CN101781221A - Preparation method of O-desmethylvenlafaxine - Google Patents

Preparation method of O-desmethylvenlafaxine Download PDF

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CN101781221A
CN101781221A CN201010110258A CN201010110258A CN101781221A CN 101781221 A CN101781221 A CN 101781221A CN 201010110258 A CN201010110258 A CN 201010110258A CN 201010110258 A CN201010110258 A CN 201010110258A CN 101781221 A CN101781221 A CN 101781221A
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hydroxyphenyl
chloride
dimethylamide
desmethylvenlafaxine
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CN201010110258A
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吕华
吴剑峰
周航
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上海凯米侬医药科技有限公司
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Abstract

The invention relates to a preparation method of O-desmethylvenlafaxine. The method comprises the following special steps: 1. performing chlorination to p-hydroxyphenylacetic acid in aprotic organic solvent at room temperature, then reacting with dimethylamine aqueous solution to prepare 2-(4-hydroxyphenyl)-N,N-dimethylformamide; 2. using 2-(4-hydroxyphenyl)-N,N-dimethylformamide and cyclohexanone to perform condensation reaction at 0 to -78 DEG C under the action of butyl lithium and prepare 2-(1-hdroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylformamide; and 3. using lithium aluminium hydride to reduce 2-(1-hdroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylformamide. The preparation method of O-desmethylvenlafaxine provided by the invention is characterized in that the raw materials are accessible, the entire preparation contains only three steps, the preparation processes are simplified, the reaction conditions are mild, the operation is convenient and safe and the yield is high.

Description

一种o-去甲基文拉法辛的制备方法 Methyl o- to one kind of preparing venlafaxine

技术领域 FIELD

[0001] 本发明涉及一种o-去甲基文拉法辛的制备新工艺。 [0001] The present invention relates to a new process of o- desmethylvenlafaxine.

背景技术 Background technique

[0002] 文拉法辛(venlafaxine),即(±) _1_[2-( 二甲基氨基)_1_(4_乙氧基苯基)乙 [0002] Venlafaxine (venlafaxine), i.e. (±) _1_ [2- (dimethylamino) _1_ (4_ ethoxyphenyl) acetate

基]环己醇,是一类抗抑郁药,文拉法辛的作用是抑制去甲肾上腺素和5-羟色胺的再摄取, Yl] cyclohexanol, is an antidepressant, venlafaxine effect is to inhibit norepinephrine and serotonin reuptake,

可替代三环抗抑郁剂和选择性再摄取抑制剂。 Alternatively tricyclic antidepressants and selective re-uptake inhibitors. 文拉法辛具有如下结构式: [0003] Venlafaxine has the following structural formula: [0003]

[0004] 0-去甲基文拉法辛(O-desmethylvenlafaxin),即4- [2- ( 二甲基氨基)_1_ (1_羟基环己基)乙基]苯酚,英文名称为4-(2-(dimethylamino)-l-(l-hydroxycyclohexyl) ethyl) phenol,其结构式为: [0005] [0004] 0- desmethylvenlafaxine (O-desmethylvenlafaxin), i.e., 4- [2- (dimethylamino) _1_ (1_-hydroxycyclohexyl) ethyl] phenol, the English name is 4- (2 - (dimethylamino) -l- (l-hydroxycyclohexyl) ethyl) phenol, its structural formula is: [0005]

[0006] 是文拉法辛(venlafaxine)的活性代谢物;目前美国惠氏公司已完成相关的临床试验,并于2007年3月获FDA的生产批文。 [0006] is venlafaxine (venlafaxine) of the active metabolite; the US Wyeth Company has completed related to clinical trials, and in March 2007 won FDA approval of production. 与文拉法辛的作用机制相同,0-去甲基文拉法辛也是通过抑制5-羟色胺以及去甲肾上腺素的再摄取来发挥药理作用,但其较文拉法辛副作用小,适应症宽。 The same action mechanism of venlafaxine, O-desmethylvenlafaxine is also exert pharmacological effects through inhibition of serotonin and norepinephrine reuptake, venlafaxine relatively small but its side effects, indications width.

