CN105330638A - Method for synthesizing doxepin hydrochloride by utilizing o-toluic acid as raw material - Google Patents

Method for synthesizing doxepin hydrochloride by utilizing o-toluic acid as raw material Download PDF

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CN105330638A
CN105330638A CN 201510835636 CN201510835636A CN105330638A CN 105330638 A CN105330638 A CN 105330638A CN 201510835636 CN201510835636 CN 201510835636 CN 201510835636 A CN201510835636 A CN 201510835636A CN 105330638 A CN105330638 A CN 105330638A
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substitution
reaction
lithium
nucleophilic
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苏子轩
屈孝銘
肖祖华
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苏州黄河制药有限公司
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D313/00Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02Seven-membered rings
    • C07D313/06Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
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Abstract

The invention discloses a method for synthesizing doxepin hydrochloride by utilizing o-toluic acid as a raw material. The method comprises the steps: with wide-source o-toluic acid as a starting raw material, sequentially performing benzyl halogenation, intramolecular substitution, cyclization, nucleophilic addition, elimination reaction, nucleophilic substitution, nucleophilic substitution and neutralization reaction to obtain salazosulfapyridine. In a nucleophilic substitution reaction of step 8, an organic lithium compound is added to an ether solvent, so that the organic lithium compound and dimethylamine form ammonio-lithium salt (which is specified in the original PDF); then, the ammonio-lithium salt and a halide generate an alkylation reaction; therefore, the yield of tertiary amine is improved, and then the yield and the purity of final doxepin hydrochloride are guaranteed.

Description

一种以邻甲基苯甲酸为原料的盐酸多塞平的合成方法 A method of synthesis of raw material o-methylbenzoic acid hydrochloride doxepin

技术领域 FIELD

[0001] 本发明涉及盐酸多塞平的技术领域,尤其涉及一种以邻卤甲基苯甲酸为原料合成盐酸多塞平的方法。 [0001] The present invention relates to the field of doxepin hydrochloride, in particular, relates to a method for o-toluic acid halide multi doxepin hydrochloride synthesized.

背景技术 Background technique

[0002] 盐酸多塞平,化学名称为N,N-二甲基-3-二苯并(b,e)_噁庚英-11 (6H)亚基-1-丙胺酸盐的顺反异构体的混合物。 [0002] doxepin hydrochloride, the chemical name is N, N- dimethyl-3-dibenzo (b, e) _ oxepin -11 (6H) -1-propanamine salt subunit cistron iso the mixture body configuration. 其CAS号为1229-29-4,结构式为 CAS Number 1229-29-4 thereof, of the formula

[0003] [0003]

Figure CN105330638AD00061

[0004] 盐酸多塞平是用于治疗抑郁症及焦虑性神经症的药,其作用在于抑制中枢神经系统对5-羟色胺及去甲肾上腺素的再摄取,从而使突触间隙中这二种神经递质浓度增高而发挥抗抑郁作用,也具有抗焦虑和镇静作用。 [0004] Doxepin hydrochloride is a drug for the treatment of depression and anxiety neurosis that act to inhibit the central nervous system serotonin and norepinephrine reuptake, such that these two synaptic cleft neurotransmitter concentration increased and antidepressant effect, but also has anti-anxiety and sedative effects. 盐酸多塞平口服吸收好,生物利用度为13-45%,半衰期(丨1/2)为8-12小时,表观分布容积以(1)9-33171^。 Doxepin hydrochloride oral absorption, bioavailability of 13-45%, half-life (Shu 1/2) is 8-12 hours, to apparent volume of distribution (1) ^ 9-33171. 主要在肝脏代谢,活性代谢产物为去甲基化物。 Primarily metabolized in the liver to active metabolites thereof demethylation. 代谢物自肾脏排泄,老年病人对本品的代谢和排泄能力下降 Metabolite excretion from the kidney, elderly patients decline of metabolism and excretion ability of this product

[0005] 中国专利CN102924486A公开了一种盐酸多塞平的制备方法。 [0005] Chinese Patent CN102924486A discloses a method for preparing a hydrochloride of doxepin. 该方法包括CN偶联反应,即使用Ni(0Α〇)2/ΡΡ1^φ系将胺基化合物接到。 The method comprises the coupling reaction CN, i.e., the use of Ni (0Α〇) 2 / ΡΡ1 ^ φ to the amine-based compound. 虽然该步骤的反应的催化剂Ni(OAc) 2 较为廉价易得,但是该步反应的收率较低,且产品的纯度较低。 Although Ni catalyst the reaction step (OAc) 2 is more readily available and inexpensive, but the low yield of this step, and low product purity.

发明内容 SUMMARY

[0006] 有鉴于此,本发明提供一种以邻甲基苯甲酸为原料合成盐酸多塞平的方法,经该方法得到的提纯产品的纯度较高和收率。 [0006] Accordingly, the present invention provides a method of o-toluic acid synthesized multi doxepin hydrochloride, the higher the yield and purity of the obtained product was purified by this method.

[0007] -种以邻甲基苯甲酸为原料合成盐酸多塞平的方法,包括以下步骤: [0007] - o-methylbenzoate method for the synthesis of doxepin hydrochloride, comprising the steps of:

[0008] (1)将邻甲基苯甲酸与N-卤代丁二酰亚胺在光照条件下于乙腈溶剂中进行发生苄基卤代反应,得到邻卤甲基苯甲酸(化合物J),反应式如下, [0008] (1) o-methylbenzoic acid with N- halosuccinimide benzylation halogenation reaction occurs in an acetonitrile solvent in the light conditions, to give o-halo-methylbenzoic acid (Compound J), the following reaction formula,

[0009] [0009]

Figure CN105330638AD00071

[0010] (2)将化合物J以硅藻土负载氟化铯为催化剂于乙腈溶剂中进行分子内取代反应,得到苯酞(化合物H),反应式如下, [0010] (2) Compound J celite load cesium fluoride intramolecular substitution reaction, to give phthalide (Compound H) in an acetonitrile solvent and as a catalyst, the following reaction formula,

[0011] [0011]

Figure CN105330638AD00072

[0012] (3)将化合物J与苯酚在甲醇钠的醇溶剂中进行取代反应,得到化合物I,反应式如下, [0012] (3) The phenol compound J with sodium methoxide in an alcohol solvent substitution reaction, to give a compound I, the following reaction formula,

[0013] [0013]

Figure CN105330638AD00073

[0014] (4)将所述化合物I在无水氯化铝的催化下在DMS0溶剂中进行环化反应,得到6, 11-二氢二苯并[b,e]噁庚英-11-酮(化合物A),反应式如下, [0014] (4) The cyclization reaction of Compound I in a solvent in the catalytic DMS0 anhydrous aluminum chloride to give 6, 11-dihydro-dibenzo [b, e] oxepin -11- one (compound A), the following reaction formula,

[0015] [0015]

Figure CN105330638AD00074

[0016] (5)将6, 11-二氢二苯并[b,e]噁庚英-11-酮(化合物A)与3-氯丙烷基叔丁基醚(化合物B)在加入镁粉且以THF和/或无水乙醚为溶剂的条件下进行亲核加成反应,得到羟基类化合物(化合物C),反应式如下, [0016] (5) 6, 11-dihydro-dibenzo [b, e] oxepin-11-one (Compound A) and 3-chloropropyl alkyl tert-butyl ether (compound B) is added magnesium powder and with THF and / or a nucleophilic addition of anhydrous diethyl ether under the conditions of the reaction solvent to give the hydroxy compound (compound C), the following reaction formula,

[0017] [0017]

Figure CN105330638AD00081

[0018] (6)向所述羟基类化合物在强碱的醇溶剂中加热进行消除反应,得到烯烃类化合物(化合物D),反应式如下, [0018] (6) heating elimination reaction to give an olefin compound (Compound D) in a strong base in an alcoholic solvent to the hydroxy compound, the following reaction formula,

