WO2020010765A1 - 一种特布他林中间体的合成方法 - Google Patents

一种特布他林中间体的合成方法 Download PDF

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WO2020010765A1
WO2020010765A1 PCT/CN2018/114814 CN2018114814W WO2020010765A1 WO 2020010765 A1 WO2020010765 A1 WO 2020010765A1 CN 2018114814 W CN2018114814 W CN 2018114814W WO 2020010765 A1 WO2020010765 A1 WO 2020010765A1
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acid
solvent
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dibenzyloxyacetophenone
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张保献
胡杰
王学元
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北京盈科瑞创新药物研究有限公司
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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
    • C07C45/63—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 introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups

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  • the invention belongs to the field of medicine and chemical industry, and particularly relates to a method for synthesizing a key intermediate of terbutaline.
  • Terbutaline 5- (1-hydroxy-2-tert-butylaminoethyl) benzene-1,3-diphenol, CAS is 23031-25-6, and its molecular formula is C 12 H 19 NO 3.
  • the structural formula is as follows:
  • Terbutaline is a short-acting ⁇ 2-receptor agonist COPD treatment drug developed by AstraZeneca. It is a clinically recommended drug for patients with mild to moderate COPD. Terbutaline inhalants have lower dose-dependent side effects than other short-acting beta2-receptor agonists on the market.
  • the terbutaline compound patent (SE335359) was applied by the Swedish Draco Company on October 19, 1966, and has no Chinese family patent.
  • the patent uses 3,5-dibenzyloxyacetophenone as a starting material, and 2- (N-benzyl tert-butylamino) -1- (3,5-dibenzyloxybenzene) is obtained through bromination and condensation reaction.
  • Base Ethyl ketone hydrogen sulfate, and then debenzylated by hydrogenation reduction to prepare terbutaline, dissolved in water, adjusted to pH 5.5 with alkali, evaporated to dryness, and purified by crystallization of a large amount of methanol.
  • terbutaline's synthetic process has many disadvantages such as complex synthetic process, poor operability, difficult purification, difficult removal of impurities, low yield, difficult processing waste generated, and non-compliance with the national green environmental protection concept. such as:
  • Chinese invention patent CN201310560213.5 filed by Anhui Hengxing Pharmaceutical Co., Ltd. discloses a high-purity terbutaline sulfate industrialized production method, which uses bambuterol hydrochloride as a starting material to synthesize tebutamine sulfate through alkaline hydrolysis and salt formation. Talim.
  • This method has the following disadvantages: hydrolysis of polyphenols is extremely easy to oxidize under alkaline conditions; large amounts of solvents are used in the purification process, and the purification effect is poor. Impurities, burning residues and other indicators are difficult to meet the quality standards; high cost, Banbuterol itself The price is high and the input and output returns are insufficient.
  • Chinese invention patent CN201510758230.9 applied by Shandong Dyne Marine Biopharmaceutical Co., Ltd. discloses a synthesis method of terbutaline sulfate, which solves the high-risk hydrogenation operations such as high-pressure hydrogenation and methyl esters in the existing synthesis method of terbutaline sulfate.
  • Terbutaline. This route uses liquid bromine as a brominated reagent, the production operation is extremely unsafe, and the resulting product has a lot of impurities and is difficult to remove, which is not suitable for industrial production.
  • the preparation method of terbutaline sulfate disclosed by the Chinese invention patent CN201710080371.9 applied by Hangzhou Baicheng Pharmaceutical Technology Co., Ltd. uses 3,5-dihydroxyacetophenone as the raw material, and the bromination is directly performed by using a bromination reagent without protecting the hydroxyl group. After the reaction, the carbonyl group is reduced, then condensed with tert-butylamine, and finally salted with sulfuric acid to obtain terbutaline sulfate, but it uses CuBr 2 as a brominating reagent, ethyl acetate and chloroform as a mixed solvent, and then uses diatomaceous earth Filtration is performed to obtain the brominated product.
  • the mixed solvent cannot be recovered and applied, and a large amount of solid waste and heavy metal salts are difficult to handle.
  • the present invention provides a synthesis method of terbutaline intermediate.
  • the method provided by the present invention adopts a single solvent for reaction, can be recycled, the process is simplified, the post-processing operation is simple, and the key steps are using dibromide as a bromination reagent, which is environmentally friendly and pollution-free. considerable.
  • a synthesis method of terbutaline intermediate includes the following steps:
  • the solvent A is any one of organic solvents. More preferably, the solvent A is selected from any one of ethyl acetate, dichloromethane, and chloroform.
  • the amount of the solvent A to be added is 4-15 times (weight to volume ratio) of the compound I, and preferably, the amount of the solvent A is 5 to 10 times (weight to volume ratio) of the compound I.
  • the amount of the solvent A is within the above range, not only the introduction of excessive reaction solvents is avoided, but also the reaction can be effectively promoted, and the yield and purity of the product can be effectively improved.
  • the acid catalyst is one or more selected from the group consisting of sulfuric acid, hydrochloric acid, acetic acid, citric acid, tartaric acid, p-toluenesulfonic acid, and trifluoroacetic acid.
  • the catalyst is selected from sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid.
  • the amount of the acid catalyst added is 8% to 30% (weight ratio) of the compound I, and preferably, the amount of the acid catalyst is 10% to 25% (weight ratio) of the compound I.
  • the compound I is 3,5-dibenzyloxyacetophenone, and the structural formula is:
  • the brominated reagent is dibromohein, which has the following structural formula:
  • the mass ratio of the compound I to the brominating reagent in step S1 is 100: 40-100. If the mass ratio of the compound I to the brominated reagent is not within the above range, the yield and purity of the special step intermediates are greatly reduced, or the special step intermediates are not even obtained.
  • dibromohein as a brominating reagent, not only the purity of the obtained terbactin intermediate is greatly improved, but also the terbateline intermediate can be obtained in a high yield. In addition, dibromide is easily degraded, and it is environmentally friendly and pollution-free.
  • the reaction time in step S1 is determined according to the degree of progress of the reaction, and the reaction time is preferably 4-8 hours.
  • the reaction temperature in step S1 is 20 to 60 ° C (for example, 20/30/40/50/60 ° C), and preferably 20 to 40 ° C.
  • the reaction in step S1 is preferably performed under nitrogen protection.
  • the number of washing times in step S2 is preferably 1-3 times, and more preferably 3 times.
  • the acid catalyst and some water-soluble impurities can be removed by water washing to purify the product.
  • the solvent B in step S3 is one or more of methanol, acetone, ethanol, and isopropanol, and preferably methanol.
  • the amount of solvent B added is 1-8 times (weight to volume ratio) of compound I.
  • the amount of solvent B is added 1-5 times (weight to volume ratio) of compound I.
  • steps S2 and S3 are preferably performed at a temperature of 10-15 ° C.
  • a high-purity free intermediate is synthesized by the present invention, and the intermediate is used for subsequent operations to ensure higher purity and have a very high reaction yield.
  • the invention quantitatively adds a single reaction solvent as the reaction environment according to the amount of the intermediate, avoids the introduction of excessive reaction solvents, reduces the operation difficulty, simplifies the process, saves man-hours, reduces costs, and is environmentally friendly.
  • the last step of the present invention does not require refining and recrystallization, and it is only necessary to transfer crystals with the aid of conventional solvents, avoiding the use of a large amount of solvents and the use of high energy consumption operating conditions.
  • the method of the present invention greatly reduces the difficulty of post-reaction treatment, the product content is high, the reaction solvent can be recycled, the brominated reagent is easily degraded, and the environmental protection pressure is greatly reduced.
  • the starting material compound I that is, 3,5-dibenzyloxyacetophenone and dibromohein were purchased from Damas-beta Company, and other reagents can be obtained through commercially available channels.
  • the solvents, reagents and raw materials used in the present invention are all commercially available chemically pure or analytically pure products.
  • the purity of the compounds was measured using an S6000 high performance liquid chromatograph (purchased from Huapu Keyi (Beijing) Technology Co., Ltd.), and the structure was measured using a Bruker Avance 400MHz nuclear magnetic resonance spectrometer (purchased from Bruker, Germany).
  • the filtrate was placed in a reaction flask under reduced pressure distillation, concentrated to dryness, 5 times (weight to volume ratio) methanol was added and stirred for 30 minutes, reduced to 10- It was crystallized at 15 ° C for 2h and suction filtered to obtain 89 g of a white crystalline solid with a yield of 71.9% and a purity of 99.83%.
  • the filtrate was placed in a reaction flask under reduced pressure distillation, concentrated to dryness, reduced to room temperature, and added 1 times (weight to volume) methanol and stirred for 30 minutes Lowered to 10-15 ° C for 2h and crystallized for 2h, and filtered by suction to obtain 85g of white crystalline solid with a yield of 65.79% and a purity of 99.77%.
  • the filtrate was placed in a reaction flask under reduced pressure distillation, concentrated to dryness, 5 times (weight to volume ratio) methanol was added and stirred for 30 minutes, reduced to 10- Crystallize at 15 ° C for 2h and suction filter to obtain 71 g of white crystalline solid with a yield of 50.94% and a purity of 76.28%.
  • the filtrate was placed in a reaction flask under reduced pressure distillation, concentrated to dryness, 5 times (weight to volume ratio) methanol was added and stirred for 30 minutes, reduced to 10- Crystallize at 15 ° C for 2h and suction filter to obtain 68 g of white crystalline solid with a yield of 49.85% and a purity of 75.27%.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供了一种特布他林中间体的合成方法。本发明所提供的方法采用单一溶媒进行反应，可回收利用，工艺简化，后处理操作简单，关键步骤采用二溴海因作为溴代试剂，绿色环保无污染，所获得的产品纯度高、收率可观。

Description

一种特布他林中间体的合成方法 技术领域
本发明属于医药化工领域，具体涉及一种特布他林关键中间体的合成方法。
背景技术
特布他林：5-(1-羟基-2-叔丁基氨基乙基)苯-1,3-二酚，CAS为23031-25-6，分子式为C 12H 19NO 3，结构式如下：
Figure PCTCN2018114814-appb-000001
特布他林是由阿斯利康公司研发的短效β2-受体激动剂型COPD治疗药物，为轻、中度COPD患者的临床推荐用药。相较其他已上市的短效β2-受体激动剂，特布他林吸入剂具有更低的剂量依赖性副作用。
特布他林化合物专利(SE335359)由瑞典德拉科公司于1966年10月19日申请，无中国同族专利。该专利以3,5-二苄氧基苯乙酮为起始原料，经溴代、缩合反应制得2-(N-苄基叔丁胺基)-1-(3,5-二苄氧基苯基)乙酮硫酸氢盐，再经氢化还原脱苄，制得特布他林，加水溶解，碱调pH值至5.5，蒸干水分，大量甲醇结晶纯化。
目前特布他林的合成工艺均存在合成工艺复杂，可操作性差，纯化困难，杂质难去除、收率低、产生的工艺废料垃圾难处理，不符合国家绿色环保理念等诸多缺陷。比如：
安徽恒星制药有限公司申请的中国发明专利CN201310560213.5公开了一种高纯度硫酸特布他林工业化生产方法，其以盐酸班布特罗为起始原料经碱性水解、成盐合成硫酸特布他林。此种方法存在以下缺点：碱性条件下水解多酚极易氧化；精制过程溶剂用量大，纯化效果差，杂质含量、炽灼残渣等指标难以满足质量标准要求；成本高，班布特罗本身价格较高，投入和产出收益不足。
山东达因海洋生物制药股份有限公司申请的中国发明专利 CN201510758230.9公开了一种硫酸特布他林合成方法，其解决了现有硫酸特布他林合成方法存在高压氢化等高危操作以及甲基锂、偶氮甲烷等高危试剂、成本较高的技术问题，采用3,5-二羟基苯乙酮为原料，通过羟基保护、溴代反应、羰基还原、缩合反应、与硫酸成盐，得到硫酸特布他林。该路线使用液溴为溴代试剂，生产操作极不安全，并且生成产物杂质较多，难以除去，不适合工业化生产。
杭州百诚医药科技股份有限公司申请的中国发明专利CN201710080371.9公开的硫酸特布他林制备方法，采用3,5-二羟基苯乙酮为原料，不用保护羟基直接用溴代试剂进行溴代反应，之后羰基还原，再与叔丁胺缩合，最后与硫酸成盐得到硫酸特布他林，但其选用CuBr 2作为溴代试剂，用乙酸乙酯和氯仿作为混合溶剂进行反应，然后用硅藻土进行过滤，得到溴代产物，混合溶媒没有办法回收套用，并且产生大量的固体废弃物以及重金属盐难以处理。
Riley HA,Gray AR和中国科学院上海药物研究所的殷敦祥等人公开了一种硫酸特布他林的制备方法(“硫酸特布他林的合成”，中国医药工业杂志，1999,30(1))，合成得到2-(N-苄基叔丁胺基)-1-(3,5-二苄氧基苯基)乙醇后，进一步氢化脱苄，合成硫酸特布他林。但此方法过程繁琐，纯度低。并且生成二氧化硒的废物，不利于环保。
发明内容
技术问题
为了解决上述技术问题，本发明提供了一种特布他林中间体的合成方法。本发明所提供的方法采用单一溶媒进行反应，可回收利用，工艺简化，后处理操作简单，关键步骤采用二溴海因作为溴代试剂，绿色环保无污染，所获得的产品纯度高、收率可观。
解决方案
本发明是通过以下技术方案实现的：
一种特布他林中间体的合成方法，包括如下步骤：
S1：将化合物Ⅰ溶于溶剂A中，加入溴代试剂和酸催化剂，反应；
S2：反应完毕后，抽滤，收集滤液，水洗，除水干燥，减压蒸馏、浓缩 至干，得到浓缩物；
S3：浓缩物加入溶剂B搅拌，析出白色结晶性物质，抽滤，即得化合物Ⅱ。化学反应方程式如下：
Figure PCTCN2018114814-appb-000002
本发明所述的合成方法，其中步骤S1中，溶剂A为有机溶媒中的任意一种，进一步优选的，溶剂A选自乙酸乙酯、二氯甲烷和氯仿中的任意一种。溶剂A的加入量为化合物Ⅰ的4-15倍(重量体积比)，优选的，溶剂A的加入量为化合物Ⅰ的5-10倍(重量体积比)。溶剂A的加入量为上述范围内时，不仅避免了过多反应溶剂的引入，还能够有效促进反应进行，有效提高产品的收率和纯度。
本发明所述方法中，其中步骤S1中，所述酸催化剂为选自硫酸、盐酸、醋酸、柠檬酸、酒石酸、对甲苯磺酸、三氟乙酸中的一种或几种，优选的，酸催化剂选自硫酸、对甲苯磺酸或三氟乙酸。酸催化剂的加入量为化合物Ⅰ的8％～30％(重量比)，优选的，酸催化剂的加入量为化合物Ⅰ的10％～25％(重量比)。通过以上述范围加入酸催化剂，能够以非常高的反应效率进行反应，从而能够得到高收率和高纯度的特步他林中间体。
本发明所述方法中，其中所述化合物Ⅰ为3,5-二苄氧基苯乙酮，结构式为：
Figure PCTCN2018114814-appb-000003
溴代试剂为二溴海因，结构式如下：
Figure PCTCN2018114814-appb-000004
优选的，步骤S1中化合物Ⅰ与溴代试剂的质量比为100:40-100。如果化合物Ⅰ与溴代试剂的质量比不在上述范围内，特步他林中间体的收率和纯度大幅降低，或者甚至得不到所述特步他林中间体。
另外，在本发明中，通过采用二溴海因作为溴代试剂，不仅大幅提高了所得特步他林中间体的纯度，还能以高收率得到特步他林中间体。而且，二 溴海因容易降解，绿色环保无污染。
本发明所述的方法中，其中步骤S1中反应时长根据反应的进行程度来确定，优选反应时长为4-8h。
本发明所述的方法中，其中步骤S1中的反应温度为20～60℃(例如20/30/40/50/60℃)，优选20～40℃。
本发明所述的方法中，其中步骤S1中的反应优选在氮气保护下进行。
本发明所述的方法中，其中步骤S2中的水洗次数优选为1-3次，更优选为水洗3次。通过水洗可以除去酸催化剂及一些易溶于水的杂质，纯化产物。
本发明所述的方法中，其中步骤S3中溶剂B为甲醇、丙酮、乙醇、异丙醇中的一种或多种，优选为甲醇。溶剂B的加入量为化合物Ⅰ的1-8倍(重量体积比)，优选的，溶剂B的加入量为化合物Ⅰ的1-5倍(重量体积比)。
本发明所述的方法中，其中步骤S2和S3优选在温度10-15℃下进行。
有益效果
采用上述技术方案所产生的有益效果在于：
1.本发明合成得到高纯度的游离的中间体，利用该中间体进行后续操作，保证较高的纯度，同时具有非常高的反应收率。
2.本发明根据中间体的量定量加入单一反应溶剂作为反应环境，避免了过多反应溶剂的引入，减小了操作难度，简化工艺，节约工时，降低成本，绿色环保。
3.本发明最后一步无需精制重结晶，仅仅借助常规溶剂转晶即可，避免了大量溶剂的使用和高能耗操作条件的使用。
4.本发明方法大大降低了反应后处理难度，产品含量高，反应溶剂均可回收利用，溴代试剂容易降解，大大降低了环保压力。
具体实施方式
以下将详细说明本发明的各种示例性实施例、特征和方面。
另外，为了更好的说明本发明，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本发明同样可以实施。下列实施例仅用于说明本发明，而不应视为限制本发明的范围。凡依照本发明内容进行的任何本领域的等同替换，均属于本发明的保护范围。
本发明的化学反应中，起始原料化合物Ⅰ即3,5-二苄氧基苯乙酮以及二溴海因均购自damas-beta公司，其它试剂均可通过市售途径得到。本发明中使用的溶剂、试剂和原料等均为市售化学纯或分析纯产品。
以下实施例中化合物纯度测定使用S6000高效液相色谱仪(购自华谱科仪(北京)科技有限公司)，结构测定使用Bruker Avance 400MHz型核磁共振波谱仪(购自德国Bruker公司)。
实施例1
将100g式Ⅰ化合物加入10倍(重量体积比)乙酸乙酯中，加入25g对甲苯磺酸和64g的二溴海因，氮气置换3次，常压下25℃避光搅拌5h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，加入4倍(重量体积比)甲醇搅拌35min，降至10-15℃析晶1.5h，抽滤，得白色结晶性固体95g，收率76.76％，纯度99.37％。
1HNMR(400MHz，CDCl 3)：δ(ppm)：4.415(2H,s)，5.108(4H,s)，6.878(1H,m)，7.234-7.237(2H,m)，7.284-7.469(10,m)。
13CNMR(100MHz，CDCl 3)：δ(ppm)：31.22，70.76，108.09-108.19，137.91-129.00，138.50，138.10，160.43，191.17。
实施例2
将100g式Ⅰ化合物加入5倍(重量体积比)乙酸乙酯中，加入20g三氟乙酸和80g的二溴海因，氮气置换3次，常压下25℃避光搅拌4h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，加入5倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体89g，收率71.9％，纯度99.83％。
实施例3
将100g式Ⅰ化合物加入8倍(重量体积比)二氯甲烷中，加入18g对甲苯磺酸和70g的二溴海因，氮气置换3次，常压下25℃避光搅拌5h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，降至室温，加入3倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体93g，收率75.14％，纯度99.0％。
实施例4
将100g式Ⅰ化合物加入9倍(重量体积比)氯仿中，加入15g三氟乙酸和 64g的二溴海因，氮气置换3次，常压下25℃避光搅拌6h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，降至室温，加入5倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体90g，收率72.72％，纯度99.82％。
实施例5
将100g式Ⅰ化合物加入4倍(重量体积比)二氯甲烷中，加入8g硫酸和40g的二溴海因，氮气置换3次，常压下25℃避光搅拌6h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，降至室温，加入1倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体85g，收率65.79％，纯度99.47％。
实施例6
将100g式Ⅰ化合物加入15倍(重量体积比)氯仿中，加入30g对甲苯磺酸和100g的二溴海因，氮气置换3次，常压下25℃避光搅拌6h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，降至室温，加入8倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体84g，收率66.97％，纯度99.34％。
实施例7
将100g式Ⅰ化合物加入10倍(重量体积比)乙酸乙酯中，加入25g对甲苯磺酸和80g的液溴，氮气置换3次，常压下25℃避光搅拌4h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，加入5倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体71g，收率50.94％，纯度76.28％。
实施例8
将100g式Ⅰ化合物加入5倍(重量体积比)氯仿中，加入20g三氟乙酸和64g的四丁基溴化铵，氮气置换3次，常压下25℃避光搅拌4h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，加入5倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体68g，收率49.85％，纯度75.29％。
实施例9
将100g式Ⅰ化合物加入10倍(重量体积比)乙酸乙酯中，加入10g对甲 苯磺酸和38g的二溴海因，氮气置换3次，常压下25℃避光搅拌6h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，降至室温，加入3倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体71g，收率52.32％，纯度80.58％。
实施例10
将100g式Ⅰ化合物加入10倍(重量体积比)乙酸乙酯中，加入25g三氟乙酸和102g的二溴海因，氮气置换3次，常压下25℃避光搅拌6h。抽滤，抽滤液置于反应瓶中，水洗三次，除水并干燥，抽滤液置于反应瓶中减压蒸馏，浓缩至干，降至室温，加入2倍(重量体积比)甲醇搅拌30min，降至10-15℃析晶2h，抽滤，得白色结晶性固体69g，收率53.09％，纯度79.52％。

Claims (12)

  1. 一种特布他林中间体的合成方法，其特征在于，包括如下步骤：
    S1：将3,5-二苄氧基苯乙酮溶于溶剂A中，加入溴代试剂和酸催化剂，反应；
    S2：反应完毕后，抽滤，收集滤液，水洗，除水干燥，减压蒸馏、浓缩至干，得到浓缩物；
    S3：浓缩物加入溶剂B搅拌，析出白色结晶性物质，抽滤，即得所述中间体。
  2. 如权利要求1所述的合成方法，其中，所述溴代试剂为二溴海因。
  3. 如权利要求1-2任一项所述的合成方法，其中，所述步骤S1中，3,5-二苄氧基苯乙酮与溴代试剂的质量比为100:40-100。
  4. 如权利要求1-3任一项所述的合成方法，其中所述步骤S1中，所述酸催化剂为选自硫酸、盐酸、醋酸、柠檬酸、酒石酸、对甲苯磺酸、三氟乙酸中的一种或几种，优选的，酸催化剂选自硫酸、对甲苯磺酸、三氟乙酸中的一种。
  5. 如权利要求1-4任一项所述的合成方法，其中，所述酸催化剂的加入量为3,5-二苄氧基苯乙酮的8％～30％，以重量比计；
    优选地，所述酸催化剂的加入量为3,5-二苄氧基苯乙酮的10％～25％，以重量比计。
  6. 如权利要求1-5任一项所述的合成方法，其中所述步骤S1中溶剂A选自乙酸乙酯、二氯甲烷和氯仿中的任意一种。
  7. 如权利要求1-6任一项所述的合成方法，其中，所述溶剂A的加入量为3,5-二苄氧基苯乙酮的4～15倍，以重量体积比计；
    优选地，所述溶剂A的加入量为3,5-二苄氧基苯乙酮的5～10倍，以重量体积比计。
  8. 如权利要求1-7任一项所述的合成方法，其中，所述步骤S1中的反应温度为20～60℃，优选20～40℃；
    优选地，所述步骤S2和所述步骤S3中的反应温度为10～15℃。
  9. 如权利要求1-8任一项所述的合成方法，其中，所述步骤S1中的反应优选在氮气保护下进行；
    优选地，所述步骤S1中的反应时长为4～8h。
  10. 如权利要求1-9任一项所述的合成方法，其中，所述步骤S2中的水洗次数优选为1-3次，更优选为水洗3次。
  11. 如权利要求1-10任一项所述的合成方法，其中，步骤S3中溶剂B为甲醇、丙酮、乙醇、异丙醇中的一种或多种，优选为甲醇。
  12. 如权利要求1-11任一项所述的合成方法，其中，所述溶剂B的加入量为3,5-二苄氧基苯乙酮的1～8倍，以重量体积比计；
    优选地，所述溶剂B的加入量为3,5-二苄氧基苯乙酮的1～5倍，以重量体积比计。
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