CN107056685A - A kind of synthetic method of doxylamine succinate - Google Patents

A kind of synthetic method of doxylamine succinate Download PDF

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CN107056685A
CN107056685A CN201710049966.8A CN201710049966A CN107056685A CN 107056685 A CN107056685 A CN 107056685A CN 201710049966 A CN201710049966 A CN 201710049966A CN 107056685 A CN107056685 A CN 107056685A
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acid
hour
doxylamine
synthetic method
reaction
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戴新荣
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Zhuhai Hairuide Biological Technology Co Ltd
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Zhuhai Hairuide Biological Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms

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Abstract

The invention discloses a kind of synthetic method of doxylamine succinate, following three-step reaction is specifically included：1st, acetophenone and 2 bromopyridines synthesize 2 pyridinylphenyl carbinol methines under the conditions of butyl lithium；2nd, 2 pyridinylphenyl carbinol methines and 2 dimethylamino chloroethanes generate doxylamine free alkali under organic base effect；3rd, doxylamine free alkali finally generates doxylamine succinate with butanedioic acid into salt.This synthetic method raw material is easy to get, high income, cost are low, each step product need not can all obtain that qualified products, technique are simple, post processing is simple, peace is reliable entirely for technique, is adapted to industrialized production through chromatogram post separation.

Description

A kind of synthetic method of doxylamine succinate
Technical field
The invention belongs to medical science and technical field of organic synthesis, and in particular to a kind of ethanolamines antihistamine drug amber The synthetic method of amber acid doxylamine.
Background technology
Doxylamine succinate is a class ethanolamines medicine, with antihistamine effect, cholinolytic effect and significant town Quiet effect, its active low feature of gastrointestinal side effect by force, it is adaptable to a variety of anaphylaxis dermatosis, hay fever, allergia nose Inflammation, asthmatic bronchitis etc., doxylamine succinate belongs to non-mental, the non-prescribed medicine of non-control, in October, 1978 FDA Ratify the doxylamine 25mg tablets listing of CHATTEM companies, be used to help mitigate difficulty falling asleep, turn into OTC, 1996 within 1979 Year September approval and the imitation medicine listing of the approval LNK of in August, 2004 companies.FDA approvals on April 8th, 2013 Diclegis (ambers Sour doxylamine and puridoxine hydrochloride) it is oral sustained release piece, for treating, nausea occurs for the gestation not good to conservative processing reaction With vomiting women.
The chemical synthesising technology of current doxylamine succinate be all using 2- acetylpyridines as initiation material, with iodobenzene or The Grignard reagent reactings generation important intermediate 2- pyridinylphenyl carbinol methines that bromobenzene is made, 2- pyridinylphenyl methyl Generation doxylamine is N, N- dimethyl -2- [1- phenyl -1- to methanol under organic base effect with 2- dimethylamino chloroethanes again (2- pyridines) ethyoxyl] ethamine is finally to obtain doxylamine succinate into salt with butanedioic acid.Chinese patent CN102108059 Patent discloses one kind using 2- acetylpyridines as initiation material, during the Grignard reagent reactings generation being made with bromobenzene is important Mesosome 2- pyridinylphenyl carbinol methines, then doxylamine is generated under organic base effect with 2- dimethylamino chloroethanes, the method： 1st, (129-134 DEG C/0.5mmHg) rectifying of the irrealizable high vacuum of industrial mass production is employed to 2- pyridinylphenyl first Base methanol is purified；2nd, final products doxylamine is needed by column chromatographic isolation and purification, and this purification process will be realized greatly The production of technical scale metaplasia is impossible；3rd, yield is low；4th, it is 101-103 DEG C that fusing point is relatively low, and not reaching United States pharmacopoeia specifications will Ask as 103-108 DEG C, it is clear that be that purity is inadequate, can just make fusing point relatively low；4th, poisonous benzene accessory substance can be produced.As shown in formula one：
The method that Chinese patent CN103524403 is disclosed and CN102108059 are basically identical, are simply replaced with iodobenzene Bromobenzene, initiation material is also 2- acetylpyridines, and the method overcomes the part shortcoming of CN102108059 patents presence, without height Vacuum distillation purifies 2- pyridinylphenyl carbinol methines, but can not meet the requirement of industrialized production, and 1, prepare 2- pyrroles Piperidinyl phenylmethylcarbinol need to be purified with mixed solvent crystallization or column chromatography for separation, and not provide melting point data；2nd, final production Product doxylamine needs to purify by column chromatography；3rd, poisonous benzene accessory substance can be produced.As shown in formula two：
Chinese patent is disclosed with CN105001149 prepares important intermediate 2- pyrroles with 2- benzoyl pyridines and bromomethane The synthetic method of piperidinyl phenylmethylcarbinol, the method is, using 2- benzoyl pyridines as initiation material, to be made with bromomethane Grignard reagent reactings synthesize important intermediate 2- pyridinylphenyl carbinol methines, the initiation material 2- benzene that the technique is used Formylpyridine is commercial to be difficult to obtain, cost is high, is gas under bromomethane normal temperature in addition, and transportation and storage condition is harsh, no It is adapted to industrialized production.As shown in formula three：
In summary, prepare at present doxylamine succinate chemical synthesising technology exist it is many it is not enough as yield is low, after The cumbersome, cost of processing is high, toxicity is big, it is impossible to industrialized production etc., therefore, research and development one are safe and reliable, raw material is easy to get, High income, cost are low, post processing is simple, and the doxylamine succinate technique for being adapted to industrialized production is significant.
The content of the invention
Based on this, in order to overcome the defect of above-mentioned prior art, the invention provides a kind of new doxylamine succinate Chemical synthesis process.