[0019] [0019]

Figure CN105330638AD00082

[0020] (7)将所述烯烃类化合物在氢卤酸下进行亲核取代反应,得到卤代物(化合物E), 反应式如下, [0020] (7) to the olefinic compound in the nucleophilic substitution reaction of a hydrogen halide acid, to give halide (Compound E), the following reaction formula,

Figure CN105330638AD00083

[0022] 其中,化合物E中X为一C1、一Br或一I; [0022] wherein the compound E X is a C1, Br, or a a I;

[0023] (8)将所述卤代物同二甲胺在加入有机锂化合物于醚的溶剂中下进行亲核取代反应,得到多塞平(化合物F),反应式如下, [0023] (8) the halide with dimethylamine in a solvent under an organic lithium compound is added in ether to nucleophilic substitution reaction to yield doxepin (Compound F.), The following reaction formula,

[0024] [0024]

Figure CN105330638AD00091

[0025] (9)将所述多塞平同盐酸进行中和反应,得到柳氮磺吡啶(化合物G),反应式如下, [0025] (9) the doxepin neutralization reaction with hydrochloric acid to give sulfasalazine (Compound G), the following reaction formula,

Figure CN105330638AD00092

[0027] 前述,步骤(1)所说的苄基卤代反应,其N-卤代丁二酰亚胺的用量为稍微过量。 [0027] the step (1) halogenation of said benzyl, N- halosuccinimide in an amount to a slight excess. 例如1:1.02~1.05。 Example 1: 1.02 to 1.05. 为了抑制苯环上的取代,反应的温度以较低为宜,例如优选为10~ 20°C,反应的时间无特别限定。 In order to suppress substituted on the benzene ring, the reaction temperature is preferably lower, for example, preferably 10 ~ 20 ° C, the reaction time is not particularly limited. 至于乙腈溶剂的用量,其可以根据产物提纯等实际需要做常规的选择,其对用量的多少对反应收率无影响。 As to the amount of acetonitrile solvent which can be like the actual product was purified according to conventional selection needs to be done, it has no influence on the yield of how much amount. 光照的具体条件无限定,例如可采用可见光。 Indefinite specific illumination conditions, for example, visible light may be employed.

[0028] 前述,步骤(2)所说的分子内取代反应为羧基与苄基位卤原子发生亲核取代生成内酯化合物。 [0028] the step (2) to substitution reaction with a carboxyl benzylic halogen atom the nucleophilic substitution of the lactone compound in said molecule. 该反应中所采用的硅藻土负载氟化铯可采用本领域用到的硅藻土负载氟化铯,例如可参照硕士论文"环氧化物与胺的催化加成反应研究"所记载的方法来获得该催化剂。 Celite load cesium fluoride employed in this reaction can be used in the present art Celite load cesium fluoride, for example, reference to method Thesis "catalytic addition of epoxides with amines Reaction" described in the catalyst is obtained. 硅藻土负载氟化铯能够提供出氟负离子,其具有较强的亲核性,且无其它亲核产物的副产物。 Celite load cesium fluoride can be provided a fluorine anion, with a strong nucleophilic, and no other byproducts nucleophilic product. 较好地,娃藻土负载氟化铯的用量为〇. 05~0. 15,以化合物J的质量为1计。 The amount of cesium Preferably, baby diatomaceous earth fluoride square load. 05 ~ 0.15, mass Compound J is 1 meter. 乙腈的用量为2. 5~8,以化合物J的质量为1计。 Acetonitrile is used in an amount of 2.5 to 8 mass Compound J is 1 meter. 该反应的温度为优选30~50°C,反应的时间优选为12~20h。 The reaction temperature is preferably 30 ~ 50 ° C, the reaction time is preferably 12 ~ 20h.

[0029] 前述,步骤(3)中,由于苯酚的酚羟基还可与苯酞进行酯交换反应而开环,为了弥补苯酚因该反应所导致的消耗,苯酚较佳地为过量,例如两者的比例可以为1:1. 05~ 1. 15。 [0029] The aforementioned step (3), a ring-opening due to the phenolic hydroxyl group of phenol may also phthalide ester exchange reaction, in order to compensate for consumption by the reaction of phenol resulting phenol is preferably an excess of, for example, both the ratio may be 1: 1. 05 ~ 1.15. 于本发明中不对取代反应的温度和时间做限定,例如温度可为50~60°C,于此温度下取代反应的时间可以为3~6h。 Substituted in the present invention does not make the reaction temperature and time is defined, for example, the temperature may be 50 ~ 60 ° C, at this temperature the reaction time may be unsubstituted 3 ~ 6h. 甲醇钠的醇溶剂用量较好地为3~10,以邻卤甲基苯甲酸甲酯与苯酚的总质量为1计。 The amount of sodium methoxide in an alcohol solvent, preferably from 3 to 10, based on the total mass of o-methylbenzoate halide and phenol is 1 meter. 甲醇钠的醇溶剂的具体组成在此不做限定,其组成对反应的收率等无明显影响。 The specific composition of sodium methoxide in an alcoholic solvent which is not limited, the composition had no effect on the yield of the reaction and the like.

[0030] 前述,步骤(4)中,该环化反应为苯甲酸基与异苯环发生苯环上的亲电取代。 [0030] the step (4), the cyclization reaction is an electrophilic substituent on the benzene ring of benzoic acid group and isobutyl benzene ring occurs. 较好地,环化反应的温度为95~105°C,环化反应的时间为6~12h。 Preferably, the cyclization reaction temperature is 95 ~ 105 ° C, the cyclization reaction time is 6 ~ 12h. 较佳地,无水氯化铝的用量为10~40%,以化合物I的质量为100%计。 Preferably, the amount of anhydrous aluminum chloride is 10 to 40% by mass of compound I as 100%. DMSO的用量为3~8。 DMSO in an amount of 3 to 8.

[0031] 步骤(5)的亲核加成反应,首先3-氯丙烷基叔丁基醚在THF和/或无水乙醚为溶 [0031] Step (5) The nucleophilic addition reaction, first of all 3-chloropropyl alkyl tert-butyl ether in THF and / or diethyl ether is dissolved in dry

Figure CN105330638AD00101

剂中同镁粉发生反应生成Grignard试剂, 试剂中的3-丙烷基叔丁基醚的碳负离子与采用SN2机理对6, 11-二氢二苯并[b,e]噁庚英-11-酮上的羰基进行进攻以发生加成。 Generating agent reacts with the magnesium Grignard reagent, the reagent of 3-tert-butyl ether propane carbanion with the use of the SN2 mechanism 6, 11-dihydro-dibenzo [b, e] oxepin -11- ketone carbonyl group to attack an addition.

[0032] 本发明不对上述6, 11-二氢二苯并[b,e]噁庚英-11-酮、3-氯丙烷基叔丁基醚的物质量作出特别限定。 Not above 6, 11-dihydro-dibenzo [b, e] oxepin-11-one, 3-chloropropyl of substance alkyl tert-butyl ether [0032] The present invention is made particularly limited. 为了提高6, 11-二氢二苯并[b,e]噁庚英-11-酮的转化率,可使得3_氯丙烷基叔丁基醚稍微过量,两者的物质量可以1:1. 1~1.5。 In order to improve 6, 11-dihydro-dibenzo [b, e] oxepin conversion of the 11-one, may be so-chloropropyl 3_ alkyl tert-butyl ether in slight excess, of substance both may be 1: 1 1 to 1.5. 亲核加成反应的温度以35~40°C为宜。 Nucleophilic addition reaction temperature is preferably in the 35 ~ 40 ° C. 于此反应温度的前提下,反应时间较佳地为2~5h。 Under the premise of this reaction temperature, the reaction time is preferably 2 ~ 5h.

