CN102924424A - Method for synthesizing doxepin hydrochloride - Google Patents

Method for synthesizing doxepin hydrochloride Download PDF

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CN102924424A
CN102924424A CN 201210388828 CN201210388828A CN102924424A CN 102924424 A CN102924424 A CN 102924424A CN 201210388828 CN201210388828 CN 201210388828 CN 201210388828 A CN201210388828 A CN 201210388828A CN 102924424 A CN102924424 A CN 102924424A
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doxepin
reaction
hydrochloric acid
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hydrochloride
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CN 201210388828
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CN102924424B (en )
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杨颖瑾
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苏州弘森药业有限公司
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of products other than chlorine, adipic acid, caprolactam, or chlorodifluoromethane, e.g. bulk or fine chemicals or pharmaceuticals
    • Y02P20/58Recycling
    • Y02P20/584Recycling of catalysts

Abstract

The invention provides a method for synthesizing doxepin hydrochloride. The method comprises the following steps of: 1, carrying out an addition reaction on 6,11-dihydrobenz [b,e] oxepin-11-one and 3-chloropropyl-methyl tert-butyl ether to obtain alcohol compounds; 2, removing hydroxyl from the alcohol compounds under the condition of concentrated hydrochloric acid to obtain olefin compounds; 3, reacting the olefin compounds with thionyl chloride in a reaction solvent to obtain chloride; 4, coupling the chloride with N,N-dimethyl methylamine to obtain doxepin; and 5, preparing the doxepin into hydrochloride of the doxepin to obtain the doxepin hydrochloride. An Ni(OAc)2/PPh3 system is creatively used in C-N coupling reaction in the step 4, thus the doxepin hydrochloride has the characteristics of good reaction selectivity, high yield and environmental friendliness; and the catalyst is can be recycled after being simply filtered, thus the production cost is greatly lowered. The whole method has the advantages of simpleness in operation, and easy obtaining and low cost of raw materials, accords with the requirement of industrial production, and is expected to be industrially applied.

Description

一种合成盐酸多塞平的方法 Multi a synthetic method of doxepin hydrochloride

技术领域 FIELD

[0001] 本发明属于化学合成领域,具体涉及一种合成盐酸多塞平的方法。 [0001] The present invention belongs to the field of chemical synthesis, particularly relates to a method of synthesizing doxepin hydrochloride.

背景技术 Background technique

[0002] 盐酸多塞平(Doxepin Hydrochloride)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。 [0002] doxepin hydrochloride (Doxepin Hydrochloride) is a drug used to treat depression and anxiety neurosis that act to inhibit the central nervous system and to serotonin reuptake of norepinephrine, so that the synaptic cleft in these two neurotransmitters play a higher concentration of the 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(tl/2)为8-12小时,表观分布容积(Vd)9_33L/kg。 Doxepin hydrochloride oral absorption, bioavailability of 13-45%, half-life (tl / 2) is 8-12 hours, apparent volume of distribution (Vd) 9_33L / kg. 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. 其化学名为N,N-二甲基-3-二苯并[b,6]-{恶}庚英-11(6H)亚基-I-丙胺盐酸盐顺反异构体混合物,CAS号:1229-29-4.盐酸多塞平的结构式如下: Its chemical name is N, N- dimethyl-3-dibenzo [b, 6] - ylidene -I- propylamine hydrochloride a mixture of cis and trans isomers evil {} heptanoic England -11 (6H), CAS number: 1229-29-4 doxepin hydrochloride following structural formula:

[0003] [0003]

cCb cCb

.HCI .HCI

I I

Doxepin Hydrochioride Doxepin Hydrochioride

盐酸多-速乎 Multi hydrochloride - Speed ​​Down

[0004] 至今为止关于盐酸多塞平的全合成有一些报道(如专利US20100179215,US20100179214, US20100305326)。 [0004] So far on the total synthesis of doxepin hydrochloride there were some reports (such as patents US20100179215, US20100179214, US20100305326). 其中涉及到第四部碳氮偶联的反应,大多数还是使用一些苛刻的操作条件或贵金属试剂,如Pd、Pt、Ru、Rh等。 Wherein the fourth portion of the reaction involves the coupling of a carbonitride, or the use of some of the most demanding operating conditions or a noble metal reagent, such as Pd, Pt, Ru, Rh and the like. 这里不仅涉及到催化剂成本高、操作繁琐等缺点外,还涉及到催化剂的循环使用及对环境的污染等问题。 Here not only to the disadvantage of the high cost of the catalyst, and the like complicated operations, but also it involves the recycling of catalyst and environmental pollution problems. 而这步偶联反应关系到整个盐酸多塞平的合成。 Relationship between this step and the coupling reaction throughout the synthesis doxepin hydrochloride. 在这种条件下开发出绿色环保、低成本无毒、可循环使用的催化剂就显得尤为重要。 Under these conditions the development of green, low-cost, non-toxic, reusable catalyst is particularly important. 令人欣慰的是发明人意外发现Ni催化剂对于本步反应有奇特的效果,反应收率高,副产物少,关键催化剂价廉易得,可循环使用,因此,本发明将Ni (OAc)2/PPh3催化体系运用到盐酸多塞平的合成中。 Gratifying that the inventors surprisingly found that the Ni catalyst for the reaction of the present step has a peculiar effect, reaction yield, less by-products, the key catalyst cheap, can be recycled, therefore, the present invention is the Ni (OAc) 2 / PPh3 catalyst system applied to the synthesis of doxepin hydrochloride. 同时,对反应路线进行了整体的优化和改进,得到了一种理想的合成盐酸多塞平的方法。 Meanwhile, the reaction routes and improve overall optimized to obtain a desirable method of synthesis of doxepin hydrochloride.

发明内容 SUMMARY

[0005] 本发明的目的在于提供一种能够简单、绿色环保、整体收率高的合成盐酸多塞平的方法。 [0005] The object of the present invention is to provide a simple, environmental protection, the overall yield of the synthesis method of doxepin hydrochloride.

[0006] 为实现发现目的,本发明采用如下技术方案: [0006] To achieve the object of the discovery, the present invention adopts the following technical solution:

[0007] 一种合成盐酸多塞平的方法,包括以下步骤: [0007] A synthetic method of doxepin hydrochloride, comprising the steps of:

[0008] (I) 6,11-二氢二苯并[b,e]噁庚英_11_酮和3_氯丙基-叔丁基醚进行加成反应得醇类化合物;[0009] (2)所述醇类化合物在浓盐酸条件下消去羟基得到烯烃类化合物; [0008] (I) 6,11- dihydro-dibenzo [b, e] oxepin-one and 3_ chloropropyl _11_ - tert-butyl ether addition reaction to obtain an alcohol compound; [0009] (2) elimination of the hydroxyl group in alcohols under conditions of concentrated hydrochloric acid to give the olefinic compounds;

[0010] (3)所述烯烃类化合物在反应溶剂中与二氯亚砜反应得到氯代物; [0010] (3) The olefinic compound is reacted with thionyl chloride to give chlorides in a reaction solvent;

[0011] (4)所述氯代物和N,N-二甲基甲胺偶联得到多塞平; [0011] (4) The chlorides and N, N- dimethylmethanamine yielded doxepin;

[0012] (5)将多塞平制成其盐酸盐,即得。 [0012] (5) which is made of doxepin hydrochloride, i.e., too.

