CN105237467A - Preparation method of doxylamine succinate - Google Patents
Preparation method of doxylamine succinate Download PDFInfo
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- CN105237467A CN105237467A CN201510612214.9A CN201510612214A CN105237467A CN 105237467 A CN105237467 A CN 105237467A CN 201510612214 A CN201510612214 A CN 201510612214A CN 105237467 A CN105237467 A CN 105237467A
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- 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
Abstract
The invention discloses a preparation method of doxylamine succinate. The preparation method comprises following steps: step 1, 2-pyridyl phenyl methyl carbinol is dissolved in an organic solvent, and is reacted with 2-dimethylaminoethyl chloride hydrochloride at high temperature, after reaction, target product N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)oxethyl]ethylamine is obtained via quenching extracting separation; and step 2, N,N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxethyl]ethylamine obtained in the step 1 and succinic acid are subjected to salt forming in an organic solvent; and finished product N,N-dimethyl-2-(1-phenyl-1-(2-pyridine)ethoxy)ethanamine succinate (doxylamine succinate) is obtained via cooling crystallization. The preparation method is simple, safe, and reliable, is high in doxylamine succinate yield, and is suitable for industrialized enlarged production; and post-treatment is simple and convenient.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of preparation method of doxylamine succinate.
Background technology
Doxylamine succinate belongs to ethanol class antihistamine drug, and have antihistamine effect, cholinolytic effect and significant sedative-hypnotic property, it is applicable to multiple anaphylaxis dermatosis, spring fever, allergic rhinitis, asthmatic bronchitis etc.; Because it produces sleepiness by suppressing central nervous system, be therefore also used as the short-term treatment of soporific for insomnia.
In October, 1978, FDA ratified the doxylamine succinate 25mg tablet listing of CHATTEM company, alleviated difficulty falling asleep for helping.Within 1979, become OTC (nonprescription drugs).In September, 1996 is ratified, and in August, 2004, LNK company was as imitation medicine official listing.The OTC antihistamine drug that doxylamine succinate is slept as assisting therapy, its clinical safety is effective, general reaction rate is high, better tolerance.
The synthetic method program of existing doxylamine succinate is complicated, patent CN201310456159 reports 2-pyridinylphenyl carbinol methine, dimethylamino monochloroethane hydrochloride and sodium amide and refluxes more than 8 hours in toluene or dimethylbenzene, sodium amide is inorganic super base, reflux in the high boiling solvent such as toluene, dimethylbenzene for a long time, large to conversion unit damage, dimethylamino monochloroethane hydrochloride is lower boiling severe toxicity organic reagent, boiling point only 50 DEG C, reflux for a long time in dimethylbenzene, serious harm operator ' s health; The aftertreatment of reaction needs column chromatography or utilizes the difference of product and impurity pKa value, and regulate pH to carry out abstraction purification, cost is higher, complicated operation, is unfavorable for industrial amplification production.In the salt-forming reaction of finished product doxylamine succinate, the patent acetone such as CN201310456159 and CN201010275180 make solvent, N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine and succsinic acid salify, but doxylamine succinate in acetone solvability is larger, yield is lower, and each crystallization yield only has about 80%, and needs repeatedly crystallization; Finished product purity is not high, single assorted close to 0.1%.Therefore develop new synthesis technique, simplify the operation step, reduce costs, improve productive rate and purity, significant to the synthesis of doxylamine succinate.
Summary of the invention
In order to solve the deficiency existed in the disclosed synthetic routes such as CN20131045619 and CN201010275180, the present invention carries out process optimization to said synthesis route, a kind of optimal preparation technology of doxylamine succinate is provided, this technique simply, safely, efficiently, simplify synthetic operation, reduce cost, improve productive rate, bring up to 99.93% by the HPLC purity of finished product, single mixing controls below 0.03%.
The technical solution adopted in the present invention is as described below:
A preparation method for doxylamine succinate, comprises the following steps:
The preparation of S1.N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine:
2-pyridinylphenyl carbinol methine is dissolved in organic solvent, adds sodium amide and dimethylamino monochloroethane hydrochloride under ice bath, pyroreaction, react complete, ice bath cools, and through cancellation, extraction, dry organic phase, underpressure distillation solvent, obtains target product 2-pyridylmethyl methyl alcohol;
S2. the preparation of doxylamine succinate:
Step S1. is prepared N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine is dissolved in organic solvent, add succsinic acid at a certain temperature, to lower the temperature after salify crystallization, suction filtration, organic solvent washing obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate (i.e. doxylamine succinate).
N as above; the preparation method of N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine; S1. described concrete steps are as follows: ice bath 0-5 DEG C, 2-pyridinylphenyl carbinol methine is dissolved in dimethylbenzene, under nitrogen protection; add sodium amide; stir 15-30 minute, add dimethylamino monochloroethane hydrochloride, 0-5 DEG C is stirred 15-30 minute; slowly be warming up to 140 DEG C, return stirring reaction 50min-70min.
N as above, the preparation method of N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine, S1. the described 2-pyridinylphenyl carbinol methine described in concrete steps S1 and the mol ratio of sodium amide are 1:(2-5), preferred 1:3.5.
N as above, the preparation method of N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine, S1. the described 2-pyridinylphenyl carbinol methine described in concrete steps S1 and the mol ratio of dimethylamino monochloroethane hydrochloride are 1:(4-8), preferred 1:6.
N as above, the preparation method of N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine, aftertreatment described in S1 comprises the following steps: reaction system is cooled to 0-5 DEG C, drip 20-30% ammonium chloride, stir 30 minutes, stratification, discard water layer, add 3-5% dilute hydrochloric acid, abundant mixing, stratification, abandon organic phase, aqueous phase adds 20-30% aqueous sodium carbonate and ethyl acetate, stratification after abundant mixing, anhydrous sodium sulfate drying ethyl acetate layer, suction filtration underpressure distillation removing ethyl acetate, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine.
N as above, the preparation method of N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate, S2. described concrete steps are as follows: by N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine 20-30 DEG C is dissolved in the mixing solutions of Virahol and ethyl acetate, stirring adds succsinic acid, is warming up to 50-60 DEG C, back flow reaction 0.5-1 hour, slow cooling to 0-5 DEG C, stirring and crystallizing 3-5 hour.
The preparation method of N, N-dimethyl-2-as above [1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate, the volume ratio of the Virahol described in S2 and ethyl acetate mixed solvent is (0.5-2): 1, preferred 1:1.
N as above; the preparation method of N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate; aftertreatment described in S2 comprises the following steps: suction filtration under nitrogen protection; filter cake is respectively with Virahol and ethyl acetate washing; p > 0.08,45-50 DEG C of drying under reduced pressure 6-8 hour; obtain white solid N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate.
Beneficial effect of the present invention in sum:
Synthetic method craft of the present invention is simple, and be swift in response, transformation efficiency is high, reaction side reaction is few, and aftertreatment is simple, avoids the troublesome operation such as column chromatography, the finished product doxylamine succinate yield that salifying process obtains is high, purity is good, only primary crystallization, and purity can reach more than 99.9%, single mixing all is less than 0.05%, avoid in literature procedures and need periodic crystallisation, and the situation that yield and purity are not high, be applicable to industrialized production.
Accompanying drawing explanation
Fig. 1 is the mass spectrum of doxylamine succinate;
Fig. 2 is the hydrogen spectrum of doxylamine succinate;
Fig. 3 is the carbon spectrum of doxylamine succinate.
Fig. 4 is the liquid phase purity collection of illustrative plates of the doxylamine succinate that embodiment 1 technique prepares.
Fig. 5 is the gas phase purity collection of illustrative plates of the doxylamine succinate that embodiment 1 technique prepares.
Embodiment
Below in conjunction with embodiment, the present invention is described further:
Present invention process route is as follows:
Comprise the following steps:
The preparation of S1.N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine:
2-pyridinylphenyl carbinol methine is dissolved in dimethylbenzene; nitrogen protection; add sodium amide; stir; add dimethylamino monochloroethane hydrochloride again, about 140 DEG C back flow reaction, lower the temperature system after having reacted and carry out aftertreatment; obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine crude product.
S2: the synthesis of doxylamine succinate
Step S1. is prepared crude product N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] the dissolved solution of ethamine is in organic solvent, add succsinic acid afterwards, be warming up to about 60 DEG C to react completely, N is obtained, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate white solid through aftertreatment.
Contriver monitored the reaction times in S1. step in above-mentioned operational path, and concrete data are as shown in table 1,
In table 1S1. step, the differential responses time is on the impact of principal product purity
According to table 3 data, within reaction 1h, start material material 2-pyridinylphenyl carbinol methine, can reduce along with the prolongation in reaction times, when reaction is more than 1h, along with the prolongation in reaction times, end product can be degraded into starting material; Other impurity except starting material, minimum when reacting 1h, along with the prolongation in reaction times, foreign matter content increases gradually.So when 1h, it is the most complete that reaction is carried out, and in reaction solution, foreign matter content is minimum.