In order to realize foregoing invention purpose, this invention takes following technical scheme：
A kind of synthetic method of doxylamine succinate, comprises the following steps：
(1) it is, 2-10 by the weight ratio of ether solvent and 2- bromopyridines：1 ratio, adds 2- bromine pyrroles in ether solvent Pyridine, is then added dropwise the butyl lithium n-hexane that molar concentration is 2.5MOL/L under the conditions of -80~0 DEG C of anhydrous and oxygen-free into reaction solution The molar ratio of solution, the butyl lithium hexane solution and 2- bromopyridines is 0.9~1.2：1, equality of temperature reaction 1 hour, so Continue that the solution being made up of acetophenone and ether solvent, the throwing of the 2- bromopyridines and acetophenone is added dropwise at -80~0 DEG C afterwards It is 0.9~1.2 to expect mol ratio：1, equality of temperature is allowed to warm to less than -30 DEG C after reacting 30 minutes, and reacts 2-3 at this temperature Hour, then the hydrochloric acid solution for controlling temperature to be slowly added into 10-20% below 0 DEG C under nitrogen protection make reacting liquid pH value be 3- 4, organic layer is separated, organic layer is extracted once with 10-20% hydrochloric acid solution again, and aqueous phase merges is washed with the ether solvent reclaimed 1~2 time, aqueous phase first makes pH value be 9-10 and cool to precipitation Huang after -5~0 DEG C with the alkalization of 20% ammoniacal liquor again with activated carbon decolorizing Filter cake will be divided with yellow solid is obtained after 0-5 DEG C of water washing after the addition ether solvent dissolving of obtained solid after color solid, filtering Go out aqueous phase and dry to decolourize, filter, cooling to -5~0 DEG C after the partial solvent that is concentrated under reduced pressure out is crystallized, and obtains white crystals As important intermediate 2- pyridinylphenyls carbinol methine；
(2), 2- pyridinylphenyls carbinol methine is added and is heated to reflux making reaction system moisture content small in toluene or dimethylbenzene In 0.1%, reaction solution is cooled into room temperature, under high degree of agitation and nitrogen protection, it is 30-50 DEG C to control reacting liquid temperature, point Criticize and be slowly added into phase highly basic or alkali metal, be warming up at 60 DEG C to react 1 hour and reacted 1 hour at 70 DEG C again, at 80 DEG C Reaction 1 hour, at being reacted 1 hour, 100 DEG C at 90 DEG C at reaction 1 hour, 110 DEG C back flow reaction 1 hour until added alkali is complete Portion's reaction is finished；The mol ratio for having phase highly basic or alkali metal and 2- pyridinylphenyl carbinol methines is 0.9-1.5：1；Then At 90-100 DEG C of cooling, 2- dimethylamino chloroethanes toluene or xylene solution were added in 5-6 hours, the 2- pyridine radicals The molar ratio of phenylmethylcarbinol and 2- dimethylamino chloroethanes is 1：0.8~2,100 DEG C were heated to reflux after 18-28 hours Cool, frozen water quenching reaction is added dropwise under nitrogen protection at 15-25 DEG C, after stirring 1 hour, separate aqueous phase, organic phase continues to use Frozen water is washed, and separates aqueous phase, organic phase, which adds 15-20% organic acid solns, makes reaction solution pH=3-4, after stirring 30 minutes, Aqueous phase is separated, is repeated twice, and uses all aqueous phases, aqueous phase is again with toluene or dimethylbenzene backwash 2~3 times is reclaimed, and room temperature adds Enter and filtered after activated carbon decolorizing, filtrate is at 15-25 DEG C plus 10% sodium hydroxide makes pH be 10-11, adds hexamethylene extraction Aqueous phase three times, organic phase is secondary with the washing of 10-15% salt again, after anhydrous sodium sulfate drying, is concentrated under reduced pressure at 45 DEG C dry Yellow oil is doxylamine, chemical entitled N, N- dimethyl -2- [1- phenyl -1- (2- pyridines) ethyoxyl] ethamine；
(3), the doxylamine for obtaining step (2) is dissolved in the organic solvent of 2~10 weight, is added medicinal carbon and is taken off After color, butanedioic acid is added at 45-50 DEG C, separate out crystallization, be slowly cooled to 10 DEG C, stirred crystallization suction filtration after 1 hour, then with pre- Cold organic solvent washing, vacuum drying produces doxylamine succinate crystallization；The mol ratio of the doxylamine and butanedioic acid For 1：0.8-1.2.
In wherein some embodiments, step 1) described in ether solvent be ether, propyl ether, isopropyl ether, butyl ether, methyl- tert One or more in butyl ether, tetrahydrofuran, preferably ether, isopropyl ether, tetrahydrofuran.Most preferably isopropyl ether.
In wherein some embodiments, step 1) described in the weight ratio of ether solvent and 2- bromopyridines be 3-6:1.
In wherein some embodiments, the weight ratio of the ether solvent and 2- bromopyridines is 4：1.
In wherein some embodiments, step 1) described in reaction temperature be -70~-30 DEG C.
In wherein some embodiments, the reaction temperature is -65~-55 DEG C.
In wherein some embodiments, step 1) described in the weight ratio of ether solvent and solid be 1~10：1.
In wherein some embodiments, the weight ratio of the ether solvent and solid is 2~4：1.
In wherein some embodiments, the weight ratio of the ether solvent and solid is 2：1.
In wherein some embodiments, step 1) described in the rate of charge of n-BuLi normal hexane solution and 2- bromopyridines be 1~1.1：1.
In wherein some embodiments, the rate of charge of the n-BuLi normal hexane solution and 2- bromopyridines is 1.05：1.
In wherein some embodiments, step 1) described in 2- bromopyridines and acetophenone molar ratio for 1.0~ 1.1：1.
In wherein some embodiments, the molar ratio of the 2- bromopyridines and acetophenone is 1.05：1.
In wherein some embodiments, organic acid described in step (2) be formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, oneself two Acid, ethanedioic acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzoic acid, phenylacetic acid, phthalic acid, terephthalic acid (TPA), penta One or more in acid, caproic acid, capric acid, stearic acid, palmitic acid, acrylic acid, preferably acetic acid, propionic acid, maleic acid, ethanedioic acid, One or more in malonic acid, particularly preferred acetic acid.
In wherein some embodiments, have described in step (2) phase highly basic or alkali metal be sodium tert-butoxide/potassium, sodium hydride/ Potassium, Sodamide/potassium or metal simple-substance lithium, sodium or potassium, preferably sodium hydride/potassium, Sodamide/potassium or metal simple-substance sodium, particularly preferably Sodamide.
