【结 构 式】 |
【分子编号】42239 【品名】di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate;PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER 【CA登记号】229625-50-7 |
【 分 子 式 】C9H20ClO4P 【 分 子 量 】258.681862 【元素组成】C 41.79% H 7.79% Cl 13.71% O 24.74% P 11.97% |
合成路线1
该中间体在本合成路线中的序号:(IV)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.
【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:(IV)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.
【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:(II)The condensation of BMS-207147 (I) with phosphoric acid di-tert-butyl chloromethyl triester (II) by means of NaH in THF gives the phosphoric triester (III), which is finally hydrolyzed with TFA in dichloromethane and treated with Na2CO3 to provide the target disodium salt.
【1】 Ueda, Y.; Barbour, N.; Bronson, J.J.; et al.; BMS-379224, a water-soluble prodrug of ravuconazole. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-817. |
【2】 Hudyma, T.W.; Golik, J.; Ueda, Y.; Chen, C.-P.; Matiskella, J.D. (Bristol-Myers Squibb Co.); Water soluble prodrugs of azole cpds.. EP 1284737; US 6362172; WO 0152852 . |
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) | 60212 | 4-{2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile | C22H17F2N5OS | 详情 | 详情 | |
(II) | 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 |
(III) | 60217 | {[2-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl]oxy}methyl bis(1,1-dimethylethyl) phosphate | C31H36F2N5O5PS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(XI)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 .
【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 |
合成路线5
该中间体在本合成路线中的序号: (XI)Condensation of compound (XXIX) or its free base with 1-benzoylpiperazine hydrochloride (IX) in the presence of CDI in DMF at 10 °C yields the corresponding carboxamide (XXX), which by Ullmann-Goldberg-Buchwald reaction with 3-methyl-1,2,4-triazole (III) using CuI, t-DAMCH and KOH in acetonitrile/H2O followed by addition of LiBr affords the lithium salt of azaindole (X), isolated as KBr co-crystal (XXXI). Finally, selective N-alkylation of compound (XXXI) with di-tert-butyl chloromethyl phosphate (XI) in the presence of K3PO4 and Et4NI or K2CO3 in acetonitrile/CH2Cl2 results in the phosphate ester (XIV) , which is finally hydrolyzed using AcOH in water .
【1】 Chen, K., Risatti, C., Bultman, M. et al. Synthesis of the 6-azaindole containing HIV-1 attachment inhibitor pro-drug, BMS-663068. J Org Chem 2014, 79(18): 8757-67. |
【2】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038709. |
【3】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038710. |
【4】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038711. |
【5】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038712. |
【6】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038716. |
【7】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038717. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(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 |
(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 |
(IX) | 67606 | 1-benzoylpiperazine;4-Benzoylpiperazine;N-Benzoylpiperazine;(Phenyl)(piperazin-1-yl)methanone | 13754-38-6 | C11H14N2O | 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 | |
(XXIX) | 67622 | 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid hydrobromide | C10H7BrN2O4.HBr | 详情 | 详情 | |
(XXX) | 67623 | 1-(4-benzoylpiperazin-1-yl)-2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione | C21H19BrN4O4 | 详情 | 详情 | |
(XXXI) | 67624 | lithium potassium 3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-ide bromide | C24H22LiN7O4.KBr | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号:(VII)Chlorination of 5-fluorouracil (I) by means of POCl3 gives 2,4-dichloro-5-fluoropyrimidine (II), which is condensed with the pyrido-[3,2-b][1,4]oxazin-3-one derivative (III) to afford the secondary amine (IV). Then, subsequent displacement of the remaining chlorine of pyrimidine (IV) with 3,4,5-trimethoxyaniline (V) yields the substituted pyrimidine-2,4-diamine (VI) . Condensation of pyridooxazinone derivative (VI) with di-tert-butyl chloromethyl phosphate (VII) prepared by chlorination of potassium di-tert-butylphosphate (VIII) with ClSO3CH2Cl by means of Bu4NHSO4 in CH2Cl2/H2O – in the presence of Cs2CO3 in acetone or DMF gives a mixture of three N-substituted regioisomers, which are then subjected to either column chromatography or crystallization on MTBE to provide the major N-substituted oxazinone (IX). Hydrolysis of the t-butyl ester groups of (IX) by means of AcOH in H2O or TFA in CH2Cl2 affords free acid (X) , which is finally treated with aqueous or IPA/H2O NaOH .
Alternatively, condensation of pyridooxazinone (VI) and chloromethyl phosphate (VII) with Cs2CO3 in DMAC at 40 °C affords the N-substituted oxazinone (IX), which is directly hydrolyzed by means of AcOH in H2O, and the phosphoric acid (X) is submitted to purification by crystallization on DMF .
【1】 Singh, R., Atuegbu, A., Ramphal, J. et al. (Rigel Pharmaceuticals, Inc.).Pyrimidinediamine kinase inhibitors. US 2010179134, WO 2010078369. |
【2】 Felfer, U., Giselbrecht, K.-H., Wolberg, M. (Rigel Pharmaceuticals, Inc.). Synthesis of N4-(2,2-dimethyl-4-[dihydrogen phosphonoxy]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine disodium salt. US 2011003986, WO 2011002999. |
【3】 Bhamidipati, S., Singh, R., Sun, T., Masuda, E. (Rigel Pharmaceuticals, Inc.). Prodrug salts of 2,4-pyrimidinediamine compounds and their uses. EP 2078026, JP 2010510322, WO 2008064274. |
【4】 Singh, R., Bhamidipati, S., Masuda, E., Stella, V.J., Sun, T. (Rigel Pharmaceuticals, Inc.). Prodrugs of 2,4-pyrimidinediamine compounds and their uses. CA 2591948, EP 1856135, EP 2161275, JP 2008527048, US 2006211657, US 7449458, WO 2006078846. |
【5】 Singh, R., Bhamidipati, S., Stella, V.J., Sun, T. (Rigel Pharmaceuticals, Inc.). Prodrugs of 2,4-pyrimidinediamine compounds and their uses. US 7563892. |
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) | 29241 | 5-fluoro-2,4(1H,3H)-pyrimidinedione;5-fluorouracil;5-Fluoro-2,4-pyrimidinedione;5-Fluoropyrimidine-2,4-dione | 51-21-8 | C4H3FN2O2 | 详情 | 详情 |
(II) | 45722 | 2,4-dichloro-5-fluoropyrimidine;2,4-Dichloro-5-fluorouracil | C4HCl2FN2 | 详情 | 详情 | |
(III) | 68776 | 6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one | 1002726-62-6 | C9H11N3O2 | 详情 | 详情 |
(IV) | 68777 | 6-((2-chloro-5-fluoropyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one | C13H11ClFN5O2 | 详情 | 详情 | |
(V) | 31545 | 3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine;3,4,5-Trimethoxybenzenamine;[3,4,5-Tris(methyloxy)phenyl]amine | 24313-88-0 | C9H13NO3 | 详情 | 详情 |
(VI) | 68778 | 6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one | C22H23FN6O5 | 详情 | 详情 | |
(VII) | 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 |
(VIII) | 68779 | potassium di-tert-butyl phosphate | C8H18KO4P | 详情 | 详情 | |
(IX) | 68780 | di-tert-butyl ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl) phosphate | C31H42FN6O9P | 详情 | 详情 | |
(X) | 68781 | (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl dihydrogen phosphate | C23H26FN6O9P | 详情 | 详情 |