[0013] 其中,本发明优选所述的步骤I为:用量比为1:1-1:1.5的6,11-二氢二苯并[b, e]噁庚英-11-酮和3-氯丙基-叔丁基醚在催化剂的作用下在无水乙醚中进行加成反应,反应回流得醇类化合物,更优选用量比为I :1. 2。 [0013] wherein, preferably the present invention as Step I: a ratio of 1: 1.5 and 6,11-dihydro-dibenzo [b, e] oxepin-11-one and 3: 1-1 chloropropyl - tert-butyl ether over a catalyst of the addition reaction in anhydrous diethyl ether, the reaction was refluxed to give an alcohol compound, more preferably a ratio of I: 1 2..

[0014] 本发明说明书中,所述的6,11- 二氢二苯并[b,e]噁庚英-11-酮(CAS:4504-87-4)即下文所述的环酮。 [0014] In the present specification, the 6,11-dihydro-dibenz [b, e] oxepin-11-one (CAS: 4504-87-4) i.e. below the cyclic ketone.

[0015] 此外,步骤I中,无水乙醚作为溶剂滴加,其体积用量为6,11-二氢二苯并[b,e]·噁庚英-I I-酮重量的5. 5-6. 3倍,,所述的催化剂为镁粉,催化剂的投放量为6,11-二氢二苯并[b,e]噁庚英-11-酮的I. 8-2. 2倍,反应时间为2_5h,温度为35_40°C。 [0015] Further, in step I, the dropwise addition of anhydrous diethyl ether as solvent, the volume thereof in an amount of 6,11-dihydro-dibenz [b, e] · British -I I- hept-one 5. 5- wt evil ,, 6.3 times the delivery quantity of the catalyst is magnesium, the catalyst is 6,11-dihydro-dibenz [b, e] oxepin-11-one of I. 8-2. 2-fold, The reaction time is 2_5h, temperature 35_40 ° C.

[0016] 本步骤中,无水乙醚的滴加速度为其用量的2%_6%每分钟,在该滴加速度下,6,11- 二氢二苯并[b,e]噁庚英-11-酮和3-氯丙基-叔丁基醚能够实现更理想的加成反应。 [0016] In this step, for the acceleration of anhydrous ether dropwise amount _6% 2% per minute, the drop in acceleration, 6,11-dihydro-dibenz [b, e] oxepin -11- one and 3-chloropropyl - t-butyl ether enables more preferably an addition reaction.

[0017] 步骤2中醇类化合物在浓盐酸条件下保持沸腾,浓盐酸的用量为反应底物的2-10倍;反应时间为5-8h。 [0017] Step 2. Alcohols kept boiling under conditions of concentrated hydrochloric acid, concentrated hydrochloric acid is used in an amount of 2-10 times the reaction substrate; reaction time is 5-8h.

[0018] 步骤3中反应溶剂为苯或甲苯,烯烃类化合物与二氯亚砜的用量比为1:1-1:1. 5,,反应在110-120°c下加热回流2-4h,优选烯烃类化合物与二氯亚砜的用量比为1:1. 2,反应在115°C下加热回流3h。 [0018] Step 3 in benzene or toluene as the reaction solvent, the olefinic compound with thionyl chloride ratio of 1: 1-1: 15,, the reaction was heated at reflux for 2-4h at 110-120 ° c, preferred olefinic compound with thionyl chloride ratio of 1: 1, the reaction was heated at reflux for 3h at 115 ° C.

[0019] 步骤4以Ni (OAc)2作为反应催化剂,三苯基膦作为配体。 [0019] In Step 4 Ni (OAc) 2 as a reaction catalyst, triphenylphosphine as a ligand.

[0020] 本发明优选所述的步骤4具体为:在催化剂的作用下,氯代物和N,N- 二甲基甲胺在DMF于35-45°C条件下反应4_6h,优选在40°C条件下反应5h,偶联得到多塞平。 [0020] Step 4 according to the present invention preferably specifically: in the presence of catalyst, chlorides and N, N- dimethyl-methylamine in DMF at 35-45 ° C conditions 4_6h, preferably at 40 ° C the reaction conditions 5h, yielded doxepin.

[0021] 该步骤4中,氯代物和N,N- 二甲基甲胺的用量比为1:1-1:1. 5,催化剂的投放量为2-8%,配体与氯代物的用量比为8:1-12:1,优选氯代物和N,N-二甲基甲胺的用量比为1:1. 1,催化剂的投放量为5%,配体与氯代物的用量比为10:1。 [0021] In the step 4, chlorides and N, N- dimethylmethanamine with an equivalent ratio of 1: 1-1: 15, the amount of catalyst is served 2-8%, ligand Chlorides with the ratio of 8: 1-12: 1, preferably chlorides and N, N- dimethylmethanamine by equivalent ratio of 1: 11, the delivery amount of the catalyst is 5%, ligand Chlorides amount ratio 10: 1.

[0022] 此外,本发明所述的合成方法步骤1-4均还包括对各步骤所得产物粗品进行重结晶的操作,具体的重结晶为本领域技术人员所掌握,本发明优选采用石油醚对步骤1-4所得中间产物进行重结晶处理,使整个合成方法的产率及纯度进一步得到保障。 [0022] In addition, the synthesis step of the method of the present invention are 1-4 further comprising the step of each crude product was obtained operating recrystallization, recrystallization specific to those skilled in the master, the present invention is preferably of petroleum ether step 1-4 resultant intermediate product was recrystallized, purity and the yield of the overall method of synthesis is further guaranteed.

[0023] 本发明优选所述的步骤5为:多塞平在浓盐酸中,以135-145° C反应15_18h得到盐酸多塞平,多塞平与浓盐酸的用量比为1:4-1:6,优选多塞平在浓盐酸中,以140°C反应16h得到盐酸多塞平,多塞平与浓盐酸的用量比为1:5。 [0023] Preferably, the present invention Step 5: doxepin in concentrated hydrochloric acid, at 135-145 ° C to give a reaction 15_18h doxepin hydrochloride, doxepin with concentrated hydrochloric acid ratio of 1: 4-1 : 6, preferably doxepin in concentrated hydrochloric acid, the reaction to 140 ° C 16h to give doxepin hydrochloride, doxepin with concentrated hydrochloric acid ratio of 1: 5.