[0007] US7026508及US6689912公布了0-去甲基文拉法辛的制备方法,如下: [0008]甲基化 [0007] US7026508 and US6689912 published a method for the preparation of 0- desmethylvenlafaxine, as follows: [0008] Methylation

[0009] 该方法采用对甲氧基苯乙氰作为起始原料,先与环己酮亲核加成,然后直接还原氰基,再使得胺甲基化,最后脱除O-甲基,得到O-去甲基文拉法辛;这种方案起始原料剧毒不易得,氰基还原条件苛刻,甲基化反应条件不易控制,副产物多。 [0009] The method using acetophenone cyanide as starting materials, first with a nucleophilic addition of cyclohexanone, and then direct reduction of the cyano, again so AMINOMETHYLATED, methyl O- finally removed to give O- desmethylvenlafaxine; toxic starting materials such programs not easy, reducing harsh conditions cyano, methyl reaction conditions difficult to control, multi-product.

[0010] 因此,开发适于工业化量产的原料易得、反应条件温和、操作简便安全、收率高的工艺路线非常必要。 [0010] Thus, the development of suitable for industrial mass production of raw materials, mild reaction conditions, easy and safe operation, high yield process route is necessary.

发明内容 SUMMARY

[0011] 本发明的目的在于提供一种o-去甲基文拉法辛的制备方法,该方法原料易得、反 [0011] The object of the present invention is to provide a method for preparing methyl o- to venlafaxine, the process raw materials, trans

应条件温和、操作简便安全、收率高。 Conditions should be mild, safe and easy operation, high yield.

[0012] 为达到上述目的,本发明提供了一种的制备方法,包含以下具体步骤: [0012] To achieve the above object, the present invention provides a preparation method comprising the following specific steps:

[0013] 步骤l,常温,在非质子性有机溶剂中,将对羟基苯乙酸酰氯化,然后与二甲胺水溶 [0013] Step L, at room temperature, in an aprotic organic solvent, will hydroxyphenylacetic acid chloride, then with aqueous dimethylamine

液反应制备2- (4-羟基苯基)-N, N- 二甲酰胺; Was prepared by reacting 2- (4-hydroxyphenyl) -N, N- dimethylamide;

[0014] 步骤2,在(TC〜-78t:,在丁基锂的作用下,使得2-(4-羟基苯基)-N, N-二甲酰胺与环己酮发生縮合反应,制备2- (1-羟基环己基)-2- (4-羟基苯基)-N, N- 二甲酰胺; [0015] 步骤3,采用氢化铝锂还原2- (1-羟基环己基)-2- (4-羟基苯基)-N, N- 二甲酰胺。 [0016] 所述的步骤l中的非质子有机溶剂为二氯甲烷,三氯甲烷或l,2-二氯乙烷。 [0017] 所述的步骤1中采用的酰氯化试剂为氯化亚砜或草酰氯。 [0018] 所述的步骤l还包含: [0014] Step 2, in (TC~-78t :, under the action of butyllithium, such 2- (4-hydroxyphenyl) -N, N- dimethylamide and cyclohexanone condensation reaction Preparation 2 - (1-hydroxy-cyclohexyl) -2- (4-hydroxyphenyl) -N, N- dimethylamide; [0015] step 3, using lithium aluminum hydride reduction of 2- (1-hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, N- dimethylamide. [0016] step l in said aprotic organic solvent is methylene chloride, chloroform or l, 2- dichloroethane. [0017 ] step 1 using the acid chloride reagent is thionyl chloride or oxalyl chloride [0018] l further comprising the step of:

[0019] 步骤1. l,将对羟基苯乙酸酰氯化,除去溶剂,得到干燥的对羟基苯乙酰氯; [0019] Step 1. l, will hydroxyphenylacetic acid chloride, the solvent was removed to give a dry p-hydroxyphenyl chloride;

[0020] 步骤1. 2,向二甲胺水溶液中,滴加上述步骤1. 1得到的对羟基苯乙酰氯。 [0020] Step 1.2, the aqueous solution of dimethylamine, the above step was added dropwise acetyl chloride obtained paraben 1.1.

[0021] 所述的步骤l中对羟基苯乙酸与氯化亚砜或草酰氯的摩尔比为l : 1.5至1 : 3; [0021] In the step l p-hydroxyphenyl acetic acid with thionyl chloride or oxalyl chloride molar ratio of l: for 1.5 to 1: 3;

对羟基苯乙酰氯与二甲胺水溶液的摩尔比为i : 2至i : 6。 The molar ratio of the aqueous solution of the acid chloride with dimethylamine hydroxyacetophenone as i: 2 to i: 6.

[0022] 所述的步骤1中对羟基苯乙酸与氯化亚砜或草酰氯的摩尔比为1 : 2 ;对羟基苯 [0022] 1 molar ratio of p-hydroxyphenyl acetic acid with thionyl chloride or oxalyl chloride in the steps of 1: 2; p-hydroxybenzoate

乙酰氯与二甲胺水溶液的摩尔比为i : 3。 The molar ratio of dimethylamine aqueous solution acetyl chloride i: 3. [0023] 所述的步骤2还包含: [0023] 2 further comprising the step of:

[0024] 步骤2. 1, N2保护下,2-(4-羟基苯基)-N, N_ 二甲酰胺溶入四氢呋喃溶齐U,降温至-78°C ,搅拌下滴加丁基锂,保温反应4小时; The [0024] Step 2. 1, N2 protection, 2- (4-hydroxyphenyl) -N, N_ dimethylamide was dissolved in tetrahydrofuran homogeneous solution U, cooled to -78 ° C, under stirring butyllithium, incubated for 4 hours;

[0025] 步骤2. 2,向上述步骤2. 1所得的溶液中,滴加环己酮,继续保温反应4小时,制备2- (1-羟基环己基)-2- (4-羟基苯基)-N, N- 二甲酰胺。 [0025] Step 2.2, obtained in the above step 2.1 was added dropwise cyclohexanone, the reaction was continued for 4 hours, Preparation of 2- (1-hydroxy-cyclohexyl) -2- (4-hydroxyphenyl ) -N, N- dimethylamide.

[0026] 所述的步骤2中,2-(4-羟基苯基)-N, N_ 二甲酰胺、丁基锂和环己酮的摩尔比为 [0026] The molar ratio of the step 2, the 2- (4-hydroxyphenyl) -N, N_ dimethylamide, cyclohexanone and butyl lithium to

i : i. 8 : 1.1至i : 3 : 3。 i:. i 8: 1.1 to i: 3: 3.

[0027] 所述的步骤2中,2-(4-羟基苯基)-N, N_ 二甲酰胺、丁基锂和环己酮的摩尔比为 [0027] The molar ratio of the step 2, the 2- (4-hydroxyphenyl) -N, N_ dimethylamide, cyclohexanone and butyl lithium to

i : 2. i : i. 5。 i: 2. i:. i 5.

[0028] 所述的步骤3中,反应温度为25°C〜5(TC,所述的2_(1_羟基环己基)-2_(4_羟基苯基)-N, N-二甲酰胺与氢化铝锂按摩尔比为1 : 0.5至1 : 2;进一步地,优先选择为 [0028] In the step 3, the reaction temperature is 25 ° C~5 (TC, according 2_ (1_-hydroxycyclohexyl) -2_ (4_ hydroxyphenyl) -N, N- dimethylamide and lithium aluminum hydride in a molar ratio 1: 0.5 to 1: 2; Furthermore, preference is

i : L i: L

[0029] 本发明以对羟基苯乙酸为原料经氯化亚砜或草酰氯活化酰基,再与二甲胺水溶液生成2- (4-羟基苯基)-N, N- 二甲酰胺,该2- (4-羟基苯基)-N, N- 二甲酰胺在丁基锂的催化作用下,与环己酮縮合,发生亲核加成反应得到2- (l-羟基环己基)-2- (4-羟基苯基)-N, N-二甲酰胺,再经氢化铝锂还原得到O-去甲基文拉法辛。 [0029] In the present invention, p-hydroxyphenyl acetic acid as raw materials thionyl chloride or oxalyl chloride activated acyl group, and then with an aqueous solution of dimethylamine to produce 2- (4-hydroxyphenyl) -N, N- dimethylamide of the 2 - (4-hydroxyphenyl) -N, N- dimethylamide butyllithium in catalysis, cyclohexanone condensation, nucleophilic addition reaction occurs to give 2- (l- hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, N- dimethylamide, then O- desmethylvenlafaxine obtained by reduction with lithium aluminum hydride. 其反应方程式为: [0030]<formula>formula see original document page 5</formula> Reaction equation is: [0030] <formula> formula see original document page 5 </ formula>

[0031] 在制备化合物3时,减少了氯化亚砜或草酰氯的用量,从而减少了污染,且以二甲胺水溶液为原料,不需要引入有机溶剂和有机碱,然后经过滤直接得到产品,含量>98%, 产率> 85% ;反应条件温和,减少污染,适合工业化生产。 [0031] Compound 3 is prepared, reducing the amount of thionyl chloride or oxalyl chloride, thus reducing pollution, and with an aqueous solution of dimethylamine as the raw material, does not require the introduction of an organic solvent and an organic base, then the product obtained directly by filtration content of> 98%, a yield of> 85%; mild reaction conditions, reduce pollution, suitable for industrial production.

[0032] 在制备化合物4时,没有对羟基进行保护,直接加入1. 8〜3倍(摩尔量)的丁基锂;减少了反应步骤(上保护基和去保护基),使成本降低,总产率提高。 [0032] Preparation of compound 4-butyllithium in, there is no protection of the hydroxyl group, was added directly to 1 8~3 times (molar amount); reducing reaction step (protecting groups and deprotection on), so that cost reduction, The total yield increase. [0033] 本发明提供的0-去甲基文拉法辛的制备方法,原料廉价易得,整个制备过程只有3步,反应步骤简化,反应条件温和,操作方便安全,收率高。 [0033] Preparation 0- desmethylvenlafaxine of the present invention provides, cheap raw materials, only three steps throughout the preparation, a simplified reaction steps, mild reaction conditions, easy and safe operation, high yield.

具体实施方式 Detailed ways

[0034] 以下根据实施例具体介绍本发明的优选实施方式。 [0034] The following preferred specific embodiments described embodiment of the present invention according to an embodiment. [0035] 1、2-(4-羟基苯基)-N,N-二甲酰胺(3)的制备 Preparation of [0035] 1,2- (4-hydroxyphenyl) -N, N- dimethylamide (3)

[0036] 将对羟基苯乙酸2(10g),二氯甲烷(50ml)加入到100ml反应瓶中,降温至(TC ,慢慢滴加10ml氯化亚砜。反应2h,蒸去二氯甲烷,得到酰氯。 [0036] will hydroxyphenylacetic acid 2 (10g), dichloromethane (50ml) was added to a 100ml reaction flask was cooled to (the TC, 10ml of thionyl chloride was slowly added dropwise. The reaction 2h, dichloromethane was distilled off, been chloride.

[0037] 将50ml 二甲胺水溶液加入100ml反应瓶中,滴加酰氯,反应lh,用纯乙酸乙酯薄层层析(TLC), Rf为0.7,薄层显示反应完全后,过滤得产品(3),烘干得到类白色粉末状固体9. 8g(纯度98 % )。 After [0037] An aqueous solution of dimethylamine was added 50ml 100ml reaction bottle, was added dropwise the acid chloride, the reaction LH, thin layer chromatography with pure ethyl acetate (TLC), Rf 0.7, TLC showed the reaction was complete, the product was filtered to give ( 3), dried to give an off-white powdery solid 9. 8g (98% purity). 力NMR(DMS0-d6) S :9. 22 (1H) , 7. 01 (2H) , 6. 71 (2H) , 3. 54 (2H), 2. 96(3H),2.81(3H)。 Force NMR (DMS0-d6) S: 9 22 (1H), 7. 01 (2H), 6. 71 (2H), 3. 54 (2H), 2. 96 (3H), 2.81 (3H)..

[0038] 2、2-(l-羟基环己基)-2-(4-羟基苯基)-N,N-二甲酰胺(4)的制备 -N, prepared [0038] 2,2- (l- hydroxycyclohexyl) -2- (4-hydroxyphenyl) N- dimethylamide (4)

[0039] 将4-羟基(N, N- 二甲基)苯乙酰胺3(9. 8g)加入250ml反应瓶中,N2保护,加入 [0039] 4-hydroxy (N, N- dimethyl) phenylacetamide 3 (9. 8g) was added 250ml reaction flask, N2 protection, was added

100ml THF,搅拌下降温至_78°C ,滴加2M的丁基锂60ml,保温反应4h。 100ml THF, stirred under cooling to _78 ° C, dropwise addition of 60ml 2M butyllithium, the reaction incubated 4h. 滴加17g环己酮,继 17g of cyclohexanone was added dropwise, followed

续保温反应4h,采用薄层层析(TLC)指示反应进程,溶剂为乙酸乙酯/石油醚=1 : 2,产 Continued reaction was incubated 4h, thin layer chromatography (TLC) indicated the reaction process, the solvent is ethyl acetate / petroleum ether = 1: 2, producing

物的Rf值为0. 4。 Rf value was 0.4. 反应完成后,加入饱和的氯化铵水溶液,并用乙酸乙酯萃取,无水硫酸镁 After completion of the reaction, saturated aqueous ammonium chloride solution and extracted with ethyl acetate, dried over anhydrous magnesium

干燥,过滤,蒸干溶剂,得到2- (1-羟基环己基)-2- (4-羟基苯基)-N, N- 二甲酰胺(4) 13g, Dried, filtered and the solvent evaporated to dryness to give 2- (1-hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, N- dimethylamide (4) 13g,

呈黄色油状物(纯度63%)。 As a yellow oil (purity 63%).

[0040] 3、 0-去甲基文拉法辛(1)的合成 [0040] 3, O-desmethylvenlafaxine Synthesis (1)

[0041] 将2-(l-羟基环己基)-2-(4-羟基苯基)-N,N-二甲酰胺4(13g)加入到250ml反应瓶中,Nj呆护,加入100ml THF,加入1. 5g氢化锂铝,反应搅拌过夜,采用薄层层析(TLC) 指示反应进程,溶剂为甲醇/二氯甲烷=1 : 2,产物的Rf值为0.4。 [0041] The 2- (l- hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, N- dimethyl amide 4 (13g) was added to a 250ml reaction flask, Nj stay protection, was added 100ml THF, 1. 5g of lithium aluminum hydride was added and the reaction was stirred overnight, thin layer chromatography (TLC) indicated the reaction process, the solvent is methanol / dichloromethane = 1: 2, Rf value 0.4 of the product. 薄层显示反应完成后, 加入1MHC1 10ml搅拌30分钟,加入饱和NaHC03水溶液调ffl至7-8, 二氯甲烷萃取,蒸干溶剂。 After completion of the reaction a thin display, a stirring 1MHC1 10ml 30 min, saturated aqueous NaHC03 ffl adjusted to 7-8, extracted with dichloromethane, the solvent was evaporated. 加入无水乙醇重结晶,得到白色粉末状固体产品(1)5. 8g(纯度98X) ?H NMR(DMS0-d6) S :9. 22 (1H) , 7. 01 (2H) , 6. 71 (2H) , 5. 32 (1H) , 3. 00 (1H) , 2. 76 (1H) , 2. 36 (1H) , 2. 15 (6H), 1. 7〜0. 8(卿。 Anhydrous recrystallized from ethanol to give the product as a white powdery solid (1) 5 8g (purity 98X) H NMR (DMS0-d6) S:.?. 9 22 (1H), 7. 01 (2H), 6. 71 (2H), 5. 32 (1H), 3. 00 (1H), 2. 76 (1H), 2. 36 (1H), 2. 15 (6H), 1. 7~0. 8 (Qing.

