benzyl 2-(triphenylphosphoranylidene)acetate -Drug Synthesis Database

【结构式】

【分子编号】22668

【品名】benzyl 2-(triphenylphosphoranylidene)acetate

【CA登记号】

【分子式】C₂₇H₂₃O₂P

【分子量】410.452182

【元素组成】C 79.01% H 5.65% O 7.8% P 7.55%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(VI)

The esterification of bromoacetic acid (I) with benzyl alcohol (II) gives the corresponding ester (III), which by reaction with triphenylphosphine (IV) in hot toluene yields the phosphonium bromide (V). The reaction of (V) with NaOH in water-dichloromethane affords benzyl(triphenylphosphoranylidene) acetate (VI), which is submitted to a Wittig condensation with 5-(hydroxymethyl)-2-pyrrolidone (VII) in the presence of Dess-Martin periodinane (DMPI) giving benzyl 3-(5-oxo-2-pyrrolidinyl)-2(E) propenoate (VIII). The acylation of (VIII) with 4-methoxybenzoyl chloride (IX) by means of triethylamine in hot toluene yields the corresponding amide (X), which is finally hydrogenated and deprotected with H2 over Pd/C in THF.

参考文献中间体

合成目标

【1】 Huang, C.C.; Synthesis of carbon-14 labeled 1-(4-methoxybenzoyl. J Label Compd Radiopharm 1987, 24, 6, 675.

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)	23660	2-Bromoacetic acid	79-08-3	C₂H₃BrO₂	详情	详情
(II)	18710	Benzyl alcohol; Phenylmethanol	100-51-6	C₇H₈O	详情	详情
(III)	12869	benzyl 2-bromoacetate	5437-45-6	C₉H₉BrO₂	详情	详情
(IV)	12437	Triphenylphosphine; Triphenyl phosphine	603-35-0	C₁₈H₁₅P	详情	详情
(V)	22667	[2-(benzyloxy)-2-oxoethyl](triphenyl)phosphonium bromide		C₂₇H₂₄BrO₂P	详情	详情
(VI)	22668	benzyl 2-(triphenylphosphoranylidene)acetate		C₂₇H₂₃O₂P	详情	详情
(VII)	10079	5-(Hydroxymethyl)-2-pyrrolidinone	62400-75-3	C₅H₉NO₂	详情	详情
(VIII)	22670	benzyl (E)-3-(5-oxo-2-pyrrolidinyl)-2-propenoate		C₁₄H₁₅NO₃	详情	详情
(IX)	22671	4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride	100-07-2	C₈H₇ClO₂	详情	详情
(X)	22672	benzyl (E)-3-[1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinyl]-2-propenoate		C₂₂H₂₁NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIX)

Synthesis of intermediate (I): 1c) The bromination of diketene (XIII) followed by reaction with diphenylmethanol gives diphenylmethyl 4-bromoacetoacetate (XIV), which by cyclization with thiourea by means of K2CO3 yields diphenylmethyl 2-(2-aminothiazol-4-yl)acetate (XV). The reaction of (XV) with benzyloxycarbonyl chloride and pyridine affords the protected compound (XVI), which is formylated with diphenyl methyl formiate (XVII) and NaH to afford diphenyl methyl 2-(2-benzyloxycarbonylamino)thiazol-4-yl-3-hydroxyacrylate (XVIII) The Wittig condensation of (XVIII) with benzyl triphenylphosphoranylidene acetate (XIX) gives diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4-(benzyloxycarbonyl)-2-butenoate (XX), which is selectively hydrolyzed with trifluoroacetic acid and anisole lo acid.

参考文献中间体

合成目标

【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(I)	22689	(Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid		C₂₃H₂₀N₂O₆S	详情	详情
(XIII)	11367	4-Methylene-2-oxetanone; Acetyl ketene	674-82-8	C₄H₄O₂	详情	详情
(XIV)	22715	benzhydryl 4-bromo-3-oxobutanoate		C₁₇H₁₅BrO₃	详情	详情
(XV)	22716	benzhydryl 2-amino-1,3-thiazole-4-carboxylate		C₁₇H₁₄N₂O₂S	详情	详情
(XVI)	22717	benzhydryl 2-[[(benzyloxy)carbonyl]amino]-1,3-thiazole-4-carboxylate		C₂₅H₂₀N₂O₄S	详情	详情
(XVII)	22718	benzhydryl formate		C₁₄H₁₂O₂	详情	详情
(XVIII)	22719	benzhydryl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-3-hydroxy-2-propenoate		C₂₇H₂₂N₂O₅S	详情	详情
(XIX)	22668	benzyl 2-(triphenylphosphoranylidene)acetate		C₂₇H₂₃O₂P	详情	详情
(XX)	22721	1-benzhydryl 5-benzyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate		C₃₆H₃₀N₂O₆S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The Wittig condensation of diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4 yl-2-formyl acetate with benzyloxycarbonylmethylene triphenylphosphorane (II) in toluene or dioxane gives 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4 (benzyloxycarbonyl)-2-butenoic acid diphenylmethyl ester (III), which is hydrolyzed partiaily wth trifluoroacetic acid and anisole to the 2-butenoic acid (IV). The condensation of (IV) with 7-beta-amino-3-cephem-4-carboxylic acid benzyl ester (V) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane affords the protected final product (VI), which is finally debenzylated by means of AlCl3 and anisole in methylene chloride.