[0024] 本发明所述的溶剂使用前都经过处理,除浓盐酸可直接使用外,其他溶剂使用前均经氢化钙干燥再减压蒸馏。 [0024] The solvent used prior to the present invention are treated, in addition to concentrated hydrochloric acid can be used directly, but other solvents before use were dried over calcium hydride and distilled under reduced pressure.

[0025] 本发明所用的盐酸为体积百分比浓度为35-40%,优选37%的浓盐酸。 As used [0025] The present invention is a hydrochloric acid concentration of 35-40% volume percent, preferably 37% concentrated hydrochloric acid.

[0026] 整个反应路线见下所示: [0026] The overall reaction scheme shown below:

[0027]0 [0027] 0

Figure CN102924424AD00051

[0028] 采用上述技术方案,本发明具有如下有益效果: [0028] With the above technical solution, the present invention has the following advantages:

[0029] I、整个合成方法简单可控,反应路径科学合理,总收率可达62%。 [0029] I, overall synthetic method is simple and controllable, the reaction path of scientific and rational, the total yield of 62%.

[0030] 2、对于整个合成中的第四步偶联反应,创造性地使用Ni/PPhJt化体系,使反应收率高,副产物少,选择性好,可达99%以上。 [0030] 2, for the fourth step of the coupling reaction throughout the synthesis, the creative use of Ni / PPhJt of the system, the reaction yield, less by-products, good selectivity up to 99%.

[0031] 3、Ni不同于其他贵金属催化剂,反应完经简单过滤就可以继续循环使用,最重要的是价廉易得,大大节约了生产成本。 [0031] 3, Ni unlike other precious metal catalyst, the reaction was complete by simple filtration cycle can continue to use, the most important is cheap, greatly reduce the production cost.

[0032] 4、本发明涉及到的五步合成腐蚀性小,对环境友好,符合清洁生产的要求,有利于工业化生产,符合和谐社会的低碳的宗旨。 [0032] 4, the present invention relates to a small five-step synthesis corrosive, environmentally friendly, in line with requirements of clean production, in favor of industrial production, in line with the purpose of a harmonious society of low-carbon.

具体实施方式 detailed description

[0033] 以下实施例用于说明本发明,但不用来限制本发明的范围。 [0033] The following examples serve to illustrate the present invention but are not intended to limit the scope of the present invention.

[0034] 实施例I [0034] Example I

[0035] (I) [0035] (I)

[0036] [0036]

Figure CN102924424AD00052

[0037] 在2升的反应器中加入O. 8升的无水四氢呋喃和143g的镁粉,500g的环酮原料和895g的3-氯丙基-叔丁基醚,将O. 4升的无水乙醚分半小时滴加到反应器中,保持体系微沸状态,滴加完毕向体系中通入氩气,继续回流2h。 [0037] O. was added in a 2 liter reactor 8 liters of anhydrous tetrahydrofuran and 143g of magnesium powder, 500g of the starting material cyclic ketone and 895g of 3-chloropropyl - tert-butyl ether. 4 liters of the O. anhydrous diethyl ether was added dropwise to a half hour the reactor system to maintain micro-boiling state, the addition was complete the system was purged with argon, continued refluxed for 2h. 反应完毕将体系冷却后倒入饱和氯化铵溶液中,加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用石油醚重结晶得到产品698g,HPLC纯度分析>99%,收率90%。 After completion of the reaction system was cooled poured into saturated ammonium chloride solution, and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, to give 698g product obtained crude product was recrystallized from petroleum ether, HPLC analysis for purity> 99%, 90% yield. 产品分子式=C21H26O3,分子量:326. 43。 Product formula = C21H26O3, molecular weight: 32,643. 熔点:124-126。 Melting point: 124-126. C,LC-MS :326. 46,元素分析:C 77. 27%, H 8. 03%, O 14. 70%。 C, LC-MS:. 326 46, Elemental analysis: C 77. 27%, H 8. 03%, O 14. 70%.

[0038] (2) [0038] (2)

[0039] [0039]

Figure CN102924424AD00061

[0040] 在2升的耐压釜中加入上步反应得到的产品690g,再加入浓盐酸1500g,密闭耐压釜加热至沸腾,控制体系压力表为3MPa,反应5h。 [0040] A 2-liter pressure-resistant autoclave reaction product obtained above Step 690g, 1500g of concentrated hydrochloric acid was added, closed pressure reactor was heated to boiling, 3MPa pressure gauge control system, the reaction 5h. 反应完毕冷却,蒸掉多余的溶剂,得到的粗产品用石油醚重结晶得到产品619g,HPLC纯度分析>98%,收率95%,产品分子式:C21H24O2,分子量:308. 41。 After the reaction was cooled, excess solvent is distilled off, the crude product obtained was recrystallized from petroleum ether to give the product 619g, HPLC analysis for purity> 98%, 95% yield, product molecular formula: C21H24O2, molecular weight: 30,841. 熔点:112-114° C,LC-MS:308. 48,元素分析:C 81. 78%, H Melting point: 112-114 ° C, LC-MS:. 308 48, Elemental analysis: C 81. 78%, H

7. 84%, O 10. 78%ο 7. 84%, O 10. 78% ο

[0041] (3) [0041] (3)

[0042] [0042]

Figure CN102924424AD00062

[0043] 在2升的耐压釜中加入上步反应得到的产品615g及O. 8升的苯,将283g的二氯亚砜溶于O. 4升的苯,在室温条件下分一小时滴加到耐压釜中,滴加完毕将耐压釜密闭加热至回流,反应2h。 [0043] A 2 liter pressure vessel of the product 615g was obtained from O. 8 liters of benzene and the thionyl chloride was dissolved in 283g O. 4 liters of benzene, divided one hour at room temperature was added dropwise to the autoclave, the addition was complete the autoclave was heated to reflux sealed, the reaction 2h. 反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用石油醚重结晶得到产品431g,HPLC纯度分析>99%,收率80%,产品分子式=C17H15ClO,分子量:270. 75。 After the reaction was added ethyl acetate three times, dried over anhydrous sodium sulfate 5h, to give 431g product obtained crude product was recrystallized from petroleum ether, HPLC analysis for purity> 99%, 80% yield, the product of the formula = C17H15ClO, molecular weight: 270 75. 熔点:107-110° C,LC-MS:270. 80,元素分析:C 75. 41%,H 5. 58%, Cl 13. 09%, O5. 91%。 Melting point: 107-110 ° C, LC-MS:. 270 80, Elemental analysis: C 75. 41%, H 5. 58%, Cl 13. 09%, O5 91%..

[0044] (4) [0044] (4)

[0045] [0045]

Figure CN102924424AD00063

[0046] 在2升的反应器中加入上步反应得到的产品430g及I. 2升的DMF作溶剂,再加Λ 79g N, N- 二甲基甲胺,两当量的碳酸钾,再分别加入5%的Ni (OAc)2和10%的PPh3,于40° C条件下反应5h。 [0046] A 2-liter reactor was obtained from the product of I. and 430g of 2 liters DMF used as a solvent, plus Λ 79g N, N- dimethylmethanamine, two equivalents of potassium carbonate, and then were 5% of Ni (OAc) 2 and 10% of PPh3, the reaction at 40 ° C for 5h conditions. 反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用石油醚重结晶即得到产品多塞平435g,HPLC纯度分析>99%,收率98%。 After the reaction was added ethyl acetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from petroleum ether to obtain product doxepin 435g, HPLC analysis of purity> 99%, yield 98%. 产品分子式=C19H21NO,分子量:279. 38。 Product formula = C19H21NO, molecular weight: 27,938. 熔点:182-184° C,LC-MS:279. 30,元素分析:C 81. 68%, H7. 58%, N 5. 01%, O 5. 73%。 Melting point: 182-184 ° C, LC-MS:. 279 30, Elemental analysis:. C 81. 68%, H7 58%, N 5. 01%, O 5. 73%.

[0047] (5) [0047] (5)

Figure CN102924424AD00071

[0049] 在2升的耐压釜中加入上步反应得到的产品430g,再加入浓盐酸900g,密闭耐压釜加热至140° C,控制体系压力表为3MPa,反应I 5h。 [0049] A 2 liter pressure vessel of the product was obtained from 430g, concentrated hydrochloric acid was added 900g, closed pressure reactor was heated to 140 ° C, a pressure gauge control system of 3MPa, the reaction I 5h. 反应完毕冷却至室温经过滤、干燥得到产品422g,HPLC纯度分析>98%,收率87%。 After the reaction was cooled to room temperature and was filtered and dried to give the product 422g, HPLC analysis for purity> 98%, yield 87%. 产品分子式=C19H22ClNO,分子量:315. 84。 Product formula = C19H22ClNO, molecular weight: 31,584. LC-MS :315. 80,元素分析:C 72. 25%, H 7. 02%, Cl 11. 23%, N 4. 43%, O 5. 07%。 LC-MS:. 315 80, Elemental analysis: C 72. 25%, H 7. 02%, Cl 11. 23%, N 4. 43%, O 5. 07%.

[0050] 实施例2 [0050] Example 2

[0051] [0051]

Figure CN102924424AD00072

[0053] 在4升的反应器中加入2升的无水四氢呋喃和280g的镁粉,IKg的环酮原料和 [0053] 2 liters of a 4 liter reactor of anhydrous tetrahydrofuran and 280g of magnesium powder, IKg cyclic ketone starting material and

I. 9Kg的3-氯丙基-叔丁基醚,将I升的无水乙醚分半小时滴加到反应器中,保持体系微沸状态,滴加完毕向体系中通入氩气,继续回流2h。 I. 9Kg of 3-chloropropyl - tert-butyl ether, the I liter of anhydrous ethyl ether was added dropwise to a half hour the reactor system to maintain micro-boiling state, the addition was complete the system was purged with argon, continued reflux 2h. 反应完毕将体系冷却后倒入饱和氯化铵溶液中,加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用石油醚重结晶得到产品I. 42Kg, HPLC纯度分析>99%,收率88%。 After completion of the reaction system was poured into a cooled saturated ammonium chloride solution, and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, to obtain the crude product obtained was recrystallized product I. 42Kg petroleum ether, HPLC purity analysis> 99 %, yield 88%. 产品分子式=C21H26O3,分子量:326. 43。 Product formula = C21H26O3, molecular weight: 32,643. 熔点:124-126。 Melting point: 124-126. C,LC-MS :326. 46,元素分析:C 77. 27%, H 8. 03%, O 14. 70%。 C, LC-MS:. 326 46, Elemental analysis: C 77. 27%, H 8. 03%, O 14. 70%.

[0054] (2) [0054] (2)

[0055] [0055]

Figure CN102924424AD00073

[0056] 在4升的耐压釜中加入上步反应得到的产品I. 4Kg,再加入浓盐酸3Kg,密闭耐压釜加热至沸腾,控制体系压力表为3MPa,反应5h。 [0056] added to a 4 liter pressure vessel of the product was obtained from I. 4Kg, 3Kg of concentrated hydrochloric acid was added, closed pressure reactor was heated to boiling, 3MPa pressure gauge control system, the reaction 5h. 反应完毕冷却,蒸掉多余的溶剂,得到的粗产品用石油醚重结晶得到产品I. 21Kg,HPLC纯度分析>98%,收率93%,产品分子式:C21H24O2,分子量:308. 41。 After the reaction was cooled, excess solvent is distilled off, the crude product obtained was recrystallized from petroleum ether to give product I. 21Kg, HPLC analysis for purity> 98%, yield 93%. The product formula: C21H24O2, molecular weight: 30,841. 熔点:112-114° C,LC-MS:308. 48,元素分析:C 81. 78%, H7. 84%, O 10. 78%ο Melting point: 112-114 ° C, LC-MS:. 308 48, Elemental analysis: C 81. 78%, H7 84%, O 10. 78% ο.

[0057] (3) [0057] (3)

[0058] [0058]

Figure CN102924424AD00081

[0059] 在4升的耐压釜中加入上步反应得到的产品1.2Kg及1.6升的苯,将0.56敁的二氯亚砜溶于O. 8升的苯,在室温条件下分一小时滴加到耐压釜中,滴加完毕将耐压釜密闭加热至回流,反应2h。 [0059] added to a 4 liter pressure vessel of the product was obtained from 1.6 liters of benzene and 1.2Kg, 0.56 Dian thionyl chloride dissolved in benzene O. 8 liters, divided one hour at room temperature was added dropwise to the autoclave, the addition was complete the autoclave was heated to reflux sealed, the reaction 2h. 反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用石油醚重结晶得到产品O. 86Kg, HPLC纯度分析>99%,收率79%,产品分子式=C17H15ClO,分子量:270. 75。 After the reaction was added ethyl acetate three times, dried over anhydrous sodium sulfate 5h, to obtain the crude product obtained was recrystallized product O. 86Kg petroleum ether, HPLC analysis for purity> 99%, 79% yield, the product of the formula = C17H15ClO, molecular weight : 27075. 熔点:107-110° C,LC_MS:270. 80,元素分析:C 75. 41%, H 5. 58%, Cl13. 09%, O 5. 91%。 Melting point: 107-110 ° C, LC_MS:. 270 80, Elemental analysis: C 75. 41%, H 5. 58%, Cl13 09%, O 5. 91%..

