CN108101838B - 一种度鲁特韦中间体的合成方法及其有关物质检测方法 - Google Patents
一种度鲁特韦中间体的合成方法及其有关物质检测方法 Download PDFInfo
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- BQVRPJBLLRHDAM-UHFFFAOYSA-N methyl 1-(2,2-dihydroxyethyl)-4-oxo-3-phenylmethoxypyridine-2-carboxylate Chemical compound O=C1C=CN(CC(O)O)C(C(=O)OC)=C1OCC1=CC=CC=C1 BQVRPJBLLRHDAM-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000000126 substance Substances 0.000 title claims abstract description 24
- 238000001514 detection method Methods 0.000 title claims abstract description 16
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000004440 column chromatography Methods 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003480 eluent Substances 0.000 claims description 11
- 239000012071 phase Substances 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical compound CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003643 water by type Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 abstract description 12
- 229960002542 dolutegravir Drugs 0.000 abstract description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000926 separation method Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 235000019445 benzyl alcohol Nutrition 0.000 abstract description 2
- HFLMYYLFSNEOOT-UHFFFAOYSA-N methyl 4-chloro-3-oxobutanoate Chemical compound COC(=O)CC(=O)CCl HFLMYYLFSNEOOT-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 abstract 2
- -1 2, 2-dimethoxyethyl Chemical group 0.000 description 13
- LVPMIMZXDYBCDF-UHFFFAOYSA-N isocinchomeronic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)N=C1 LVPMIMZXDYBCDF-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- REVROVKRCYLCAT-UHFFFAOYSA-N dimethyl 4-oxo-3-phenylmethoxypyran-2,5-dicarboxylate Chemical compound O1C=C(C(=O)OC)C(=O)C(OCC=2C=CC=CC=2)=C1C(=O)OC REVROVKRCYLCAT-UHFFFAOYSA-N 0.000 description 3
- BLUIJYAEOVJVJS-UHFFFAOYSA-N methyl 3-oxo-4-phenylmethoxybutanoate Chemical compound COC(=O)CC(=O)COCC1=CC=CC=C1 BLUIJYAEOVJVJS-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 229940068561 atripla Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960004742 raltegravir Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 2