[0033] 于前述生成Grignard试剂的反应中,以化合物A质量为1计算,镁粉的加入量可以为2~2. 4,溶剂的加入量可以为5~7。 [0033] Grignard reagent in the reaction in order to calculate A mass of Compound 1, magnesium powder may be added in an amount of 2 to 2.4, the solvent may be added in an amount of 5 to 7. 溶剂的组成形式不做特别的限定,可以单独使用THF,单独使用无水乙醚,以及任何配比地混合使用THF和无水乙醚。 Composition in the form of a solvent is not particularly limited, and may be used alone THF, anhydrous diethyl ether alone, and a mixture of any ratio of the THF and dry ether.

[0034] 于步骤(6)中,前述的消除反应为E2机理,即羟基类化合物羟基的邻位碳上的氢的离去和羟基的离去是同步进行。 [0034] In step (6), the E2 elimination reaction mechanism, leaving leaving hydrogen and hydroxy on a carbon vicinal hydroxy compound that is a hydroxyl group are carried out simultaneously. 至于该消除反应的温度以65~80°C为宜,消除反应的时间为2~4h。 As the elimination reaction temperature ~ 80 [deg.] C to preferably 65, eliminate the reaction time is 2 ~ 4h. 以反应底物羟基类化合物的质量为1计算,强碱的醇溶剂的用量较佳地为1.5~5。 Mass hydroxy compounds calculated reaction substrate 1, a strong base is used in an amount of alcoholic solvent is preferably from 1.5 to 5. 强碱的醇溶剂的质量浓度可以为10~70%。 Concentration of alcohol solvent strong base may be 10 to 70%. 这里,质量浓度在以强碱为溶质的前提下来计算。 Here, in order to calculate the concentration as a solute alkali premise down. 强碱可采用本领域常用的,例如氢氧化钾、氢氧化钠,还可以为甲醇钠,乙醇纳等。 Commonly used in the art may be employed a strong base, such as potassium hydroxide, sodium hydroxide, may also be sodium methoxide, sodium ethanol and the like.

[0035] 于步骤(7)中,亲核取代反应即为醚键的断裂。 [0035] In step (7), a nucleophilic substitution is the ether bond cleaving reaction. 该反应的机理为SN1,第一步醚键的0原子在氢离子的作用下形成烊盐;第二步,烊盐解离出叔丁碳正离子,生成羟基;第三步,该羟基化合物与X负离子结合,形成卤代物。 The reaction is SN1 mechanism, the first step an ether bond is formed molten salt 0 atoms in the action of hydrogen ions; the second step, a molten salt dissociation tert carbenium ion generating hydroxyl group; a third step, the hydroxy compound in conjunction with anion X, halide formed. 亲核取代反应的温度可以为50~60°C,反应的时间可以为1. 5~4h。 Nucleophilic substitution reaction temperature may be 50 ~ 60 ° C, the reaction time may range from 1. 5 ~ 4h. 氢卤酸的用量为1~2,以化合物D的物质量为1。 Hydrohalic acid is used in an amount of 1 to 2, mass compounds D is 1. 氢卤酸的百分质量浓度为5~30%。 Percent hydrohalogenic acid concentration is 5 to 30%. 为保证亲核的反应活性,氢卤酸优选为氢碘酸。 To ensure reactive nucleophilic, preferably a hydrohalic acid, hydroiodic acid.

[0036] 于步骤(8)中,有机锂化合物与二甲胺形成铵锂盐 [0036] In step (8), the organic lithium compound and a lithium salt to form an ammonium dimethylamine

Figure CN105330638AD00102

,接着该铵锂盐与卤代物进行烷基化反应。 Followed by the ammonium halide salt with lithium alkylation. 采用有机锂化合物提高了胺中氮原子的亲核性,进行烷基化反应可以提高三级胺的收率。 An organolithium compound increases the nucleophilicity of the amine nitrogen atom, alkylation reaction may increase the yield of the tertiary amine.

[0037] 有机锂化合物即R-Li。 [0037] i.e. an organolithium compound R-Li. 这里的R为烷氧基,例如直链或支链烷烃,较佳地为(;~ C4直链烷烃基,使用较为广泛的正丁基锂;R可以为芳基,例如苯基。为了保证有机锂化合物不丧失反应活性,可现制先用。有机锂化合物的制备方法可采用本领域熟知的方法,比如正丁基锂可从氯丁烷与金属锂在戊烷或其他液体烷烃中反应制得。甲基锂、苯基锂等可从相应的卤代烃来制备。有机锂化合物的用量为0. 1~0. 8,以化合物E的质量为1计算。 Where R is an alkoxy group, e.g. a straight-chain or branched paraffins, preferably a (; ~ C4 straight chain alkanyl, more widely used n-butyl lithium; R may be an aryl group such as phenyl order to guarantee. an organolithium compound without loss of reactivity, can be made now by prior method known in the art of preparing an organic lithium compound may be employed, such as n-butyl lithium can be reacted with lithium metal from chlorobutane pentane or other liquid alkane prepared. methyl lithium, phenyl lithium can be prepared from the corresponding halogenated hydrocarbons. the amount of the organic lithium compound is 0.1 ~ 0.8, mass of a compound E is calculated.

[0038] 对于醚的形式不做限定,较佳地,醚中的碳链不要过长,例如醚选自乙醚、甲基乙基醚、丙醚中的任意一种或两种以上。 [0038] is not limited to the form of ethers, preferably, the carbon chain ether is not too long, for example, an ether selected from diethyl ether, methyl ethyl ether, propyl ether, any one or two or more kinds. 醚的用量为2~8,以化合物E的质量为1计算。 Ether in an amount of 2 to 8, as a mass of compound E 1 is calculated. 基于反应的较佳效果,亲核取代反应的温度为40~50°C,反应时间为2~5h。 Based on the preferred effect of the reaction, a nucleophilic substitution reaction temperature is 40 ~ 50 ° C, the reaction time is 2 ~ 5h.

[0039] 于步骤(9)中,中和反应的温度为130~150°C,所述反应的时间为16~20h。 [0039] In step (9), and the reaction temperature is 130 ~ 150 ° C, the reaction time is 16 ~ 20h. 应当理解的是,由于该反应体系为水相,为了达到130~150°C的温度,可在加压的情况下进行。 It will be appreciated that since the reaction system is an aqueous phase, in order to achieve a temperature of 130 ~ 150 ° C may be made in the case of a pressurized. 对具体压力不做限定,比如3~4MPa。 It is not limited to specific pressure, such as 3 ~ 4MPa. 盐酸的质量浓度为30~38%,较好地为37. 7%左右的浓盐酸。 Mass concentration of hydrochloric acid of 30 to 38%, preferably about 37.7% of concentrated hydrochloric acid. 为了使得多塞平彻底被中和,可保证盐酸为微过量,例如盐酸的用量为1. 05~ 1. 2,以化合物F的物质量为1计算。 In order to make doxepin completely neutralized, to ensure a slight excess of hydrochloric acid, for example hydrochloric acid in an amount of 1.05 ~ 1.2, mass of a compound F is calculated.

[0040] 本发明以来源广泛的邻甲基苯甲酸为起始原料,依次通过苄基位卤代、分子内取代、环化、亲核加成、消除反应、亲核取代、亲核取代、中和反应,得到柳氮磺吡啶。 [0040] In the present invention, a wide range of sources of o-toluic acid as a starting material, followed by benzylic halo, substituted intramolecular cyclization, nucleophilic addition, elimination reactions, nucleophilic substitution, nucleophilic substitution, the neutralization reaction, to give sulfasalazine. 得到于第7步的亲核取代反应步骤中,采用有机锂化合物于醚的溶剂中,这样使得机锂化合物与二甲 Obtained in Step 7 nucleophilic substitution reaction step, the organic lithium compound in an ether solvent such that the organic lithium compound and dimethyl

Figure CN105330638AD00111

,接着该铵锂盐与卤代物进行烷基化反应,提高三级胺的收率,由此保证了最终盐酸多塞平的收率和纯度。 Followed by the ammonium halide salt with lithium alkylation reaction, to increase the yield of the tertiary amine, thereby ensuring doxepin hydrochloride final yield and purity.

