间体

【1】 Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.; Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 276.
【2】 Carpino, P.A.; Jardine, D.P.A.; Lefker, B.A.; Ragan, J.A. (Pfizer Inc.); Growth-hormone secretagogues. EP 0869968; JP 1999501945; WO 9724369 .

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)	28112	(2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid		C₁₅H₂₁NO₅	详情	详情
(II)	28100	methyl (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoate		C₁₆H₂₃NO₅	详情	详情
(III)	28101	methyl (2R)-2-amino-3-(benzyloxy)propanoate		C₁₁H₁₅NO₃	详情	详情
(IV)	18471	N-(tert-butoxycarbonyl)-2-methylalanine	30992-29-1	C₉H₁₇NO₄	详情	详情
(V)	28102	methyl (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoate		C₂₀H₃₀N₂O₆	详情	详情
(VI)	28103	(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid		C₁₉H₂₈N₂O₆	详情	详情
(VII)	28104	tert-butyl 2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1,1-dimethyl-2-oxoethylcarbamate		C₁₃H₂₀N₂O₆	详情	详情
(VIII)	28105	(2R)-2-amino-3-(benzyloxy)propionic acid		C₁₀H₁₃NO₃	详情	详情

合成路线2

Methyl 4-oxopiperidine-3-carboxylate (IX) was protected as the tert-butyl carbamate (X) with Boc2O. This was alkylated with benzyl bromide in the presence of NaH to provide the racemic benzyl derivative (XI). Subsequent cyclization of (XI) with methylhydrazine produced the pyrazolopyridine (XII), which was deprotected with trifluoroacetic acid. The resulting amine (XIII) was then coupled with dipeptide (VI) using EDC and HOBt to afford the diastereomeric amides (XIV). After chromatographic isolation of the (R,R)-diastereoisomer, acid deprotection of the Boc group furnished the title compound.

参考文献中间体

【1】 Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.; Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 276.
【2】 Carpino, P.A.; Jardine, D.P.A.; Lefker, B.A.; Ragan, J.A. (Pfizer Inc.); Growth-hormone secretagogues. EP 0869968; JP 1999501945; WO 9724369 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12091	1-Methylhydrazine; Monomethyl hydrazine	60-34-4	CH₆N₂	详情	详情
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(VI)	28103	(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid		C₁₉H₂₈N₂O₆	详情	详情
(IX)	28106	methyl 4-oxo-3-piperidinecarboxylate	56026-52-9	C₇H₁₁NO₃	详情	详情
(X)	28107	1-(tert-butyl) 3-methyl 4-oxo-1,3-piperidinedicarboxylate		C₁₂H₁₉NO₅	详情	详情
(XI)	28108	1-(tert-butyl) 3-methyl 3-benzyl-4-oxo-1,3-piperidinedicarboxylate		C₁₉H₂₅NO₅	详情	详情
(XII)	28109	tert-butyl 3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate		C₁₉H₂₅N₃O₃	详情	详情
(XIII)	28110	3a-benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one		C₁₄H₁₇N₃O	详情	详情
(XIV)	28111	tert-butyl 2-([(1R)-2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-1-[(benzyloxy)methyl]-2-oxoethyl]amino)-1,1-dimethyl-2-oxoethylcarbamate		C₃₃H₄₃N₅O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)