- 229940014075 tivicay Drugs 0.000 description 2
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 108010002459 HIV Integrase Proteins 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940111682 isentress Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/89—Inverse chromatography
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- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Health & Medical Sciences (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种度鲁特韦中间体的合成方法及其有关物质检测方法，以4‑氯乙酰乙酸甲酯和苯甲醇为起始物料，只需四步反应即得到了度鲁特韦中间体度鲁特韦中间体i，反应条件简单，反应中用到的溶剂只有甲苯一种，原料易得，且得到的产物后处理纯化均采用柱层析法，每一步得到的产物的收率都高达90％以上，适宜工业化生产；度鲁特韦中间体i的有关物质检测方法采用高效液相色谱法，经检测，度鲁特韦中间体i有关物质含量为99.6％，各杂质的分离度均大于3.0，分离度较好。
Description
技术领域
本发明属于药物化学领域，具体涉及一种度鲁特韦中间体的合成方法及其有关物质检测方法。
背景技术
度鲁特韦(Dolutegravir)，其化学名称为(4R,12aS)-N-[(2,4-二氟苯基)甲基]-3,4,6,8,12,12a-六氢-7-羟基-4-甲基-6,8-二氧代-2H-吡啶并[1’,2’:4,5]吡嗪并[2,1-b][1,3]噁嗪-9-甲酰胺，CAS登记号为1051375-16-6，其结构式如式(1)所示，度鲁特韦是英国制药巨头葛兰素史克(GSK)旗下抗HIV新药，2013年8月12日美国食品和药物管理局(FDA)批准用于既往已治疗过、或初治HIV-1成人和12岁及以上和体重至少40千克儿童感染者。
Dolutegravir是日服一次的药物,在III期临床试验中达到了与默沙东HIV/AIDS药物雷特格韦(Raltegravir,Isentress)相匹敌的疗效。雷特格韦日服2次,这2者均为HIV整合酶的抑制剂。FDA的官员表示，艾滋病感染人群需要依据个人具体情况进行有针对性的治疗，Tivicay将为患者提供新的选择。在一年前进行的一项研究中，患者接受48周的Tivicay治疗后，有88％的患者病情有明显改善，优于Gilead公司的Atripla。分析师预计，Dolutegravir有望成为年销售额达数十亿美元的重磅药物，同时将成为吉利德生物公司(Gilead Sciences)世界最畅销HIV复合药物Atripla的强有力竞争者。
2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯是度鲁特韦合成中的一个基础且关键的中间体，对于度鲁特韦成品的合成研究有着重要的意义，现有的合成中间体2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯以麦芽酚[式(2)]为起始物料，合成路线较长，步骤较为繁琐，涉及的溶剂种类和原料较多，不利于大规模的生产，涉及的检测方法较多，不利于检测方法的开发和实际的检测。
发明内容
本发明的目的在于提供一种度鲁特韦中间体的合成方法及其有关物质检测方法，只需四步反应即得到了度鲁特韦中间体2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯，反应条件简单，反应中用到的溶剂只有甲苯一种，原料易得，适宜工业化生产。
本发明的目的可以通过以下技术方案实现：
一种度鲁特韦中间体的合成方法，度鲁特韦中间体i的合成路线为：
具体合成步骤为：
S1、化合物a和化合物b在碳酸铯的作用下，以甲苯为溶剂反应后纯化得到化合物c；
S2、化合物c与化合物d在甲醇钠的作用下，以甲苯为溶剂缩合反应后纯化得到化合物e；
S3、化合物e与化合物f在叔丁醇钠的作用下，以甲苯为溶剂成环反应后纯化得到化合物g；
S4、化合物g与溶剂甲苯在加热回流下，逐滴加入化合物h，取代后纯化得到度鲁特韦中间体i。
进一步，步骤S1所述的化合物a、化合物b和碳酸铯的当量比为：1:1.0-1.5:2-5；所述的反应温度为105-110℃，所述的反应时间为8-12h。
进一步，步骤S2所述的化合物c、化合物d和甲醇钠的当量比为：1:2-3.5:1-1.5；所述的反应温度为100-110℃，所述的反应时间为3-5h。
进一步，步骤S3所述的化合物e、化合物f和叔丁醇钠的当量比为：1:1.2-1.6:0.5-0.8；所述的反应温度为105-110℃，所述的反应时间为6-8h。
进一步，步骤S4所述的化合物g和化合物h的当量比为：1:1.1-1.3；所述的反应温度为95-105℃，所述的反应时间为2-3h。
进一步，反应得到的化合物c、化合物e、化合物g和化合物i粗产物的纯化方法均采用柱层析法，化合物c粗产物的柱层析法采用石油醚：二氯甲烷＝10:3为洗脱剂；化合物e粗产物的柱层析法采用石油醚:甲醇＝5:1为洗脱剂；化合物g粗产物的柱层析法采用正己烷:乙酸乙酯＝9:4为洗脱剂；化合物i粗产物的柱层析法采用正己烷:乙酸乙酯：甲醇＝12:3:2为洗脱剂。
一种度鲁特韦中间体的有关物质检测方法，度鲁特韦中间体i的有关物质检测采用高效液相色谱法，所用的色谱柱为反相色谱柱，所述的反相色谱柱的填充剂十八烷基硅烷键合硅胶或辛烷基硅烷键合硅胶；波长为210nm,柱温为30℃，将度鲁特韦中间体i采用稀释剂溶解后，注入高效液相色谱仪，进样量为10ul，采用梯度洗脱方法，以0.1％的磷酸水溶液为水相，以乙腈为有机相，其中，所述的洗脱梯度为：
其中，流速为0.8-1.2ml/min。
进一步，所述的反相色谱柱采用waters XBridge C18 5μm,4.6×150mm型号的色谱柱。
进一步，所述的稀释剂为甲醇，所述的度鲁特韦中间体的浓度为0.3-0.8mg/ml。
进一步，所述的流速为1.0ml/min。
本发明的有益效果：
本发明提供了一种度鲁特韦中间体的合成方法及其有关物质检测方法，以4-氯乙酰乙酸甲酯和苯甲醇为起始物料，只需四步反应即得到了度鲁特韦中间体2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯，反应条件简单，反应中用到的溶剂只有甲苯一种，原料易得，且得到的产物后处理纯化均采用柱层析法，每一步得到的产物的收率都高达90％以上，适宜工业化生产；度鲁特韦中间体i的有关物质检测方法采用高效液相色谱法，分析方法简单，条件较为普遍，易操作，经检测，得到2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯的有关物质含量为99.6％，各杂质的分离度均大于3.0，分离度较好。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
实施例1
4-(苄氧基)-3-氧代丁酸甲酯的合成
在反应瓶中加入50mol4-氯乙酰乙酸甲酯、60mol苯甲醇、20mol碳酸铯和500ml甲苯，将反应瓶放入油浴锅中，加热至110℃，回流12h，反应完毕后，冷却至室温，过滤，旋转蒸发除去甲苯溶剂，之后采用然后用柱层析法分离粗产物，洗脱剂为石油醚:二氯甲烷＝10:3，从而得到了4-(苄氧基)-3-氧代丁酸甲酯，收率为92％；
实施例2
4-苄氧基-2-((二甲氨基)亚甲基)-3-乙酰乙酸甲酯的合成
将实施例1中得到的4-(苄氧基)-3-氧代丁酸甲酯40mol与120molN,N-二甲基甲酰胺二甲基缩醛、40mol甲醇钠和400ml甲苯放入反应瓶中，接着将反应瓶放入油浴锅中，加热至100℃，回流5h，反应完毕后，冷却至室温，往反应瓶中加入饱和氯化钠溶液和3％的盐酸，摇晃10分钟后分层，将有机层倒出，采用旋转蒸发仪除去溶剂，得到粗产物，之后采用然后用柱层析法分离粗产物，洗脱剂为石油醚:甲醇＝5:1，从而得到了4-苄氧基-2-((二甲氨基)亚甲基)-3-乙酰乙酸甲酯，收率为95％；
实施例3
4-氧-3-苄氧基-4H-吡喃-2,5-二羧酸二甲酯的合成
将实施例2得到的4-苄氧基-2-((二甲氨基)亚甲基)-3-乙酰乙酸甲酯30mol与45mol草酸二甲酯、15mol叔丁醇钠和300ml甲苯放入反应瓶中，接着将反应瓶放入油浴锅中，加热至105℃，回流6h，反应完毕后，冷却至室温，过滤，旋转蒸发除去甲苯溶剂，之后采用然后用柱层析法分离粗产物，洗脱剂为正己烷:乙酸乙酯＝9:4，从而得到了4-氧-3-苄氧基-4H-吡喃-2,5-二羧酸二甲酯，收率为90％；
实施例4
2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯的合成
将实施例3中得到的4-氧-3-苄氧基-4H-吡喃-2,5-二羧酸二甲酯10mol与100ml甲苯加入到反应瓶中，接着将反应瓶放入油浴锅中，加热至100℃，有回流时，逐滴加入12mol氨基乙醛缩二甲醇，加入完毕后继续回流3h，反应完毕后，冷却至室温，旋转蒸发除去甲苯溶剂，之后采用然后用柱层析法分离粗产物，洗脱剂为正己烷:乙酸乙酯：甲醇＝12:3:2，得到了2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯，收率为91％；
实施例5
2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯的有关物质检测：其有关物质检测采用高效液相色谱法，色谱柱选用waters XBridge C185μm,4.6×150mm,波长为210nm,柱温为30℃，检测物的浓度为0.5mg/ml，以甲醇为稀释剂，进样量为10ul，流速为1ml/min，以0.1％的磷酸水溶液为水相，以乙腈为有机相，洗脱梯度为：
经有关物质检测，得到2,5-吡啶二甲酸,1-(2,2-二甲氧基乙基)-1,4-二氢-4-氧-3-苄氧基-2,5-二甲酯的含量为99.6％，各杂质的分离度均大于3.0，分离度较好。
以上内容仅仅是对本发明的构思所作的举例和说明，所属本技术领域的技术人员对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，只要不偏离发明的构思或者超越本权利要求书所定义的范围，均应属于本发明的保护范围。
Claims (5)
1.一种度鲁特韦中间体的合成方法，其特征在于：度鲁特韦中间体i的合成路线为：
具体合成步骤为：
S1、化合物a和化合物b在碳酸铯的作用下，以甲苯为溶剂反应后纯化得到化合物c；
步骤S1所述的化合物a、化合物b和碳酸铯的当量比为：1:1.0-1.5:2-5；所述的反应温度为105-110℃，所述的反应时间为12h；
S2、化合物c与化合物d在甲醇钠的作用下，以甲苯为溶剂缩合反应后纯化得到化合物e；
步骤S2所述的化合物c、化合物d和甲醇钠的当量比为：1:2-3.5:1-1.5；所述的反应温度为100-110℃，所述的反应时间为5h；
S3、化合物e与化合物f在叔丁醇钠的作用下，以甲苯为溶剂成环反应后纯化得到化合物g；
步骤S3所述的化合物e、化合物f和叔丁醇钠的当量比为：1:1.2-1.6:0.5-0.8；所述的反应温度为105-110℃，所述的反应时间为6h；
S4、化合物g与溶剂甲苯在加热回流下，逐滴加入化合物h，取代后纯化得到度鲁特韦中间体i；
步骤S4所述的化合物g和化合物h的当量比为：1:1.1-1.3；所述的反应温度为95-105℃，所述的反应时间为3h；
反应得到的化合物c、化合物e、化合物g和化合物i粗产物的纯化方法均采用柱层析法，化合物c粗产物的柱层析法采用石油醚：二氯甲烷＝10:3为洗脱剂；化合物e粗产物的柱层析法采用石油醚:甲醇＝5:1为洗脱剂；化合物g粗产物的柱层析法采用正己烷:乙酸乙酯＝9:4为洗脱剂；化合物i粗产物的柱层析法采用正己烷:乙酸乙酯：甲醇＝12:3:2为洗脱剂；
该度鲁特韦中间体i的有关物质检测方法为：
度鲁特韦中间体i的有关物质检测采用高效液相色谱法，所用的色谱柱为反相色谱柱，所述的反相色谱柱的填充剂十八烷基硅烷键合硅胶或辛烷基硅烷键合硅胶；波长为210nm,柱温为30℃，度鲁特韦中间体i采用稀释剂溶解后，注入高效液相色谱仪，进样量为10ul，采用梯度洗脱方法，以0.1％的磷酸水溶液为水相，以乙腈为有机相，其中，所述的洗脱梯度为：
其中，流速为0.8-1.2ml/min；
步骤S4制得的度鲁特韦中间体i的含量为99.6％。
2.一种度鲁特韦中间体的有关物质检测方法，其特征在于：度鲁特韦中间体i的有关物质检测采用高效液相色谱法，所用的色谱柱为反相色谱柱，所述的反相色谱柱的填充剂十八烷基硅烷键合硅胶或辛烷基硅烷键合硅胶；波长为210nm,柱温为30℃，度鲁特韦中间体i采用稀释剂溶解后，注入高效液相色谱仪，进样量为10ul，采用梯度洗脱方法，以0.1％的磷酸水溶液为水相，以乙腈为有机相，其中，所述的洗脱梯度为：
其中，流速为0.8-1.2ml/min；
度鲁特韦中间体i的结构式如下
3.根据权利要求2所述的一种度鲁特韦中间体的有关物质检测方法，其特征在于：所述的反相色谱柱采用waters XBridge C185μm,4.6×150mm型号的色谱柱。
4.根据权利要求2所述的一种度鲁特韦中间体的有关物质检测方法，其特征在于：所述的稀释剂为甲醇，所述的度鲁特韦中间体的浓度为0.3-0.8mg/ml。
5.根据权利要求2所述的一种度鲁特韦中间体的有关物质检测方法，其特征在于：所述的流速为1.0ml/min。
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