参考文献中间体

合成目标

【1】 Yoshida, T.; Synthesis and biological properties of 7Beta-[(Z)-2-(2-amino-4-thiazoyl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxilic acid (7432-S), a new oral cephem antibiotic. J Antibiot 1987, 40, 10, 1468.
【2】 Hamashima, Y. (Shionogi & Co. Ltd.); 7-Carboxyalkenoylamido-3-cephem-4-carboxylic acid derivs.. EP 0136721; ES 8604602; ES 8605278; ES 8700222; GB 2154580; GB 2198727; JP 1985078987; JP 1985163884; JP 1985246388; US 4634697; US 4748170 .
【3】 Castaner, J.; Prous, J.; 7432-S. Drugs Fut 1987, 12, 12, 1117.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	24153	benzhydryl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-3-oxopropanoate	C₂₇H₂₂N₂O₅S	详情	详情
(II)	22668	benzyl 2-(triphenylphosphoranylidene)acetate	C₂₇H₂₃O₂P	详情	详情
(III)	22721	1-benzhydryl 5-benzyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate	C₃₆H₃₀N₂O₆S	详情	详情
(IV)	22689	(Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid	C₂₃H₂₀N₂O₆S	详情	详情
(V)	24157	benzyl (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₁₄H₁₄N₂O₃S	详情	详情
(VI)	24158	benzyl (6R,7R)-7-[[(Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₇H₃₂N₄O₈S₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

Saponification of ethyl adamantyloxyacetate (I), followed by treatment of the resultant carboxylic acid (II) with oxalyl chloride gives rise to acid chloride (III). This is then condensed with benzyl (triphenylphosphoranylidene)acetate (IV) to produce the phosphoranylidene keto ester (V). Subsequent oxidative cleavage of phosphorane (V) with oxone under phase transfer conditions leads to diketo ester (VI). Cyclization between diketo ester (VI), cyclohexanecarboxaldehyde (VII) and ammonium acetate in hot AcOH affords imidazole (VIII). The benzyl ester group of (VIII) is removed by catalytic hydrogenolysis, yielding acid (IX), which is further coupled with benzyl 3-aminobenzoate (X) to furnish amide (XI). Finally, benzyl ester hydrogenolysis in the presence of Pd/C provides the target compound (1,2).

参考文献中间体

合成目标

【1】 Gastrin and cholecystokinin receptor ligands. JP 2002529455; US 6479531; WO 0027823 .
【2】 Kalindjian, S.B.; Mesens, J.L.; Black, J.W.; Hull, R.A.D.; Shankley, N.P.; Andries, L.J. (James Black Foundation Ltd.; Janssen Pharmaceutica NV); Pharmaceutical compsns. comprising proton pump inhibitors and gastrin/cholecystokinin receptor ligands. WO 0185167 .

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)	64427	ethyl 2-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)acetate		C₁₄H₂₂O₃	详情	详情
(II)	64428	2-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)acetic acid		C₁₂H₁₈O₃	详情	详情
(III)	64429	2-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)acetyl chloride		C₁₂H₁₇ClO₂	详情	详情
(IV)	22668	benzyl 2-(triphenylphosphoranylidene)acetate		C₂₇H₂₃O₂P	详情	详情
(V)	64430	phenylmethyl 3-oxo-4-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)-2-(triphenyl-lambda~5~-phosphanylidene)butanoate		C₃₉H₃₉O₄P	详情	详情
(VI)	64449	phenylmethyl 2,3-dioxo-4-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)butanoate		C₂₁H₂₄O₅	详情	详情
(VII)	33694	cyclohexanecarbaldehyde	2043-61-0	C₇H₁₂O	详情	详情
(VIII)	64450	phenylmethyl 2-cyclohexyl-5-[(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)methyl]-1H-imidazole-4-carboxylate		C₂₈H₃₆N₂O₃	详情	详情
(IX)	64461	2-cyclohexyl-5-[(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)methyl]-1H-imidazole-4-carboxylic acid		C₂₁H₃₀N₂O₃	详情	详情
(X)	64462	phenylmethyl 3-aminobenzoate		C₁₄H₁₃NO₂	详情	详情
(XI)	64463	phenylmethyl 3-[({2-cyclohexyl-5-[(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)methyl]-1H-imidazol-4-yl}carbonyl)amino]benzoate		C₃₅H₄₁N₃O₄	详情	详情

Extended Information