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【结 构 式】 
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【药物名称】PF-06460031;GMI-1070 【化学名称】(1R,2R,3S,5R)-2-(6-Deoxy-α-L-galactopyranosyloxy)-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylcarboxamido)-5-[N-[2-[2-[2-oxo-2-(3,6,8-trisulfonaphthalen-1-ylamino)ethoxy]ethoxy]acetamido]ethyl]carbamoyl]cyclohexyl 3-O-[1(S)-carboxy-2-cyclohexylethyl]-2-O-(phenylcarbonyl)-β-D-galactopyranoside;8-[13-[5(R)-[2-O-Benzoyl-3-O-[1(S)-carboxy-2-cyclohexylethoxy]-β-D-galactopyranosyloxy]-4(R)-(6-deoxy-α-L-galactopyranosyloxy)-3(S)-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylcarboxamido)cyclohexyl]-8,13-dioxo-3,6-dioxa-9,12-diaza-1(R)-tridecanamido]naphthalene-1,3,6-trisulfonic acid 【CA登记号】 【 分 子 式 】C58H74N6O31S3 【 分 子 量 】1447.425 |
【开发单位】GlycoMimetics, Inc. (US); licensed to Pfizer, Inc. (US) 【药理作用】Pan-Selectin Antagonist；Treatment of Sickle Cell Disease |
合成路线1
GMI-1070 is prepared by condensation of 8-amino-1,3,6-naphthalenetrisulfonic acid (I) with ethylene bis(glycolic acid) (II) by means of HATU and DIEA in DMF to afford the mono amide (III), which is finally coupled with the primary amine (IV) [prepared by condensation of methyl ester (V) with ethylenediamine (VI) at 70°C] by means of HATU and DIEA in DMF .
| 【1】 Magnani, J.L., Patton, J.T. Jr., Sarkar, A.K., Svarovsky, S.A., Ernst, B. (GlycoMimetics, Inc.). Heterobifunctional pan-selectin inhibitors. EP 1934236, EP 2264043, JP 2009507031, US 2007054870, US 7728117, WO 2007028050. |
| 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) | 68483 | 8-amino-1,3,6-naphthalenetrisulfonic acid；1-Aminonaphthalene-3,6,8-trisulfonic acid | 117-42-0 | C10H9NO9S3 | 详情 | 详情 |
| (II) | 68484 | 2,2'-(ethane-1,2-diylbis(oxy))diacetic acid;2,2'-[1,2-ethanediylbis(oxy)]bis-Acetic acid;(Ethylenedioxy)diacetic acid;1,2-Bis(carboxymethoxy)ethane;2,5-Dioxa-1,6-hexanedicarboxylic acid;3,6-Dioxaoctane-1,8-dioic acid;3,6-Dioxaoctanedioic acid;Ethylenebis(glycolic acid);[2-(Carboxymethoxy)ethoxy]acetic acid | 23243-68-7 | C6H10O6 | 详情 | 详情 |
| (III) | 68485 | 2-(2-(2-oxo-2-((3,6,8-trisulfonaphthalen-1-yl)amino)ethoxy)ethoxy)acetic acid | C16H17NO14S3 | 详情 | 详情 | |
| (IV) | 68487 | C42H59N5O18 | 详情 | 详情 | ||
| (V) | 68486 | (2R)-2-(((2S,3S,4R,5R,6S)-2-(((1S,3R,5S)-5-((2-aminoethyl)carbamoyl)-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-2-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-3-(benzoyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)oxy)-3-cyclohexylpropanoic acid | C41H55N3O19 | 详情 | 详情 | |
| (VI) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
合成路线2
Intermediate (V) is prepared by treatment of ethyl β-D-thiogalactopyranoside (VII) with Bu2SnO in MeOH, followed by regioselective alkylation with triflate (VIII) in the presence of CsF in DME to afford ether (IX), which by subsequent esterification with benzoyl chloride (X) by means of pyridine and DMAP gives tribenzoate (XI). Coupling of thioglycoside (XI) with the acceptor alcohol (XII) in the presence of DMTST in CH2Cl2 yields adduct (XIII), which is then subjected to reductive acylation with orotic acid chloride (XIV) by means of PPh3 in CH2Cl2 to provide amide (XV). Finally, compound (XV) is debenzylated by hydrogenolysis with H2 over Pd/C in dioxane/H2O, followed by selective didebenzoylation by means of NaOMe in MeOH .
