(2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid -Drug Synthesis Database

【结构式】

【分子编号】38084

【品名】(2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid

【CA登记号】

【分子式】C₁₇H₁₅NO₄

【分子量】297.31044

【元素组成】C 68.68% H 5.09% N 4.71% O 21.53%

与该中间体有关的原料药合成路线共 6 条

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

该中间体在本合成路线中的序号：(V)

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

合成目标

【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

该中间体在本合成路线中的序号：(V)

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

合成目标

【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

该中间体在本合成路线中的序号：(V)

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

合成目标

【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

合成路线4

该中间体在本合成路线中的序号：(V)

参考文献中间体

合成目标

【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5

该中间体在本合成路线中的序号：(V)

参考文献中间体

合成目标

【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6

该中间体在本合成路线中的序号：(V)

Acid hydrolysis of the acetamido group of (V) gave amino acid (XI), which was further esterified with HCl in MeOH. The resulting amino ester (XII) was then protected as the tert-butyl carbamate (XIII) and the methyl ester was hydrolyzed to carboxylic acid (XIV) by means of LiOH. Coupling of (XIV) with 3-aminopropionitrile (XV) using BOP reagent provided the N-cyanoethyl amide (XVI). Elaboration of the tetrazole ring (XVII) was carried out by treatment of (XVI) with trimethylsilyl azide, diisopropyl azodicarboxylate and triphenyl phosphine. The Boc group of (XVII) was then deprotected by treatment with formic acid. The resulting amine (XVIII) was condensed with formaldehyde, followed by reaction of the intermediate trimeric hexahydrotriazine with diphenyl phosphite to furnish alpha-aminophosphonate (XIX). Basic cleavage of the cyanoethyl group of (XIX) produced the N-dealkylated tetrazole (XX). Finally, basic hydrolysis of phosphonate ester groups of (XX) gave rise to the title compound.

参考文献中间体

合成目标

【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
(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)	38092	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-dibenzo[b,d]furan-3-ylpropanoate		C₂₁H₂₃NO₅	详情	详情
(XIV)	38093	(2S)-2-[(tert-butoxycarbonyl)amino]-3-dibenzo[b,d]furan-3-ylpropionic acid		C₂₀H₂₁NO₅	详情	详情
(XV)	38094	3-aminopropanenitrile	151-18-8	C₃H₆N₂	详情	详情
(XVI)	38095	tert-butyl (1S)-2-[(2-cyanoethyl)amino]-1-(dibenzo[b,d]furan-3-ylmethyl)-2-oxoethylcarbamate		C₂₃H₂₅N₃O₄	详情	详情
(XVII)	38096	tert-butyl (1S)-1-[1-(2-cyanoethyl)-1H-1,2,3,4-tetraazol-5-yl]-2-dibenzo[b,d]furan-3-ylethylcarbamate		C₂₃H₂₄N₆O₃	详情	详情
(XVIII)	38097	3-[5-[(1S)-1-amino-2-dibenzo[b,d]furan-3-ylethyl]-1H-1,2,3,4-tetraazol-1-yl]propanenitrile		C₁₈H₁₆N₆O	详情	详情
(XIX)	38098	diphenyl ([(1S)-1-[1-(2-cyanoethyl)-1H-1,2,3,4-tetraazol-5-yl]-2-dibenzo[b,d]furan-3-ylethyl]amino)methylphosphonate		C₃₁H₂₇N₆O₄P	详情	详情
(XX)	38099	diphenyl [[(1S)-2-dibenzo[b,d]furan-3-yl-1-(1H-1,2,3,4-tetraazol-5-yl)ethyl]amino]methylphosphonate		C₂₈H₂₄N₅O₄P	详情	详情

Extended Information