CGS-35066, -Drug Synthesis Database

【结构式】

【药物名称】CGS-35066

【化学名称】3-(Dibenzo[b,d]furan-3-yl)-2(S)-(phosphonomethylamino)propionic acid

【CA登记号】

【分子式】C₁₆H₁₆NO₆P

【分子量】349.28282

【开发单位】Novartis (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Endothelin-Converting Enzyme Inhibitors, Neprilysin Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

The chiral amino acid (V) was prepared by two alternative procedures. Heck coupling between 3-iododibenzofuran (I) and methyl 2-acetamidoacrylate (II) in the presence of palladium diacetate afforded the alpha,beta-unsaturated alpha-amido ester (III), which was hydrogenated over Pd/C to yield the racemic saturated ester (IV). Incubation of (IV) with alcalase led to the enantiospecific hydrolysis of the S-enantiomer to give the required S-carboxylic acid (V). The unreacted R-enantiomer (VI) was recycled by epimerization in the presence of DBU.

参考文献中间体

【1】 Blanchard, L.; De Lombaert, S.; Stamford, L.B.; et al.; Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. J Med Chem 2000, 43, 3, 488.

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)	38080	3-iododibenzo[b,d]furan		C₁₂H₇IO	详情	详情
(II)	38081	methyl 2-(acetamido)acrylate	35356-70-8	C₆H₉NO₃	详情	详情
(III)	38082	methyl (E)-2-(acetamido)-3-dibenzo[b,d]furan-3-yl-2-propenoate		C₁₈H₁₅NO₄	详情	详情
(IV)	38083	methyl 2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate		C₁₈H₁₇NO₄	详情	详情
(V)	38084	(2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid		C₁₇H₁₅NO₄	详情	详情
(VI)	38085	methyl (2R)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate		C₁₈H₁₇NO₄	详情	详情

合成路线2

In a different procedure, biaryl formation via ortho palladation of diaryl ether (VII) provided the desired dibenzofuran (VIII) along with a small amount of regioisomer (IX). Kinetic resolution with alcalase produced the S-carboxylic acid (V), whereas the R-ester (X) was recycled by base-catalyzed epimerization.

参考文献中间体

【1】 Blanchard, L.; De Lombaert, S.; Stamford, L.B.; et al.; Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. J Med Chem 2000, 43, 3, 488.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	38084	(2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid	C₁₇H₁₅NO₄	详情	详情
(VII)	38086	ethyl 2-(acetamido)-3-(3-phenoxyphenyl)propanoate	C₁₉H₂₁NO₄	详情	详情
(VIII)	38087	ethyl 2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate	C₁₉H₁₉NO₄	详情	详情
(IX)	38088	ethyl 2-(acetamido)-3-dibenzo[b,d]furan-2-ylpropanoate	C₁₉H₁₉NO₄	详情	详情
(X)	38089	ethyl (2R)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate	C₁₉H₁₉NO₄	详情	详情

合成路线3

Acid hydrolysis of the acetamido group of (V) gave amino acid (XI), which was further esterified with HCl in MeOH yielding ester (XII). Condensation of amino ester (XII) with formaldehyde, followed by reaction of the intermediate trimeric hexahydrotriazine with diphenyl phosphite furnished alpha-aminophosphonate (XIII). Finally, acid hydrolysis of carboxylate and phosphonate ester groups of (XIII) gave rise to the title compound.

参考文献中间体

【1】 Blanchard, L.; De Lombaert, S.; Stamford, L.B.; et al.; Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. J Med Chem 2000, 43, 3, 488.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	38084	(2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid	C₁₇H₁₅NO₄	详情	详情
(XI)	38090	(2S)-2-amino-3-dibenzo[b,d]furan-3-ylpropionic acid	C₁₅H₁₃NO₃	详情	详情
(XII)	38091	methyl (2S)-2-amino-3-dibenzo[b,d]furan-3-ylpropanoate	C₁₆H₁₅NO₃	详情	详情
(XIII)	38100	methyl (2S)-3-dibenzo[b,d]furan-3-yl-2-[[(diphenoxyphosphoryl)methyl]amino]propanoate	C₂₉H₂₆NO₆P	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)