In wherein some embodiments, the mol ratio for having phase highly basic or alkali metal and 2- pyridinylphenyl carbinol methines For 1~1.2：1.
In wherein some embodiments, the mol ratio for having phase highly basic or alkali metal and 2- pyridinylphenyl carbinol methines For 1.1：1.
In wherein some embodiments, the 2- pyridinylphenyls carbinol methine rubs with feeding intake for 2- dimethylamino chloroethanes You are than being 1：1~1.5.
In wherein some embodiments, the 2- pyridinylphenyls carbinol methine rubs with feeding intake for 2- dimethylamino chloroethanes You are than being 1：1.2.
In wherein some embodiments, organic solvent described in step (3) be ethanol, isopropanol, acetone, butanone, acetonitrile, One or more in tetrahydrofuran, methyl tertiary butyl ether(MTBE), isopropyl ether, ethyl, methyl acetate, preferably isopropanol, third One kind in ketone, butanone, isopropyl ether, ethyl, the one or more of methyl acetate, particularly preferably acetone, ethyl Or two kinds.
In wherein some embodiments, organic solvent described in step (3) is 3~6 times of weight of doxylamine.
In wherein some embodiments, organic solvent described in step (3) is 4 times of weight of doxylamine.
In wherein some embodiments, the mol ratio of doxylamine and butanedioic acid described in step (3) is 1：0.9-1.1.
In wherein some embodiments, the mol ratio of doxylamine and butanedioic acid described in step (3) is 1：1.
The synthetic method of the doxylamine succinate of the present invention, step (1) adds 10- after -30 DEG C are reacted 2-3 hours 20% hydrochloric acid solution makes reaction solution pH 3-4, it is therefore an objective to make product 2- pyridinylphenyls carbinol methine and a small amount of unreacted 2- Bromopyridine into salt so as to by organic phase be transferred to aqueous phase, it is other to still remain in organic phase into the organic matter of salt；On the other hand by It is complete in raw material conversion, so target product can be separated out directly with solid forms from aqueous phase after aqueous phase alkalizes through 20% ammoniacal liquor, This remarkable advantage can not accomplish in currently available technology, prior art purification of target product 2- pyridinylphenyl methyl first Alcohol either chromatogram post separation or uses irrealizable high vacuum rectification.Step (2) reaction first uses reaction solution cooling after terminating Inorganic salts are removed in washing, and product doxylamine then is transferred into aqueous phase with aqueous solutions of organic acids, why can be turned doxylamine Aqueous phase is moved on to, is and the unreacted raw material 2- pyridinylphenyl carbinol methines because product doxylamine can be with organic acid into salt Can not be remained in because alkalescence is weaker with organic acid into salt in organic phase, thus by add organic acid and product doxylamine into Product and other impurity effectively can be particularly unreacted raw material 2- pyridinylphenyl carbinol methines and be separated by salt, Aqueous phase is again with toluene or dimethylbenzene backwash 2~3 times is reclaimed, to remove unreacted raw material 2- phenylmethylcarbinols and not Cheng Yuyou Machine acid into salt other organic impurities, merge organic phase use and be washed with water it is secondary after be concentrated under reduced pressure to give unreacting material 2- pyrroles Piperidinyl phenylmethylcarbinol, recoverable after being recrystallized with ether solvent.Doxylamine material liquid used in step (3) Phase purity have to be larger than 99.0%, and the crystallization of final product doxylamine succinate otherwise can be made unqualified.Compared with prior art, The invention has the advantages that：
The synthetic method raw material of the doxylamine succinate of the present invention is easy to get, high income, cost are low, each step product not Need can to obtain that qualified products, technique are simple, post processing is simple, peace is reliable entirely for technique, is adapted to industrialization through chromatogram post separation Big production.The doxylamine succinate purity 99.80% that synthetic method synthesis through the present invention is obtained, list is miscellaneous to be less than 0.10%, It is 103-108 DEG C that fusing point, which meets USP requirement, yield 95.0-96.0%, and three step total recoverys are 71.0-73.0%.
Embodiment
The present invention is further discussed below with reference to specific embodiment, the present invention does not address part and is applied to prior art.Under Face provides the specific embodiment of the present invention, but embodiment is merely to be described in further detail the present invention, is not intended to limit the present invention Claim.
Raw material used in following examples, is derived from commercially available.
A kind of synthetic method of doxylamine succinate of the present invention, comprises the following steps：
1st, acetophenone and 2- bromopyridines synthesize 2- pyridinylphenyl carbinol methines under the conditions of butyl lithium；
2nd, 2- pyridinylphenyls carbinol methine and 2- dimethylamino chloroethanes the generation doxylamine trip under organic base effect From alkali；
3rd, doxylamine free alkali finally generates doxylamine succinate with butanedioic acid into salt.
The synthetic method of the doxylamine succinate of embodiment 1
The synthetic method reaction equation of the doxylamine succinate of the present embodiment is as follows：
Including synthesis step in detail below：
A, addition absolute ether 1850G and 2- bromopyridine 370G (moisture content 0.05%, GC purity in anhydrous response kettle 99.50%, 2.34MOL), cool to after -65 DEG C with nitrogen displacement three times to ensure reaction system anaerobic, then control reaction solution Temperature (about needs 4-6 small for 983.54ML (about 670G, 2.46MOL) 2.5M butyl lithium normal hexane solution is added dropwise at -65~-55 DEG C When), finish, equality of temperature is reacted 1 hour.Then be added dropwise under the conditions of -65~-55 DEG C by 270.0G acetophenones (2.25MOL) and 400G dry diisopropyl ethers composition solution (about 3 hours), finish, equality of temperature react 0.5 hour after, be warming up at -40 to -35 DEG C after Continuous stirring 3 hours, is finished, the lower control temperature of nitrogen protection adds 500G frozen water and 800G 20% hydrochloric acid at 0-5 DEG C makes it PH value is 3-4, separates organic layer, and organic layer is washed once with 10% hydrochloric acid solution 200ML, and organic phase reclaims ether.Aqueous phase is closed And wash secondary with ether 200ML is reclaimed, aqueous phase adds 5G activated carbons and decolourized 0.5 hour at 20-25 DEG C, right and use 1000ML 20% ammoniacal liquor carries out alkalization at 10-20 DEG C makes PH=9-10, finishes, cools to 0-5 DEG C of precipitation yellow solid, filtering, filter cake Yellow solid 450G is obtained after being washed with 0-5 DEG C of frozen water, aqueous phase is separated simultaneously after adding 1200ML 30-35 DEG C of stirring and dissolving of isopropyl ether 20G anhydrous sodium sulfate dryings, filtering are added, filtrate decompression is concentrated into cumulative volume about 1000-1200ML, and -5~0 DEG C of cooling is stirred Mix crystallization, centrifugation, 30 DEG C be dried under reduced pressure, obtain white crystals 2- pyridinylphenyl carbinol methine 398.50G, yield 89.0% (with Acetophenone is raw material meter), purity 99.60%, fusing point is 38-40 DEG C.
