CN104072348B - 5‑(5‑溴‑2‑甲基苯基)‑1‑(4‑氟苯基)戊烷‑1,4‑二酮及其制备方法和应用 - Google Patents
5‑(5‑溴‑2‑甲基苯基)‑1‑(4‑氟苯基)戊烷‑1,4‑二酮及其制备方法和应用 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 title claims abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 title claims abstract description 5
- -1 aminomethyl phenyl Chemical group 0.000 title abstract description 3
- UUAAALCIWZDBDT-UHFFFAOYSA-N 1-fluoro-4-pentylbenzene Chemical compound CCCCCC1=CC=C(F)C=C1 UUAAALCIWZDBDT-UHFFFAOYSA-N 0.000 title abstract 2
- 125000005594 diketone group Chemical group 0.000 title abstract 2
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
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- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
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- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
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- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims 1
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- 125000003944 tolyl group Chemical group 0.000 claims 1
- 229960001713 canagliflozin Drugs 0.000 abstract description 6
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- SEENCYZQHCUTSB-UHFFFAOYSA-N 5-bromo-2-methylbenzoic acid Chemical class CC1=CC=C(Br)C=C1C(O)=O SEENCYZQHCUTSB-UHFFFAOYSA-N 0.000 description 1
- HCEQQASHRRPQFE-UHFFFAOYSA-N 5-chloro-n-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2-methoxybenzamide;3-(diaminomethylidene)-1,1-dimethylguanidine;hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N.COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 HCEQQASHRRPQFE-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
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- Organic Chemistry (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了式I化合物5‑(5‑溴‑2‑甲基苯基)‑1‑(4‑氟苯基)戊烷‑1,4‑二酮及其制备方法和应用。以式I化合物为原料，在硫化试剂的存在下反应，即制得抗II型糖尿病药物Canagliflozin的中间体式X化合物。本发明方法所需原料及试剂价格相对便宜，成本低廉，操作简捷安全，收率良好，同时环境污染小，有很好的经济效应，适宜工业生产。
Description
技术领域
本发明涉及式I化合物5-(5-溴-2-甲基苯基)-1-(4-氟苯基)戊烷-1,4-二酮及其制备方法和应用，特别是涉及该式I化合物作为中间体用于制备抗II型糖尿病药物Canagliflozin的中间体式X化合物。
背景技术
强生研发的Canagliflozin属于选择性II型钠-葡萄糖转运子(SGLT-2)抑制剂，美国食品药品监督管理局(FDA)的一个顾问小组建议FDA批准该糖尿病新药Canagliflozin，其有望成为美国批准的第一个SGLT2抑制剂糖尿病药物，结构式如下：
从上述结构可以看出，Canagliflozin主要由芳环侧链X与D-葡萄糖偶联而得，其中芳环侧链X的结构如下：
