cyclopropanecarbaldehyde -Drug Synthesis Database

【结构式】

【分子编号】26463

【品名】cyclopropanecarbaldehyde

【CA登记号】1489-69-6

【分子式】C₄H₆O

【分子量】70.09104

【元素组成】C 68.55% H 8.63% O 22.83%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Taxane intermediates (XIII) and (XIV) were prepared by two related ways. Wittig condensation of cyclopropanecarboxaldehyde (I) with methoxycarbonylmethylenetriphenyl phosphorane (II) gave methyl trans-cyclopropylacrylate (III). This was oxidized with potassium ferricyanide in the presence of OsO4 and the chiral catalyst 1,4-bis(9-O-dihydroquinidyl)phthalazine to furnish (2S,3R)-diol (IV). After conversion of (IV) to tosylate (V), its cyclization by means of K2CO3 produced epoxide (VI). Subsequent epoxide opening with NaN3 gave azide (VII), which was hydrogenated in the presence of Pd/C and di tert-butyl dicarbonate to furnish carbamate (VIII). Treatment of (VIII) with isopropenyl methyl ether (IX) and pyridinium tosylate, followed by ester hydrolysis, produced oxazolidine (X). This was coupled to protected taxane (XI) by means of DCC and DMAP to provide ester (XII). Oxazolidine hydrolysis in (XII) with formic acid, followed by reprotection of the amine with Boc2O, furnished intermediate (XIII). Optionally, the trichloroethoxycarbonyl groups of (XIII) were removed upon treatment with Zn and AcOH to produce intermediate (XIV).

参考文献中间体

合成目标

【1】 Tsujihari, K.; Hashiyama, T.; Ohashi, M.; Nakanishi, N. (Tanabe Seiyaku Co., Ltd.); Baccatin derivs. and processes for preparing the same. CA 2162759; EP 0712854; JP 1997151181; US 5589502 .

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)	26463	cyclopropanecarbaldehyde	1489-69-6	C₄H₆O	详情	详情
(II)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(III)	26464	methyl (E)-3-cyclopropyl-2-propenoate		C₇H₁₀O₂	详情	详情
(IV)	26465	methyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropanoate		C₇H₁₂O₄	详情	详情
(V)	26466	methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-[[(4-methylphenyl)sulfonyl]oxy]propanoate		C₁₄H₁₈O₆S	详情	详情
(VI)	26467	methyl (2R,3R)-3-cyclopropyl-2-oxiranecarboxylate		C₇H₁₀O₃	详情	详情
(VII)	26468	methyl (2R,3S)-3-azido-3-cyclopropyl-2-hydroxypropanoate		C₇H₁₁N₃O₃	详情	详情
(VIII)	26469	methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoate		C₁₂H₂₁NO₅	详情	详情
(IX)	26470	3-methoxy-1-butene		C₅H₁₀O	详情	详情
(X)	26471	(4S,5R)-3-(tert-butoxycarbonyl)-4-cyclopropyl-2,2-dimethyl-1,3-oxazolidine-5-carboxylic acid		C₁₄H₂₃NO₅	详情	详情
(XI)	23892	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₃₅H₃₈Cl₆O₁₄	详情	详情
(XII)	26472	methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate		C₄₉H₅₉Cl₆NO₁₈	详情	详情
(XIII)	26473	methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate		C₄₆H₅₅Cl₆NO₁₈	详情	详情
(XIV)	26474	methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate		C₄₀H₅₃NO₁₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

Coupling of this imidazolide (VII) with the lithium salt of (S)-4-methyloxazolidine-2-one (VIII) at low temperature, followed by acid hydrolysis of the acetate ester furnished carbamate (IX). Mono-N-demethylation of (IX) to give secondary amine (X) was achieved by photochemical reaction with iodine and NaOAc. Finally, reductive alkylation with cyclopropanecarboxaldehyde (XI) in the presence of NaBH3CN produced the title cyclopropylmethylamino derivative.

参考文献中间体

合成目标

【1】 Waid, P.; Dalton, C.R.; Randolph, J.T.; Greer, J.; Nichols, C.J.; Haviv, F.; Mort, N.A.; Sauer, D.R. (Abbott Laboratories Inc.); Macrolide LHRH antagonists. WO 0012522 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	38159	(3aS,4R,7R,8S,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-1-(4-chlorophenethyl)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl 1H-imidazole-1-carboxylate		C₄₅H₆₅ClN₄O₁₂	详情	详情
(VIII)	38160	(4S)-4-methyl-1,3-oxazolidin-2-one		C₄H₇NO₂	详情	详情
(IX)	38161			C₄₄H₆₆ClN₃O₁₃	详情	详情
(X)	38162			C₄₃H₆₄ClN₃O₁₃	详情	详情
(XI)	26463	cyclopropanecarbaldehyde	1489-69-6	C₄H₆O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

Treatment of (VII) with iodine and sodium acetate under irradiation of a halogen lamp produced N-demethylation to furnish (VIII). Further demethylation of (VIII) to give (IX) was achieved by a similar treatment with iodine and tripotassium phosphate. Finally, reductive condensation of (IX) with cyclopropanecarbaldehyde (X) in the presence of sodium cyanoborohydride yielded the bis(cyclopropylmethyl) derivative.

参考文献中间体

合成目标

【1】 Randolph, J.; Haviv, F.; Bruncko, M.; Crawford, B.W.; Dalton, C.R.; Frey, L.M.; Kaminski, M.A.; Greer, J.; Sauer, D.R.; Mort, N.A. (Abbott Laboratories Inc.); 3',3'-N-Bis-substd. macrolide LHRH antagonists. US 5972898; WO 9950276 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	33114	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione		C₄₇H₇₄ClFN₂O₁₃	详情	详情
(VIII)	33115	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-10-[[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-10-[[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione		C₄₆H₇₂ClFN₂O₁₃	详情	详情
(IX)	33116	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-4-amino-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-1-(3-chloro-4-fluorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-4-amino-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-1-(3-chloro-4-fluorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione		C₄₅H₇₀ClFN₂O₁₃	详情	详情
(X)	26463	cyclopropanecarbaldehyde	1489-69-6	C₄H₆O	详情	详情

Extended Information