MS:200[M+1]+
1H-NMR：(400MHZ, CDCl), δ 1.96 (3H, s), 5.86 (1H, s), 7.18-7.36 (5H, m), 7.50-7.60 (2H, m), 7.65 (1H, dt), 8.55 (1H, m).
B, the addition 2- pyridinylphenyl carbinol methine 398.50G (2.00MOL) in 3000L reactor, are then added A point water is heated to reflux after toluene 1200ML, stirring and dissolving, after moisture content detection is less than 0.1%, reaction solution room temperature is cooled into, so Sodamide 86.0G (2.20MOL) is slowly added into batches under high degree of agitation and nitrogen protection afterwards, strict temperature control when adding Sodamide Reaction solution is added portionwise at 30-50 DEG C, finishes, reaction at 60 DEG C is warming up to after nitrogen displacement reacts 1 at 70 DEG C again within 1 hour Hour, then react 1 hour, reacted at 90 DEG C 1 hour, back flow reaction 1 at 100 DEG C of reactions 1 hour, 110 DEG C at 80 DEG C again Hour is until Sodamide reacts completely.Then cool at 95-100 DEG C, added at 5-6 hours by 258.0G 2- dimethylamino chlorine The solution of ethane (2.40MOL) and 500ML toluene composition, finishes, reaction solution is heated to reflux 28 hours, reaction terminates, and cools, 300G frozen water is added dropwise to be quenched reaction, split-phase at 15-25 DEG C under nitrogen protection, toluene mutually continues to be washed 2 times with 300G, split-phase, It is organic be added to 20% acetic acid solution 720G, at 25-30 DEG C stir 0.5 hour, separate aqueous phase, organic phase uses 20% second again Acid solution 100G is extracted 2 times, and last time detection organic phase sees whether product is turning fully to aqueous phase, merges aqueous phase, organic to subtract each other Press the unreacted raw material 2- pyridinylphenyl carbinol methines of concentration and recovery.Aqueous phase is with toluene 100ML × backwash 2 times is reclaimed, in room Temperature adds 5G activated carbon decolorizings 1 hour, filtering, and filtrate is at 15-25 DEG C plus 10% sodium hydroxide adjusts PH=10-11, when PH is closed Add thiacyclohexane after lattice：800ML, 600ML, 400ML extract three times, aqueous phase blowdown, organic salt solution 300ML of addition 15%, 300ML, 300ML is washed three times, crosses anhydrous sodium sulfate drying, and dry yellow oil doxylamine i.e. N, N- bis- is concentrated under reduced pressure at 45 DEG C Methyl -2- [1- phenyl -1- (2- pyridines) ethyoxyl] ethamine 460.50g, liquid phase purity 99.48%, yield 85.28%.
MS:271[M+1]+
1H-NMR：(400MHZ, CDCl), δ 1.96 (3H, s), 2.28 (6H, s), 2.58 (2H, m), 3.42 (2H, m), 7.11-7.26 (4H, m), 7.40 (2H, m), 7.56-7.62 (2H, m), 8.56 (1H, m).
C, 460.50G doxylamines are added in acetone 1850G, after stirring dissolved clarification, butanedioic acid is added at 45-50 DEG C 202G, reaction solution can slowly separate out a large amount of white crystals after butanedioic acid slowly reacts dissolving, be cooled to 5-10 DEG C of stirred crystallization 1 Hour.Suction filtration is crystallized, and crystallization is washed with a small amount of acetone, 50 DEG C are dried in vacuo to obtain doxylamine succinate 633.5G, purity 99.80%, list is miscellaneous to be less than 0.10%, and it is 103-108 DEG C, yield 95.60%, three step total recoverys that fusing point, which meets USP requirement, For 72.50%.
1H-NMR：(400MHZ, CDCl), δ 1.98 (3H, s), 2.54 (4H, s), 2.80 (6H, s), 3.20 (2H, m), 3.65 (2H, m) 7.18-7.28 (4H, m), 7.35 (2H, m), 7.56-7.62 (2H, m), 8.56 (1H, m).
The synthetic method of the doxylamine succinate of embodiment 2
The synthetic method reaction equation of the doxylamine succinate of the present embodiment is as follows：
Including synthesis step in detail below：
A, addition anhydrous tetrahydro furan 1450G and 2- bromopyridine 370G (moisture content 0.05%, GC purity in anhydrous response kettle 99.50%, 2.34MOL), cool to after -65 DEG C with nitrogen displacement three times to ensure reaction system anaerobic, then control reaction solution Temperature (about needs 4-6 small for 983.54ML (about 670G, 2.46MOL) 2.5M butyl lithium normal hexane solution is added dropwise at -65~-55 DEG C When), finish, equality of temperature is reacted 1 hour.Then be added dropwise under the conditions of -65 to -55 DEG C by 270.0G acetophenones (2.25MOL) and 400G dry diisopropyl ethers composition solution (about 3 hours), finish, equality of temperature react 0.5 hour after, be warming up at -40 to -35 DEG C after Continuous stirring 3 hours, is finished, the lower control temperature of nitrogen protection adds 500G frozen water and 800G 20% hydrochloric acid at 0-5 DEG C makes it PH value is 3-4, separates organic layer, and organic layer is washed once with 10% hydrochloric acid solution 200ML, and organic phase reclaims ether.Aqueous phase is closed And wash secondary with ether 200ML is reclaimed, aqueous phase adds 5G activated carbons and had decolourizes 0.5 hour at 20-25 DEG C, so and uses 1000ML 20% ammoniacal liquor carries out alkalization at 10-20 DEG C makes PH=9-10, finishes, cools to 0-5 DEG C of precipitation yellow solid, filtering, filter cake Yellow solid 450G is obtained after being washed with 0-5 DEG C of frozen water, adds and aqueous phase is separated after 1200ML 30-35 DEG C of stirring and dissolving of isopropyl ether and is added Enter 20G anhydrous sodium sulfate dryings, filter, filtrate decompression is concentrated into cumulative volume about 1000-1200ML, cool -5 to 0 DEG C of stirrings Crystallization, centrifugation, 30 DEG C be dried under reduced pressure, obtain white crystals 2- pyridinylphenyl carbinol methine 394.02G, yield 88.0% is (with benzene Ethyl ketone is raw material meter), purity 99.51%, fusing point is 38-40 DEG C.