| 【1】 Magnani, J.L., Patton, J.T. Jr., Sarkar, A.K., Svarovsky, S.A., Ernst, B. (GlycoMimetics, Inc.). Heterobifunctional pan-selectin inhibitors. EP 1934236, EP 2264043, JP 2009507031, US 2007054870, US 7728117, WO 2007028050. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 68486 | (2R)-2-(((2S,3S,4R,5R,6S)-2-(((1S,3R,5S)-5-((2-aminoethyl)carbamoyl)-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-2-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-3-(benzoyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)oxy)-3-cyclohexylpropanoic acid | C41H55N3O19 | 详情 | 详情 | |
| (VII) | 68488 | Ethyl 1-thio-β-D-galactopyranoside;Ethyl 1-deoxy-1-thio-β-D-galactopyranoside;(2S,3S,4R,5S,6R)-2-(ethylthio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;β-D-thiogalactopyranoside | 56245-60-4 | C8H16O5S | 详情 | 详情 |
| (VIII) | 68489 | (R)-benzyl 3-cyclohexyl-2-(((trifluoromethyl)sulfonyl)oxy)propanoate | C17H21F3O5S | 详情 | 详情 | |
| (IX) | 68490 | (R)-benzyl 3-cyclohexyl-2-(((2S,3S,4R,5S,6R)-2-(ethylthio)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)oxy)propanoate | C24H36O7S | 详情 | 详情 | |
| (X) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XI) | 68495 | (2S,3S,4R,5S,6R)-2-((benzoyloxy)methyl)-4-(((R)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl)oxy)-6-(ethylthio)tetrahydro-2H-pyran-3,5-diyl dibenzoate | C45H48O10S | 详情 | 详情 | |
| (XII) | 68493 | (1S,3S,4R,5R)-methyl 3-azido-5-hydroxy-4-(((2S,3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexanecarboxylate | C35H41N3O8 | 详情 | 详情 | |
| (XIII) | 68494 | (2S,3S,4R,5S,6R)-2-(((2S,5S)-3-azido-5-(methoxycarbonyl)-2-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-6-((benzoyloxy)methyl)-4-(((R)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl)oxy)tetrahydro-2H-pyran-3,5-diyl dibenzoate | C78H83N3O18 | 详情 | 详情 | |
| (XIV) | 68491 | orotic acid chloride;Orotoylchloride;Orotyl chloride;1,2,3,6-tetrahydro-2,6-dioxo-4-Pyrimidinecarbonylchloride | 3346-64-3 | C5H3ClN2O3 | 详情 | 详情 |
| (XV) | 68492 | (2S,3S,4R,5S,6R)-2-((benzoyloxy)methyl)-4-(((R)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl)oxy)-6-(((2S,3R,5S)-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-5-(methoxycarbonyl)-2-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)tetrahydro-2H-pyran-3,5-diyl dibenzoate | C83H87N3O21 | 详情 | 详情 |
合成路线3
The acceptor alcohol (XII) is synthesized by esterification of shikimic acid (XVI) with MeOH in the presence of H2SO4 to give methyl shikimate (XVII), which is then protected as the 3,4-acetonide (XIX) by transketalization with 2,2-dimethoxypropane (XVIII) by means of TsOH in acetonitrile. Hydrogenation of compound (XIX) over PtO2/C in MeOH affords the saturated ester (XX), which by acetylation with Ac2O in the presence of pyridine and DMAP in CH2Cl2 affords acetate (XXI). Deprotection of compound (XXI) by means of 80% aqueous AcOH at 80 °C provides diol (XXII), which is regioselectively converted to tosylate (XXIII) with TsCl in pyridine. Substitution of tosylate (XXIII) with NaN3 in DMF at 80 °C yields the corresponding azide (XXIV), which is then condensed with thioglycoside (XXV) by means of Br2 and Et4NBr in CH2Cl2/DMF/cyclohexene to obtain ether (XXVI). Finally, intermediate (XXVI) is submitted to deacetylation and simultaneous epimerization by means of NaOMe in MeOH, followed by reesterification with CH2N2 in Et2O .
| 【1】 Magnani, J.L., Patton, J.T. Jr., Sarkar, A.K., Svarovsky, S.A., Ernst, B. (GlycoMimetics, Inc.). Heterobifunctional pan-selectin inhibitors. EP 1934236, EP 2264043, JP 2009507031, US 2007054870, US 7728117, WO 2007028050. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 68493 | (1S,3S,4R,5R)-methyl 3-azido-5-hydroxy-4-(((2S,3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexanecarboxylate | C35H41N3O8 | 详情 | 详情 | |
| (XVI) | 29907 | (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid; Shikimic acid | 138-59-0 | C7H10O5 | 详情 | 详情 |
| (XVII) | 29908 | methyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate | C8H12O5 | 详情 | 详情 | |
| (XVIII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIX) | 29909 | methyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XX) | 68500 | (3aS,7S,7aS)-methyl 7-hydroxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-5-carboxylate | C11H18O5 | 详情 | 详情 | |
| (XXI) | 68499 | (3aS,7S,7aS)-methyl 7-acetoxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-5-carboxylate | C13H20O6 | 详情 | 详情 | |
| (XXII) | 68498 | (3R,4S,5S)-methyl 3-acetoxy-4,5-dihydroxycyclohexanecarboxylate | C10H16O6 | 详情 | 详情 | |
| (XXIII) | 68497 | (3R,4S,5S)-methyl 3-acetoxy-4-hydroxy-5-(tosyloxy)cyclohexanecarboxylate | C17H22O8S | 详情 | 详情 | |
| (XXIV) | 68496 | (3R,4S,5R)-methyl 3-acetoxy-5-azido-4-hydroxycyclohexanecarboxylate | C10H15N3O5 | 详情 | 详情 | |
| (XXV) | 68502 | (3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-2-(ethylthio)-6-methyltetrahydro-2H-pyran | C29H34O4S | 详情 | 详情 | |
| (XXVI) | 68501 | (3S,4S,5R)-methyl 3-acetoxy-5-azido-4-(((2R,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexanecarboxylate | C37H43N3O9 | 详情 | 详情 |