CN1134419C - 有用的昔多芬中间体及其制备 - Google Patents
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- 238000002360 preparation method Methods 0.000 title abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
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- 238000000034 method Methods 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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- VHSXOOIDWUWCII-UHFFFAOYSA-N 2-methyl-4-nitro-5-propylpyrazole-3-carbonyl chloride Chemical compound CCCC1=NN(C)C(C(Cl)=O)=C1[N+]([O-])=O VHSXOOIDWUWCII-UHFFFAOYSA-N 0.000 abstract 1
- 150000003936 benzamides Chemical class 0.000 abstract 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 abstract 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 abstract 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 238000007363 ring formation reaction Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- -1 benzoyl imines Chemical class 0.000 description 6
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- 125000004193 piperazinyl group Chemical group 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
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- 238000004458 analytical method Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- ZPOLNCDBPYJDSE-UHFFFAOYSA-N 3-[4-[bis(2-chloroethyl)amino]phenyl]-2-formamidopropanoic acid Chemical compound O=CNC(C(=O)O)CC1=CC=C(N(CCCl)CCCl)C=C1 ZPOLNCDBPYJDSE-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 150000003217 pyrazoles Chemical group 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KGGHWIKBOIQEAJ-UHFFFAOYSA-N 2-fluorobenzamide Chemical compound NC(=O)C1=CC=CC=C1F KGGHWIKBOIQEAJ-UHFFFAOYSA-N 0.000 description 1
- RAAGZOYMEQDCTD-UHFFFAOYSA-N 2-fluorobenzoyl chloride Chemical compound FC1=CC=CC=C1C(Cl)=O RAAGZOYMEQDCTD-UHFFFAOYSA-N 0.000 description 1
- OEDUIFSDODUDRK-UHFFFAOYSA-N 5-phenyl-1h-pyrazole Chemical compound N1N=CC=C1C1=CC=CC=C1 OEDUIFSDODUDRK-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HHRFWSALGNYPHA-UHFFFAOYSA-N [N].C1CNCCN1 Chemical compound [N].C1CNCCN1 HHRFWSALGNYPHA-UHFFFAOYSA-N 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
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- 235000019341 magnesium sulphate Nutrition 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