[0060] (4) [0060] (4)

[0061] [0061]

Figure CN102924424AD00082

[0062] 在4升的反应器中加入上步反应得到的产品O. 85Kg及2. 5升的DMF作溶剂,再加入160g N, N- 二甲基甲胺,两当量的碳酸钾,再分别加入5%的Ni (OAc)2和10%的PPh3,于40° C条件下反应5h。 [0062] added to a 4 liter reactor the product was obtained from O. 85Kg and 2.5 l of DMF as solvent, was added 160g N, N- dimethylmethanamine, two equivalents of potassium carbonate, and then 5%, respectively, Ni (OAc) 2 and 10% of PPh3, the reaction at 40 ° C for 5h conditions. 反应完毕加乙酸乙酯萃取三次,用无水硫酸钠干燥5h,得到的粗产品用石油醚重结晶即得到产品多塞平O. 85Kg,HPLC纯度分析>99%,收率96%。 After the reaction was added ethyl acetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from petroleum ether to obtain product doxepin O. 85Kg, HPLC analysis of purity> 99%, yield 96%. 产品分子式:C19H21NO,分子量:279. 38。 Product Molecular formula: C19H21NO, molecular weight: 27,938. 熔点:182-184°C,LC-MS:279. 30,元素分析:C 81. 68%,H 7. 58%, N5. 01%, O 5. 73%。 Melting point: 182-184 ° C, LC-MS:. 279 30, Elemental analysis: C 81. 68%, H 7. 58%, N5 01%, O 5. 73%..

[0063] (5) [0063] (5)

Figure CN102924424AD00083

[0065] 在4升的耐压釜中加入上步反应得到的产品O. 85Kg,再加入浓盐酸I. 8Kg,密闭耐压釜加热至140°C,控制体系压力表为3MPa,反应15h。 [0065] added to a 4 liter pressure-resistant autoclave product was obtained from the O. 85Kg, and then concentrated hydrochloric acid was added I. 8Kg, closed pressure reactor was heated to 140 ° C, pressure gauge control system 3MPa, reactions 15h. 反应完毕冷却至室温经过滤、干燥得到产品O. 84Kg,HPLC纯度分析>98%,收率85%。 After the reaction was cooled to room temperature and was filtered and dried to give the product O. 84Kg, HPLC analysis for purity> 98%, yield 85%. 产品分子式=C19H22ClNO,分子量:315. 84。 Product formula = C19H22ClNO, molecular weight: 31,584. LC-MS :315. 80,元素分析:C 72. 25%, H 7. 02%, Cl 11. 23%, N 4. 43%, O 5. 07%。 LC-MS:. 315 80, Elemental analysis: C 72. 25%, H 7. 02%, Cl 11. 23%, N 4. 43%, O 5. 07%.

[0066] 实施例3 [0066] Example 3

[0067] 与实施例I相比,本实施例的区别仅在于: [0067] Compared with Example I, the difference between the present embodiment only in that:

[0068] 步骤I为:用量比为1:1. 2的6,11-二氢二苯并[b,e]噁庚英_11_酮和3_氯丙基-叔丁基醚在催化剂的作用下在无水乙醚中进行加成反应,反应回流得醇类化合物。 [0068] Step I is: a ratio of 1: 6,11-dihydro-dibenz 1 and 2 [b, e] oxepin-one and 3_ chloropropyl _11_ - tert-butyl ether in the catalyst under the effect of the addition reaction in anhydrous diethyl ether, the reaction was refluxed to give an alcohol compound. 其中,无水乙醚作为溶剂滴加,其体积用量为6,11-二氢二苯并[b,e]噁庚英-11-酮重量的5. 8倍,其滴加速度为其用量的5%每分钟,所述的催化剂为镁粉,镁粉的投放量为6,11- 二氢二苯并[b,e]噁庚英-11-酮的2倍,反应时间为3h,温度为38°C。 Wherein, as the solvent of anhydrous ether was added dropwise, a volume amount of 6,11-dihydro-dibenz [b, e] 5. 8 times the weight of the one oxepin -11-, for which the acceleration amount of dropping 5 % per minute, the catalyst is magnesium powder, magnesium powder delivery quantity is 6,11-dihydro-dibenz [b, e] 2-fold oxepin-11-one, and the reaction time was 3h, the temperature is 38 ° C.

[0069] 步骤2中醇类化合物在浓盐酸条件下保持沸腾,浓盐酸的用量为反应底物的6倍;反应时间为6h。 [0069] Step 2. Alcohols kept boiling under conditions of concentrated hydrochloric acid, the amount of concentrated hydrochloric acid is 6 times that of the reaction substrate; reaction time of 6h.

[0070] 步骤3中反应溶剂为苯,烯烃类化合物与二氯亚砜的用量比为1:1.2,反应在115°C下加热回流3h。 [0070] Step 3 in the reaction solvent is benzene, the olefinic compound with thionyl chloride in an equivalent ratio of 1: 1.2, the reaction was heated at reflux for 3h at 115 ° C.

[0071] 步骤4具体为:在催化剂的作用下,氯代物和N,N_ 二甲基甲胺在DMF于40° C条件下反应5h,偶联得到多塞平。 [0071] Step 4 specifically is: under the action of a catalyst, chlorides and N, N_-dimethyl-methylamine in DMF at 40 ° C under the reaction conditions 5h, yielded doxepin. 其中,氯代物和N,N-二甲基甲胺的用量比为1:1. 1,催化剂的投放量为5%,配体与氯代物的用量比为10:1。 Wherein, chlorides and N, N- dimethylmethanamine by equivalent ratio of 1: 11, the delivery amount of the catalyst is 5%, with a ratio of ligand to Chlorides of 10: 1.

[0072] 步骤5为:多塞平在浓盐酸中,以140°C反应16h得到盐酸多塞平,多塞平与浓盐酸的用量比为1:5。 [0072] Step 5: doxepin in concentrated hydrochloric acid, the reaction to 140 ° C 16h to give doxepin hydrochloride, doxepin with concentrated hydrochloric acid ratio of 1: 5.

[0073] 本实施例所得盐酸多塞平的纯度为98%,总收率为62%。 Purity [0073] embodiment of the present embodiment Doxepin hydrochloride obtained was 98%, 62% overall yield.

[0074] 实施例4 [0074] Example 4

[0075] 与实施例I相比,本实施例的区别仅在于:步骤I为:用量比为1:1的6,11-二氢二苯并[b,e]噁庚英-11-酮和3-氯丙基-叔丁基醚在催化剂的作用下在无水乙醚中进行加成反应,反应回流得醇类化合物。 [0075] Compared with Example I, the difference is only in the present embodiment: Step I is: a ratio of 1: 1 and 6,11-dihydro-dibenzo [b, e] oxepin-11-one and 3-chloropropyl - tert-butyl ether in dry ether addition reaction under the action of a catalyst, the reaction was refluxed to give an alcohol compound. 其中,无水乙醚其体积用量为6,11-二氢二苯并[b,e]噁庚英-11-酮重量的5. 5倍,其滴加速度为其用量的2%每分钟。 Wherein the volume of anhydrous ether in an amount of 6,11-dihydro-dibenz [b, e] 5. 5 times the weight of the one oxepin -11-, for which an amount of dropping rate of 2% per minute. 所述的催化剂为镁粉,镁粉的投放量为6,11- 二氢二苯并[b,e]噁庚英-11-酮的I. 8倍,反应时间为2h,温度为35。 Put the amount of the catalyst is magnesium, magnesium is 6,11-dihydro-dibenz [b, e] oxepin-11-one of I. 8 times, the reaction time was 2h, the temperature was 35. . .

[0076] 步骤2中醇类化合物在浓盐酸条件下保持沸腾,浓盐酸的用量为反应底物的2倍;反应时间为5h。 [0076] Step 2. Alcohols kept boiling under conditions of concentrated hydrochloric acid, concentrated hydrochloric acid is used in an amount of 2 times the reaction substrate; reaction time was 5h.

[0077] 步骤3中反应溶剂为甲苯,烯烃类化合物与二氯亚砜的用量比为1:1,反应在110°C下加热回流2h。 [0077] Step 3 is a reaction solvent is toluene, and the olefinic compound with thionyl chloride in an equivalent ratio of 1: 1, the reaction was heated at reflux for 2h at 110 ° C.

[0078] 步骤4具体为:在催化剂的作用下,氯代物和N,N_ 二甲基甲胺在DMF于35°C条件下反应4h,偶联得到多塞平。 [0078] Step 4 specifically is: under the action of a catalyst, chlorides and N, N_-dimethyl-methylamine in DMF at 35 ° C the reaction conditions 4h, yielded doxepin. 其中,氯代物和N,N- 二甲基甲胺的用量比为1: 1,催化剂的投放量为2%,配体与氯代物的用量比为8:1。 Wherein, chlorides and N, N- dimethylmethanamine with an equivalent ratio of 1: 1, the delivery amount of the catalyst was 2%, with a ratio of ligand to Chlorides to 8: 1.

[0079] 步骤5为:多塞平在浓盐酸中,以135°C反应15h得到盐酸多塞平,多塞平与浓盐酸的用量比为1:4。 [0079] Step 5: doxepin in concentrated hydrochloric acid, the reaction to 135 ° C 15h to give doxepin hydrochloride, doxepin with concentrated hydrochloric acid ratio of 1: 4.

[0080] 本实施例所得盐酸多塞平的纯度为99%,总收率为60%。 Purity [0080] The present embodiment Doxepin hydrochloride obtained was 99%, the total yield was 60%.

[0081] 实施例5 [0081] Example 5

[0082] 与实施例I相比,本实施例的区别仅在于:步骤I为:用量比为1:1. 5的6,11-二氢二苯并[b,e]噁庚英-11-酮和3-氯丙基-叔丁基醚在催化剂的作用下在无水乙醚中进行加成反应,反应回流得醇类化合物。 [0082] Compared with Example I, the difference is only in the present embodiment: Step I is: a ratio of 1: 1 6,11-dihydro-5 and dibenzo [b, e] oxepin-11. - one and 3-chloropropyl - tert-butyl ether in dry ether addition reaction under the action of a catalyst, the reaction was refluxed to give an alcohol compound. 其中,无水乙醚其体积用量为6,11-二氢二苯并[b, e]噁庚英-11-酮重量的6.3倍,其滴加速度为其用量的6%每分钟。 Wherein the volume of anhydrous ether in an amount of 6,11-dihydro-dibenz [b, e] 6.3 times by weight of 11-one oxepin, which for dropping amount of 6% per minute. 所述的催化剂为镁粉,镁粉的投放量为6,11-二氢二苯并[b,e]噁庚英-11-酮的2. 2倍,反应时间为5h,温度为40。 Put the amount of the catalyst is magnesium, magnesium is 6,11-dihydro-dibenz [b, e] 2. 2-fold oxepin-11-one, and the reaction time was 5h, the temperature was 40. . .

[0083] 步骤2中醇类化合物在浓盐酸条件下保持沸腾,浓盐酸的用量为反应底物的10倍;反应时间为8h。 [0083] Step 2. Alcohols kept boiling under conditions of concentrated hydrochloric acid, concentrated hydrochloric acid is used in an amount 10 times that of the reaction substrate; reaction time of 8h.

[0084] 步骤3中反应溶剂为甲苯,烯烃类化合物与二氯亚砜的用量比为1:1. 5,反应在120°C下加热回流4h。 [0084] Step 3 is a reaction solvent is toluene, and the olefinic compound with thionyl chloride in an equivalent ratio of 1: 1.5, the reaction was heated at reflux for 4h at 120 ° C.

[0085] 步骤4具体为:在催化剂的作用下,氯代物和N,N- 二甲基甲胺在DMF于45°C条件下反应6h,偶联得到多塞平。 [0085] Step 4 specifically is: under the action of a catalyst, chlorides and N, N- dimethyl-methylamine in DMF at 45 ° C the reaction conditions 6h, yielded doxepin. 其中,氯代物和N,N- 二甲基甲胺的用量比为I: I. 5,催化剂的投放量为8%,配体与氯代物的用量比为12:1。 Wherein, chlorides and N, N- dimethylmethanamine use ratio of I: I. 5, the delivery amount of the catalyst was 8%, with the ratio of ligand to Chlorides to 12: 1.

[0086] 步骤5为:多塞平在浓盐酸中,以145°C反应18h得到盐酸多塞平,多塞平与浓盐酸的用量比为1:6。 [0086] Step 5: doxepin in concentrated hydrochloric acid, at 145 ° C for 18h to give doxepin hydrochloride, doxepin concentrated hydrochloric acid and the equivalent ratio of 1: 6.

[0087] 本实施例所得盐酸多塞平的纯度为98%,总收率为62%。 Purity [0087] The present embodiment Doxepin hydrochloride obtained was 98%, 62% overall yield.

[0088] 实施例6 [0088] Example 6

[0089] 与实施例I相比,本实施例的区别仅在于:步骤I为:用量比为1:1. 3的6,11-二氢二苯并[b,e]噁庚英-11-酮和3-氯丙基-叔丁基醚在催化剂的作用下在无水乙醚中进行加成反应,反应回流得醇类化合物。 [0089] Compared with Example I, the difference is only in the present embodiment: Step I is: a ratio of 1: 3 1 6,11-dihydro-dibenz [b, e] oxepin -11 - one and 3-chloropropyl - tert-butyl ether in dry ether addition reaction under the action of a catalyst, the reaction was refluxed to give an alcohol compound. 其中,无水乙醚其体积用量为6,11-二氢二苯并[b, e]噁庚英-I I-酮重量的5. 9倍,所述的催化剂为镁粉,镁粉的投放量为6,11-二氢二苯并[b,e]噁庚英-11-酮的I. 9倍,反应时间为2-5h,温度为35_40°C。 Wherein the volume of anhydrous ether in an amount of 6,11-dihydro-dibenz [b, e] 5. 9 times by weight of one I- oxepin -I, the catalyst is magnesium powder, magnesium powder delivery in an amount of 6,11-dihydro-dibenz [b, e] I. oxepin-11-one is 9 times, the reaction time is 2 to 5h, temperature 35_40 ° C.

[0090] 步骤2中醇类化合物在浓盐酸条件下保持沸腾,浓盐酸的用量为反应底物的5倍;反应时间为6h。 [0090] Step 2. Alcohols kept boiling under conditions of concentrated hydrochloric acid, concentrated hydrochloric acid is used in an amount of 5 times the reaction substrate; reaction time of 6h.

[0091] 步骤3中反应溶剂为苯,烯烃类化合物与二氯亚砜的用量比为1:1.3,反应在115°C下加热回流3h。 [0091] Step 3 in the reaction solvent is benzene, the olefinic compound with thionyl chloride in an equivalent ratio of 1: 1.3, the reaction was heated at reflux for 3h at 115 ° C.

[0092] 步骤4具体为:在催化剂的作用下,氯代物和N,N_ 二甲基甲胺在DMF于42° C条件下反应6h,偶联得到多塞平。 [0092] Step 4 specifically is: under the action of a catalyst, chlorides and N, N_-dimethyl-methylamine in DMF at 42 ° C the reaction conditions 6h, yielded doxepin. 其中,氯代物和N,N- 二甲基甲胺的用量比为I: I. 3,催化剂的投放量为5%,配体与氯代物的用量比为8:1。 Wherein, chlorides and N, N- dimethylmethanamine use ratio of I: I. 3, put the amount of the catalyst is 5%, with a ratio of ligand to Chlorides to 8: 1.

[0093] 步骤5为:多塞平在浓盐酸中,以142°C反应17h得到盐酸多塞平,多塞平与浓盐酸的用量比为1:5。 [0093] Step 5: doxepin in concentrated hydrochloric acid, the reaction to 142 ° C 17h to give doxepin hydrochloride, doxepin with concentrated hydrochloric acid ratio of 1: 5.

[0094] 本实施例所得盐酸多塞平的纯度为99%,总收率为62%。 Purity [0094] The present embodiment Doxepin hydrochloride obtained was 99%, 62% overall yield.

[0095] 虽然,上文中已经用一般性说明、具体实施方式及试验,对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。 [0095] Although the above has been generally described with specific embodiments and test, made a detailed description of the invention, but on the basis of the present invention, it can make some modifications or improvements, which in terms of skilled in the art It is obvious. 因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。 Accordingly, such modifications without departing from the spirit of the present invention is based on the improvement made or, belong to the scope of the invention as claimed.

Claims (10)