MS:200[M+1]+
1H-NMR：(400MHZ, CDCl), δ 1.96 (3H, s), 5.86 (1H, s), 7.18-7.36 (5H, m), 7.50-7.60 (2H, m), 7.65 (1H, dt), 8.55 (1H, m).
B, the addition 2- pyridinylphenyl carbinol methine 394.02G (1.98MOL) in 3000ML reactor, are then added A point water is heated to reflux after toluene 1200ML, stirring and dissolving, after moisture content detection is less than 0.1%, reaction solution room temperature is cooled into, so 60% sodium hydride 87.01G (2.175MOL) is slowly added into batches under high degree of agitation and nitrogen protection afterwards, when adding sodium hydride Strict temperature control reaction solution is added portionwise at 30-50 DEG C, finishes, is warming up to after nitrogen displacement at 60 DEG C and reacts 1 hour again 70 React 1 hour, then reacted 1 hour at 80 DEG C again at DEG C, reacted at 90 DEG C 1 hour, at 100 DEG C of reactions 1 hour, 110 DEG C Back flow reaction 1 hour is until sodium hydride reacts completely.Then cool at 95-100 DEG C, added at 5-6 hours by 255.28G2- bis- The solution of methylamino chloroethanes (2.37MOL) and 500ML toluene composition, finishes, reaction solution is heated to reflux 28 hours, reaction knot Beam, cooling is added dropwise 300G frozen water to be quenched reaction, split-phase, toluene mutually continues to wash 2 with 300G under nitrogen protection at 15-25 DEG C It is secondary, split-phase, it is organic be added to 20% acetic acid solution 720G, at 25-30 DEG C stir 0.5 hour, separate aqueous phase, organic phase is again Extracted 2 times with 20% acetic acid solution 100G, last time detection organic phase sees whether product is turning fully to aqueous phase, merge aqueous phase, Organic phase, which is concentrated under reduced pressure, reclaims the raw material 2- pyridinylphenyl carbinol methines of end reaction.Aqueous phase is with reclaiming the backwash of toluene 100ML × 2 It is secondary, add 5G activated carbon decolorizings 1 hour in room temperature, filtering, filtrate is at 15-25 DEG C plus 10% sodium hydroxide adjusts PH=10-11, Add thiacyclohexane after PH is qualified：800ML, 600ML, 400ML are extracted three times, aqueous phase blowdown, organic salt solution 300ML of addition 15%, 300ML, 300ML are washed three times, cross anhydrous sodium sulfate drying, be concentrated under reduced pressure at 45 DEG C dry yellow oil doxylamine i.e. N, N- dimethyl -2- [1- phenyl -1- (2- pyridines) ethyoxyl] ethamine 459.75G, liquid phase purity 99.55%, yield 86.0%.
MS:271[M+1]+
1H-NMR：(400MHZ, CDCl), δ 1.96 (3H, s), 2.28 (6H, s), 2.58 (2H, m), 3.42 (2H, m), 7.11-7.26 (4H, m), 7.40 (2H, m), 7.56-7.62 (2H, m), 8.56 (1H, m).
C, by 459.75G doxylamines add ethyl 2000G, stirring dissolved clarification after, add butanedioic acid at 45-50 DEG C 201G, reaction solution can slowly separate out a large amount of white crystals after butanedioic acid slowly reacts dissolving, be cooled to 5-10 DEG C of stirred crystallization 1 Hour.Suction filtration is crystallized, and washes crystallization with a small amount of ethyl acetate, doxylamine succinate 627.15G, purity are dried in vacuo to obtain at 50 DEG C 99.81%, list is miscellaneous to be less than 0.10%, and fusing point meets USP requirement for 103-108 DEG C, and yield 95.02%, three steps are always received Rate is 71.90%.
1H-NMR：(400MHZ, CDCl), δ 1.98 (3H, s), 2.54 (4H, s), 2.80 (6H, s), 3.20 (2H, m), 3.65 (2H, m) 7.18-7.28 (4H, m), 7.35 (2H, m), 7.56-7.62 (2H, m), 8.56 (1H, m).
