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【结 构 式】

【分子编号】36512

【品名】2-(diethoxyphosphoryl)acetic acid

【CA登记号】3095-95-2

【 分 子 式 】C6H13O5P

【 分 子 量 】196.139982

【元素组成】C 36.74% H 6.68% O 40.79% P 15.79%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(II)

The esterification of myricerone (I) with 2-(diethoxyphosphoryl)acetic acid (II) by means of CDI gives the corresponding ester (III), which is condensed with the benzaldehyde (IV) by means of DBU and LiCl in DMF yielding the expected condensation product (V). Finally, this compound is hydrolyzed with LiOH in aqueous DME, and treated with aqueous NaOH to obtain the target sodium salt. The intermediate benzaldehyde (IV) has been obtained as follows: The reduction of 5-hydroxy-2-nitrobenzaldehyde (VI) with TiCl3 gives 2-amino-5-hydroxybenzaldehyde (VII), which is then condensed with maleic acid monomethyl ester monochloride (VIII).

1 Konoike, T.; et al.; Practical large-scala synthesis of endothelin receptor antagonist S-0139. Org Process Res Dev 1999, 3, 5, 347.
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) 36511 (6aR,6bR,12aR)-6a-(hydroxymethyl)-2,2,6b,9,9,12a-hexamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylic acid C30H46O4 详情 详情
(II) 36512 2-(diethoxyphosphoryl)acetic acid 3095-95-2 C6H13O5P 详情 详情
(III) 36513 (6aR,6bR,12aR)-6a-([[2-(diethoxyphosphoryl)acetyl]oxy]methyl)-2,2,6b,9,9,12a-hexamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylic acid C36H57O8P 详情 详情
(IV) 36514 methyl (E)-4-(2-formyl-4-hydroxyanilino)-4-oxo-2-butenoate C12H11NO5 详情 详情
(V) 36515 (6aR,6bR,12aR)-6a-([[(E)-3-(5-hydroxy-2-[[(E)-4-methoxy-4-oxo-2-butenoyl]amino]phenyl)-2-propenoyl]oxy]methyl)-2,2,6b,9,9,12a-hexamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylic acid C44H57NO9 详情 详情
(VI) 14942 5-hydroxy-2-nitrobenzaldehyde 42454-06-8 C7H5NO4 详情 详情
(VII) 36516 2-amino-5-hydroxybenzaldehyde C7H7NO2 详情 详情
(VIII) 36517 methyl (E)-4-chloro-4-oxo-2-butenoate C5H5ClO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(II)

The esterification of myricerone ethyleneketal (IX) with 2-(diethoxyphosphoryl)acetic acid (II) by means of CDI gives the corresponding ester (X), which is condensed with the benzaldehyde (IV) by means of DBU and LiCl in DMF yielding the expected condensation product (XI). The hydrolysis of (XI) with LiOH in aqueous DME affords the free acid (XII), which is treated with HCl in THF/water to eliminate the ketal protecting group providing the target compound as free acid (XII). Finally, this compound is treated with aqueous NaOH to obtain the target sodium salt.

1 Konoike, T.; et al.; Practical large-scala synthesis of endothelin receptor antagonist S-0139. Org Process Res Dev 1999, 3, 5, 347.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 36512 2-(diethoxyphosphoryl)acetic acid 3095-95-2 C6H13O5P 详情 详情
(IV) 36514 methyl (E)-4-(2-formyl-4-hydroxyanilino)-4-oxo-2-butenoate C12H11NO5 详情 详情
(IX) 36518   C32H50O5 详情 详情
(X) 36519   C38H61O9P 详情 详情
(XI) 36520   C46H61NO10 详情 详情
(XII) 36521   C45H59NO10 详情 详情

合成路线3

该中间体在本合成路线中的序号:(IV)

Acylation of 6-amino-4-(3-chloro-4-fluorophenylamino)-7-[tetrahydrofuran-3(S)-yloxy]quinazoline (I) with the acid chloride generated from bromocrotonic acid (II) and oxalyl chloride leads to the bromocrotonamide (III), which is finally submitted to bromide displacement with dimethylamine (1). Scheme1.
In an alternative method, aminoquinazoline (I) is acylated with diethylphosphonoacetic acid (IV) by means of carbonyldiimidazole in THF to give the phosphonoacetamide (V), which is finally condensed with (dimethylamino)acetaldehyde diethyl acetal (VI) under basic conditions (2). Scheme 1.

1 Himmelsbach, F., Langkopf, E., Solca, F., Jung, B., Baum, A., Blech, S. (Boehringer Ingelheim Pharma GmbH & Co., KG). Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof. DE 10063435, EP 1345910, JP 2004516283, US 2002173509, US 2006100223, US 7019012, WO 0250043.
2 Soyka, R., Rall, W., Kulinna, C., Sieger, P., Schnaubelt, J. (Boehringer Ingelheim Pharma GmbH & Co., KG). Process for preparing amino crotonyl compounds. DE 10349113, EP 1678165, JP 2007510624, US 2005085495, WO 2005037824.
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) 65710 N4-(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4,6-quinazolinediamine 314771-76-1 C18H16ClFN4O2 详情 详情
(II) 50563 (E)-4-bromo-2-butenoic acid 13991-36-1 C4H5BrO2 详情 详情
(III) 65711     C22H19BrClFN4O3 详情 详情
(IV) 36512 2-(diethoxyphosphoryl)acetic acid 3095-95-2 C6H13O5P 详情 详情
(V) 65712     C24H27ClFN4O6 详情 详情
(VI) 65713 2,2-Diethoxy-N,N-dimethylethylamine; (Dimethylamino)acetaldehyde diethyl acetal 3616-56-6 C8H19NO2 详情 详情
Extended Information