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- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种有用的昔多芬中间体及其制备方法，该中间体通过取代的苯甲酰氯与1-甲基-4-硝基-3-正丙基吡唑-5-甲酰胺反应，或由取代的苯甲酰胺与1-甲基-4-硝基-3-正丙基吡唑-5-甲酰氯反应制成，该中间体经对其分子中的硝基进行还原，环合为吡唑并嘧啶酮衍生物。
Description
本发明涉及一种抗阳痿药物昔多芬的中间体及其制备方法。
昔多芬为美国辉瑞公司1990年发明的一种治疗男性阳痿的药物，1998年在世界范围内上市。
中国专利91104162公开了昔多芬的一种制备方法，该方法通过哌嗪基团与5-苯基-吡唑并嘧啶酮主体进行磺酰胺化反应实现两个基团连接，其中吡唑并嘧啶酮环主体是通过前体4-(2-乙氧基苯甲酰氨基)-1-甲基-3-正丙基吡唑-5-甲酰胺的环合反应形成的。
中国专利94192386公开了昔多芬的治疗阳痿的应用。
中国专利97113261公开了制备昔多芬结构中吡唑并嘧啶酮部分的环合反应，该环合反应是在哌嗪基团与苯磺酰基团连接后进行的，即通过4-[2-乙氧基-5-(4-甲基哌嗪-1-基磺酰基)苯甲酰氨基]-1-甲基-3-正丙基吡唑-5-甲酰胺环合而成。
本发明的研究人员发明了一种与上述专利公开的，制备昔多芬结构中吡唑并嘧啶酮部分的环合反应不同的环合方法。该方法所采用的环合前体是1-甲基-4-硝基-3-正丙基吡唑-5-甲酰-2-取代或/和5-取代的苯甲酰亚胺，通过对其分子中的硝基进行还原，并同时一步环合为吡唑并嘧啶酮，该环合反应条件温和，缩短了制备吡唑并嘧啶酮的反应步骤，相应提高了制备昔多芬结构中吡唑并嘧啶酮主体部分的合成产率，本发明还涉及到结构如下式的上述合成方法中的有用的中间体。
其中R1代表卤素，氢，烷氧基，
R2代表氢，磺酰基，磺酰氯，4-甲基哌嗪基磺酰基。
本发明是通过以下合成路线实现的
其中R1代表卤素，氢，烷氧基，
R2代表氢，磺酰基，磺酰氯，4-甲基哌嗪基磺酰基。
以下实施例对本发明作进一步说明
1-甲基-4-硝基-3-正丙基吡唑-5-甲酰-2-氟
2-苯甲酰亚胺的制备(方法一)
冰浴冷却下，将溶有16.0g(0.1mol)2-氟苯甲酰氯的二氯甲烷溶液100ml，滴加到100ml含有8.4g(0.04mol)1-甲基-4-硝基-3-正丙基吡唑-5-甲酰胺、0.08g DMAP、14.0ml(0.1ml)三乙胺的二氯甲烷/DMF混合溶液中。加料完毕，室温下搅拌反应12小时，TLC检测原料转化完全，将其倾入到500ml水中，产生大量固体，滤集固体，洗涤。滤液用二氯甲烷萃取两次，合并滤液，无水硫酸镁干燥，过滤，减压蒸发溶剂，得淡黄色固体，重8.6g，产率65％，mp.89～90℃。元素分析(C15H15FN4O4)理论值(％)：C53.89、H.4.49、N16.77、F5.69。实测值(％)：C54.2、H4.51、N16.77、F5.84。MS(m/z)：335.1(分子离子峰)。1HMNR(CDCl3)：δ1.02(t，J＝7.36Hz，3H，正丙基，-CH3)，δ1.71～1.81(m，2H，正丙基中的第一个CH2)，δ2.93(t，J＝7.48Hz，2H，正丙基中的第二个CH2)，δ3.91(s，3H，-NCH3)，δ7.21～7.24(m，1H，苯环H)，δ7.30～7.35(m，1H，苯环H)，δ7.62～7.65(m，1H，苯甲酰基对位H)，δ7.98～8.02(m，1H，苯甲酰基邻位H)，δ9.73～9.76(brs，1H，-CONHCO-)。IR：1730cm-1(s，-CONHCO-)，1694cm-1(s，-CONHCO-。
1-甲基-4-硝基-3-正丙基吡唑-5-甲酰-2-氟
苯甲酰亚胺的制备(方法二)
冰浴冷却下，将含有23.2g(0.1mol)1-甲基-4-硝基-3-正丙基吡唑-5-甲酰氯的二氯甲烷溶液100ml，滴加到100ml溶有5.6g(0.04mol)2-氟苯甲酰胺、0.08g DMAP、14.0ml(0.1ml)三乙胺的二氯甲烷溶液中。加料完毕，室温下搅拌反应12小时，TLC检测原料转化完全，将其倾入到500ml蒸馏水中，产生大量固体，滤集固体，洗涤。滤液用二氯甲烷萃取两次，合并滤液，无水硫酸镁干燥，过滤，减压蒸发溶剂，得淡黄色固体，重9.1g，产率69％，mp.89～90℃。
1-甲基-4-硝基-3-正丙基吡唑-5-甲酰-2-氟-5-(4-甲基
哌嗪-1-基磺酰基)苯甲酰亚胺的制备
室温下，将6.7g(0.02mol)1-甲基-4-硝基-3-正丙基吡唑-5-甲酰-2-氟苯甲酰亚胺分批加入到15.0ml氯磺酸中，加料完毕，将体系升温到60～70℃，反应2小时，然后冷却到室温，加入5.4ml氯化亚砜，在室温下搅拌4小时，中止反应，将反应混合物慢慢倾入215g碎冰中，分别用200ml和100ml二氯甲烷萃取，合并萃取液，用100ml饱和氯化钠水溶液洗涤，无水硫酸镁干燥后，过滤，减压蒸发溶剂，得油状物。加入25ml二氯甲烷使之溶解，向其中滴加0.76g(7.5×10-3mol)三乙胺和1.2g(0.012mol)N-甲基哌嗪。加料完毕，室温下继续搅拌反应2小时，TLC检测原料转化完全，用35ml饱和碳酸钠水溶液洗涤，无水硫酸镁干燥，浓缩得蜡状固体，重7.2g，产率75％，MS(m/z)：477.1(分子离子峰)。1HNMR(CDCl3)δ1.01(t，J＝7.36Hz，3H，正丙基-CH3)，δ1.81～1.91(m，2H，正丙基中的第二个CH2)，δ2.30(t，J＝7.48Hz，3H，哌嗪-NCH3)，δ2.51(t，J＝4.80Hz，4H，哌嗪环上氮甲基端CH2)，δ2.93(t，J＝7.48Hz，正丙基中的第二个CH2)，δ3.15(brs 4H，哌嗪环上磺酰基端CH2)，δ4.27(s，3H，吡唑环上-NCH3)，δ7.40(dd，J1＝8.64Hz，J2＝11.56Hz，1H苯环H)，δ7.86～7.89(m，1H苯环H)，δ8.65(dd，J1＝2.42Hz，J2＝6.08Hz，苯环H)，9.73～9.76(brs，1H，-CONHCO-)。IR：1730cm-1(s，-CONHCO-)，1690cm-1(s，-CONHCO-)5-(2-氟苯基)-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]-嘧
