chloro(iodo)methane -Drug Synthesis Database

【结构式】

【分子编号】42238

【品名】chloro(iodo)methane

【CA登记号】593-71-5

【分子式】CH₂ClI

【分子量】176.38405

【元素组成】C 6.81% H 1.14% Cl 20.1% I 71.95%

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：(A)

Treatment of cinnarizine (I) with phosphate (IV) in acetonitrile in the presence of the proton scavenger 1,2,2,6,6-pentamethylpiperidine affords cinarizinium chloride (II), which is finally treated with TFA in benzene to yield the target trifluoroacetate derivative. Phosphate (IV) can be obtained from phosphite (III) by first treatment with KHCO3 and KMnO4 followed by conversion to tetramethylammonium di-tert-butylphosphate by means of tetramethylammonium hydroxide and final treatment with chloroiodomethane (A) in refluxing dimethoxyethane.

参考文献中间体

合成目标

【1】 Krise, J.P.; et al.; Novel prodrug approach for tertiary amines: Synthesis and preliminary evaluation of N-phosphonooxymethyl prodrugs. J Med Chem 1999, 42, 16, 3094.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	42238	chloro(iodo)methane	593-71-5	CH₂ClI	详情	详情
(I)	42242	1-benzhydryl-4-[(E)-3-phenyl-2-propenyl]piperazine	298-57-7	C₂₆H₂₈N₂	详情	详情
(II)	42243	4-benzhydryl-1-([[di(tert-butoxy)phosphoryl]oxy]methyl)-1-[(E)-3-phenyl-2-propenyl]piperazin-1-ium chloride		C₃₅H₄₈ClN₂O₄P	详情	详情
(III)	42237	di(tert-butyl) phosphonate	13086-84-5	C₈H₁₉O₃P	详情	详情
(IV)	42239	di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate；PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER	229625-50-7	C₉H₂₀ClO₄P	详情	详情

合成路线2

该中间体在本合成路线中的序号：(A)

Loxapine (I) is treated with phosphate (IV) in acetonitrile in the presence of the proton scavenger 1,2,2,6,6-pentamethylpiperidine to afford loxapinium chloride (II), which is finally treated with TFA in benzene to yield the target trifluoroacetate derivative. Phosphate (IV) can be obtained from phosphite (III) by treatment with KHCO3 and KMnO4 followed by conversion to tetramethylammonium di-tert-butylphosphate by means of tetramethylammonium hydroxide and final treatment with chloroiodomethane (A) in refluxing dimethoxyethane.

参考文献中间体

合成目标

【1】 Krise, J.P.; et al.; Novel prodrug approach for tertiary amines: Synthesis and preliminary evaluation of N-phosphonooxymethyl prodrugs. J Med Chem 1999, 42, 16, 3094.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	42238	chloro(iodo)methane	593-71-5	CH₂ClI	详情	详情
(I)	42240	11-(4-methyl-1-piperazinyl)dibenzo[b,f][1,4]oxazepine		C₁₈H₁₉N₃O	详情	详情
(II)	42241	4-dibenzo[b,f][1,4]oxazepin-11-yl-1-([[di(tert-butoxy)phosphoryl]oxy]methyl)-1-methylpiperazin-1-ium chloride		C₂₇H₃₉ClN₃O₅P	详情	详情
(III)	42237	di(tert-butyl) phosphonate	13086-84-5	C₈H₁₉O₃P	详情	详情
(IV)	42239	di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate；PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER	229625-50-7	C₉H₂₀ClO₄P	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

Cyclocondensation of formic hydrazide (I) with thioacetamide (II) at 150 °C gives 3-methyl-1,2,4-triazole (III), which by condensation with 7-chloro-4-methoxy-pyrrolo[2,3-c]pyridine (IV) in the presence of CuI and K2CO3 at 173 °C provides 4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine (V). Friedel-Crafts acylation of compound (V) with methyl chloro(oxo)acetate (VI) using AlCl3 in CH2Cl2/MeNO2 affords the keto ester (VII), which is hydrolyzed using NaOH in MeOH to yield the carboxylic acid (VIII). Condensation of acid (VIII) with 1-benzoylpiperazine (IX) by means of EDC and Et3N in DMF gives piperazinamide (X). Treatment of intermediate (X) with NaH and I2 in THF followed by N-alkylation of di-tert-butyl chloromethyl phosphate (XI) (obtained by the chloromethylation of the tetrabutylammonium salt of di-tert-butyl hydrogen phosphate (XII) with chloroiodomethane (XIII) optionally in benzene) in acetone/H2O, or the direct condensation of intermediate (X) with chloromethyl phosphate (XI) in the presence of CsCO3 and KI in NMP affords the di-tert-butyl phosphate ester (XIV). Finally, O-deprotection of intermediate (XIV) is performed by treatment with TFA in CH2Cl2, or by heating in acetone/H2O at 40 °C .

参考文献中间体

合成目标

【1】 Ueda, Y., Connolly, T.P., Kadow, J.F. et al. (Bristol-Myers Squibb Co.). Prodrugs of piperazine and substituted piperidine antiviral agents. CN 101941990; US 7745625; EP 1725569; JP 2007529519; US 2005209246; WO 2005090367.

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)	15486	formic hydrazide; Formylhydrazine	624-84-0	CH₄N₂O	详情	详情
(II)	19170	ethanethioamide	62-55-5	C₂H₅NS	详情	详情
(III)	67601	3-methyl-1,2,4-triazole；3-Methyltriazole；3-Methyl-1H-1,2,4-triazole；3-Methyl-4H-1,2,4-triazole	7170-01-6	C₃H₅N₃	详情	详情
(IV)	67602	7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridine		C₈H₇ClN₂O	详情	详情
(V)	67603	4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine		C₁₁H₁₁N₅O	详情	详情
(VI)	26971	2-methoxy-2-oxoacetyl chloride	5781-53-3	C₃H₃ClO₃	详情	详情
(VII)	67604	methyl 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate		C₁₄H₁₃N₅O₄	详情	详情
(VIII)	67605	2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid		C₁₃H₁₁N₅O₄	详情	详情
(IX)	67606	1-benzoylpiperazine;4-Benzoylpiperazine;N-Benzoylpiperazine;(Phenyl)(piperazin-1-yl)methanone	13754-38-6	C₁₁H₁₄N₂O	详情	详情
(X)	67607	1-(4-benzoylpiperazin-1-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione		C₂₄H₂₃N₇O₄	详情	详情
(XI)	42239	di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate；PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER	229625-50-7	C₉H₂₀ClO₄P	详情	详情
(XII)	67608	tetra-tert-butylammonium di-tert-butyl phosphate		C₈H₁₈O₄P.C₁₆H₃₆N	详情	详情
(XIII)	42238	chloro(iodo)methane	593-71-5	CH₂ClI	详情	详情
(XIV)	67609	(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl di-tert-butyl phosphate		C₃₃H₄₂N₇O₈P	详情	详情

Extended Information