  1. 1. 一种合成盐酸多塞平的方法,其特征在于:包括以下步骤: (1)将6,11-二氢二苯并[b,e]噁庚英-11-酮和3-氯丙基-叔丁基醚进行加成反应得醇类化合物; (2)所述醇类化合物在浓盐酸条件下消去羟基得到烯烃类化合物; (3)所述烯烃类化合物在反应溶剂中与二氯亚砜反应得到氯代物; (4)所述氯代物和N,N- 二甲基甲胺偶联得到多塞平; (5)将多塞平制成其盐酸盐,即得。 A multi-level synthesis method hydrochloride plug, characterized by: comprising the steps of: (1) 6,11-dihydro-dibenz [b, e] oxepin-11-one and 3-chloropropyl yl - t-butyl ether to give an addition reaction of an alcohol compound; (2) elimination of the hydroxyl group in alcohols under conditions of concentrated hydrochloric acid to give an olefin compound; (3) the olefin compound in a reaction solvent and dichloro the reaction to give chloro sulfoxide thereof; (4) the chlorides and N, N- dimethylmethanamine yielded doxepin; (5) made into its hydrochloride salt of doxepin, ie.
  2. 2.根据权利要求I所述的合成盐酸多塞平的方法,其特征在于:所述的步骤I为:用量比为1:1-1:1. 5的6,11- 二氢二苯并[b, e]卩惡庚英-I I-酮和3-氯丙基-叔丁基醚在催化剂的作用下,在无水乙醚中进行加成反应,反应回流得醇类化合物,优选用量比为I :1. 2。 2. The method for the synthesis of multiple I doxepin hydrochloride claim, wherein: said step I is: a ratio of 1: 1-1: 1 5 6,11-dihydro-dibenz [b, e] oxepin -I I- Jie-one and 3-chloropropyl - t-butyl ether under the action of a catalyst, an addition reaction is carried out in anhydrous diethyl ether, the reaction was refluxed to give an alcohol compound, preferably in an amount ratio of I:. 1 2.
  3. 3.根据权利要求2所述的合成盐酸多塞平的方法,其特征在于:所述步骤I中,无水乙醚作为溶剂滴加,其体积用量为6,11-二氢二苯并[b,e]噁庚英-I I-酮重量的5. 5-6. 3倍,其滴加速度为其用量的2%-6%每分钟;所述的催化剂为镁粉,催化剂的投放量为6,11-二氢二苯并[b,e]噁庚英-11-酮的I. 8-2. 2倍,反应时间为2_5h,温度为35_40°C。 3. The method of claim 2 in hydrochloric acid synthesis doxepin claim, wherein: said step I, a solution of anhydrous diethyl ether as solvent, the volume thereof in an amount of 6,11-dihydro-dibenzo [b ., e] 5. 5-6 3 times the weight of the one oxepin -I I-, which amounts for dropping 2-6% per minute; the quantity of magnesium powder catalyst is run, the catalyst was 6,11-dihydro-dibenzo [b, e] oxepin-11-one of I. 8-2. 2 times, the reaction time is 2_5h, temperature 35_40 ° C.
  4. 4.根据权利要求I所述的合成盐酸多塞平的方法,其特征在于:步骤2中醇类化合物在浓盐酸条件下保持沸腾,浓盐酸的用量为反应底物的2-10倍;反应时间为5-8h。 The method of claim I in hydrochloric acid synthesis doxepin claim, wherein: the step 2 is kept boiling alcohols under conditions of concentrated hydrochloric acid, concentrated hydrochloric acid is used in an amount of 2-10 times the reaction substrate; reaction time is 5-8h.
  5. 5.根据权利要求I所述的合成盐酸多塞平的方法,其特征在于:所述步骤3中反应溶剂为苯或甲苯,烯烃类化合物与二氯亚砜的用量比为1:1-1:1. 5,反应在110-120°c下加热回流2-4h,优选烯烃类化合物与二氯亚砜的用量比为1:1. 2,反应在115°C下加热回流3h。 5. The method of claim I in hydrochloric acid synthesis doxepin claim, wherein: said step 3 in the reaction solvent is benzene or toluene, an olefin compound with thionyl chloride and an equivalent ratio of 1: 1-1 : 15, the reaction was heated at reflux for 2-4h 110-120 ° c, preferably an olefinic compound with thionyl chloride in an equivalent ratio of 1: 1, the reaction was heated at reflux for 3h at 115 ° C.
  6. 6.根据权利要求I所述的合成盐酸多塞平的方法,其特征在于:所述的步骤4以Ni (OAc)2作为反应催化剂,三苯基膦作为配体。 6. The method for the synthesis of multiple I doxepin hydrochloride claim, wherein: said step 4 Ni (OAc) 2 as a reaction catalyst, triphenylphosphine as a ligand.
  7. 7.根据权利要求I或6所述的合成盐酸多塞平的方法,其特征在于:所述的步骤4为:在催化剂的作用下,氯代物和N,N- 二甲基甲胺在DMF于35-45°C条件下反应4_6h,优选在40°C条件下反应5h,偶联得到多塞平。 The synthetic I Doxepin hydrochloride or a method according to claim 6, wherein: said step 4 is: under the action of a catalyst, chlorides and N, N- dimethyl-methylamine in DMF 4_6h reaction conditions at 35-45 ° C, preferably for 5h at 40 ° C under conditions yielded doxepin.
  8. 8.根据权利要求7所述的合成盐酸多塞平的方法,其特征是:所述的步骤4中氯代物和N,N- 二甲基甲胺的用量比为1:1-1:1. 5,催化剂的投放量为2-8%,配体与氯代物的用量比为8:1-12:1,优选氯代物和N,N- 二甲基甲胺的用量比为I: I. I,催化剂的投放量为5%,配体与氯代物的用量比为10:1。 8. The method according doxepin hydrochloride synthesis according to claim 7, wherein: said step 4 Chlorides and N, N- dimethylmethanamine with ratio of 1: 1-1: 1 5, the delivery amount of the catalyst was 2-8%, with the ratio of ligand to Chlorides 8: 1-12: 1, preferably chlorides and N, N- dimethylmethanamine use ratio of I: I . delivery amount I, the catalyst is 5%, with a ratio of ligand to Chlorides of 10: 1.
  9. 9.根据权利要求I所述的合成盐酸多塞平的方法,其特征在于:所述步骤5为:多塞平在浓盐酸中,以135-145°C反应15-18h得到盐酸多塞平,多塞平与浓盐酸的用量比为1:4-1:6,优选多塞平在浓盐酸中,以140° C反应16h得到盐酸多塞平,多塞平与浓盐酸的用量比为1:5。 Doxepin 9. The method according to claim I of the hydrochloric acid synthesis, wherein: said Step 5: doxepin in concentrated hydrochloric acid, at 135-145 ° C to give a reaction 15-18h doxepin hydrochloride , doxepin with concentrated hydrochloric acid ratio of 1: 4-1: 6, preferably doxepin in concentrated hydrochloric acid, the reaction to 140 ° C 16h to give doxepin hydrochloride, doxepin and the ratio of concentrated hydrochloric acid 1: 5.
  10. 10.根据权利要求I所述的合成盐酸多塞平的方法,其特征在于:所述的浓盐酸的体积百分比浓度为35-40%,优选37%。 10. The method of doxepin hydrochloride synthesis according to claim I in claim 1, characterized in that: the volume percent of concentrated hydrochloric acid concentration of 35-40%, preferably 37%.
CN 201210388828 2012-09-04 2012-10-15 Method for synthesizing doxepin hydrochloride CN102924424B (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN105085464A (en) * 2015-08-17 2015-11-25 苏州统华药品有限公司 Synthesis method of doxepin hydrochloride
CN105085465A (en) * 2015-08-17 2015-11-25 苏州黄河制药有限公司 Method for synthesizing doxepin hydrochloride by taking halomethyl o-toluate as raw material
CN105111181A (en) * 2015-08-17 2015-12-02 苏州黄河制药有限公司 Synthetic method of doxepin hydrochloride using methylbenzoate as raw materials
CN105330638A (en) * 2015-11-26 2016-02-17 苏州黄河制药有限公司 Method for synthesizing doxepin hydrochloride by utilizing o-toluic acid as raw material
CN105367538A (en) * 2015-11-26 2016-03-02 苏州黄河制药有限公司 Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042971A1 (en) * 2006-05-19 2009-02-12 Somaxon Pharmaceuticals, Inc. Method of using low-dose doxepin for the improvement of sleep
US20100179215A1 (en) * 2006-05-19 2010-07-15 Somaxon Pharmaceuticals, Inc. Doxepin isomers and isomeric mixtures and methods of using the same to treat sleep disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042971A1 (en) * 2006-05-19 2009-02-12 Somaxon Pharmaceuticals, Inc. Method of using low-dose doxepin for the improvement of sleep
US20100179215A1 (en) * 2006-05-19 2010-07-15 Somaxon Pharmaceuticals, Inc. Doxepin isomers and isomeric mixtures and methods of using the same to treat sleep disorders

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN105085464A (en) * 2015-08-17 2015-11-25 苏州统华药品有限公司 Synthesis method of doxepin hydrochloride
CN105085465A (en) * 2015-08-17 2015-11-25 苏州黄河制药有限公司 Method for synthesizing doxepin hydrochloride by taking halomethyl o-toluate as raw material
CN105111181A (en) * 2015-08-17 2015-12-02 苏州黄河制药有限公司 Synthetic method of doxepin hydrochloride using methylbenzoate as raw materials
CN105330638A (en) * 2015-11-26 2016-02-17 苏州黄河制药有限公司 Method for synthesizing doxepin hydrochloride by utilizing o-toluic acid as raw material
CN105367538A (en) * 2015-11-26 2016-03-02 苏州黄河制药有限公司 Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material

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