具体实施方式 detailed description

[0041 ] 下面结合实施例来进一步说明本发明的技术方案。 [0041] The following examples further illustrate the binding aspect of the present invention.

[0042] 实施例1 [0042] Example 1

[0043] 在20L的反应容器中置入乙腈、邻甲基苯甲酸、N-溴代丁二酰亚胺,采用水浴将温度控制在10°C,在搅拌条件下反应4h。 [0043] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 10 ° C, under stirring for 4h. 采用公知的分离方法,分离出邻溴甲基苯甲酸。 A known separation method, separation of o-bromomethyl-benzoic acid. 将此命名为化合物J。 This compound is named J.

[0044] 在20L的反应容器中置入化合物J、用量为0. 05的硅藻土负载氟化铯(以化合物J的质量为1计)、用量为2. 5的乙腈(以化合物J的质量为1计),将温度调至30°C,在搅拌调节下回流20h。 [0044] placed in a 20L reaction container, Compound J, diatomaceous earth in an amount of 0.05 to load cesium fluoride (compound J as a mass basis), acetonitrile in an amount of 2.5 (in Compound J 1 is a mass basis), and the temperature was adjusted to 30 ° C, with stirring under reflux for 20h adjustment. 然后,采用公知的手段分离出反应苯酞。 Then, a known means for separating the reaction phthalide.

[0045] 在20L的反应容器中置入苯酞、用量为3的甲醇钠的乙醇溶剂(苯酞与苯酚的总质量为1计),调节反应液的温度为50°C后,开始滴入物质量为1. 05的苯酚(以苯酞的物质量为1计),滴加时间为lh。 After [0045] placed in a 20L reaction vessel phthalide, 3 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), the reaction solution temperature adjusted to 50 ° C, was added dropwise start phenol was 1.05 mass (in mass was 1 meter phthalide), dropwise over lh. 滴加完毕后,恒温反应5h后采用公知的分离方法,得到邻甲酸甲酯苄基苯基醚,将此命名为化合物I。 After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0046] 将上述化合物I、用量为10 %的无水氯化铝(以化合物I的质量为100 %为计)、 用量为3的DMS0(以化合物I的质量为1计)置入反应容器中,调节温度至95°C。 [0046] The above compound I, in an amount of 10% anhydrous aluminum chloride (mass of Compound I was 100% basis), the amount of DMS0 3 (mass basis Compound I 1) into a reaction vessel , the temperature was adjusted to 95 ° C. 待反应的时间为12h。 The reaction time is to be 12h. 采用公知的分离手段分离出6, 11-二氢二苯并[b,e]噁庚英-11-酮。 Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0047] 在20L的反应容器中置入6, 11-二氢二苯并[b,e]噁庚英-11-酮、1. 1倍摩尔数于6, 11-二氢二苯并[b,e]噁庚英-11-酮的3-氯丙烷基叔丁基醚、2倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的镁粉、取全部THF的五分之二(5倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的THF),并加热到35°C使之反应。 [0047] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.1-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2 times the mass 6, 11-dihydro-dibenzo [b, e] oxepin-11-one magnesium in , taking all of fifths THF (5 to 6 times by mass, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) and heated to 35 ° C and allowed to react. 待反应启动后,滴加剩余的3/5 的THF。 After the reaction started, the remaining 3/5 of THF was added dropwise. 待滴加完毕向体系中通入氢气,回流。 Was added dropwise to the system to be completed into hydrogen, reflux. 当总共反应为5h后,停止反应。 After a total reaction 5h, the reaction was stopped. 再将体系冷却后倒入饱和氯化铵溶液中,加乙酸乙酯萃取二次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶,得到羟基类化合物。 After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0048] 在20L的反应容器中置入上述羟基类化合物、1. 5倍于羟基类化合物质量的氢氧化钠的乙醇溶液(质量浓度l〇wt% ),加热至65°C,消除反应2h后停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到烯烃类化合物。 [0048] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 1.5 times the mass of hydroxy compound class of sodium hydroxide (concentration l〇wt mass%), was heated to 65 ° C, 2h elimination reaction after the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0049] 在20L的反应容器中置入上述烯烃类化合物、1倍质量于烯烃类化合物的加的盐酸的水溶液入(质量浓度为5wt% ),加热至50°C,使之亲核取代反应。 [0049] placed in a 20L reaction vessel of the olefin compound, in an aqueous solution plus 1 times the mass of the olefinic compound hydrochloride (concentration of 5wt%), and heated to 50 ° C, so that a nucleophilic substitution reaction . 待反应的时间为4h 后,停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到卤代物。 The reaction time is to be after 4h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0050] 在20L的反应容器中置入上述卤代物、0. 1倍质量于卤代物的甲基锂、2倍质量于卤代物的乙醚,加热至40°C,使之亲核取代反应。 [0050] placed in a 20L reaction vessel above halide, 0.1 times the mass of methyl lithium halides to 2 times the mass of the halide in diethyl ether, heated to 40 ° C, so that the nucleophilic substitution reaction. 待反应的时间为5h后,停止反应,反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶即得到多塞平。 The reaction time is to be after 5h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0051] 在20L的耐压反应容器中置入上述多塞平、1. 05倍物质量于多塞平的盐酸(质量浓度为30wt% ),控制压力于3~4MPa,加热至130°C,使之中和反应。 [0051] 20L is placed in a pressure reactor above doxepin, 1.05 times the mass of material in the doxepin hydrochloride (concentration of 30wt%), the control pressure to 3 ~ 4MPa, and heated to 130 ° C , and among the responses. 待反应的时间为20h 后,应完毕冷却至室温经过滤、干燥得到盐酸多塞平。 Time after to be reacted for 20 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. 本例中总收率为37. 9%,经HPLC测得其纯度为99. 2%。 In this embodiment overall yield 37.9%, measured by HPLC obtaining 99.2% purity.

[0052] 实施例2 [0052] Example 2

[0053] 在20L的反应容器中置入乙腈、邻甲基苯甲酸、N-溴代丁二酰亚胺,采用水浴将温度控制在20°C,在搅拌条件下反应2h。 [0053] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 20 ° C, under stirring for 2h. 采用公知的分离方法,分离出邻卤甲基苯甲酸。 A known separation method, separation of o-toluic acid halide.

[0054] 在20L的反应容器中置入化合物J、用量为0. 05~0. 15的硅藻土负载氟化铯(以化合物J的质量为1计)、用量为2. 5~8的乙腈(以化合物J的质量为1计),将温度调至30~50°C,在搅拌调节下回流12~20h。 [0054] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. 然后,采用公知的手段分离出反应苯酞。 Then, a known means for separating the reaction phthalide.

