ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】38069

【品名】ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate

【CA登记号】

【分子式】C₈H₁₄O₄

【分子量】174.19676

【元素组成】C 55.16% H 8.1% O 36.74%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

The condensation of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of NaOEt in ethanol gives (3aS,4aR)-3-oxo-3,3a,4,4a-tetrahydro-1H-cyclopropa[c]furan-3a-carboxylic acid ethyl ester (III), which is selectively reduced at the lactone group by means of sodium borohydride in ethanol to yield (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The protection of (IV) with 2,2-dimethoxypropane (V) and Ts-OH in DMF affords the cyclic acetonide (VI), which is reduced with LiBH4 in THF to provide the hydroxymethyl acetonide (VII). The protection of the OH group of (VII) with benzyl bromide and NaH in DMF gives the benzyl ether (VIII), which is treated with HCl in THF/water to cleave the acetonide ring and yield the bis hydroxymethyl compound (IX). The acylation of (IX) with benzoyl chloride and pyridine affords the dibenzoate (X), which is debenzylated with H2 over Pd/C in ethanol/acetic acid to provide (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropanemethanol (XI). The reaction of (XI) with Ts-OH and DMAP in dichloromethane gives the corresponding tosylate (XII), which is condensed with 6-O-benzylguanine (XIII) by means of K2CO3 in DMF to yield the fully protected nucleoside (XIV). The hydrolysis of the benzoyl group of (XIV) by means of NaOMe in methanol affords the dihydroxy compound (XV), which is finally debenzylated by means of HCl in ethanol/water to provide the target guanine cyclopropyl nucleoside.

参考文献中间体

合成目标

【1】 Sekiyama, T.; et al.; Synthesis and antiviral activity of novel acyclic nucleosides: Discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses. J Med Chem 1998, 41, 8, 1284.
【2】 Hatsuya, S.; Sekiyama, T.; Tsuji, T.; Iwayama, S.; Okunishi, M. (Ajinomoto Co., Inc.); Cyclopropane deriv.. EP 0502690; JP 1993194421; US 5342840; US 5449840 .

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)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(II)	38067	(2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin	51594-55-9	C₃H₅ClO	详情	详情
(III)	38068	ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate		C₈H₁₀O₄	详情	详情
(IV)	38069	ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate		C₈H₁₄O₄	详情	详情
(V)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(VI)	53924	ethyl (1R,7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate		C₁₁H₁₈O₄	详情	详情
(VII)	53925	[(7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methanol		C₉H₁₆O₃	详情	详情
(VIII)	53926	benzyl [(7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methyl ether; (1S,7R)-1-[(benzyloxy)methyl]-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]octane		C₁₆H₂₂O₃	详情	详情
(IX)	53927	[(1R,2R)-2-[(benzyloxy)methyl]-2-(hydroxymethyl)cyclopropyl]methanol		C₁₃H₁₈O₃	详情	详情
(X)	53928	{(1R,2S)-2-[(benzoyloxy)methyl]-2-[(benzyloxy)methyl]cyclopropyl}methyl benzoate		C₂₇H₂₆O₅	详情	详情
(XI)	53929	[(1R,2S)-2-[(benzoyloxy)methyl]-2-(hydroxymethyl)cyclopropyl]methyl benzoate		C₂₀H₂₀O₅	详情	详情
(XII)	53930	[(1R,2R)-2-[(benzoyloxy)methyl]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl benzoate		C₂₇H₂₆O₇S	详情	详情
(XIII)	14383	6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine	19916-73-5	C₁₂H₁₁N₅O	详情	详情
(XIV)	53931	{(1R,2S)-2-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-2-[(benzoyloxy)methyl]cyclopropyl}methyl benzoate		C₃₂H₂₉N₅O₅	详情	详情
(XV)	53932	[(1S,2R)-1-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-2-(hydroxymethyl)cyclopropyl]methanol	n/a	C₁₈H₂₁N₅O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The reaction of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of sodium ethoxide in refluxing ethanol gives the 3-oxa-2-oxobicyclic compound (III), which by reduction with NaBH4 in ethanol yields (1S,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The reaction of (IV) with diphenyldiazomethane by means of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in dichloroethane affords (1R,7R)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylic acid ethyl ester (V), which is reduced with LiBH4 in THF giving the carbinol (VI). The reaction of (VI) with CBr4 and triphenylphosphine in dichloromethane yields the bromomethyl derivative (VII), which is condensed with 5-(2-(E)-bromovinyluracil (VIII) by means of K2CO3 and 18-crown-6 in hot DMF affording the expected addition compound (IX). Finally, this compound is deprotected with HCl in methanol.

参考文献中间体

合成目标

【1】 Onishi, T.; Mukai, C.; Sekiyama, T.; Tsuji, T.; Iwayama, S.; Okunishi, M. (Ajinomoto Co., Inc.); Bis(hydroxymethyl)cyclopropylmethyl pyrimidine derivs.,their preparation and their use as anti-viral agents. EP 0649840; JP 1995165731; US 5496824 .
【2】 Onishi, T.; Mukai, C.; Nakagawa, R.; et al.; Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety. J Med Chem 2000, 43, 2, 278.

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)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(II)	38067	(2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin	51594-55-9	C₃H₅ClO	详情	详情
(III)	38068	ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate		C₈H₁₀O₄	详情	详情
(IV)	38069	ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate		C₈H₁₄O₄	详情	详情
(V)	38070	ethyl (1R,7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate		C₂₁H₂₂O₄	详情	详情
(VI)	38071	[(7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methanol		C₁₉H₂₀O₃	详情	详情
(VII)	38072	(1R,7S)-1-(bromomethyl)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane		C₁₉H₁₉BrO₂	详情	详情
(VIII)	38073	5-[(E)-2-bromoethenyl]-2,4(1H,3H)-pyrimidinedione	69304-49-0	C₆H₅BrN₂O₂	详情	详情
(IX)	38074	5-[(E)-2-bromoethenyl]-1-[[(7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methyl]-2,4(1H,3H)-pyrimidinedione		C₂₅H₂₃BrN₂O₄	详情	详情

Extended Information