Screened by organic solvent in operational path step S2, reaction test yield, purity are as shown in the table.
In table 2S2. step, different solvents is on the impact of doxylamine succinate salify yield and purity
| Solvent | Yield (%) | HPLC purity (%) |
| Acetone | 80 | 99.88 |
| Acetonitrile | 78 | 99.81 |
| Tetrahydrofuran (THF) | 86 | 99.75 |
| Ethanol | 52 | 99.70 |
| Methylene dichloride | 76 | 99.72 |
| DMF | 65 | 99.65 |
| Virahol | 85 | 99.92 |
| Ethyl acetate | 96 | 99.85 |
| Virahol: ethyl acetate (1:1) | 93 | 99.93 |
| Virahol: ethyl acetate (1:2) | 95 | 99.90 |
| Virahol: ethyl acetate (3:2) | 90 | 99.91 |
| Virahol: ethyl acetate (2:1) | 88 | 99.90 |
Below enumerate preferred process concrete operation step of the present invention.
Embodiment 1:
Reaction equation is as follows:
The synthesis of S1:N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine
The 2-pyridinylphenyl carbinol methine of 200g is dissolved in 1L dimethylbenzene, pass into nitrogen protection, 222g sodium amide is added at 0-5 DEG C, stir 15-30 minute, add 1.07kg dimethylamino monochloroethane hydrochloride, 0-5 DEG C is stirred 15-30 minute, slowly be warming up to 140 DEG C, return stirring reaction 1h, react complete and be cooled to 0-5 DEG C, drip 20-30% ammonium chloride 500ml, stir 30 minutes, stratification, discard water layer, add 3-5% dilute hydrochloric acid 300ml, abundant mixing 15 minutes, stratification, abandon organic phase, aqueous phase adds 300ml, 20-30% aqueous sodium carbonate and 1L ethyl acetate, stratification after abundant mixing, anhydrous sodium sulfate drying ethyl acetate layer, suction filtration underpressure distillation removing ethyl acetate, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine yellow oil 266.3g, yield 98%.
S2: the synthesis of doxylamine succinate
Step S1. is prepared the N of 136g, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine is in the 20-30 DEG C of mixing solutions being dissolved in Virahol and ethyl acetate (volume ratio 1:1), stirring adds 59.5g succsinic acid, be warming up to 60 DEG C, stirring reaction 0.5-1 hour, slow cooling is to 0-5 DEG C, stirring and crystallizing 3-5 hour, suction filtration under nitrogen protection, filter cake is respectively with 100ml Virahol and the washing of 200ml ethyl acetate, filter cake is at p > 0.08, 45-50 DEG C of drying under reduced pressure 6-8 hour, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate white solid 181.8g, content 99.99%, , maximum absorption wavelength 262nM, yield 93%, fusing point 105-106.5 DEG C, total recovery 91%, HPLC purity 99.93% as shown in Figure 4, GC purity 99.90% as shown in Figure 5, mass-spectrometric data as shown in Figure 1, MS:271.2 [M+H]
+.
Embodiment 2:
Reaction equation is as follows:
The synthesis of S1:N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine
The 2-pyridinylphenyl carbinol methine of 200g is dissolved in 1L dimethylbenzene, pass into nitrogen protection, 254g sodium amide is added at 0-5 DEG C, stir 15-30 minute, add 1.39kg dimethylamino monochloroethane hydrochloride, 0-5 DEG C is stirred 15-30 minute, slowly be warming up to 140 DEG C, return stirring reaction 1h, react complete and be cooled to 0-5 DEG C, drip 20-30% ammonium chloride 500ml, stir 30 minutes, stratification, discard water layer, add 3-5% dilute hydrochloric acid 300ml, abundant mixing 15 minutes, stratification, abandon organic phase, aqueous phase adds 300ml, 20-30% sodium bicarbonate aqueous solution and 1L ethyl acetate, stratification after abundant mixing, anhydrous sodium sulfate drying ethyl acetate layer, suction filtration underpressure distillation removing ethyl acetate, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine yellow oil 269.0g, yield 99%.