[0055] 在20L的反应容器中置入苯酞、用量为10的甲醇钠的乙醇溶剂(苯酞与苯酚的总质量为1计),调节反应液的温度为60°C后,开始滴入物质量为1. 15的苯酚(以苯酞的物质量为1计),滴加时间为lh。 After [0055] phthalide placed in 20L reaction vessel, an amount of sodium methoxide in 10 ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 60 ° C, was added dropwise start phenol was 1.15 mass (in mass was 1 meter phthalide), dropwise over lh. 滴加完毕后,恒温反应5h后采用公知的分离方法,得到邻甲酸甲酯苄基苯基醚,将此命名为化合物I。 After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0056] 将上述化合物I、用量为40 %的无水氯化铝(以化合物I的质量为100 %为计)、 用量为8的DMS0 (以化合物I的质量为1计)置入反应容器中,调节温度至105°C。 [0056] The above compound I, in an amount of 40% anhydrous aluminum chloride (mass of Compound I was 100% basis), in an amount of DMS0 8 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 105 ° C. 待反应的时间为6h。 The reaction time is to be for 6h. 采用公知的分离手段分离出6, 11-二氢二苯并[b,e]噁庚英-11-酮。 Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0057] 在20L的反应容器中置入6, 11-二氢二苯并[b,e]噁庚英-11-酮、1. 5倍摩尔数于6, 11-二氢二苯并[b,e]噁庚英-11-酮的3-氯丙烷基叔丁基醚、2. 4倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的镁粉、取全部THF的五分之二(5~7倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的THF),并加热到40°C使之反应。 [0057] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.5-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.4 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 40 ° C reaction. 待反应启动后,滴加剩余的3/5的THF。 After the reaction started, the remaining 3/5 of THF was added dropwise. 待滴加完毕向体系中通入氢气,回流。 Was added dropwise to the system to be completed into hydrogen, reflux. 当总共反应为2h后,停止反应。 When the total reaction 2h, the reaction was stopped. 再将体系冷却后倒入饱和氯化铵溶液中,加乙酸乙酯萃取二次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶,得到羟基类化合物。 After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0058] 在20L的反应容器中置入上述羟基类化合物、5倍于羟基类化合物质量的氢氧化钠的乙醇溶液(质量浓度70wt% ),加热至80°C,消除反应lh后停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到烯烃类化合物。 [0058] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 5 times the mass of hydroxy compound class of sodium hydroxide (concentration of 70wt%), was heated to 80 ° C, the reaction was stopped after the elimination reaction LH, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0059] 在20L的反应容器中置入上述烯烃类化合物、2倍质量于烯烃类化合物的加的氢溴酸的水溶液入(质量浓度为30wt% ),加热至60°C,使之亲核取代反应。 [0059] placed in a 20L reaction vessel of the olefin compound, in an aqueous solution of 2 times the mass of the olefinic compound added hydrobromic acid (concentration of 30wt%), and heated to 60 ° C, so that nucleophilic Substitution reaction. 待反应的时间为1. 5h后,停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到卤代物。 The reaction time is to be after the 1. 5h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0060] 在20L的反应容器中置入上述卤代物、0. 8倍质量于卤代物的苯基锂、8倍质量于卤代物的乙醚,加热至50°C,使之亲核取代反应。 [0060] placed in a 20L reaction vessel above halide, 0.8 times the mass of phenyl lithium halide to 8 times the mass of the halide in diethyl ether, heated to 50 ° C, so that the nucleophilic substitution reaction. 待反应的时间为2h后,停止反应,反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶即得到多塞平。 The reaction time is to be after 2h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0061] 在20L的耐压反应容器中置入上述多塞平、1. 2倍物质量于多塞平的盐酸(质量浓度为38wt% ),控制压力于3~4MPa,加热至150°C,使之中和反应。 [0061] 20L is placed in a pressure reactor above doxepin, 1.2 times the mass of material in the doxepin hydrochloride (concentration of 38wt%), the control pressure to 3 ~ 4MPa, and heated to 150 ° C , and among the responses. 待反应的时间为16h 后,应完毕冷却至室温经过滤、干燥得到盐酸多塞平。 Time after to be reacted for 16 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. 本例中总收率为39. 7%,经HPLC测得其纯度为99. 4%。 In this embodiment overall yield 39.7%, measured by HPLC obtaining 99.4% purity.

[0062] 实施例3 [0062] Example 3

[0063] 在20L的反应容器中置入乙腈、邻甲基苯甲酸、N-溴代丁二酰亚胺,采用水浴将温度控制在15°C,在搅拌条件下反应3h。 [0063] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, under stirring for 3h. 采用公知的分离方法,分离出邻溴甲基苯甲酸。 A known separation method, separation of o-bromomethyl-benzoic acid.

[0064] 在20L的反应容器中置入化合物J、用量为0. 05~0. 15的硅藻土负载氟化铯(以化合物J的质量为1计)、用量为2. 5~8的乙腈(以化合物J的质量为1计),将温度调至30~50°C,在搅拌调节下回流12~20h。 [0064] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. 然后,采用公知的手段分离出反应苯酞。 Then, a known means for separating the reaction phthalide.

[0065] 在20L的反应容器中置入苯酞、用量为6的甲醇钠的乙醇溶剂(苯酞与苯酚的总质量为1计),调节反应液的温度为55°C后,开始滴入物质量为1. 10的苯酚(以苯酞的物质量为1计),滴加时间为lh。 After [0065] phthalide placed in 20L reaction vessel, an amount of sodium methoxide in ethanol solvent 6 (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start phenol was 1.10 mass (in mass was 1 meter phthalide), dropwise over lh. 滴加完毕后,恒温反应3. 5h后采用公知的分离方法,得到邻甲酸甲酯苄基苯基醚,将此命名为化合物I。 After the dropwise addition, the reaction temperature after 3. 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0066] 将上述化合物I、用量为25 %的无水氯化铝(以化合物I的质量为100 %为计)、 用量为6. 5的DMS0 (以化合物I的质量为1计)置入反应容器中,调节温度至100°C。 [0066] Anhydrous aluminum above compound I, in an amount of 25% of the chloride (compound I mass is 100% basis), in an amount of DMS0 6. 5 (in compound I is a mass basis) into the reaction vessel temperature is adjusted to 100 ° C. 待反应的时间为9h。 The reaction time is to be 9h. 采用公知的分离手段分离出6, 11-二氢二苯并[b,e]噁庚英-11-酮。 Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0067] 在20L的反应容器中置入6, 11-二氢二苯并[b,e]噁庚英-11-酮、1. 3倍摩尔数于6, 11-二氢二苯并[b,e]噁庚英-11-酮的3-氯丙烷基叔丁基醚、2. 2倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的镁粉、取全部THF的五分之二(5~7倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的THF),并加热到38°C使之反应。 [0067] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.3-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.2 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 38 ° C reaction. 待反应启动后,滴加剩余的3/5的THF。 After the reaction started, the remaining 3/5 of THF was added dropwise. 待滴加完毕向体系中通入氢气,回流2h。 Was added dropwise to the system to be completed into hydrogen, refluxed for 2h. 当总共反应为3. 5h后,停止反应。 After a total reaction 3. 5h, the reaction was stopped. 再将体系冷却后倒入饱和氯化铵溶液中,加乙酸乙酯萃取二次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶,得到羟基类化合物。 After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0068] 在20L的反应容器中置入上述羟基类化合物、3倍于羟基类化合物质量的氢氧化钠的乙醇溶液(质量浓度40wt% ),加热至75°C,消除反应1. 5h后停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到烯烃类化合物。 [0068] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 3-hydroxysteroid times the mass of the compound of sodium hydroxide (concentration of 40wt%), and heated to 75 ° C, 1. 5h the reaction stopped after elimination the reaction was cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0069] 在20L的反应容器中置入上述烯烃类化合物、1. 5倍质量于烯烃类化合物的加的氢碘酸的水溶液入(质量浓度为18wt% ),加热至55°C,使之亲核取代反应。 [0069] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 18wt%), was heated to 55 ° C, so nucleophilic substitution reaction. 待反应的时间为2h后,停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到卤代物。 The reaction time is to be after 2h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0070] 在20L的反应容器中置入上述卤代物、0. 4倍质量于卤代物的正丁基锂、5倍质量于卤代物的乙醚,加热至45°C,使之亲核取代反应。 [0070] placed in a 20L reaction vessel above halide, 0.4 times the mass of the halide in n-butyllithium, in diethyl ether five times the mass of halide and heated to 45 ° C, so that a nucleophilic substitution reaction . 待反应的时间为3. 5h后,停止反应,反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶即得到多塞平。 The reaction time is to be 3. After 5h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0071] 在20L的耐压反应容器中置入上述多塞平、1. 12倍物质量于多塞平的盐酸(质量浓度为34wt% ),控制压力于3~4MPa,加热至140°C,使之中和反应。 [0071] 20L is placed in a pressure reactor above doxepin, 1.12 times the mass of material in the doxepin hydrochloride (concentration of 34wt%), the control pressure to 3 ~ 4MPa, and heated to 140 ° C , and among the responses. 待反应的时间为18h 后,应完毕冷却至室温经过滤、干燥得到盐酸多塞平。 Time after to be reacted for 18 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. 本例中总收率为40. 2%,经HPLC测得其纯度为99. 5%。 In this embodiment overall yield 40.2%, measured by HPLC obtaining 99.5% purity.