啶-7-酮的制备
将6.6g(0.02mol)1-甲基-4-硝基-3-正丙基吡唑-5-甲酰-2-氟苯甲酰亚胺溶于10ml无水乙醇，升温到65℃，然后搅拌下分批加27.0g(0.12mol)SnCl2.2H2O固体，加料速度控制系温度不超70℃，然后维持此温度下搅拌反应2～3小时，TLC检测原料转化完全。将反应混合物冷却到室温，冰水冷却下滴加2mol.L-1NaOH水溶液调节pH7～8，用4×100ml二氯甲烷萃取，无水硫酸镁干燥12小时，过滤，减压蒸除溶剂，得白色粉未，重4.6g产率为81％。mp161-163℃。元素分析(C15H15FN4O)：理论值(％)：C62.94、H5.24、N19.58、F6.64。实测值(％)：C62.82、H5.26、N19.52、F6.70。MS(m/z)：287.1(分子离子峰)。1HMNR(CDCl3)：δ1.03(t，J＝7.36Hz，3H，正丙基，-CH3)，δ1，81～1.91(m，2H，正丙基中的第一个CH2)，δ2.93(t，J＝7.48Hz，2H，正丙基中的第二个CH2)，δ4.27(s，3H，-NCH3)，δ7.18～7.24(m，1H，苯环H)，δ7.32～7.36(m，1H，苯环H)，δ7.50～7.52(m，1H，苯甲酰基对位H)，δ8.28～8.33(m，1H，苯甲酰基邻位H)，δ9.76～9.79(s，1H，-CONH-)。IR：1693cm-1(s，-CONH-)。
5-[2-氟-5-(4-甲基哌嗪-1-基磺酰基)苯基]-1-甲基-3-正丙基
-1，6-二氢-7H-吡唑并[4，3-d]-嘧啶-7-酮的制备
将9.5g(0.02mol)1-甲基-4-硝基-3-正丙基吡唑-5-甲酰-2-氟-5-(4-甲基哌嗪-1-基磺酰基)苯甲酰亚胺溶于15ml无水乙醇，升温到65℃，然后搅拌下分批加27.0g(0.12mol)SnCl2.2H2O固体，加料速度控制系温度不超70℃，然后维持此温度下搅拌反应2～3小时，TLC检测原料转化完全。将反应混合物冷却到室温，冰水冷却下滴加2mo1.L-1NaOH水溶液调节pH7～8，用4×100ml二氯甲烷萃取，无水硫酸镁干燥12小时，过滤，减压蒸除溶剂，得白色粉未，重7.6g产率为85％。mp172～173℃。元素分析(C20H25FN6O35)理论值(％)：C53.57、H5.58、N18.75、F4.24、S7.14。实测值(％)：C53.29、H5.61、N18.60、F4.39、S7.20。MS(m/z)：449.1(分子离子峰)。1HMNR(CDCl3)：δ1.02(t，J＝7.36Hz，3H，正丙基，-CH3)，δ1.81～1.91(m，2H，正丙基中的第一个CH2)，δ2.30(t，J＝7.48Hz，3H，哌嗪氮甲基氢)，δ2.53(t，J＝4.80Hz，4H，哌嗪环上氮甲基端CH2)，δ2.93(t，J＝7.44Hz，2H，正丙基中的第二个CH2)，δ3.15(brs，4H，哌嗪环上磺酰基端CH2)，4.28(s，3H，吡唑环上氮甲基氢)，δ7.39(dd，J1＝8.64Hz，J2＝11.56Hz，1H，苯环H)，δ7.88～7.92(m，1H，苯环H)，δ8.68(dd，J1＝2.44Hz，J2＝6.14Hz苯环H)。IR：1702cm-1(s，-CONH-)。
Claims (3)
1.结构如下式的化合物
其中R1代表卤素，氢，烷氧基，
R2代表氢，磺酰基，磺酰氯，4-甲基哌嗪基磺酰基。
2.制备权利要求1化合物的方法
用如下反应式表示：
其中R1代表卤素，氢，烷氧基，
R2代表氢，磺酰基，磺酰氯，4-甲基哌嗪基磺酰基。
3、权利要求1化合物用于制备下式化合物
其中R1代表卤素，氢，烷氧基，
R2代表氢，磺酰基，磺酰氯，4-甲基哌嗪基磺酰基。
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| CNB991111532A CN1134419C (zh) | 1999-07-27 | 1999-07-27 | 有用的昔多芬中间体及其制备 |
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| CN1281851A CN1281851A (zh) | 2001-01-31 |
| CN1134419C true CN1134419C (zh) | 2004-01-14 |
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| US8071765B2 (en) | 2006-12-21 | 2011-12-06 | Topharman Shanghai Co., Ltd. | Process for the preparation of sildenafil and intermediates thereof |
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