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【结 构 式】 
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【分子编号】16166 【品名】chloromethyl pivalate 【CA登记号】18997-19-8 |
【 分 子 式 】C6H11ClO2 【 分 子 量 】150.60484 【元素组成】C 47.85% H 7.36% Cl 23.54% O 21.25% |
合成路线1
该中间体在本合成路线中的序号：(II)The title butyric acid prodrug was prepared by condensation of butyric acid (I) with chloromethyl pivalate (II) in the presence of Et3N in acetone.
| 【1】 Nudelman, A.; Shaklai, M.; Rephaeli, A. (Bar-Ilan University); Biologically active carboxylic acid esters. EP 0302349; JP 1998152436; JP 1998152454 . |
| 【2】 Nudelman, A.; et al.; Novel anticancer prodrugs of butyric acid. 2. J Med Chem 1992, 35, 4, 687. |
合成路线2
该中间体在本合成路线中的序号：(V)Adefovir dipivoxil can be obtained by two similar ways: 1) The reaction of adenine (I) with 2-(diisopropoxyphosphorylmethoxy)ethyl methanesulfonate (II) by means of cesium carbonate in DMF gives the expected condensation product (III), which is converted into the phosphonic acid (IV) by treatment with trimethylsilyl bromide in acetonitrile (1). Finally, this compound is condensed with chloromethyl pivalate (V) by means of N,N'-dicyclohexylmorpholine-4-carboxamidine in DMF. 2) The final condensation of the phosphonic acid (IV) can also be performed with iodomethyl pivalate (VI) in pyridine.
| 【1】 Benzaria, S.; Pélicano, H.; Johnson, R.; Maury, G.; Imbach, J.-L.; Aubertin, A.-M.; Obert, G.; Gosselin, G.; Synthesis, in vitro antiviral evaluation, and stability studies of bis(S-acyl-2-thioethyl) ester derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as potential PMEA prodrugs with improved oral bioavailability. J Med Chem 1996, 39, 25, 4958-65. |
| 【2】 Prous, J.; Graul, A.; Castaner, J.; Adefovir Dipivoxil. Drugs Fut 1997, 22, 8, 825. |
| 【3】 Starrett, J.E. Jr.; Mansuri, M.M.; Martin, J.C.; Tortolani, D.R.; Bronson, J.J. (Bristol-Myers Squibb Co.); Prodrug of phosphonates. EP 0481214; JP 1992230694 . |
| 【4】 Starrett, J.E. Jr.; Tortolani, D.R.; Russell, J.; Hitchcock, M.J.M.; Whiterock, V.; Martin, J.C.; Mansuri, M.M.; Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). J Med Chem 1994, 37, 12, 1857-64. |
| 【5】 Starrett, J.E. Jr.; et al.; Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine. Antivir Res 1992, 19, 3, 267-73. |
| 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) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (II) | 16163 | 2-[(diisopropoxyphosphoryl)methoxy]ethyl methanesulfonate | C10H23O7PS | 详情 | 详情 | |
| (III) | 16164 | diisopropyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C14H24N5O4P | 详情 | 详情 | |
| (IV) | 16165 | [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid | C8H12N5O4P | 详情 | 详情 | |
| (V) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |
| (VI) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)An optimized process for large-scale production of adefovir dipivoxil has been reported: The reaction of adenine (I) with 1,3-dioxolan-2-one (II) by means of NaOH in hot DMF gives 9-(2-hydroxyethyl)adenine (III), which is condensed with diethyl p-toluenesulfonyloxymethylphosphonate (IV) by means of sodium tert-butoxide, (instead of NaH, originally used) in DMF yielding 9-[2-(diethylphosphonomethoxy)ethyl]adenine (V). The hydrolysis of intermediate (V) by means of TMS-Br in hot acetonitrile affords the phosphonic acid (VI), which is finally condensed with chloromethyl pivalate (VII) by means of triethylamine in hot N-methylpyrrolidine.
| 【1】 Dudzinski, P.W.; Kelly, D.E.; Yu, R.H.; Rohloff, J.C.; Schultze, L.M.; Process optimization in the synthesis of 9-[2-(diethylphosphonomethoxy)ethyl]adenine: Replacement of sodium hydride with sodium tert-butoxide as the base for oxygen alkylation. Org Process Res Dev 1999, 3, 1, 53. |
| 【2】 Kelly, D.E.; Lee, T.T.K.; Prisbe, E.J.; Schultze, L.M.; Arimilli, M.N.; Manes, L.V.; Munger, J.D. Jr. (Gilead Sciences Inc.); Nucleotide analog compsns.. WO 9904774 . |
| 【3】 Dahl, T.C.; Yuan, L.-C.J. (Gilead Sciences Inc.); Pharmaceutical formulations. WO 0035460 . |
| 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) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (II) | 32802 | 1,3-dioxolan-2-one | 96-49-1 | C3H4O3 | 详情 | 详情 |
| (III) | 39672 | 2-(6-amino-9H-purin-9-yl)-1-ethanol | C7H9N5O | 详情 | 详情 | |
| (IV) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (V) | 39673 | diethyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C12H20N5O4P | 详情 | 详情 | |
| (VI) | 16165 | [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid | C8H12N5O4P | 详情 | 详情 | |
| (VII) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：Cyclization of N-acetyl dimethylanthranilic acid (I) with acetic anhydride produced benzoxazinone (II) which, upon treatment with aqueous ammonia, furnished trimethylquinazolinone (III). Incorporation of the N-(pivaloyloxy)methyl (POM) protecting group of (III) gave (IV), and subsequent regioselective bromination with N-bromosuccinimide in the presence of AIBN yielded the 6-bromomethyl compound (V). Condensation of (V) with p-aminobenzoate derivative (VI) afforded tertiary amine (VII). After trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (VII), coupling with pentafluorophenol in the presence of DCC provided pentafluorophenyl ester (VIII). The title compound was then obtained by condensation of (VIII) with the tetrazolyl aminoester (IX) in the presence of 1-hydroxybenzotriazole, followed by basic hydrolysis of both methyl ester and POM protecting group.
| 【1】 Marsham, P.R.; et al.; Quinazoline antifolate thymidylate synthase inhibitors: replacement of glutamic acid in the C2-methyl series. J Med Chem 1995, 38, 6, 994-1004. |
| 【2】 Jackman, A.L.; Kimbell, R.; Marsham, P.R.; Boyle, F.T.; Wardleworth, M.; Brown, M.; Hennequin, L.F.; Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors. J Med Chem 1999, 42, 19, 3809. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 | |
| (I) | 27958 | 2-(acetamido)-4,5-dimethylbenzoic acid | C11H13NO3 | 详情 | 详情 | |
| (II) | 27959 | 2,6,7-trimethyl-4H-3,1-benzoxazin-4-one | C11H11NO2 | 详情 | 详情 | |
| (III) | 27960 | 2,6,7-trimethyl-4(3H)-quinazolinone | C11H12N2O | 详情 | 详情 | |
| (IV) | 27961 | [2,6,7-trimethyl-4-oxo-3(4H)-quinazolinyl]methyl pivalate | C17H22N2O3 | 详情 | 详情 | |
| (V) | 27962 | [6-(bromomethyl)-2,7-dimethyl-4-oxo-3(4H)-quinazolinyl]methyl pivalate | C17H21BrN2O3 | 详情 | 详情 | |
| (VI) | 27963 | tert-butyl 2-fluoro-4-(2-propynylamino)benzoate | C14H16FNO2 | 详情 | 详情 | |
| (VII) | 27964 | tert-butyl 4-[[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2,7-dimethyl-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]-2-fluorobenzoate | C31H36FN3O5 | 详情 | 详情 | |
| (VIII) | 27965 | 2,3,4,5,6-pentafluorophenyl 4-[[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2,7-dimethyl-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]-2-fluorobenzoate | C33H27F6N3O5 | 详情 | 详情 | |