目前，关于芳环侧链X的制备方法主要有：1)日本田边制药株式会社在专利WO2005012326A1(同族专利CN1829729A)中公开了从对氟苯硼酸和2-甲基-5-溴苯甲酸出发，经过偶联、还原等步骤制得式X化合物的合成路线，反应式如下：
2)詹森药业有限公司在专利WO2010043682A2(同族专利CN102264714A)中公开了起始原料从对氟溴苯出发，制得的格式试剂与2-溴噻吩偶联，随后与上述路线1)采用相同方式制得式X化合物的路线，反应式如下：
3)上海特化医药有限公司在专利CN102115468A中公开了条全新的路线，其以构建噻吩环为出发点，经过两步即合成式X化合物，反应式如下。但由于该方法原料制备较复杂，步骤繁琐，不适宜工业化。
发明内容
本发明所要解决的技术问题在于提供一种式I化合物5-(5-溴-2-甲基苯基)-1-(4-氟苯基)戊烷-1,4-二酮及其制备方法，和该式I化合物作为中间体用于制备抗II型糖尿病药物Canagliflozin的关键中间体式X化合物。本发明方法所需原料及试剂价格相对便宜，成本低廉，操作简捷安全，收率良好，同时环境污染小，有很好的经济效应，适宜工业生产。
所述的式I化合物5-(5-溴-2-甲基苯基)-1-(4-氟苯基)戊烷-1,4-二酮，其结构式如下：
式I化合物的制备方法，包括以下步骤：以1-(4-氟苯基)-2-烯-1-丙酮(式II)和3-(5-溴-2-甲基苯基)-2-羰基丙酸(式III)为起始原料，在催化剂和碱作用下即制得式I化合物。反应式如下：
上述方法中，所述的催化剂选自5-(2-羟乙基)-4-甲基-3-取代-噻唑嗡盐，结构式如下：
其中R为C1-C8的烷烃如甲基、乙基、正丙基、正丁基，或苄基等，X为卤素，优选为氯、溴或碘。催化剂的用量为式III用量的2％～50％mol，优选为8～20％mol。
所述的碱为C1-C10的有机碱，如三乙胺、二异丙基乙基胺、三乙烯二胺、四甲基乙二胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯等。其用量为式III摩尔用量的0.5～15eq，优选1.0～3.0eq。
所述的反应溶剂选自：C1-C4的醇类如甲醇、乙醇、异丙醇、正丁醇等，C1-C7的醚类如乙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、苯甲醚等，C3-C4的酮类如丙酮、丁酮等，乙基苯、甲苯、二甲苯，1,4－二氧六环、乙腈中的一种或多种的混合溶剂。
所述的反应温度为20～150oC，优选60～120oC。
以上述式I化合物为原料，在硫化试剂的存在下反应，制备Canagliflozin中间体X。反应式如下：
所述的硫试剂为劳氏试剂(Lawesson试剂)，其用量为式I摩尔量的0.9～2.0倍，优选1.0～1.3倍。
反应溶剂为苯或取代苯试剂，所述的取代苯如：甲苯、二甲苯、间三甲苯、三氟甲苯、硝基苯、卤代苯等。
反应温度为50～180℃，优选80～150℃。
具体实施方式
以下结合具体实施例进一步详细描述本发明的技术方案，但所述实施例不限制本发明的保护范围。最后应当说明的是，以下实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围中。
实例1 3-(5-溴-2-甲基苯基)-2-羰基丙酸(式III)的合成
3-(5-溴-2-甲基苯基)-2-羰基丙酸的合成参考Raap等人的文献(Eur.J.Org.Chem.1999,2609-2621)。
向250mL反应瓶中加入2-甲基-5-溴苯甲醛(20g，100mmol)，海因(15g，150mmol)，醋酸钠(20g，244mmol)和150mL冰醋酸，反应体系加热回流过夜，体系降温至室温，缓慢倒入500mL冰水体系中，降至室温，过滤，滤饼用500mL水洗涤至中性。收集固体，将固体加入250mL反应瓶中，加入20％NaOH溶液100mL，体系在氮气保护下回流3h，降温至20～30℃，体系用6N盐酸水溶液中和至pH＝7～8之间，加入10g碳酸氢钠固体，体系用乙酸乙酯萃取三次。水相继续用6N盐酸调pH<2，用500mL乙酸乙酯萃取水相，浓缩有机相，柱层析(PE/EA/TEA＝1/3/0.01)，得产品16g，收率63％。
MS(ESI)257.0(M+H+，100％)
实例2 5-(5-溴-2-甲基苯基)-1-(4-氟苯基)戊烷-1,4-二酮(式I)的合成
方法1)：500mL三口瓶中，加入3-(5-溴-2-甲基苯基)-2-羰基丙酸(式III，25.7g，100mmol)，1-(4-氟苯基)-2-烯-1-丙酮(式II，15g，100mmol)，三乙胺(10.1g，100mmol)，5-(2-羟乙基)-4-甲基-3-苄基-噻唑氯嗡盐(2.7g，10mmol)，乙醇150mL，体系加热至回流，15h后降温，向体系中加入10％食盐水100mL，用200mL乙酸乙酯萃取，有机相浓缩，柱层析(PE/EA＝7/1)得产物式I化合物27.6g，收率76％。
MS(ESI)363.0(M+H+，100％)
方法2)：500mL三口瓶中，加入3-(5-溴-2-甲基苯基)-2-羰基丙酸(式III，25.7g，100mmol)，1-(4-氟苯基)-2-烯-1-丙酮(式II，15g，100mmol)，三乙胺(10.1g，100mmol)，5-(2-羟乙基)-4-甲基-3-苄基-噻唑溴嗡盐(6.3g，20mmol)，1,4-二氧六环150mL，体系加热至回流，6h后降温，向体系中加入10％食盐水100mL，分液，有机相浓缩，柱层析(PE/EA＝7/1)得产物式I化合物24.8g，收率68％。