[0072] 实施例4 [0072] Example 4

[0073] 在20L的反应容器中置入乙腈、邻甲基苯甲酸、N-溴代丁二酰亚胺,采用水浴将温度控制在15°C,在搅拌条件下反应4h。 [0073] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, under stirring for 4h. 采用公知的分离方法,分离出邻卤甲基苯甲酸。 A known separation method, separation of o-toluic acid halide.

[0074] 在20L的反应容器中置入化合物J、用量为0. 05~0. 15的硅藻土负载氟化铯(以化合物J的质量为1计)、用量为2. 5~8的乙腈(以化合物J的质量为1计),将温度调至30~50°C,在搅拌调节下回流12~20h。 [0074] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. 然后,采用公知的手段分离出反应苯酞。 Then, a known means for separating the reaction phthalide.

[0075] 在20L的反应容器中置入苯酞、用量为5的甲醇钠的乙醇溶剂(苯酞与苯酚的总质量为1计),调节反应液的温度为55°C后,开始滴入物质量为1. 15的苯酚(以苯酞的物质量为1计),滴加时间为lh。 After [0075] phthalide placed in 20L reaction vessel, 5 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start phenol was 1.15 mass (in mass was 1 meter phthalide), dropwise over lh. 滴加完毕后,恒温反应5h后采用公知的分离方法,得到邻甲酸甲酯苄基苯基醚,将此命名为化合物I。 After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0076] 将上述化合物I、用量为25 %的无水氯化铝(以化合物I的质量为100 %为计)、 用量为8的DMS0 (以化合物I的质量为1计)置入反应容器中,调节温度至100°C。 [0076] The above compound I, in an amount of 25% anhydrous aluminum chloride (mass of Compound I was 100% basis), in an amount of DMS0 8 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 100 ° C. 待反应的时间为12h。 The reaction time is to be 12h. 采用公知的分离手段分离出6, 11-二氢二苯并[b,e]噁庚英-11-酮。 Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0077] 在20L的反应容器中置入6, 11-二氢二苯并[b,e]噁庚英-11-酮、1. 3倍摩尔数于6, 11-二氢二苯并[b,e]噁庚英-11-酮的3-氯丙烷基叔丁基醚、2. 4倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的镁粉、取全部THF的五分之二(5~7倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的THF),并加热到40°C使之反应。 [0077] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.3-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.4 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 40 ° C reaction. 待反应启动后,滴加剩余的3/5的THF。 After the reaction started, the remaining 3/5 of THF was added dropwise. 待滴加完毕向体系中通入氢气,回流。 Was added dropwise to the system to be completed into hydrogen, reflux. 当总共反应为2h后,停止反应。 When the total reaction 2h, the reaction was stopped. 再将体系冷却后倒入饱和氯化铵溶液中,加乙酸乙酯萃取二次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶,得到羟基类化合物。 After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0078] 在20L的反应容器中置入上述羟基类化合物、5倍于羟基类化合物质量的氢氧化钠的乙醇溶液(质量浓度70wt% ),加热至80°C,消除反应lh后停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到烯烃类化合物。 [0078] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 5 times the mass of hydroxy compound class of sodium hydroxide (concentration of 70wt%), was heated to 80 ° C, the reaction was stopped after the elimination reaction LH, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0079] 在20L的反应容器中置入上述烯烃类化合物、1. 5倍质量于烯烃类化合物的加的氢碘酸的水溶液入(质量浓度为30wt% ),加热至60°C,使之亲核取代反应。 [0079] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 30wt%), and heated to 60 ° C, so nucleophilic substitution reaction. 待反应的时间为1. 5h后,停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到卤代物。 The reaction time is to be after the 1. 5h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0080] 在20L的反应容器中置入上述卤代物、0. 8倍质量于卤代物的正丁基锂、8倍质量于卤代物的乙醚,加热至50°C,使之亲核取代反应。 [0080] placed in a 20L reaction vessel above halide, 0.8 times in mass n-butyl lithium halide, eight times the mass of the halide in diethyl ether, heated to 50 ° C, so that a nucleophilic substitution reaction . 待反应的时间为2h后,停止反应,反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶即得到多塞平。 The reaction time is to be after 2h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0081] 在20L的耐压反应容器中置入上述多塞平、1. 2倍物质量于多塞平的盐酸(质量浓度为38wt% ),控制压力于3~4MPa,加热至150°C,使之中和反应。 [0081] 20L is placed in a pressure reactor above doxepin, 1.2 times the mass of material in the doxepin hydrochloride (concentration of 38wt%), the control pressure to 3 ~ 4MPa, and heated to 150 ° C , and among the responses. 待反应的时间为16h 后,应完毕冷却至室温经过滤、干燥得到盐酸多塞平。 Time after to be reacted for 16 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. 本例中总收率为41. 6%,经HPLC测得其纯度为99. 7%。 In this embodiment overall yield 41.6%, measured by HPLC obtaining 99.7% purity.

[0082] 实施例5 [0082] Example 5

[0083] 在20L的反应容器中置入乙腈、邻甲基苯甲酸、N-溴代丁二酰亚胺,采用水浴将温度控制在15°C,在搅拌条件下反应2. 5h。 [0083] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, the reaction 2. 5h under stirring. 采用公知的分离方法,分离出邻溴甲基苯甲酸。 A known separation method, separation of o-bromomethyl-benzoic acid.

[0084] 在20L的反应容器中置入邻溴甲基苯甲酸、用量为0. 05~0. 15的硅藻土负载氟化铯(以化合物J的质量为1计)、用量为2. 5~8的乙腈(以化合物J的质量为1计), 将温度调至30~50°C,在搅拌调节下回流12~20h。 [0084] placed in a 20L reaction vessel o-bromomethyl benzoic acid, diatomaceous earth in an amount of load of cesium fluoride 0.05 ~ 0.15 (in mass Compound J is 1 meter), in an amount of 2. 5-8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. 然后,采用公知的手段分离出反应苯酞。 Then, a known means for separating the reaction phthalide.

[0085] 在20L的反应容器中置入苯酞、用量为5的甲醇钠的乙醇溶剂(苯酞与苯酚的总质量为1计),调节反应液的温度为55°C后,开始滴入物质量为1. 08的苯酚(以苯酞的物质量为1计),滴加时间为lh。 After [0085] phthalide placed in 20L reaction vessel, 5 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start was 1.08 mass of phenol (mass was phthalide 1 meter), dropwise over lh. 滴加完毕后,恒温反应3h后采用公知的分离方法,得到邻甲酸甲酯苄基苯基醚,将此命名为化合物I。 After the dropwise addition, the reaction temperature after 3h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0086] 将上述化合物I、用量为25 %的无水氯化铝(以化合物I的质量为100 %为计)、 用量为5的DMS0 (以化合物I的质量为1计)置入反应容器中,调节温度至100°C。 [0086] Anhydrous aluminum above compound I, in an amount of 25% of the chloride (compound I mass is 100% basis), in an amount of DMS0 5 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 100 ° C. 待反应的时间为8h。 The reaction time is to be 8h. 采用公知的分离手段分离出6, 11-二氢二苯并[b,e]噁庚英-11-酮。 Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0087] 在20L的反应容器中置入6, 11-二氢二苯并[b,e]噁庚英-11-酮、1. 2倍摩尔数于6, 11-二氢二苯并[b,e]噁庚英-11-酮的3-氯丙烷基叔丁基醚、2. 2倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的镁粉、取全部THF的五分之二(5~7倍质量于6, 11-二氢二苯并[b,e]噁庚英-11-酮的THF),并加热到38°C使之反应。 [0087] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.2-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.2 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 38 ° C reaction. 待反应启动后,滴加剩余的3/5的THF。 After the reaction started, the remaining 3/5 of THF was added dropwise. 待滴加完毕向体系中通入氢气,回流。 Was added dropwise to the system to be completed into hydrogen, reflux. 当总共反应为2h后,停止反应。 When the total reaction 2h, the reaction was stopped. 再将体系冷却后倒入饱和氯化铵溶液中,加乙酸乙酯萃取二次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶,得到羟基类化合物。 After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0088] 在20L的反应容器中置入上述羟基类化合物、2倍于羟基类化合物质量的氢氧化钠的乙醇溶液(质量浓度40wt% ),加热至70°C,消除反应2h后停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到烯烃类化合物。 [0088] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 2 times the mass of hydroxy compound class of sodium hydroxide (concentration of 40wt%), was heated to 70 ° C, the reaction was stopped after the elimination reaction 2h, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0089] 在20L的反应容器中置入上述烯烃类化合物、1. 5倍质量于烯烃类化合物的加的氢碘酸的水溶液入(质量浓度为15wt% ),加热至50°C,使之亲核取代反应。 [0089] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 15wt%), and heated to 50 ° C, so nucleophilic substitution reaction. 待反应的时间为4h后,停止反应,冷却,蒸掉多于的溶剂,将所得到的粗产品用乙腈结晶,得到卤代物。 The reaction time is to be after 4h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0090] 在20L的反应容器中置入上述卤代物、0. 4倍质量于卤代物的正丁基锂、2~8倍质量于卤代物的乙醚,加热至45°C,使之亲核取代反应。 [0090] placed in a 20L reaction vessel above halide, 0.4 times the mass of the halide in n-butyl lithium, 2 to 8 times the mass of the halide in diethyl ether, heated to 45 ° C, so that nucleophilic Substitution reaction. 待反应的时间为3h后,停止反应, 反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用乙腈重结晶即得到多塞平。 The reaction time is to be after 3h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0091] 在20L的耐压反应容器中置入上述多塞平、1. 12倍物质量于多塞平的盐酸(质量浓度为37. 6wt% ),控制压力于3~4MPa,加热至140°C,使之中和反应。 [0091] 20L is placed in a pressure reactor above doxepin, 1.12 times the mass of material in the doxepin hydrochloride (mass concentration 37. 6wt%), the control pressure to 3 ~ 4MPa, heated to 140 ° C, allowing the reaction among. 待反应的时间为20h后,应完毕冷却至室温经过滤、干燥得到盐酸多塞平。 Time after to be reacted for 20 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. 本例中总收率为43. 9%,经HPLC 测得其纯度为99. 9%。 In this embodiment overall yield 43.9%, measured by HPLC obtaining 99.9% purity.

[0092] 由于本发明中所涉及的各工艺参数的数值范围在上述实施例中不可能全部体现, 但本领域的技术人员完全可以想象到只要落入上述该数值范围内的任何数值均可实施本发明,当然也包括若干项数值范围内具体值的任意组合。 [0092] Since the numerical ranges of the process parameters of the present invention relates can not all reflected in the above embodiments, those skilled in the art is fully conceivable as long as any number falling within the above-described embodiment of the numerical range available the present invention is, of course, also comprise any combination of a number of particular value in the value range. 此处,出于篇幅的考虑,省略了给出某一项或多项数值范围内具体值的实施例,此不应当视为本发明的技术方案的公开不充分。 Here, due to space considerations, is omitted is given a value of one or more embodiments in a range of specific values, this should not be considered disclosed aspect of the present invention is insufficient.

[0093] 申请人声明,本发明通过上述实施例来说明本发明的详细工艺设备和工艺流程, 但本发明并不局限于上述详细工艺设备和工艺流程,即不意味着本发明必须依赖上述详细工艺设备和工艺流程才能实施。 [0093] Statement Applicant, the process of the present invention will be described in detail the process and apparatus of the present invention by the above-described embodiment, but the present invention is not limited to the above detailed process equipment and processes, i.e., it does not mean that the present invention is to rely on detailed above process equipment and processes to be implemented. 所属技术领域的技术人员应该明了,对本发明的任何改进, 对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。 Those skilled in the art should be appreciated, any improvement in the present invention, an equivalent of the present invention product of each material substitutions and adding auxiliary ingredients, selection of specific ways, are within the scope and scope of the disclosure of the present invention.

Claims (9)