| (IX) | 27966 | methyl (2S)-2-amino-4-(1H-1,2,3,4-tetraazol-5-yl)butanoate | C6H11N5O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(A)The reaction of indan-5-amine (I) with acetic anhydride gives the acetamide (II), which is brominated with Br2 in acetic acid yielding the 6-bromo derivative (III). The reaction of (III) with CuCN in 1-methyl-2-pyrrolidone at 125 C affords the corresponding nitrile (IV), which is cyclized by means of H2O2 and NaOH in hot ethanol/water giving the tricyclic ketone (V). The reaction of (V) with chloromethyl pivalate (A) and potassium tert-butoxide in DMSO yields the pivaloyloxymethyl derivative (VI), which is oxidized with CrO3 and tert-butyl peroxide in dichloromethane affording the diketone (VII) (after chromatographic separation of the undesired regioisomer). The condensation of (VII) with N-(4-aminobenzoyl)-Lglutamic acid diethyl ester (VIII) by means of TsOH in refluxing DME gives the imino derivative (IX), which without isolation, is reduced to the secondary amine (X) (as a diastereomeric mixture) with NaBH3CN in methanol/acetic acid. The alkylation of the secondary amine group of (X) with propargyl bromide (XI) and CaCO3 in hot DMA yields the tertiary amine (XII), which is hydrolyzed and deprotected with first with NaOH in methanol/water, and then with aqueous HCl to provide the target compound as a diastereomeric mixture. Finally, this compound is resolved by a treatment with carboxypeptidase G2 and ZnCl2 in water that hydrolyzes selectively the undesired isomer.
| 【1】 Bavetsias, V.; Matusiak, Z.; Melin, C.; Neidle, S.; Marriott, J.H.; Boyle, F.T.; Jackman, A.L.; Chemoenzymatic preparation of the novel antifolate thymidylate synthase inhibitor N-(4-{N-[(6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}-benzoyl)-L-glutamic acid and its glutamyl cleavage product. J Chem Soc - Perkins Trans I 1999, 11, 1495. |
| 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) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |
| (I) | 21473 | 5-indanamine; 2,3-dihydro-1H-inden-5-ylamine | 24425-40-9 | C9H11N | 详情 | 详情 |
| (II) | 21474 | N-(2,3-dihydro-1H-inden-5-yl)acetamide | C11H13NO | 详情 | 详情 | |
| (III) | 31073 | N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide | C11H12BrNO | 详情 | 详情 | |
| (IV) | 31074 | N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide | C12H12N2O | 详情 | 详情 | |
| (V) | 31075 | 2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one | C12H12N2O | 详情 | 详情 | |
| (VI) | 31076 | (2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate | C18H22N2O3 | 详情 | 详情 | |
| (VII) | 31077 | (2-methyl-4,6-dioxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate | C18H20N2O4 | 详情 | 详情 | |
| (VIII) | 31078 | diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate | 13726-52-8 | C16H22N2O5 | 详情 | 详情 |
| (IX) | 31079 | diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-ylidene)amino]benzoyl]amino)pentanedioate | C34H40N4O8 | 详情 | 详情 | |
| (X) | 31080 | diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate | C34H42N4O8 | 详情 | 详情 | |
| (XI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (XII) | 31081 | diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate | C37H44N4O8 | 详情 | 详情 | |
| (XIII) | 31082 | (2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid | C27H26N4O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIXb)Condensation of (phosphoryloxy)carbapenem (XVI) with 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (XI) gave thioether (XVII). The p-nitrobenzyl ester group of (XVII) was then deprotected with Zn powder to afford carboxylic acid. Finally, treatment of (XVIII) with either iodo or chloromethyl pivalate (XIX) produced the target compound.
| 【1】 Satoh, C.; Mihira, A.; Yamamoto, S.; Hayashi, K.; Kitamura, M.; Tamai, S.; Abe, T.; Kumagai, T.; Hikida, M.; L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-64. |
| 【2】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 . |
| 【3】 Abe, T.; Kumagai, T. (Lederle (Japan), Ltd.); Carbapenem-3-carboxylic acid ester derivs.. EP 0808315; JP 1999504039; US 5886172; WO 9721712 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIXa) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 | |
| (XIXb) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |
| (XI) | 31404 | 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol | 179337-57-6 | C6H10N2S2 | 详情 | 详情 |
| (XVI) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (XVII) | 31408 | 4-nitrobenzyl (4R,5S,6S)-3-[[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C23H26N4O6S2 | 详情 | 详情 | |
| (XVIII) | 31409 | (4R,5S,6S)-3-[[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid | C16H21N3O4S2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XI)The silylated ethyl glycolate (I) is transformed into the cyclopropyl alcohol (II) by using the Kulinkovich reaction in the presence of ethylmagnesium bromide and titanium isopropoxide. Alcohol (II) is then condensed with diisopropyl (bromomethyl)phosphonate (III) to produce the alkoxymethyl phosphonate (IV). After desilylation of (IV) with ammonium fluoride, the free alcohol (V) is treated with methanesulfonyl chloride and triethylamine to provide mesylate (VI). Condensation of (VI) with 2-amino-6-chloropurine (VII) leads to the 9-substituted purine (VIII) as the major reaction product. Removal of the 6-chloro group of (VIII) by catalytic hydrogenolysis furnishes purine (IX). The phosphonate ester of (IX) is hydrolyzed to phosphonic acid (X) employing bromotrimethylsilane. Finally, condensation of (X) with chloromethyl pivalate (XI) in the presence of either N,N'-dicyclohexyl-4-morpholine-carboxamidine (DCMC) or triethylamine gives rise to the title compound
| 【1】 Hwang, J.-T.; Choi, J.-R.; Novel phosphonate nucleosides as antiviral agents. Drugs Fut 2004, 29, 2, 163. |
| 【2】 Choi, J.; Hwang, J.; Cho, D.G.; et al.; Synthesis and determination of oral bioavailability of prodrugs of a novel phosphonate nucleotide, LB80317. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1689. |
| 【3】 Pavie, J.; Lefort, A.; Zarrouk, V.; Chau, F.; Garry, L.; Leclercq, R.; Fantin, B.; Efficacies of quinupristin-dalfopristin combined with vancomycin in vitro and in experimental endocarditis due to methicillin-resistant Staphylococcus aureus in relation to cross-resistance to macrolides, lincosamides, and streptogramin B- type antibiotic. Antimicrob Agents Chemother 2002, 46, 9, 3061. |
| 【4】 Lee, C.-H.; Kim, Y.-Z.; Kim, J.-H.; Choi, T.-S.; Kim, C.-M.; Kim, J.-M.; Choi, J.-R.; Roh, K.-Y.; Cho, D.-G.; Hwang, J.-T.; Cho, W.-Y.; Jang, H.-S.; Kim, T.-K.; Cho, S.-J.; Kim, G.-W. (LG Chem Ltd.); Novel acyclic nucleoside phosphonate derivs., salts thereof and process for the preparation of the same. WO 0257288 . |
| 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) | 60566 | ethyl 2-{[tert-butyl(diphenyl)silyl]oxy}acetate | C20H26O3Si | 详情 | 详情 | |
| (II) | 60567 | 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol | C20H26O2Si | 详情 | 详情 | |
| (III) | 60568 | diisopropyl bromomethylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (IV) | 60569 | diisopropyl {[1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]oxy}methylphosphonate | C27H41O5PSi | 详情 | 详情 | |
| (V) | 60570 | diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate | C11H23O5P | 详情 | 详情 | |
| (VI) | 60571 | {1-[(diisopropoxyphosphoryl)methoxy]cyclopropyl}methyl methanesulfonate | C12H25O7PS | 详情 | 详情 | |
| (VII) | 60572 | 4-chloro-1H-benzimidazol-6-amine; 4-chloro-1H-benzimidazol-6-ylamine | C7H6ClN3 | 详情 | 详情 | |
| (VIII) | 60573 | diisopropyl ({1-[(6-amino-4-chloro-1H-benzimidazol-1-yl)methyl]cyclopropyl}oxy)methylphosphonate | C18H27ClN3O4P | 详情 | 详情 | |
| (IX) | 60574 | diisopropyl ({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate | C16H26N5O4P | 详情 | 详情 | |
| (X) | 60575 | ({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid | C10H14N5O4P | 详情 | 详情 | |
| (XI) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |