CN114369064B - 一种西地那非中间体的制备方法 - Google Patents
一种西地那非中间体的制备方法 Download PDFInfo
- Publication number
- CN114369064B CN114369064B CN202210022208.8A CN202210022208A CN114369064B CN 114369064 B CN114369064 B CN 114369064B CN 202210022208 A CN202210022208 A CN 202210022208A CN 114369064 B CN114369064 B CN 114369064B
- Authority
- CN
- China
- Prior art keywords
- preparation
- pyrazole
- propyl
- carboxylic acid
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229960003310 sildenafil Drugs 0.000 title claims abstract description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007069 methylation reaction Methods 0.000 claims abstract description 10
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 7
- QYPSYPPSHXDFLV-UHFFFAOYSA-N 5-propyl-1h-pyrazole-3-carboxylic acid Chemical compound CCCC1=CC(C(O)=O)=NN1 QYPSYPPSHXDFLV-UHFFFAOYSA-N 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 13
- SUALHSUMUQQLJP-UHFFFAOYSA-N ethyl 5-propyl-1h-pyrazole-3-carboxylate Chemical compound CCCC1=CC(C(=O)OCC)=NN1 SUALHSUMUQQLJP-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 9
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 3
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- PZMXDLWWQHYXGY-UHFFFAOYSA-N 4-amino-1-methyl-3-propylpyrazole-5-carboxamide Chemical compound CCCC1=NN(C)C(C(N)=O)=C1N PZMXDLWWQHYXGY-UHFFFAOYSA-N 0.000 description 2
- -1 4-methylpiperazine-1-sulfonyl Chemical group 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 208000010228 Erectile Dysfunction Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- ZPSRHLWRTVNGSM-UHFFFAOYSA-N ethyl 2-methyl-5-propylpyrazole-3-carboxylate Chemical compound CCCC=1C=C(C(=O)OCC)N(C)N=1 ZPSRHLWRTVNGSM-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- MDKAAWDKKBFSTK-UHFFFAOYSA-N 2-ethoxybenzoyl chloride Chemical compound CCOC1=CC=CC=C1C(Cl)=O MDKAAWDKKBFSTK-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000005957 chlorosulfonylation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- LJDZFAPLPVPTBD-UHFFFAOYSA-N nitroformic acid Chemical compound OC(=O)[N+]([O-])=O LJDZFAPLPVPTBD-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960002639 sildenafil citrate Drugs 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种西地那非中间体的制备方法包括如下步骤：在4‑二甲氨基吡啶与四丁基溴化铵的存在下，3‑正丙基‑1H‑吡唑‑5‑羧酸乙酯与磷酸三甲酯进行N‑甲基化反应，得到1‑甲基‑3‑正丙基‑1H‑吡唑‑5‑羧酸乙酯。
Description
技术领域
本发明属于药物合成技术领域，具体涉及一种西地那非中间体的制备方法。
背景技术
西地那非是一种5型磷酸二酯酶(PDE-5)的选择性抑制剂，而PDE-5是对cGMP专属的一种磷酸二酯酶亚型,是高效治疗男性勃起功能障碍(ED)的药物。西地那非的化学名为：1-甲基-3-正丙基-5-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯基]-1,6-二氢-7H-吡唑并[4,2-d]吡啶-7-酮枸橼酸盐，一般以其商业名称Viagra广为人知。枸橼酸西地那非的化学结构如下所示：
西地那非主要的合成路线以4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺(式I)和2-乙氧基苯甲酰氯或2-乙氧基苯甲酰酸为起始原料，经缩合反应、嘧啶酮环合反应、氯磺酰化再与N-甲基哌嗪缩合，成盐得到枸橼酸西地那非。
因此，4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺(式：I)，是合成西地那非的一个关键中间体。
文献报道的该中间体的合成路线是以2-戊酮为原料，在乙醇钠存在下与草酸二乙酯缩后，与水合肼环合得到吡唑环，再与硫酸二甲酯反应进行甲基化，进行水解得到羧酸，后用混酸硝化得到硝基羧酸物，再使用氯化亚砜氯化，得到酰氯后氨解得酰胺，最后还原硝基得到4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺。反应式如下所示：
该合成路线涉及7个中间体，其以2-戊酮与草酸二乙酯反应得到中间体1、经过水合肼环合得到中间体2、中间体2经过使用硫酸二甲酯进行N-甲基化得到中间体3、中间体3再经过水解、硝化、酰氯化、酰胺化、还原得到中间体7(式：I)。
上述现有技术中，中间体3的制备使用硫酸二甲酯进行N-甲基化，硫酸二甲酯属高毒物,在工业生产过程中大量使用硫酸二甲酯可能会造成严重的污染和中毒事件。为了避免在生产过程中使用硫酸二甲酯可能会造成严重的污染和中毒事件的发生，本发明进行了制备方法的技术改造。
发明内容
为了解决上述技术问题，本发明提供如下技术方案。
一种合成西地那非的中间体式I的制备方法，包括如下步骤(1)：在4-二甲氨基吡啶与四丁基溴化铵的存在下，3-正丙基-1H-吡唑-5-羧酸乙酯与磷酸三甲酯进行N-甲基化反应，得到中间体-1即1-甲基-3-正丙基-1H-吡唑-5-羧酸乙酯，
根据本发明的制备方法，上述反应中，其反应温度为85～110℃，优选95～100℃。
根据本发明的制备方法，其反应压力为表压0.10～0.20Mpa。优选的，反应压力为表压0.10～0.15Mpa。
根据本发明的制备方法，3-正丙基-1H-吡唑-5-羧酸乙酯与4-二甲基吡啶的摩尔用量比0.8～1.2∶1，磷酸三甲酯的摩尔用量为3-正丙基-1H-吡唑-5-羧酸乙酯的1.5-3倍，四丁基溴化铵的用量为3-正丙基-1H-吡唑-5-羧酸乙酯的0.1～0.3倍。优选的，3-正丙基-1H-吡唑-5-羧酸乙酯∶磷酸三甲酯∶四丁基溴化铵∶4-二甲基吡啶的摩尔用量比为1∶2∶0.1∶1.1。
根据本发明的制备方法，所述N-甲基化反应完成后，以碱液中和，二氯甲烷提取，浓缩，减压蒸馏得到中间体-1。
根据本发明的制备方法，包括如下步骤，以得到中间体式I化合物：
有益效果：
本发明方法改进了制备1-甲基-3-正丙基-1H-吡唑-5-羧酸乙酯(中间体-1)的反应试剂。现有技术中使用硫酸二甲酯与3-正丙基-1H-吡唑-5-羧酸乙酯进行N-甲基化反应，硫酸二甲酯属于高毒性性类试剂。本发明采用了低毒性的甲基化试剂磷酸三甲酯，并且研究了反应条件，发现在助剂存在下，调整反应压力，使用低毒性磷酸三甲酯可制得产率很高的中间体-1。
具体实施方式
下文将结合具体实施例对本发明的制备方法做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
1-甲基-3-正丙基-1H-吡唑-5-羧酸乙酯(中间体-1)的制备：
向5L压力釜中加入3-正丙基-1H-吡唑-5-羧酸乙酯(起始物料)(550g，3.00mol)、新蒸馏的磷酸三甲酯(841g，6.00mol)，室温搅拌至溶解完全，加入4-二甲氨基吡啶110g(0.90mol)与四丁基溴化铵97g(0.30mol)，拧紧反应釜盖。搅拌下慢慢加热，稳定内温至95～100℃后，用排气阀与氮气调节表压约0.10～0.15MPa，保温搅拌反应15小时，冷却，慢慢泄掉压力。
将反应液转移至5L反应瓶中，冷却下用饱和碳酸钠溶液中和反应，当无气泡溢出后，使用二氯甲烷500ml×3萃取，合并二氯甲烷萃取液，在40～60℃常压蒸馏出二氯甲烷，减压蒸馏掉过量的磷酸三甲酯60～90℃/5～8mmHg，收集主馏分150～170℃/5～8mmHg，得到中间体-1无色油状物488.7g，收率：83.0％。
本发明在该实施例的操作步骤下，进行了一系列反应条件的研究，实验条件和实验结果如下表所示：
表1
表2
表3
中间体-2的制备：
向5L三口瓶中加入中间体-1(392g，2.00mol)，加入6N氢氧化钠水溶液970ml，加热至回流反应1.5小时，降温至40℃以下，加入水970ml，滴加6N盐酸970ml进行中和，滴加完毕后，析出固体，搅拌下降温至15～20℃，保温搅拌1小时，抽滤，500×3ml纯化水洗涤，抽干，固体在50～55℃鼓风干燥12小时，得白色固体293g，收率：87.1％。熔点：151～153℃。
中间体-3的制备：
向3L三口瓶中加入浓硫酸450ml与发烟硝酸382ml，搅拌下控制内温65℃以下，分5批次加入中间体-2(280g，1.66mol)，加完后在60～65℃保温反应15小时，冷却至室温，将反应液倒入装有碎冰1200g的塑料桶中，边倒边搅拌，析出白色固体，冷却至室温，抽滤，固体用冷水300ml×3次洗涤后，抽干，湿物料在50～55℃鼓风干燥15小时，得白色固体346g，收率：97.5％。熔点：122～124℃。中间体-4的制备：
向3L三口瓶中加入中间体-3(330g，1.55mol)，加入二氯亚砜990ml，慢慢加热回流，搅拌反应4小时。降温至40～55℃，减压浓缩掉过量的二氯亚砜，加入丙酮660ml，搅拌溶解剩余物。
将溶解物慢慢倒入装有碎冰990g与浓氨水990ml的塑料桶中，边倒边搅拌，析出淡黄色固体(pH≈10)，搅拌10分钟，抽滤，固体用冷水250ml次洗涤后，抽干，湿物料在50～55℃鼓风干燥15小时，得淡黄色固体280g，收率：75.5％。熔点：142～143℃。
中间体-5的制备：
向3L三口瓶中加入中间体-4(260g，1.23mol)、乙醇1050ml，搅拌下加入二水氯化亚锡(833g，3.69mol)，加热至回流反应4小时，撤掉热浴，降温至30℃以下，冰水浴控制内温30℃以下，用2N氢氧化钠调节至pH≈10，冷却至室温，使用二氯甲烷1050ml×3提取，合并提取液，滤液用500ml纯化水洗涤一次，分取二氯甲烷相，减压浓缩，室温下向剩余物中加入异丙醚520ml，搅拌1小时，过滤析出固体，使用冷的异丙醚200ml洗涤滤饼一次，抽干，湿物料在40～50℃鼓风干燥12小时，得到类白色固体196g，收率：87.5％。熔点：99～101℃。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (3)
1.一种合成西地那非的中间体-1的制备方法，包括如下步骤（1）：在4-二甲氨基吡啶与四丁基溴化铵的存在下，3-正丙基-1H-吡唑-5-羧酸乙酯与磷酸三甲酯进行N-甲基化反应，得到中间体-1即1-甲基-3-正丙基-1H-吡唑-5- 羧酸乙酯，
；反应温度为95～100℃，反应压力为表压0.10～0.15Mpa，所述3-正丙基-1H-吡唑-5-羧酸乙酯∶磷酸三甲酯∶四丁基溴化铵∶4-二甲氨基吡啶的摩尔用量比为1∶2∶0.1∶1.1。
2.根据权利要求1所述的制备方法，所述N-甲基化反应完成后，以碱液中和，二氯甲烷提取，浓缩，减压蒸馏得到中间体-1。
3.一种合成西地那非的中间体式I的制备方法，包括如下步骤，其中由起始物料到中间体-1的步骤如权利要求1所述，
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210022208.8A CN114369064B (zh) | 2022-01-10 | 2022-01-10 | 一种西地那非中间体的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210022208.8A CN114369064B (zh) | 2022-01-10 | 2022-01-10 | 一种西地那非中间体的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114369064A CN114369064A (zh) | 2022-04-19 |
| CN114369064B true CN114369064B (zh) | 2023-12-19 |
Family
ID=81144791
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210022208.8A Active CN114369064B (zh) | 2022-01-10 | 2022-01-10 | 一种西地那非中间体的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114369064B (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102762568A (zh) * | 2009-12-23 | 2012-10-31 | 伊兰药品公司 | 作为polo样激酶的抑制剂的蝶啶酮 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10017511B2 (en) * | 2014-01-30 | 2018-07-10 | Council Of Scientific & Industrial Research | Pyrazolopyrimidinones for the treatment of impotence and process for the preparation thereof |
-
2022
- 2022-01-10 CN CN202210022208.8A patent/CN114369064B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102762568A (zh) * | 2009-12-23 | 2012-10-31 | 伊兰药品公司 | 作为polo样激酶的抑制剂的蝶啶酮 |
Non-Patent Citations (1)
| Title |
|---|
| 张玉娟等.1-甲基-1H-吡唑-5-硼酸频哪醇酯的合成.《精细化工中间体》.2013,第43卷(第6期),第27-28，58页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114369064A (zh) | 2022-04-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2009218414B2 (en) | Process for preparing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates | |
| US20060229454A1 (en) | One-pot process for the preparation of 1,2-benzisoxazole-3-methanesulfonamide | |
| CN103724279A (zh) | 一步成环制备2-甲基-4-氨基-5-氨基甲基嘧啶的便捷合成方法 | |
| CN103664923B (zh) | 硝呋太尔的制备方法 | |
| KR100352713B1 (ko) | 방향족니트릴의제조방법 | |
| CN114369064B (zh) | 一种西地那非中间体的制备方法 | |
| CN102639546B (zh) | 制备膦酰基烷基亚氨基二乙酸的方法 | |
| CN109053679B (zh) | 戴斯马丁氧化剂的制备方法 | |
| AU728589B2 (en) | A method for preparing 3-amino substituted crotonates | |
| US4247479A (en) | Process for the manufacture of aromatic amines from α, β-unsaturated cycloaliphatic ketoximes | |
| CN100462346C (zh) | 一种异癸十异戊二烯基醇制备方法 | |
| CN114773270A (zh) | 一种二丙酸咪唑苯脲的生产制备方法 | |
| JPH01228995A (ja) | Ｎ―ホスホノ―メチル―イミノージ酢酸及び酸塩化物の製造方法 | |
| US8513413B2 (en) | Process for the preparation of nitroorotic acid | |
| US5777154A (en) | Method for preparing 3-amino substituted crotonates | |
| US4691062A (en) | Process for the production of 4-chloro-butanals | |
| JP4032861B2 (ja) | β−オキソニトリル誘導体又はそのアルカリ金属塩の製法 | |
| CN103772308B (zh) | 5-氨基-3-(1-乙基-1-甲基丙基)异噁唑中间体的制备方法和异噁草胺的制备方法 | |
| US5519140A (en) | Process for the manufacture of 2-isopropyl-4-methyl-6-hydroxypyrimine | |
| US4217449A (en) | Process for the preparation of bis-triazolylstilbenes | |
| IE50084B1 (en) | Preparation of 2-isopropylamino-pyrimidine | |
| CN117756670A (zh) | 一种利匹韦林中间体的合成方法 | |
| US3312708A (en) | Manufacture of aminoquinolines | |
| CN111423445A (zh) | 一种4-氯-5，7-二氢-6h-吡咯并[2，3-d]嘧啶-6-酮的合成方法 | |
| CN114195715A (zh) | 1-甲基-3-二氟甲基-4-吡唑酸和1-甲基-3-三氟甲基-4-吡唑酸的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |