CN103420823B - The method of synthesizing α- chloro-4-fluorophenyl benzyl ketone - Google Patents

The method of synthesizing α- chloro-4-fluorophenyl benzyl ketone Download PDF

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CN103420823B
CN103420823B CN 201310304842 CN201310304842A CN103420823B CN 103420823 B CN103420823 B CN 103420823B CN 201310304842 CN201310304842 CN 201310304842 CN 201310304842 A CN201310304842 A CN 201310304842A CN 103420823 B CN103420823 B CN 103420823B
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陈本顺
周长岳
徐秋斌
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南京欧信医药技术有限公司
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Abstract

本发明涉及化学领域,更为具体的说是涉及药物化学领域,更为具体的说是涉及α-氯-4氟苯基苄基酮的合成方法。 The present invention relates to the field of chemistry, and more specifically relates to the field of pharmaceutical chemistry, and more specifically to the synthesis of α- chloro-4-fluorophenyl benzyl ketone relates. 针对传统制备工艺中苯乙酸合成化合物(4)成本高,工艺复杂,不适应于工业化生产的问题,本发明提供了一种全新的用扁桃酸合成α-氯-4氟苯基苄基酮的合成方法。 Phenylacetic acid in the conventional process for synthesis of the compound prepared in (4) high costs, complex process, not suited to industrial production problems, the present invention provides a new synthesis of mandelic acid with α- chloro-4-fluorophenyl benzyl ketone resolve resolution. 将α位的氯代作为第一步反应,并配合相应的合成参数,从而使得以扁桃酸为起始原料,合成化合物(4)三步合成的总得率达到了67.8%,并且反应中产生的副产物少,目标产物的纯度高、纯化容易,适应于工业化生产。 The α-chloro-position as a first step reaction, and with the corresponding synthesis parameters, such as mandelic acid to the starting material, the synthesis of compound (4) synthesized in three steps total yield reached 67.8%, and produced in the reaction less by-products, the desired product of high purity, readily purified, suitable for industrial production.

Description

α-氯-4氟苯基苄基酮的合成方法 The method of synthesizing α- chloro-4-fluorophenyl benzyl ketone

技术领域 FIELD

[0001]本发明涉及化学领域,更为具体的说是涉及药物化学领域,更为具体的说是涉及氯_4氟苯基苄基酮的合成方法。 [0001] The present invention relates to the field of chemistry, and more specifically relates to the field of pharmaceutical chemistry, and more specifically to the synthesis of benzyl chloride _4-fluorophenyl ketone is directed.

背景技术 Background technique

[0002]化合物(4)是一种重要的药物中间体。 [0002] Compound (4) it is an important pharmaceutical intermediate. 目前行业内有多种化合物(4)的合成方法, 以苯乙酸为起始原料,合成化合物(4)是其中之一,其合成路线如下: There are a variety of industry Compound (4) Method to acid as the starting material, the synthesis of compound (4) is one in which synthesis route is as follows:

Figure CN103420823BD00041

[0004] 我们发现,在这种合成路线下,α位氯化的难度高,副产物多,有氯气二取代产物; 进而造成目标产物收率低,目标产物的纯化工艺要求高,投入大,因此在工业上的应用受到限制。 [0004] We have found that in this synthetic route, difficult α position chlorinated byproducts more, there are two chlorine-substituted product; thus causing the desired product yield is low, a high purification process requirements of the desired product, investment, Therefore, in the industrial application is limited.

[0005] 扁桃酸的合成较为容易,且其成本较低,因此改进扁桃酸制备化合物(4)的制备工艺是目前制药领域一个研究的重点。 [0005] Synthesis easier mandelic acid, and its low cost, thus improving the manufacturing process mandelic acid Preparation of Compound (4) is currently a focus of research in the pharmaceutical art.

[0006] 我们的目的在于:通过合成路线的改进,提高化合物(4)的产量及纯度,简化后续纯化工艺。 [0006] Our object: By improved synthetic route to improve the compound (4) of the yield and purity, to simplify the subsequent purification process. 使得以扁桃酸为起始原料合成化合物(4)满足工业化生产的需求。 Such mandelic acid as a starting material in synthesis of the compound (4) to meet the needs of industrial production.

发明内容 SUMMARY

[0007] 针对传统制备工艺中苯乙酸合成化合物(4)成本高,工艺复杂,不适应于工业化生产的问题,本发明提供了一种全新的用扁桃酸合成氯-4氟苯基苄基酮的合成方法。 [0007] The conventional manufacturing process for the synthesis of phenylacetic acid compound (4) high costs, complex process, not suited for industrial production, the present invention provides a new synthetic-chloro-4-fluorophenyl mandelic acid with benzyl ketone synthetic methods.

[0008] 本发明的技术方案如下: [0008] The aspect of the present invention is as follows:

[0009] 1、α_氯-4氟苯基苄基酮的合成方法,所述α_氯-4氟苯基苄基酮的合成路线如式1 所示: [0009] 1, synthesis α_ chloro-4-fluorophenyl benzyl ketone of the α_ Scheme chloro-4-fluorophenyl benzyl ketone as shown in formula 1:

Figure CN103420823BD00042

[0011] 2、所述化合物(3)的合成路线如式2所示: [0011] 2, the synthetic route Compound (3) as shown in Formula 2:

Figure CN103420823BD00043

[0013] 3、所述化合物(2)的合成路线如式3所示: [0013] 3, the synthetic route Compound (2) as shown in Formula 3:

Figure CN103420823BD00051

[0015] 4、进一步地,我们公开了α-氯苯乙酰氯与氟苯在溶剂中发生傅克酰基化反应生成氯_4氟苯基苄基酮,具体的合成步骤为,将α-氯苯乙酰氯溶解于有机溶剂中;在-10~0°C 的温度条件下滴入氟苯,保持反应温度在50~90°C;a-氯苯乙酰氯与氟苯的混合摩尔比为1: 1.2-1:10,a-氯苯乙酰氯与三氯化铝摩尔比为1:0.5-1:2。 [0015] 4, further, we disclose Friedel-Crafts acylation reaction of benzyl chloride _4-fluorophenyl ketone with α- fluorophenyl chlorophenyl acetyl chloride in a solvent occurs, specific synthetic steps, the chloro-α- phenylacetyl chloride is dissolved in an organic solvent; fluorobenzene was added dropwise at a temperature of -10 ~ 0 ° C, the reaction temperature was maintained at 50 ~ 90 ° C; a- chlorophenyl mixed chloride with a molar ratio of 1-fluorobenzene : 1.2-1: 10, a- chlorophenyl acetyl chloride and aluminum trichloride as a molar ratio of 1: 0.5 to 1: 2.

[0016] 5、同时,我们还公开了所述a-氯苯乙酸与酰氯化试剂反应合成a-氯苯乙酰氯;所述反应温度为20~80°C,所述a-氯苯乙酸与酰氯化试剂的混合摩尔比为1:1.1~1: 5。 [0016] 5, the same time, we also disclose the acid chloride with an acid chloride of a- reagent synthesized a- chlorophenyl acetyl chloride; the reaction temperature is 20 ~ 80 ° C, the acid chloride and a- mixing molar ratio of acid chloride forming agent is 1: 1.1 to 1: 5.

[0017] 6、同时我们还进一步公开了扁桃酸合成a-氯苯乙酰氯的步骤为: [0017] 6, we further disclose the synthesis of a- chlorophenyl mandelic acid chloride the steps of:

[0018] (1)扁桃酸和醇在酸的催化下合成扁桃酸酯;这里的醇可以是甲醇、乙醇、异丙醇等,特别优选为乙醇。 [0018] (1) Synthesis of mandelic acid and alcohol esters under catalysis mandelic acid; alcohols herein can be methanol, ethanol or isopropanol, particularly preferably ethanol. 酸可以是氯化氢、浓硫酸、对甲苯磺酸,优选氯化氢。 The acid may be hydrogen chloride, concentrated sulfuric acid, p-toluenesulfonic acid, preferably hydrogen chloride. 反应温度为30~80 °C。 The reaction temperature is 30 ~ 80 ° C. 扁桃酸和醇的混合质量比为:1:2~1:10。 Mixing mass ratio of mandelic acid and alcohol is: 1: 2 to 1:10. 扁桃酸和酸的摩尔比为:1:0.1~1:0.3。 And the molar ratio of mandelic acid is: 1: 0.1 to 1: 0.3.

[0019] (2)扁桃酸酯在二氯亚砜作用下合成a-氯苯乙酸乙酯;这一反应的温度优选为30~ 80°C。 [0019] (2) Synthesis of ethyl mandelate ester a- thionyl chloride in chlorobenzene effect; the temperature of the reaction is preferably 30 ~ 80 ° C. 反应优选在二氯亚砜、甲苯或者二氯甲烷溶剂中完成。 The reaction is preferably completed in thionyl chloride, toluene or methylene chloride solvent. 扁桃酸酯与二氯亚砜的摩尔比为 Molar ratio of mandelic acid esters with thionyl chloride is

[0020] (3)α-氯苯乙酸乙酯酸性水解成a-氯苯乙酸。 Ethyl acetate [0020] (3) α- a- chloro-chlorophenyl acidic hydrolysis into acid. 这里酸性水解是指在醋酸、盐酸或者稀硫fe水洛液中完成。 Herein refers to complete acidic hydrolysis in acetic acid, hydrochloric acid or dilute sulfuric fe Los water solution.

[0021] 7、在第四技术方案中我们进一步优选,所述溶剂是氟苯、卤代烃、或者硝基苯。 [0021] 7, in a fourth aspect, we further preferably, the solvent is a fluorophenyl, a halogenated hydrocarbon, or nitrobenzene.

[0022] 8、在第五技术方案中,我们进一步限定酰氯化试剂为二氯亚砜或者草酰氯。 [0022] 8. In a fifth aspect, we further define chloride reagent is thionyl chloride or oxalyl chloride.

[0023] 9、同时,在第五组或者是第八组技术方案中,我们优选所述的反应溶剂为二氯亚砜、草酰氯、氯代烃或者甲苯。 [0023] 9, while, in the fifth set or an eighth aspect group, the reaction is preferably a solvent for the thionyl us, oxalyl chloride, chlorinated hydrocarbons or toluene.

[0024] 采用本发明所公开的技术方案,将a位的氯代作为第一步反应,并配合相应的合成参数,从而使得以扁桃酸为起始原料,合成化合物(4)三步合成的总得率达到了67.8%,并且反应中产生的副产物少,目标产物的纯度高、纯化容易,适应于工业化生产。 [0024] The technical solution disclosed in the present invention, as a first-stage reaction chloro-bit, and with the corresponding synthesis parameters, so that the three-step synthesis to mandelic acid as a starting material, the synthesis of compound (4) reached 67.8% overall yield and less by-products generated in the reaction, the desired product of high purity, ease of purification, suitable for industrial production. 具体实施方式[0025] 实施例1 DETAILED DESCRIPTION Example 1 [0025]

Figure CN103420823BD00052

[0027]合成方法具体描述为:在1 L的三口瓶中加入152 g扁桃酸和300 mL无水乙醇,通入l〇g氯化氢,体系加热至78°c,充分反应,反应完全后将反应液浓缩得到174g扁桃酸乙酯。 [0027] The synthetic methods specifically described as: mandelic acid were added 152 g ethanol and 300 mL of dry 1 L three-necked flask, into l〇g hydrogen chloride, heated to 78 ° c, the reaction sufficiently, the reaction was complete, the reaction ethyl mandelate was concentrated to give 174g. 向浓缩液中加入131g二氯亚砜,加热至78°C,反应2h,充分反应后,加入醋酸250 ml,浓盐酸150 ml,继续加热保持100°C反应2h后,减压蒸馏,得到143g a-氯代苯乙酸,收率84%。 After the concentrate was added to 131g of thionyl chloride and heated to 78 ° C, the reaction 2h, the reaction sufficiently, acetic acid was added 250 ml, 150 concentrated hydrochloric ml, 100 ° C and heating was continued to maintain the reaction After 2h, evaporated under reduced pressure, to give 143g a- chloro acid, yield 84%. [0028] 实施例2 [0028] Example 2

Figure CN103420823BD00061

[0030] 合成方法具体描述为:取实施例1中获得的化合物(2)85 g,加入到500 ml三口瓶中,以100 mL甲苯溶液溶解后,加入二氯亚砜62g,充分溶解混匀,室温搅拌2h,然后加热,回流反应0.5h。 [0030] The synthetic methods specifically described as follows: the compound obtained in Example 1 (2) 85 g embodiments taken, added to 500 ml three-necked flask, 100 mL of toluene in the solution was dissolved, was added thionyl chloride 62g, mixed to fully dissolve at room temperature was stirred for 2h, then heated to reflux for 0.5h. 所得溶液减压浓缩至不再有液体被蒸出,得到90ga-氯代苯乙酰氯,收率95%。 The resulting solution was concentrated under reduced pressure until no more liquid is distilled off to give 90ga- chloro-phenylacetyl chloride in 95% yield.

[0031] 实施例3 [0031] Example 3

Figure CN103420823BD00062

[0033]合成方法具体描述为:在500 ml三口瓶中分别加入150g氟苯,33g三氯化铝,冷却至〇°C,滴加实施例2中获得的化合物(3)47g,滴加速度为47g/h,滴加完毕后,体系升温至80°C,保温反应4h,将反应体系降至0°C,倒入100 mL的0°C的2mol/L盐酸中。 [0033] The synthetic methods specifically described as follows: In 500 ml three-neck flask are added 150g fluorobenzene, 33g of aluminum trichloride was cooled to square ° C, the compound (3) 47g obtained in Example 2 was added dropwise embodiment, acceleration drops 47g / h, after completion of the dropwise addition, the system was heated to 80 ° C, the reaction incubated 4h, the reaction system was reduced to 0 ° C, poured into 2mol / L hydrochloric acid Add 100 mL at 0 ° C. 静置、分层, 取有机溶液层,用饱和碳酸氢钠调节pH到中性。 Standing, stratification, the organic layer was taken, the pH was adjusted to neutral with saturated sodium bicarbonate. 静置、分层,分别取有机层和水层;其中水层用20 g氟苯萃取,静置分层后取有机层,将两次获得的有机层合并,浓缩至不再有液体蒸出,得到2-氯-1-(4-氣苯基)-苯乙酮,称重为52g,收率85%。 Standing, stratification, the organic and aqueous layers were collected; wherein the water layer was extracted through 20 g of fluorobenzene, and the organic layer was taken after standing layers were separated and the organic layer was twice obtained were combined, concentrated liquid was distilled off until no , to give 2-chloro-1- (4-gas-phenyl) - acetophenone, weighing 52g, yield 85%.

[0034] 实施例4 [0034] Example 4

[0035] 依次按照实施例1至实施例3,将扁桃酸制备合成2_氯_1_( 4_氟苯基)_苯乙酮。 [0035] Example 1 successively according to Example 3, prepared mandelic acid synthesis chloro _1_ 2_ (4_ fluorophenyl) acetophenone _. [0036]同时,按照以下传统的制备方式,进行2-氯-1-(4-氟苯基)_苯乙酮的合成。 [0036] Meanwhile, according to the following conventional mode of preparation of 2- chloro-1- (4-fluorophenyl) _ Synthesis of acetophenone.

[0037] (1)苯乙酰氯的制备:取苯乙酸136 g,加入到1000 ml三口瓶中,以200 mL甲苯溶液溶解后,加入二氯亚砜120g,充分溶解混匀,室温搅拌2h,然后加热,回流反应0.5h。 [0037] Preparation of phenylacetyl chloride (1): Take acid 136 g, was added to a 1000 ml three-necked flask, 200 mL of toluene in the solution was dissolved, was added thionyl chloride 120g, mixed to fully dissolve, stirred at room temperature 2h, then heated to reflux for 0.5h. 所得溶液减压浓缩至不再有液体被蒸出,得到143g苯乙酰氯,收率95%。 The resulting solution was concentrated under reduced pressure until no liquid is evaporated, phenylacetyl chloride to give 143g, 95% yield.

[0038] (2)氟苯基苯乙酮的制备:向反应瓶中加入三氯化铝15g、氟苯62g,在冰水浴下, 滴加苯乙酰氯21g,温度控制在40°C;升温至80°C;保温搅拌5小时,TLC分析原料反应完全, 降至室温,得深绿色溶液;倾入55g碎冰与35ml 2 mo 1/L的盐酸的混合物中,控制温度在60 °C以下,分层;有机层加入120mL饱和碳酸氢钠调节pH,分层;水层用适量氟苯反提,合并有机层,浓缩至干,加入适量石油酿重结晶,得20g 4-氣苯基苯乙酮,收率69%; [0038] (2) Preparation difluorophenyl acetophenone: To the reaction flask was added aluminum trichloride 15g, fluorobenzene 62g, under ice-water bath, was added dropwise phenylacetyl chloride 21g, temperature controlled at 40 ° C; heating to 80 ° C; incubated for 5 h, TLC analysis of the feed the reaction was complete, cooled to room temperature to give a dark green solution; the mixture was poured into 55g of crushed ice and 35ml 2 mo 1 / L hydrochloric acid, the temperature was controlled at below 60 ° C layers were separated; the organic layer was added 120mL of saturated sodium bicarbonate adjust the pH, delamination; aqueous layer was back extracted with an appropriate amount of fluorobenzene, and the organic layers were combined and concentrated to dryness, adding an appropriate amount of petroleum stuffed recrystallized gas 20g 4- phenylbenzyl ethanone, 69% yield;

[0039] (3)2-氯-1-(4-氟苯基)_苯乙酮的制备:向反应瓶中加入4-氟苯基苯乙酮13 g, 二氯甲烷120 mL,室温下通入氯气6g,4-氟苯基苯乙酮反应完时,向反应瓶中加入150 mL 15%的亚硫酸钠溶液,加入150 mL饱和碳酸氢钠调节pH;分层,有机层再加入适量水洗涤,浓缩得油状物9g 2-氯-1-(4-氟苯基)-苯乙酮,收率60%; [0039] (3) 2-Chloro-1- (4-fluorophenyl) acetophenone _: added 4-fluorophenyl acetophenone reaction flask 13 g, dichloromethane 120 mL, room temperature chlorine gas 6g, when 4-fluorophenyl acetophenone completion of the reaction, 150 mL 15% sodium sulfite solution was added to the reaction flask was added 150 mL of saturated sodium bicarbonate adjust the pH; separated and the organic layer was washed with an appropriate amount of water was added , and concentrated to give an oil 9g 2- chloro-1- (4-fluorophenyl) - acetophenone, yield 60%;

[0040]传统方式的总收率为39.33%,而通过本发明公开的技术方案制备的总收率为67.8%〇 [0040] The total yield of 39.33% in a conventional manner, while the total yield produced by the present invention is disclosed aspect billion 67.8%

Claims (6)

  1. 1. a-氯-4氣苯基苄基酬的合成方法,其特征是所述a-氯-4氣苯基苄基酬的合成路线如式1所示: Method 1. Synthesis of a- gas-chloro-4-phenylbenzyl remuneration, which is shown in Scheme wherein said gas a- chloro-4-phenylbenzyl remuneration formula 1:
    Figure CN103420823BC00021
    a-氯苯乙酷氯与氣苯在溶剂中发生傅克酷基化反应生成a-氯-4氣苯基苄基酬,具体的合成步骤为,将Q-氯苯乙酷氯溶解于有机溶剂中;在-10~〇°C的溫度条件下滴入氣苯,保持反应溫度在50~90°C ;a-氯苯乙酷氯与氣苯的混合摩尔比为1:1.2-1:10,a-氯苯乙酷氯与= 氯化侣摩尔比为1:0.5-1:2; 所述化合物(3)的合成路线如式2所示: Generating a- chloro-4-phenylbenzyl pay gas a- chloroacetophenone cool air benzyl chloride with Friedel-Crafts cool glycosylation occurs in a solvent, the specific synthetic steps, the cool-chloro-Q- chloroacetophenone dissolved in an organic a solvent; benzene gas was added dropwise at a temperature of -10 ° C. square, maintaining the reaction temperature at 50 ~ 90 ° C; a- chloroacetophenone mixing cool gas with the chlorine benzene molar ratio 1: 1.2-1: 10, a- chloroacetophenone cool chloride with chlorinated companion = molar ratio of 1: 0.5 to 1: 2; the compound (3) in the synthetic route as shown in Equation 2:
    Figure CN103420823BC00022
    所述化合物(2)的合成路线如式3所示: The compound (2) is shown in Scheme 3 as Formula:
    Figure CN103420823BC00023
    在IL的S 口瓶中加入152g扁桃酸和300mL无水乙醇,通入IOg氯化氨,体系加热至78°C, 充分反应,反应完全后将反应液浓缩得到174g扁桃酸乙醋, 向浓缩液中加入13Ig二氯亚讽,加热至78°C,反应化,充分反应后,加入醋酸250mL,浓盐酸150mL,继续加热保持100°C反应化后,减压蒸馈,得到143ga-氯代苯乙酸,收率84%。 S IL is added to the jar 152g mandelic acid and 300mL of absolute ethanol, into IOg ammonium chloride, heated to 78 ° C, the reaction sufficiently, the reaction was complete, the reaction was concentrated to give 174g mandelic acid ethyl ester, was concentrated to was added thionyl 13Ig ridicule and heated to 78 ° C, the reaction, post reaction sufficiently, acetic acid was added 250mL, 150mL of concentrated hydrochloric acid, and heating continued to maintain 100 ° C after the reaction of, evaporated under reduced pressure to feed, to give chloro 143ga- acid, 84% yield.
  2. 2. 根据权利要求1所述的a-氯-4氣苯基苄基酬的合成方法,其特征是:a-氯苯乙酸与酷氯化试剂反应合成Q-氯苯乙酷氯;所述反应溫度为20~80°C,所述a-氯苯乙酸与酷氯化试剂的混合摩尔比为1:1. 5。 The synthesis method of claim 1 a- gas-chloro-4-phenylbenzyl pay claim, characterized in that: a- acid chloride is reacted with a chlorinating agent cool cool synthesis Q- chloro-chloroacetophenone; the the reaction temperature is 20 ~ 80 ° C, the acid chloride and a- cool chlorinating reagent mixing molar ratio of 1: 15.
  3. 3. 根据权利要求1所述的a-氯-4氣苯基苄基酬的合成方法,其特征是:所述a-氯苯乙酷氯与氣苯在溶剂中发生傅克酷基化反应生成O-氯-4氣苯基苄基酬的步骤中,所述溶剂是面代控或者硝基苯。 The synthesis method according to a-. 1-chloro-4-phenylbenzyl gas pay claim, wherein: Friedel-Crafts reaction yl cool the cool-chloro-a- chloroacetophenone and gas occurs in a solvent of benzene the step of generating gas O--chloro-4-phenylbenzyl remuneration, the solvent is nitrobenzene or control generation of surface.
  4. 4. 根据权利要求3所述的a-氯-4氣苯基苄基酬的合成方法,其特征是:所述面代控为氣苯。 4. The method of synthesis gas a- chloro-4-phenylbenzyl paid according to claim 3, characterized in that: the control surface is a gas substituting benzene.
  5. 5. 根据权利要求2所述的a-氯-4氣苯基苄基酬的合成方法,其特征是:酷氯化试剂为二氯亚讽或者草酷氯。 The synthesis gas a- chloro-4-phenylbenzyl paid according to claim 2, characterized in that: cool reagent is thionyl chloride or oxalyl cool Bitterness chlorine.
  6. 6. 根据权利要求2或5所述的a-氯-4氣苯基苄基酬的合成方法,其特征是:所述a-氯苯乙酸与酷氯化试剂反应合成Q-氯苯乙酷氯的步骤中,所采用的反应溶剂为二氯亚讽、草酷 The synthesis gas a- chloro-4-phenylbenzyl pay 2 or claim 5, characterized in that: a- the acid chloride is reacted with a chlorinating agent cool chloroacetophenone cool synthesis Q- chloride in step, the reaction solvent employed as thionyl Bitterness, cool grass
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1675813B1 (en) * 2003-10-13 2007-12-19 Laboratoires Serono SA Method for preparing para-phenyl alkynyl benzaldehydes
CN101230000A (en) * 2007-01-25 2008-07-30 江苏中慧药物研究有限公司;江苏中丹集团股份有限公司 Method for preparing 2-chlorin-2-aryl acetate compounds
CN101306988A (en) * 2007-05-15 2008-11-19 浙江京新药业股份有限公司 New method for synthesizing alpha-brom-4-fluoro phenylpropiophenone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1675813B1 (en) * 2003-10-13 2007-12-19 Laboratoires Serono SA Method for preparing para-phenyl alkynyl benzaldehydes
CN101230000A (en) * 2007-01-25 2008-07-30 江苏中慧药物研究有限公司;江苏中丹集团股份有限公司 Method for preparing 2-chlorin-2-aryl acetate compounds
CN101306988A (en) * 2007-05-15 2008-11-19 浙江京新药业股份有限公司 New method for synthesizing alpha-brom-4-fluoro phenylpropiophenone

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