[0042] 本发明采用廉价易得的对羟基苯乙酸2为起始原料,与二甲胺水溶液反应制备酰胺3,然后,酰胺3与环己酮縮合制备4,再还原中间体4中的羰基为亚甲基,得到目标产物0-去甲基文拉法辛1 ;该方法反应条件温和,反应步骤少,不需要对苯酚进行保护,故减少了保护和脱保护的步骤,收率高,适合工业化量产。 [0042] The present invention uses inexpensive, readily available p-hydroxyphenyl acetate 2 as a starting material, prepared by reacting the amide with aqueous dimethylamine 3, then 3 amide prepared by condensation of cyclohexanone with 4, then reduction of the carbonyl group of intermediate 4 is methylene, to give the desired product 1 0- desmethylvenlafaxine; mild reaction conditions of the process, less reaction step without phenol protection, it reduced the protection and deprotection steps, high yield, suitable for industrial mass production.

[0043] 尽管本发明的内容已经通过上述优选实施例作了详细介绍,但应当认识到上述的描述不应被认为是对本发明的限制。 [0043] While the present invention have been described in detail by the above preferred embodiments, it should be appreciated that the above description should not be construed as limiting the present invention. 在本领域技术人员阅读了上述内容后,对于本发明的多种修改和替代都将是显而易见的。 After the skilled artisan reading the foregoing, various modifications and alternatives to the present invention will be apparent. 因此,本发明的保护范围应由所附的权利要求来限定。 Accordingly, the scope of the invention be defined by the appended claims.

Claims (10)

