WO2016008351A1 - 一种坎格列净中间体2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法 - Google Patents
一种坎格列净中间体2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法 Download PDFInfo
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- WO2016008351A1 WO2016008351A1 PCT/CN2015/081952 CN2015081952W WO2016008351A1 WO 2016008351 A1 WO2016008351 A1 WO 2016008351A1 CN 2015081952 W CN2015081952 W CN 2015081952W WO 2016008351 A1 WO2016008351 A1 WO 2016008351A1
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- thiophene
- fluorophenyl
- methyl
- bromobenzyl
- borane
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- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Cc1c(Cc2ccc(-c(cc3)ccc3F)[s]2)cc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1 Chemical compound Cc1c(Cc2ccc(-c(cc3)ccc3F)[s]2)cc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 description 1
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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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- the invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of a 2-glycolic acid intermediate 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene.
- Canagliflozin can be (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl Phenyl]-D-glucitol, the structure is shown in Formula III.
- the drug was developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson Pharmaceuticals Co., Ltd., and was approved by the FDA for the treatment of type 2 diabetes with hypoglycemic drugs on March 29, 2013. It is the first sodium-glucose-cotransporter 2 approved by the FDA. (SGLT2) inhibitor.
- Chinese patent application CN103214471A reports the reduction of the starting material (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophen-2-yl]methanone to give 2-(2-methyl-5) -Bromobenzyl)-5-(4-fluorophenyl)thiophene, in the presence of an acid (BF 3 .Et 2 O or trifluoroacetic acid, methanesulfonic acid, etc.) in a suitable solvent (eg acetonitrile, dichloromethane In the above, it is treated with a silane reagent (triethylsilane, etc.) or in the presence of a base in a suitable solvent (ethylene glycol or the like) in a rare gas atmosphere at a high temperature under hydrazine hydrate.
- an acid BF 3 .Et 2 O or trifluoroacetic acid, methanesulfonic acid, etc.
- a suitable solvent eg
- the method requires the use of a silane reagent, which is expensive, flammable, and has a pungent odor; the yield is low, only 78%; and, purification by chromatography is required, and the post-treatment is cumbersome.
- the hydrazine hydrate is used for the reduction treatment, the method needs to be carried out under a rare gas atmosphere, and the reaction conditions are demanding, which is disadvantageous for industrial production; in addition, the method needs to be carried out at a high temperature of 190 ° C, and the energy consumption is large. ,high cost.
- the method uses (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophen-2-yl]methanone as a raw material, and is subjected to reduction reaction under the action of borane to obtain 2-(2) -Methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene.
- the preparation method has complete conversion, the reducing reagent is cheap, the post-treatment is simple, the obtained product has high purity, high reaction yield, simple preparation method and easy industrial application.
- the object of the invention is achieved by the following technical solutions:
- the compound (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophen-2-yl]methanone is subjected to a reduction reaction under the action of borane to give a compound of the formula (I).
- the borane may be directly used as a borane solution or a borane produced in situ.
- the borane produced in situ can be produced by reacting an alkali metal borohydride with a Lewis acid.
- the alkali metal is selected from the group consisting of sodium or potassium.
- the alkali metal borohydride is selected from the group consisting of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.
- the Lewis acid is selected from the group consisting of aluminum trichloride, trifluoroacetic acid or boron trifluoride diethyl ether.
- a process for the preparation of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene according to the present invention which is carried out in an inert solvent.
- the inert solvent is preferably selected from ethers or halogenated alkanes.
- the ether solvent is selected from the group consisting of tetrahydrofuran or dimethyltetrahydrofuran.
- the haloalkane solvent is selected from the group consisting of dichloromethane, chloroform or 1,2-dichloroethane.
- a method for preparing 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene according to the present invention wherein the reaction temperature is -20 to 85 ° C, preferably -10 ° 70 ° C.
- the method for producing 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene according to the present invention has, for example, the following advantages: (1) the reducing reagent used is inexpensive, and the process is more Safe and environmentally friendly; (2) The yield of the product is significantly improved, reaching more than 90%, even up to 97.7%; (3) no chromatographic purification is required, only organic solvent extraction and concentration are required, so the post-treatment operation is simple; 4) The reduction reaction does not need to be carried out under a rare gas atmosphere, which is advantageous for industrial production; (5) the reduction reaction does not need to be carried out at a high temperature, saving energy and reducing production cost.
- the method according to the present invention uses a direct borane solution or in situ generated borane as a reducing reagent, which is inexpensive, technically safer and environmentally friendly; (2) using the method of the present invention, the yield of the obtained product is remarkably improved, reaching 90% or more, even up to 97.7%; (3) using the method of the present invention, purification without using chromatography, only organic solvent is required Extraction and concentration, so the post-treatment operation is simple; (4) According to the method of the present invention, the reduction reaction does not need to be carried out under a rare gas atmosphere, which is advantageous for industrial production; (5) According to the method of the present invention, the reduction reaction does not need to be at a high temperature In the following, energy saving and production cost are reduced; (6) In addition, the inventors have also found that the product obtained by directly using the borane solution is superior in purity and yield as compared with the use of borane produced in situ. .
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供一种坎格列净中间体2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法。该方法包括使如式(II)所示的化合物(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮在直接使用的硼烷溶液或碱金属硼氢化物与路易斯酸反应就地产生的硼烷的作用下,在合适的溶剂和温度下还原以得到式(I)化合物2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩。该制备方法避免了使用昂贵的还原试剂,保证原料转化完全,后处理简单,所得产物纯度高,反应收率高,制备方法简便,易于工业应用。
Description
本申请要求于2014年7月18日提交中国专利局、申请号为201410344963.3发明名称为“一种坎格列净中间体的制备方法”的中国专利申请的优先权,其全部内容通过引用并入本申请中。
本发明涉及药物中间体合成领域,具体涉及一种坎格列净中间体2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法。
Canagliflozin坎格列净,即(1S)-1,5-脱氢-1-C-[3-[[5-(4-氟苯基)-2-噻吩基]甲基]-4-甲基苯基]-D-葡萄糖醇,结构如式III所示。该药品是由强生制药公司的子公司杨森制药公司研发,于2013年3月29日获FDA批准用于治疗II型糖尿病的降血糖药物,是FDA批准的首个钠-葡萄糖-协同转运蛋白2(SGLT2)抑制剂。根据坎格列净的市场占有率、糖尿病患者人数的持续上涨及患者控制血糖的难度加大,分析师们预测这款药物到2016年的销售额会超过6亿美元。结构如式I所示的2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩是合成坎格列净的重要中间体。因此,鉴于坎格列净的市场前景,对2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的合成进行研究是非常必要的。
中国专利申请CN103214471A报道了以原料(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮进行还原反应得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩,反应条件为在酸(BF3.Et2O或三氟乙酸、甲磺酸等)存在下在适当溶剂(如乙
腈,二氯甲烷等)中,用硅烷试剂(三乙基硅烷等)处理,或在碱存在下在适当溶剂(乙二醇等)中在稀有气体气氛下在高温下,用水合肼处理。一方面,该方法需要使用硅烷试剂,价格昂贵,易燃,有刺激性气味;收率低,仅为78%;并且,需要采用色谱进行纯化,后处理繁琐。另一方面,如果采用水合肼进行还原处理的话,该方法需要在稀有气体气氛下进行,反应条件要求苛刻,不利于工业化生产;另外,该方法还需要在190℃的高温下进行,能耗大,成本高。
发明内容
本发明的目的在于提供一种坎格列净中间体2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法。该方法是以(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮为原料,在硼烷的作用下经还原反应得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩。该制备方法转化完全,还原试剂价格便宜,后处理简单,所得产物纯度高,反应收率高,制备方法简便,易于工业应用。本发明的目的是通过以下技术方案实现的:
一种如式(I)所示的化合物2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法,包括以下步骤:使如式(II)所示的化合物(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮在硼烷作用下经历还原反应以得到式(I)化合物。
本发明中原料(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮的合成可按照中国专利申请CN101801371A的实施例1中所描述的来进行。
根据本发明所述的一种2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法,
所述的硼烷可以直接使用硼烷溶液或就地产生的硼烷。在一个优选实施方案中,就地产生的硼烷可以通过碱金属硼氢化物与路易斯酸反应产生。在一个优选实施方案中,碱金属选自钠或钾。在一个优选实施方案中,所述的碱金属硼氢化物选自硼氢化钠、硼氢化钾、三乙酰氧基硼氢化钠及氰基硼氢化钠等。在一个优选实施方案中,所述的路易斯酸选自三氯化铝、三氟乙酸或三氟化硼乙醚溶液。
根据本发明所述的一种2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法,所述还原反应是在惰性溶剂中进行的。在一个优选实施方案中,所述的惰性溶剂优选选自醚类或卤代烷烃。在一个优选实施方案中,醚类溶剂选自四氢呋喃或二甲基四氢呋喃。在一个优选实施方案中,卤代烷烃溶剂选自二氯甲烷、三氯甲烷或1,2-二氯乙烷。
根据本发明所述的一种2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法,反应温度为-20~85℃,优选为-10~70℃。
采用本发明的制备2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的方法具有例如如下优点:(1)所使用的还原试剂价格便宜,工艺上更安全,环境友好;(2)产物的收率显著提高,达到90%以上,甚至达到97.7%;(3)不需要采用色谱纯化,仅需采用有机溶剂萃取、浓缩,因此后处理操作简单;(4)还原反应不需要在稀有气体气氛下进行,有利于工业化生产;(5)还原反应不需要在高温下进行,节省能源,降低生产成本。
下面通过实施例来进一步说明本发明。应该注意的是:本发明的实施例仅是用于说明本发明而给出的,而不是对本发明的限制。
实施例1:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮10g,溶于四氢呋喃100ml中,加入1M硼烷四氢呋喃络合物4ml,将体系加热至50~55℃反应12小时,原料反应完全后,加入20ml水,用50ml二氯甲烷萃取后浓缩得到2-(2-
甲基-5-溴苄基)-5-(4-氟苯)噻吩9.5g,纯度99.0%,收率97.7%。
1HNMR(DMSO-d6)δ2.25(3H,s),4.15(2H,s,Ph-CH2-噻吩),6.85(1H,d,J=3.5Hz,噻吩),7.17(1H,d,J=8.0Hz),7.21(2H,quasi-t),7.31(1H,d,J=3.5Hz,噻吩),7.36(1H,dd,J=8.0,1.9Hz),7.44(1H,d,J=1.9Hz),7.60(2H,m)。
对于C18H14BrFS的分析计算值:C,59.84;H,3.91;Br,22.12;F,5.26;S,8.87。实际测量值:C,59.89;H,3.86;Br,21.93;F,5.17;S,8.85。
实施例2:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮10g,溶于四氢呋喃100ml中,加入1.5g硼氢化钠,7.1g无水三氯化铝,将体系加热至50~55℃反应12小时,原料反应完全后,加入20ml水,用100ml乙酸乙酯萃取后浓缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩9.4g,纯度98.5%,收率96.1%。
实施例3:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮20g,溶于四氢呋喃200ml中,加入4.4g硼氢化钾,14.2g无水三氯化铝,将体系加热至50~55℃反应12小时,原料反应完全后,加入40ml水,用200ml乙酸乙酯萃取后浓缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩18.4g,纯度98.6%,收率94.2%。
实施例4:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮30g,溶于四氢呋喃300ml中,加入9.0g硼氢化钠,加入1M三氟化硼乙醚络合物30ml,将体系加热至60~70℃反应12小时,原料反应完全后,加入60ml水,用300ml乙酸乙酯萃取后浓缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩28.2g,纯度97.9%,收率95.6%。
实施例5:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮10g,溶于二氯甲烷100ml中,加入1.5g硼氢化钠,加入7.3g三氟乙酸,将体系加热至40~45℃反应20小时,原料反应完全后,加入20ml水,用100ml二氯甲烷萃取后浓
缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩9.2g,纯度98.5%,收率94.1%。
实施例6:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮25g,溶于四氢呋喃250ml中,加入11.0g硼氢化钾,加入36.5g三氟乙酸,将体系加热至40~45℃反应22小时,原料反应完全后,加入50ml水,用250ml乙酸乙酯萃取2次后浓缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩22.75g,纯度97.8%,收率92.4%。
实施例7:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮10g,溶于四氢呋喃100ml中,加入10.5g三乙酰氧基硼氢化钠,加入1M硼烷四氢呋喃络合物8ml,体系加热至60~70℃反应28小时,原料反应完全后,加入20ml水,用100ml乙酸乙酯萃取2次后浓缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩9.0g,纯度96.8%,收率90.5%。
实施例8:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮15g,溶于四氢呋喃150ml中,加入1M硼烷四氢呋喃络合物30ml,使体系在-20℃到-10℃反应48小时,原料反应完全后,加入30ml水,用100ml二氯甲烷萃取后浓缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩14.25g,纯度98.9%,收率97.7%。
实施例9:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮10g,溶于四氢呋喃100ml中,加入3.0g硼氢化钠,14.2g无水三氯化铝,使体系在0~10℃反应24小时,原料反应完全后,加入20ml水,用100ml乙酸乙酯萃取后浓缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩9.2g,纯度98.0%,收率93.6%。
实施例10:
称取(5-溴-2-甲基苯基)[5-(对氟苯基)噻吩-2-基]甲酮25g,溶于1,2-二氯乙烷250ml中,加入11.0g硼氢化钾,加入36.5g三氟乙酸,将体系加热至80~85℃
反应26小时,原料反应完全后,加入50ml水,用250ml 1,2-二氯乙烷萃取2次后浓缩得到2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩22.35g,纯度98.1%,收率91.1%。
由以上实施例可以看出,与现有技术相比,根据本发明的方法使用直接的硼烷溶液或就地产生的硼烷作为还原试剂,价格便宜,工艺上更安全,是环境友好的;(2)采用本发明的方法,所获得的产物的收率显著提高,达到90%以上,甚至达到97.7%;(3)采用本发明的方法,不需要使用色谱进行纯化,仅需采用有机溶剂萃取、浓缩,因此后处理操作简单;(4)根据本发明的方法,还原反应不需要在稀有气体气氛下进行,有利于工业化生产;(5)根据本发明的方法,还原反应不需要在高温下进行,节省能源,降低生产成本;(6)另外,本发明人还发现,与使用就地产生的硼烷相比,直接使用硼烷溶液所获得的产物在纯度和收率方面均更优。
本发明提出的2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法已通过实施例进行了描述,本领域技术人员明显能在不背离本发明的内容、精神和范围的情况下对本文所描述的2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法进行改动或适当变更与组合,来实现本发明的目的。特别需要指出的是,所有相类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明的精神、范围和内容中。
Claims (10)
- 根据权利要求1所述的方法,其特征在于:所述硼烷可以直接使用硼烷溶液或就地产生的硼烷。
- 根据权利要求1或2所述的方法,其特征在于:所述还原反应在惰性溶剂中进行。
- 根据权利要求3所述的方法,其特征在于:所述的惰性溶剂选自醚或卤代烷烃。
- 根据权利要求4所述的方法,其特征在于:所述醚选自四氢呋喃或二甲基四氢呋喃。
- 根据权利要求4所述的方法,其特征在于:所述卤代烷烃选自二氯甲烷、三氯甲烷或1,2-二氯乙烷。
- 根据权利要求1-6中任一项所述的方法,其特征在于:所述还原反应在-20~85℃的温度下进行。
- 根据权利要求2-7中任一项所述的方法,其特征在于:所述就地产生的硼烷是采用碱金属硼氢化物与路易斯酸反应得到的,其中碱金属选自钠或钾。
- 根据权利要求8所述的方法,其特征在于:所述的碱金属硼氢化物选自硼氢化钠、硼氢化钾、三乙酰氧基硼氢化钠或氰基硼氢化钠。
- 根据权利要求8所述的方法,其特征在于:所述的路易斯酸选自三氯化铝、三氟乙酸或三氟化硼乙醚溶液。
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