The synthetic method of the doxylamine succinate of embodiment 3
The synthetic method reaction equation of the doxylamine succinate of the present embodiment is as follows：
Specifically include following synthesis step：
A, addition dry diisopropyl ether 1450G and 2- bromopyridine 370G (moisture content 0.05%, GC purity in anhydrous response kettle 99.50%, 2.34MOL), cool to after -65 DEG C with nitrogen displacement three times to ensure reaction system anaerobic, then control reaction solution Temperature is dropwise addition 983.54ML (about 670G) 2.5M butyl lithium normal hexanes solution (about needing 4-6 hours) at -65 to -55 DEG C, finish, Equality of temperature is reacted 1 hour.Then it is added dropwise under the conditions of -65 to -55 DEG C by 270.0G acetophenones (2.25MOL) and the anhydrous isopropyls of 400G The solution (about 3 hours) of ether composition, is finished, after equality of temperature is reacted 0.5 hour, is warming up at -40 to -35 DEG C and is continued to stir 3 hours, Finish, nitrogen protection is lower control temperature to add 500G frozen water and 800G 20% hydrochloric acid at 0-5 DEG C to make its pH value for 3-4, divide From organic layer, organic layer is washed once with 10% hydrochloric acid solution 200L, and organic phase reclaims isopropyl ether.Aqueous phase merges with recovery isopropyl Ether 200ML washes secondary, and aqueous phase, which adds 5G activated carbons, decolouring 0.5 hour at 20-25 DEG C, is existed so and with the ammoniacal liquor of 1000ML 20% Alkalization is carried out at 10-20 DEG C makes PH=9-10, finishes, cools to 0-5 DEG C of precipitation yellow solid, filtering, and filter cake is with 0-5 DEG C of frozen water Yellow solid 450G is obtained after washing, is added and is separated aqueous phase after 1200ML 30-35 DEG C of stirring and dissolving of isopropyl ether and add the anhydrous sulphur of 20G Sour sodium is dried, and filtering, filtrate decompression is concentrated into cumulative volume about 1000-1200ML, and cool -5 to 0 DEG C of stirred crystallizations, centrifugation, knot Crystalline substance reduced vacuum at 30 DEG C is dried, and obtains white crystals 2- pyridinylphenyl carbinol methine 380.40G, yield 85.0% is (with benzene Ethyl ketone is raw material meter), purity 99.20%, fusing point is 35-37 DEG C.
MS:200[M+1]+
1H-NMR：(400MHZ, CDCl), δ 1.96 (3H, s), 5.86 (1H, s), 7.18-7.36 (5H, m), 7.50-7.60 (2H, m), 7.65 (1H, dt), 8.55 (1H, m).
B, the addition 2- pyridinylphenyl carbinol methine 380.40G (1.91MOL) in 3000L reactor, are then added A point water is heated to reflux after toluene 1200ML, stirring and dissolving, after moisture content detection is less than 0.1%, reaction solution room temperature is cooled into, so Metallic sodium 48.30G (2.10MOL) is slowly added into batches under high degree of agitation and nitrogen protection afterwards, is strictly controlled when adding metallic sodium Warm reaction solution is added portionwise at 30-50 DEG C, finish, be warming up to after nitrogen displacement at 60 DEG C react 1 hour it is anti-at 70 DEG C again Answer 1 hour, then reacted 1 hour at 80 DEG C again, react 1 hour, flowed back at 100 DEG C of reactions 1 hour, 110 DEG C anti-at 90 DEG C Answer 1 hour until metallic sodium reacts completely.Then cool at 95-100 DEG C, added at 5-6 hours by 246.46G 2- dimethylamine The solution of base chloroethanes (2.29MOL) and 500ML toluene composition, finishes, reaction solution is heated to reflux 28 hours, reaction terminates, Cooling, is added dropwise 300G frozen water to be quenched reaction, split-phase, toluene mutually continues to be washed 2 times with 300G under nitrogen protection at 15-25 DEG C, Split-phase, it is organic be added to 20% acetic acid solution 720G, at 25-30 DEG C stir 0.5 hour, separate aqueous phase, organic phase is used again 20% acetic acid solution 100G is extracted 2 times, and last time detection organic phase sees whether product is turning fully to aqueous phase, merges aqueous phase, has Machine mutually depressurizes the raw material 2- pyridinylphenyl carbinol methines of concentration and recovery end reaction.Aqueous phase recovery toluene 100ML × backwash 2 It is secondary, add 5G activated carbon decolorizings 1 hour in room temperature, filtering, filtrate is at 15-20 DEG C plus 10% sodium hydroxide adjusts PH=10-11, Add thiacyclohexane after PH is qualified：800ML, 600ML, 400ML are extracted three times, aqueous phase blowdown, organic salt solution 300ML of addition 15%, 300ML, 300ML are washed three times, cross anhydrous sodium sulfate drying, be concentrated under reduced pressure at 45 DEG C dry yellow oil doxylamine i.e. N, N- dimethyl -2- [1- phenyl -1- (2- pyridines) ethyoxyl] ethamine 433.50G, liquid phase purity 99.18%, yield 84.00%.
MS:271[M+1]+
1H-NMR：(400MHZ, CDCl), δ 1.96 (3H, s), 2.28 (6H, s), 2.58 (2H, m), 3.42 (2H, m), 7.11-7.26 (4H, m), 7.40 (2H, m), 7.56-7.62 (2H, m), 8.56 (1H, m).
C, by 433.50G doxylamines add acetone 1800G, stirring dissolved clarification after, add butanedioic acid at 45-50 DEG C 190.0G, reaction solution can slowly separate out a large amount of white crystals after butanedioic acid slowly reacts dissolving, be cooled to 5-10 DEG C of stirring knot It is brilliant 1 hour.Suction filtration is crystallized, and crystallization is washed with a small amount of acetone, 50 DEG C are dried in vacuo to obtain doxylamine succinate 591.70G, purity 99.78%, list is miscellaneous to be less than 0.10%, and it is 103-108 DEG C, yield 95.0%, three step total recoverys that fusing point, which meets USP requirement, For 67.83%.
1H-NMR：(400MHZ, CDCl), δ 1.98 (3H, s), 2.54 (4H, s), 2.80 (6H, s), 3.20 (2H, m), 3.65 (2H, m) 7.18-7.28 (4H, m), 7.35 (2H, m), 7.56-7.62 (2H, m), 8.56 (1H, m).
The synthetic method of the doxylamine succinate of embodiment 4
The synthetic method reaction equation of the doxylamine succinate of the present embodiment is as follows：
Specifically include following synthesis step：
A, this operation are identical with embodiment 1A operations.
B, the addition 2- pyridinylphenyl carbinol methine 400.00G (2.00MOL) in 3000ML reaction bulb, are then added A point water is heated to reflux after toluene 1200ML, stirring and dissolving, after moisture content detection is less than 0.1%, reaction solution room temperature is cooled into, so Sodium tert-butoxide 288.5Kg (3.0MOL) is slowly added into batches under high degree of agitation and nitrogen protection afterwards, is added tight during sodium tert-butoxide Lattice temperature control reaction solution is added portionwise at 30-50 DEG C, finishes, is warming up to after nitrogen displacement at 60 DEG C and reacts 1 hour again at 70 DEG C Lower reaction 1 hour, then reacts 1 hour at 80 DEG C again, is reacted at 90 DEG C 1 hour, 100 DEG C are reacted 1 hour, and 110 DEG C next time Stream reaction 1 hour is until Sodamide reacts completely.Then cool at 95-100 DEG C, added at 5-6 hours by 258.0G 2- diformazans The solution of amido chloroethanes (2.40MOL) and 500ML toluene composition, finishes, reaction solution is heated to reflux 28 hours, reaction knot Beam, cooling is added dropwise 300G frozen water to be quenched reaction, split-phase, toluene mutually continues to wash 2 with 300G under nitrogen protection at 15-25 DEG C It is secondary, split-phase, it is organic be added to 20% acetic acid solution 600G, at 25-30 DEG C stir 0.5 hour, separate aqueous phase, organic phase is again Extracted 2 times with 20% acetic acid solution 50G, last time detection organic phase sees whether product is turning fully to aqueous phase, merge aqueous phase, have Machine mutually depressurizes the raw material 2- pyridinylphenyl carbinol methines of concentration and recovery end reaction.Aqueous phase recovery toluene 100ML × backwash 2 It is secondary, add 10G activated carbon decolorizings 1 hour in room temperature, filtering, filtrate is at 15-25 DEG C plus 10% sodium hydroxide adjusts PH=10- 11, thiacyclohexane is added after PH is qualified：800ML, 600ML, 400ML are extracted three times, aqueous phase blowdown, organic salt solution of addition 15% 300ML, 300ML, 300ML are washed three times, excessively anhydrous sodium sulfate, drying, are concentrated under reduced pressure at 45 DEG C dry that how western yellow oil is Stretching-sensitive is N, N- dimethyl -2- [1- phenyl -1- (2- pyridines) ethyoxyl] ethamine 160.8Kg, liquid phase purity 99.08%, yield 29.76%.The raw material 2- pyridinylphenyl carbinol methines 206.0G of end reaction is reclaimed out altogether.
MS:271[M+1]+
1H-NMR：(400MHZ, CDCl), δ 1.96 (3H, s), 2.28 (6H, s), 2.58 (2H, m), 3.42 (2H, m), 7.11-7.26 (4H, m), 7.40 (2H, m), 7.56-7.
62 (2H, m), 8.56 (1H, m).
C, this operation are identical with embodiment 1C operations.
The synthetic method of the doxylamine succinate of embodiment 5
The synthetic method reaction equation of the doxylamine succinate of the present embodiment is as follows：
A, this operation are identical with embodiment 2A operations.
B, the addition 2- pyridinylphenyl carbinol methine 400.00G (2.00MOL) in 3000ML reactor, are then added A point water is heated to reflux after toluene 1200ML, stirring and dissolving, after moisture content detection is less than 0.1%, reaction solution room temperature is cooled into, so Sodamide 86.0G (2.20MOL) is slowly added into batches under high degree of agitation and nitrogen protection afterwards, strict temperature control when adding Sodamide Sodamide is added portionwise at 30-50 DEG C in reaction solution, finishes, is warming up to after nitrogen displacement at 60 DEG C and reacts 1 hour again at 70 DEG C Lower reaction 1 hour, then reacts 1 hour at 80 DEG C again, is reacted at 90 DEG C 1 hour, 100 DEG C are reacted 1 hour, and 110 DEG C next time Stream reaction 1 hour is until Sodamide reacts completely.Then cool at 95-100 DEG C, added at 5-6 hours by 258.0G 2- diformazans The solution of amido chloroethanes (2.40MOL) and 500ML toluene composition, finishes, reaction solution is heated to reflux 28 hours, reaction knot Beam, cooling is added dropwise 300G frozen water to be quenched reaction, split-phase, toluene mutually continues to wash 2 with 300G under nitrogen protection at 15-25 DEG C It is secondary, split-phase, it is organic be added to 20% propionic acid solution 880G, at 25-30 DEG C stir 0.5 hour, separate aqueous phase, organic phase is again Extracted 2 times with 20% propionic acid solution 125G, last time detection organic phase sees whether product is turning fully to aqueous phase, merge aqueous phase, Organic phase, which is concentrated under reduced pressure, reclaims the raw material 2- pyridinylphenyl carbinol methines of end reaction.Aqueous phase recovery toluene 100ML × backwash 2 It is secondary, add 20G activated carbon decolorizings 1 hour in room temperature, filtering, filtrate is at 15-25 DEG C plus 10% sodium hydroxide adjusts PH=10- 11, thiacyclohexane is added after PH is qualified：800ML, 600ML, 400ML are extracted three times, aqueous phase blowdown, organic salt solution of addition 15% 300ML, 300ML, 300ML are washed three times, cross anhydrous sodium sulfate drying, and dry many hilas of yellow oil are concentrated under reduced pressure at 45 DEG C Quick i.e. N, N- dimethyl -2- [1- phenyl -1- (2- pyridines) ethyoxyl] ethamine 465.50G, liquid phase purity 99.18%, yield 86.10%.
MS:271[M+1]+
1H-NMR：(400MHZ, CDCl), δ 1.96 (3H, s), 2.28 (6H, s), 2.58 (2H, m), 3.42 (2H, m), 7.11-7.26 (4H, m), 7.40 (2H, m), 7.56-7.62 (2H, m), 8.56 (1H, m).
C, this operation are identical with embodiment 1C operations
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality Apply all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, the scope of this specification record is all considered to be.
Embodiment described above only expresses the several embodiments of the present invention, and it describes more specific and detailed, but simultaneously Can not therefore it be construed as limiting the scope of the patent.It should be pointed out that coming for one of ordinary skill in the art Say, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention Scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.