  1. 一种O-去甲基文拉法辛的制备方法,其特征在于,包含以下具体步骤:步骤1,常温,在非质子性有机溶剂中,将对羟基苯乙酸(2)酰氯化,然后与二甲胺水溶液反应制备2-(4-羟基苯基)-N,N-二甲酰胺(3);步骤2,在0℃~-78℃,在丁基锂的作用下,使得2-(4-羟基苯基)-N,N-二甲酰胺(3)与环己酮发生缩合反应,制备2-(1-羟基环己基)-2-(4-羟基苯基)-N,N-二甲酰胺(4);步骤3,采用氢化铝锂还原2-(1-羟基环己基)-2-(4-羟基苯基)-N,N-二甲酰胺(4)。 Preparing one kind of methyl O- to venlafaxine, characterized in that it comprises the following specific steps: Step 1, at room temperature, in an aprotic organic solvent, will hydroxyphenylacetic acid (2) of the acid chloride, then reacted with aqueous dimethylamine solution prepared by reacting 2- (4-hydroxyphenyl) -N, N- dimethylamide (3); step 2, at 0 ℃ ~ -78 ℃, under the action of butyllithium, so that 2- ( 4-hydroxyphenyl) -N, N- dimethylamide (3) and the condensation reaction of cyclohexanone, 2- (1-hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, N- dimethylamide (4); step 3, using lithium aluminum hydride reduction of 2- (1-hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, N- dimethylamide (4).
  2. 2. 如权利要求1所述的0-去甲基文拉法辛的制备方法,其特征在于,所述的步骤1中的非质子有机溶剂为二氯甲烷,三氯甲烷或l,2-二氯乙烷。 2. Preparation of 0- desmethylvenlafaxine method according to claim 1, wherein said step 1 in the aprotic organic solvent is dichloromethane, chloroform or l, 2- dichloroethane.
  3. 3. 如权利要求1所述的0-去甲基文拉法辛的制备方法,其特征在于,所述的步骤1中采用的酰氯化试剂为氯化亚砜或草酰氯。 3. The method as 0- desmethylvenlafaxine according to claim 1, wherein said step of using an acid chloride forming agent is thionyl chloride or oxalyl chloride.
  4. 4. 如权利要求1所述的O-去甲基文拉法辛的制备方法,其特征在于,所述的步骤1具体包含:步骤1. l,将对羟基苯乙酸(2)酰氯化,除去溶剂,得到干燥的对羟基苯乙酰氯; 步骤1. 2,向二甲胺水溶液中,滴加上述步骤1. 1得到的对羟基苯乙酰氯。 4. O- according to claim 1 preparing venlafaxine to methyl, wherein said step 1 comprises in particular: Step 1. l, will hydroxyphenylacetic acid (2) chloride, the solvent was removed, dried to give p-hydroxybenzoate chloride; step 1.2, the aqueous solution of dimethylamine, the above step was added dropwise acetyl chloride obtained paraben 1.1.
  5. 5. 如权利要求3所述的0-去甲基文拉法辛的制备方法,其特征在于,所述的步骤1中对羟基苯乙酸与氯化亚砜或草酰氯的摩尔比为1 : 1.5至1 : 3;对羟基苯乙酰氯与二甲胺水溶液的摩尔比为i : 2至i : 6。 5. 0- according to claim 3 Preparation of methyl to venlafaxine, wherein said step a p-hydroxyphenyl acetic acid with thionyl chloride or oxalyl chloride in a molar ratio of 1: 1.5 to 1: 3; the molar ratio of chloride with an aqueous solution of dimethylamine hydroxyacetophenone as i: 2 to i: 6.
  6. 6. 如权利要求5所述的0-去甲基文拉法辛的制备方法,其特征在于,所述的步骤1中对羟基苯乙酸与氯化亚砜或草酰氯的摩尔比为1 : 2;对羟基苯乙酰氯与二甲胺水溶液的摩尔比为i : 3。 6. claim 0-5 preparing venlafaxine to methyl, wherein said step a p-hydroxyphenyl acetic acid with thionyl chloride or oxalyl chloride in a molar ratio of 1: 2; molar ratio of the chloride with an aqueous solution of dimethylamine hydroxyacetophenone as i: 3.
  7. 7. 如权利要求1所述的0-去甲基文拉法辛的制备方法,其特征在于,所述的步骤2具体包含:步骤2. 1, ^保护下,2-(4-羟基苯基)-N, N-二甲酰胺(3)溶入四氢呋喃溶剂,降温至-78°C ,搅拌下滴加丁基锂,保温反应4小时;步骤2. 2,向上述步骤2. 1所得的溶液中,滴加环己酮,继续保温反应4小时,制备2- (1-羟基环己基)-2- (4-羟基苯基)-N, N- 二甲酰胺(4)。 7. The method for producing 0- desmethylvenlafaxine according to claim 1, wherein the step 2 specifically comprises: the protection step 2.1, ^, 2- (4-hydroxyphenyl yl) -N, N- dimethylamide (3) dissolved in a solvent of tetrahydrofuran, cooled to -78 ° C, butyllithium under stirring, incubated for 4 hours; step 2.2, step 2.1 to the resulting was added dropwise cyclohexanone, the reaction was continued for 4 hours, preparation of 2- (1-hydroxy-cyclohexyl) -2- (4-hydroxyphenyl) -N, N- dimethylamide (4).
  8. 8. 如权利要求l所述的0-去甲基文拉法辛的制备方法,其特征在于,所述的步骤2 中,2-(4-羟基苯基)-N, N-二甲酰胺(3)、丁基锂和环己酮的摩尔比为1 : 1.8 : 1. l至l:3:3。 8. Preparation of l-desmethylvenlafaxine according to claim 0-, wherein, in the step 2, 2- (4-hydroxyphenyl) -N, N- dimethylamide (3) the molar ratio of cyclohexanone and butyl lithium was 1: 1.8: 1. l to l: 3: 3.
  9. 9. 如权利要求8所述的0-去甲基文拉法辛的制备方法,其特征在于,所述的步骤2中, 2-(4-羟基苯基)-N,N-二甲酰胺(3)、丁基锂和环己酮的摩尔比为1 : 2.1 : 1.5。 9. The method of claim 8 prepared 0- desmethylvenlafaxine claim, wherein, in the step 2, 2- (4-hydroxyphenyl) -N, N- dimethylamide (3) the molar ratio of cyclohexanone and butyl lithium was 1: 2.1: 1.5.
  10. 10. 如权利要求1所述的0-去甲基文拉法辛的制备方法,其特征在于,所述的步骤3 中,反应温度为25°C〜50°C ,所述的2- (1-羟基环己基)-2- (4-羟基苯基)-N, N- 二甲酰胺(4)与氢化铝锂的摩尔比为l : Q.5至l : 2。 10. The method of preparing 0- desmethylvenlafaxine according to claim 1, wherein, in the step 3, the reaction temperature is 25 ° C~50 ° C, the 2- ( 1-hydroxycyclohexyl) -2- (4-hydroxyphenyl molar ratio of -N, N- dimethylamide (4) with lithium aluminum hydride) to l: Q.5 to l: 2.
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