  1. 1. 一种以邻甲基苯甲酸为原料合成盐酸多塞平的合成方法,其特征在于,包括以下步骤: (1) 将邻甲基苯甲酸与N-卤代丁二酰亚胺在光照条件下于乙腈溶剂中进行发生苄基卤代反应,得到邻卤甲基苯甲酸(化合物J),反应式如下, An o-methylbenzoic acid hydrochloride was synthesized by the synthesis method of a multi-level plug, characterized by comprising the steps of: (1) o-methylbenzoic acid with N- halosuccinimide in the light benzyl halides reaction occurs under conditions in acetonitrile solvent to afford ortho-halo-methylbenzoic acid (compound J), the following reaction formula,
    Figure CN105330638AC00021
    (2) 将化合物J以硅藻土负载氟化铯为催化剂于乙腈溶剂中进行分子内取代反应,得到苯酞(化合物H),反应式如下, (2) Compound J celite load cesium fluoride intramolecular substitution reaction, to give phthalide (compound H), the following reaction formula in an acetonitrile solvent and as a catalyst,
    Figure CN105330638AC00022
    (3) 将化合物J与苯酚在甲醇钠的醇溶剂中进行取代反应,得到化合物I,反应式如下, (3) Compound J phenol with sodium methoxide in an alcohol solvent substitution reaction, to give a compound I, the following reaction formula,
    Figure CN105330638AC00023
    (4) 将所述化合物I在无水氯化铝的催化下在DMSO溶剂中进行环化反应,得到6, 11-二氢二苯并[b,e]噁庚英-11-酮(化合物A),反应式如下, (4) The cyclization reaction of compound I in DMSO solvent under anhydrous aluminum chloride catalyst to obtain a 6, 11-dihydro-dibenzo [b, e] oxepin-11-one (Compound A), the following reaction formula,
    Figure CN105330638AC00024
    (5) 将6, 11-二氢二苯并[b,e]噁庚英-11-酮(化合物A)与3-氯丙烷基叔丁基醚(化合物B)在加入镁粉且以THF和/或无水乙醚为溶剂的条件下进行亲核加成反应,得到羟基类化合物(化合物C),反应式如下, (5) 6, 11-dihydro-dibenzo [b, e] oxepin-11-one (Compound A) and 3-chloropropyl alkyl tert-butyl ether (compound B) in THF was added to magnesium powder and and / or a nucleophilic addition of anhydrous diethyl ether under the conditions of the reaction solvent to give the hydroxy compound (compound C), the following reaction formula,
    Figure CN105330638AC00031
    (6) 向所述羟基类化合物在强碱的醇溶剂中加热进行消除反应,得到烯烃类化合物(化合物D),反应式如下, (6) heating elimination reaction to give an olefin compound (Compound D) in a strong base in an alcoholic solvent to the hydroxy compound, the following reaction formula,
    Figure CN105330638AC00032
    (7) 将所述烯烃类化合物在氢卤酸下进行亲核取代反应,得到卤代物(化合物E),反应式如下, (7) The olefinic compound nucleophilic substitution reaction, to give halide (Compound E) at a hydrohalic acid, the following reaction formula,
    Figure CN105330638AC00033
    其中,化合物E中X为一C1、一Br或一I; (8) 将所述卤代物同二甲胺在加入有机锂化合物于醚的溶剂中下进行亲核取代反应, 得到多塞平(化合物F),反应式如下, Wherein the compound E X is a C1, Br, or a a I; (8) the halide in a solvent is added to the organic lithium compound in an ether with dimethylamine nucleophilic substitution reaction, to give doxepin ( compound F.), the following reaction formula,
    Figure CN105330638AC00041
    (9)将所述多塞平同盐酸进行中和反应,得到柳氮磺吡啶(化合物G),反应式如下, (9) the doxepin with hydrochloric acid and the reaction carried out, to give sulfasalazine (Compound G), the following reaction formula,
    Figure CN105330638AC00042
  2. 2. 根据权利要求1所述的合成方法,其特征在于,步骤⑵中: 所述娃藻土负载氟化铯的用量为0. 05~0. 15,以化合物J的质量为1计; 优选地,所述乙腈的用量为2. 5~8,以化合物J的质量为1计; 优选地,所述分子内脱水反应的温度为30~50°C,反应的时间为12~20h。 2. The method of synthesis according to claim 1, wherein, in the step ⑵: The baby diatomaceous earth load cesium fluoride in an amount of 0.05 ~ 015, mass Compound J is 1 meter; preferably , the acetonitrile in an amount of 2.5 to 8, compound J is a mass basis; preferably, the temperature within said intramolecular dehydration reaction is 30 ~ 50 ° C, the reaction time is 12 ~ 20h.
  3. 3. 根据权利要求1所述的合成方法,其特征在于,步骤⑶中: 苯酞与苯酚的物质量之比为1:1. 05~1. 15 ; 优选地,所述取代反应的温度为50~60°C,所述取代反应的时间为3~6h ; 优选地,所述甲醇钠的醇溶剂用量为3~10,以苯酞与苯酚的总质量为1计。 3. The method of synthesis according to claim 1, wherein, in the step ⑶: mass ratio was phthalide and phenol is 1: 105 ~ 115; Preferably, the temperature of the reaction is a substituted time of 50 ~ 60 ° C, the substitution reaction is 3 to 6H; preferably, the amount of sodium methoxide in an alcohol solvent having 3 to 10, based on the total mass of phenol phthalide and 1 meter.
  4. 4. 根据权利要求1所述的合成方法,其特征在于,步骤⑷中: 所述无水氯化铝的用量为10~40%,以化合物I的质量为100%计; 优选地,所述DMSO的用量为3~8,以化合物I的质量为1计; 优选地,所述环化反应的温度为95~105°C,所述环化反应的时间为6~12h。 4. The method of synthesis according to claim 1, wherein, in the step ⑷: said anhydrous aluminum chloride in an amount of 10 to 40% by mass of compound I as 100%; preferably, the DMSO in an amount of 3 to 8, mass compound I 1 terms; preferably, the cyclization reaction temperature is 95 ~ 105 ° C, the cyclization reaction time is 6 ~ 12h.
  5. 5. 根据权利要求1所述的合成方法,其特征在于,步骤(5)中: 所述化合物A与化合物B的物质量之比为1:1. 1~1. 5 ; 优选地,所述亲核加成反应的温度为35~40°C,反应时间为2~5h ; 优选地,所述镁粉的加入量为2~2. 4,以化合物A质量为1计算; 优选地,所述溶剂的加入量为5~7,以化合物A质量为1计算。 The synthesis method according to claim 1, wherein the step (5): The ratio of the mass of compound A and compound B is 1: 1 to 1 5 1; Preferably, the nucleophilic addition reaction temperature is 35 ~ 40 ° C, the reaction time is 2 ~ 5H; preferably, the amount of added magnesium powder is from 2 to 24, a to calculate the mass of the compound is 1; preferably, the said solvent is added in an amount of from 5 to 7, a is a mass of the compound is calculated.
  6. 6. 根据权利要求1所述的合成方法,其特征在于,步骤(6)中: 所述消除反应的温度为65~80°C ; 优选地,所述强碱的醇溶剂的质量浓度为10~70% ; 优选地,所述强碱的醇溶剂的用量为1. 5~5,以化合物C的质量为1计算。 6. The synthesis method according to claim 1, wherein, in step (6): The elimination reaction temperature is 65 ~ 80 ° C; preferably, the solvent is an alcohol concentration of strong base is 10 ~ 70%; preferably, the amount of the alcohol solvent strong base is 1.5 - 5 to 1 mass calculated for C compound.
  7. 7. 根据权利要求1所述的合成方法,其特征在于,步骤(7)中: 所述亲核取代反应的温度为50~60°C,反应的时间为1. 5~4h ; 优选地,所述氢卤酸的用量为1~2,以化合物D的物质量为1 ; 优选地,所述氢卤酸的质量浓度为5~30%。 The synthesis method according to claim 1, wherein, in step (7): The nucleophilic substitution reaction at a temperature 50 ~ 60 ° C, the reaction time was 1. 5 ~ 4h; Preferably, the hydrohalic acid used in an amount of 1 to 2, mass compounds D is 1; preferably, the concentration of hydrohalic acid is 5 to 30%.
  8. 8. 根据权利要求1所述的合成方法,其特征在于,步骤⑶中: 所述有机锂化合物为Q~C 4直链烷烃基锂; 优选地,所述有机锂化合物的用量为0. 1~0. 8,以化合物E的质量为1计算; 优选地,所述醚选自乙醚、甲基乙基醚、丙醚中的任意一种或两种以上; 优选地,所述醚的用量为2~8,以化合物E的质量为1计算; 优选地,所述亲核取代反应的温度为40~50°C,反应时间为2~5h。 8. The synthesis method according to claim 1, wherein, in the step ⑶: the organolithium compound is Q ~ C 4 linear alkane-butyllithium; Preferably, the amount of the organic lithium compound is 0.1 . ~ 08 to 1 mass calculated for compound E; preferably, the ether is selected from any one of diethyl ether, methyl ethyl ether, propyl ether or more; preferably, the amount of ether 2 to 8, mass calculated compound E is 1; preferably, the nucleophilic substitution reaction temperature is 40 ~ 50 ° C, the reaction time is 2 ~ 5h.
  9. 9. 根据权利要求1所述的合成方法,其特征在于,步骤(9)中: 所述中和反应的温度为130~150°C,所述反应的时间为16~20h ; 优选地,所述盐酸的质量浓度为30~38% ; 优选地,所述盐酸的用量为1. 05~1. 2,以化合物F的物质量为1计算。 9. The synthesis method according to claim 1, wherein the step (9): the temperature of the neutralization reaction is 130 ~ 150 ° C, the reaction time is 16 ~ 20h; Preferably, said mass concentration of hydrochloric acid is from 30 to 38%; preferably, the amount of the hydrochloric acid is 1.05 ~ 12, compound mass F 1 is calculated.
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CN102924424A (en) * 2012-09-04 2013-02-13 苏州弘森药业有限公司 Method for synthesizing doxepin hydrochloride
CN105061386A (en) * 2015-08-17 2015-11-18 苏州黄河制药有限公司 Method for synthesizing doxepin hydrochloride by utilizing phthalic anhydride as raw material

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CN102924424A (en) * 2012-09-04 2013-02-13 苏州弘森药业有限公司 Method for synthesizing doxepin hydrochloride
CN105061386A (en) * 2015-08-17 2015-11-18 苏州黄河制药有限公司 Method for synthesizing doxepin hydrochloride by utilizing phthalic anhydride as raw material

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