Claims (9)

1. a kind of synthetic method of doxylamine succinate, it is characterised in that comprise the following steps：
(1) it is, 2-10 by the weight ratio of ether solvent and 2- bromopyridines：1 ratio, adds 2- bromopyridines in ether solvent, Then molar concentration is added dropwise into reaction solution under the conditions of -80~0 DEG C of anhydrous and oxygen-free molten for 2.5MOL/L butyl lithium n-hexane The molar ratio of liquid, the butyl lithium hexane solution and 2- bromopyridines is 0.9~1.2：1, equality of temperature reaction 1 hour, then Continue that the solution being made up of acetophenone and ether solvent is added dropwise at -80~0 DEG C, the 2- bromopyridines and feeding intake for acetophenone are rubbed You are than being 0.9~1.2：1, equality of temperature is allowed to warm to less than -30 DEG C after reacting 30 minutes, and reacts 2-3 hours at this temperature, The hydrochloric acid solution for controlling temperature to be slowly added into 10-20% below 0 DEG C under nitrogen protection again makes reacting liquid pH value be 3-4, point From organic layer, organic layer is extracted once with 10-20% hydrochloric acid solution again, and aqueous phase merges washs 1~2 with the ether solvent reclaimed It is secondary, aqueous phase first with activated carbon decolorizing again with 20% ammoniacal liquor alkalization make pH value be 9-10 and cool to after -5~0 DEG C separate out yellow consolidate Filter cake will separate water with yellow solid is obtained after 0-5 DEG C of water washing after the addition ether solvent dissolving of obtained solid after body, filtering Phase simultaneously dries decolouring, filtering, and cooling to -5~0 DEG C after the partial solvent that is concentrated under reduced pressure out is crystallized, and obtains 2- pyridinylphenyls Carbinol methine；
(2), 2- pyridinylphenyls carbinol methine is added and is heated to reflux being less than reaction system moisture content in toluene or dimethylbenzene 0.1%, reaction solution is cooled into room temperature, under high degree of agitation and nitrogen protection, it is 30-50 DEG C to control reacting liquid temperature, in batches Phase highly basic or alkali metal have been slowly added into, has been warming up at 60 DEG C to react 1 hour and is reacted 1 hour at 70 DEG C again, it is anti-at 80 DEG C Answer 1 hour, at being reacted 1 hour, 100 DEG C at 90 DEG C at reaction 1 hour, 110 DEG C back flow reaction 1 hour until added alkali it is whole Reaction is finished；The mol ratio for having phase highly basic or alkali metal and 2- pyridinylphenyl carbinol methines is 0.9-1.5：1；Then drop At warm 90-100 DEG C, by the interior addition in 5-6 hours of 2- dimethylamino chloroethanes toluene or xylene solution, the 2- pyridinylphenyls The molar ratio of carbinol methine and 2- dimethylamino chloroethanes is 1：0.8~2,100 DEG C are heated to reflux dropping after 18-28 hours Temperature, frozen water quenching reaction is added dropwise at 15-25 DEG C, after stirring 1 hour, aqueous phase is separated, organic phase continues to use ice under nitrogen protection Water washing, separates aqueous phase, organic phase, which adds 15-20% organic acid solns, makes reaction solution pH=3-4, after stirring 30 minutes, point Go out aqueous phase, repeat twice, and use all aqueous phases, aqueous phase is again with toluene or dimethylbenzene backwash 2~3 times is reclaimed, and room temperature is added Filtered after activated carbon decolorizing, filtrate is at 15-25 DEG C plus 10% sodium hydroxide makes pH be 10-11, adds hexamethylene and extracts water Xiang Sanci, organic phase is secondary with the washing of 10-15% salt again, after anhydrous sodium sulfate drying, is concentrated under reduced pressure at 45 DEG C much dry Hila is quick；
(3), the doxylamine for obtaining step (2) is dissolved in the organic solvent of 2~10 weight, adds medical active carbon decoloring Afterwards, add butanedioic acid at 45-50 DEG C, separate out crystallization, be slowly cooled to 10 DEG C, stirred crystallization suction filtration after 1 hour, then use precooling Organic solvent washing, vacuum drying, produce doxylamine succinate crystallization；The mol ratio of the doxylamine and butanedioic acid is 1：0.8-1.2.
2. the synthetic method of doxylamine succinate according to claim 1, it is characterised in that step 1) described in ethers Solvent is the one or more in ether, propyl ether, isopropyl ether, butyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran.
3. the synthetic method of doxylamine succinate according to claim 1, it is characterised in that step has described in (2) Machine acid is formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, adipic acid, ethanedioic acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzene first One kind in acid, phenylacetic acid, phthalic acid, terephthalic acid (TPA), valeric acid, caproic acid, capric acid, stearic acid, palmitic acid, acrylic acid or It is several.
4. the synthetic method of doxylamine succinate according to claim 1, it is characterised in that step has described in (2) Phase highly basic or alkali metal are sodium tert-butoxide/potassium, sodium hydride/potassium, Sodamide/potassium or metal simple-substance lithium, sodium or potassium.
5. the synthetic method of doxylamine succinate according to claim 1, it is characterised in that described to have phase highly basic or alkali The mol ratio of metal and 2- pyridinylphenyl carbinol methines is 1~1.2：1.
6. the synthetic method of doxylamine succinate according to claim 1, it is characterised in that the 2- pyridinylphenyls The molar ratio of carbinol methine and 2- dimethylamino chloroethanes is 1：1~1.5.
7. the synthetic method of doxylamine succinate according to claim 1, it is characterised in that step has described in (3) Machine solvent is ethanol, isopropanol, acetone, butanone, acetonitrile, tetrahydrofuran, methyl tertiary butyl ether(MTBE), isopropyl ether, ethyl, acetic acid One or more in methyl esters.
8. the synthetic method of doxylamine succinate according to claim 1, it is characterised in that many described in step (3) The quick mol ratio with butanedioic acid of hila is 1：0.9-1.1.
9. the synthetic method of doxylamine succinate according to claim 8, it is characterised in that the doxylamine and amber The mol ratio of amber acid is 1：1.
CN201710049966.8A 2017-01-23 2017-01-23 A kind of synthetic method of doxylamine succinate Pending CN107056685A (en)

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CN113788761A (en) * 2021-08-13 2021-12-14 丽江映华生物药业有限公司 Method and system for refining medical intermediate
CN114524765A (en) * 2021-12-27 2022-05-24 广西壮族自治区药用植物园 Method for synthesizing doxylamine succinate by base catalysis

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Application publication date: 20170818