MS(ESI)363.0(M+H+，100％)
方法3)：500mL三口瓶中，加入3-(5-溴-2-甲基苯基)-2-羰基丙酸(式III，25.7g，100mmol)，1-(4-氟苯基)-2-烯-1-丙酮(式II，15g，100mmol)，二异丙基乙基胺(38.7g，300mmol)，5-(2-羟乙基)-4-甲基-3-乙基-噻唑氯嗡盐(1.7g，8mmol)，甲苯150mL，体系加热至回流，8h后降温，向体系中加入10％食盐水100mL，分液，有机相浓缩，柱层析(PE/EA＝7/1)得产物式I化合物30g，收率82％。
MS(ESI)363.0(M+H+，100％)
方法4)：500mL三口瓶中，加入3-(5-溴-2-甲基苯基)-2-羰基丙酸(式III，25.7g，100mmol)，1-(4-氟苯基)-2-烯-1-丙酮(式II，15g，100mmol)，1,8-二氮杂二环[5.4.0]十一碳-7-烯(15.2g，100mmol)，5-(2-羟乙基)-3,4-二甲基-噻唑碘嗡盐(2.7g，10mmol)，乙腈150mL，体系加热至回流，24h后降温，向体系中加入10％食盐水100mL，用200mL乙酸乙酯萃取，有机相浓缩，柱层析(PE/EA＝7/1)得产物式I化合物28g，收率77％。
MS(ESI)363.0(M+H+，100％)
实例3 2-(5-溴-2-甲基苄基)-5-(4-氟苯基)噻吩(式X)的合成
方法1)：250mL三口瓶中加入5-(5-溴-2-甲基苯基)-1-(4-氟苯基)戊烷-1,4-二酮(式I，18g，50mmol)，甲苯100mL，劳氏试剂(20g，50mmol)，体系回流6h，TLC检测原料I全部消失后，体系降温，浓缩后柱层析(PE/EA＝3/1)，得式X化合物14g，收率78％。
MS(ESI)361.0(M+H+，100％)
方法2)：250mL三口瓶中加入5-(5-溴-2-甲基苯基)-1-(4-氟苯基)戊烷-1,4-二酮(式I，18g，50mmol)，二甲苯100mL，劳氏试剂(20g，50mmol)，体系回流8h，TLC检测原料I全部消失后，体系降温，浓缩后柱层析(PE/EA＝3/1)，得式X化合物15g，收率83％。
MS(ESI)361.0(M+H+，100％)
方法3)：250mL三口瓶中加入5-(5-溴-2-甲基苯基)-1-(4-氟苯基)戊烷-1,4-二酮(式I，18g，50mmol)，甲苯100mL，劳氏试剂(60g，150mmol)，体系回流4h，TLC检测原料I全部消失后，体系降温，浓缩后柱层析(PE/EA＝3/1)，得式X化合物15.4g，收率86％。
MS(ESI)361.0(M+H+，100％)。
Claims (11)
1.如下式I所示的化合物5-(5-溴-2-甲基苯基)-1-(4-氟苯基)戊烷-1,4-二酮：
2.权利要求1所述的式I化合物的制备方法，其特征在于，包括以下步骤，以式II化合物和式III化合物为起始原料，在催化剂和碱作用下制得式I化合物，反应式如下：
所述的催化剂选自：5-(2-羟乙基)-4-甲基-3-取代-噻唑嗡盐，结构式如下：
其中，R为C1-C8的烷烃基或苄基，X为卤素；
所述的碱选自：三乙胺、二异丙基乙基胺、三乙烯二胺、四甲基乙二胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯。
3.根据权利要求2所述的方法，其特征在于，所述催化剂的用量为式III用量的2％～50％mol。
4.根据权利要求2或3所述的方法，催化剂中R为：甲基、乙基、正丙基、正丁基或苄基，X为氯、溴或碘。
5.根据权利要求2所述的方法，其特征在于，所述的碱的用量为式III摩尔用量的0.5eq～15eq。
6.根据权利要求2所述的方法，其特征在于，反应溶剂为甲醇、乙醇、异丙醇、正丁醇、乙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、苯甲醚、丙酮、丁酮、乙基苯、甲苯、二甲苯、1,4－二氧六环、乙腈中的一种或多种的混合溶剂。
7.根据权利要求2所述的方法，其特征在于，反应温度为20～150℃。
8.一种式X化合物的制备方法，其特征在于，以式II化合物和式III化合物为起始原料，在催化剂和碱作用下制得式I化合物，以式I化合物为原料，在硫试剂的存在下反应，即得，反应式如下：
所述的催化剂选自：5-(2-羟乙基)-4-甲基-3-取代-噻唑嗡盐，结构式如下：
其中R为C1-C8的烷烃基或苄基，X为卤素；
所述的碱选自：三乙胺、二异丙基乙基胺、三乙烯二胺、四甲基乙二胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯；
所述硫试剂为劳氏试剂。
9.根据权利要求8所述的方法，其特征在于，所述的硫试剂的用量为式I化合物摩尔量的0.9～2.0倍。
10.根据权利要求8所述的方法，其特征在于，反应(2)的反应溶剂为苯或取代苯，反应温度50-180℃。
11.根据权利要求10所述的方法，其特征在于，所述的取代苯为甲苯、二甲苯、间三甲苯、三氟甲苯、硝基苯，或卤代苯。
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