S2: the synthesis of doxylamine succinate
Step S1. is prepared the N of 136g, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine is in the 20-30 DEG C of mixing solutions being dissolved in Virahol and ethyl acetate (volume ratio 1:2), stirring adds 59.5g succsinic acid, be warming up to 60 DEG C, stirring reaction 1 hour, slow cooling is to 0-5 DEG C, stirring and crystallizing 3-5 hour, suction filtration under nitrogen protection, filter cake is respectively with 100ml Virahol and the washing of 100ml ethyl acetate, filter cake is at p > 0.08, 45-50 DEG C of drying under reduced pressure 6-8 hour, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate white solid 185.8g, content 99.98%, , maximum absorption wavelength 262nM, yield 95%, fusing point 105-106.5 DEG C, total recovery 94%, HPLC purity 99.90%, GC purity 99.90%, mass-spectrometric data as shown in Figure 1, MS:271.2 [M+H]
+.
Embodiment 3:
The synthesis of S1:N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine
The 2-pyridinylphenyl carbinol methine of 200g is dissolved in 1L dimethylbenzene, pass into nitrogen protection, 190g sodium amide is added at 0-5 DEG C, stir 15-30 minute, add 0.89kg dimethylamino monochloroethane hydrochloride, 0-5 DEG C is stirred 15-30 minute, slowly be warming up to 150 DEG C, return stirring reaction 1h, react complete and be cooled to 0-5 DEG C, drip 20-30% ammonium chloride 500ml, stir 30 minutes, stratification, discard water layer, add 3-5% dilute hydrochloric acid 300ml, abundant mixing 30 minutes, stratification, abandon organic phase, aqueous phase adds 300ml, 20-30% aqueous sodium carbonate and 1L methylene dichloride, stratification after abundant mixing, anhydrous sodium sulfate drying dichloromethane layer, suction filtration underpressure distillation removing methylene dichloride, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine yellow oil 263.8g, yield 97%.
S2: the synthesis of doxylamine succinate
Step S1. is prepared the N of 136g, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine is in the 20-30 DEG C of mixing solutions being dissolved in Virahol and ethyl acetate (volume ratio 3:2), stirring adds 59.5g succsinic acid, be warming up to 60 DEG C, stirring reaction 0.5 hour, slow cooling is to 0-5 DEG C, stirring and crystallizing 3-5 hour, suction filtration under nitrogen protection, filter cake is respectively with 50ml Virahol and the washing of 200ml ethyl acetate, filter cake is at p > 0.08, 45-50 DEG C of drying under reduced pressure 6-8 hour, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate white solid 175.9g, yield 90%, content 99.98%, , maximum absorption wavelength 262nM, fusing point 105-106 DEG C, total recovery 87.3%, HPLC purity 99.91%, GC purity 99.91%, mass-spectrometric data is MS:271.2 [M+H] as shown in Figure 1
+.Doxylamine succinate hydrogen composes nuclear magnetic data as shown in Figure 2:
1h-NMR:(300MHz, DMSO): δ: 10.82 (br, 2H), 8.48-8.49 (m, 1H), 7.75-7.79 (m, 1H), 7.65-7.67 (d, J=4.8Hz, 1H), 7.37-7.39 (d, J=4.5Hz, 2H), 7.27-7.31 (t, J=4.6Hz, 2H), 7.18-7.24 (m, 2H), (3.40-3.42 t, J=3.4Hz, 2H), (2.79-2.81 t, J=3.4Hz, 2H), 2.37-2.39 (m, 10H), 1.93 (s, 3H).
Carbon composes nuclear magnetic data as shown in Figure 3,
13c-NMR:(125MHz, DMSO): δ: 174.4,164.3,148.3,145.4,136.7,128.0,126.8,126.1,122.0,120.2,81.8,59.6,58.0,44.6,30.0,23.5.
Claims (8)
1. a preparation method for doxylamine succinate, is characterized in that, comprises the following steps:
The preparation of S1.N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine:
2-pyridinylphenyl carbinol methine is dissolved in organic solvent, add acid binding agent, react with dimethylamino monochloroethane hydrochloride at a certain temperature, react complete, through cancellation, extraction, dry organic phase, underpressure distillation solvent, obtain target product 2-pyridylmethyl methyl alcohol;
S2. the preparation of doxylamine succinate:
Step S1. is prepared N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine is dissolved in organic solvent, add succsinic acid at a certain temperature, to lower the temperature after salify crystallization, suction filtration, organic solvent washing obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate.
2. the preparation method of doxylamine succinate according to claim 1; it is characterized in that; concrete grammar described in step S1.: ice bath 0-5 DEG C, 2-pyridinylphenyl carbinol methine is dissolved in dimethylbenzene, under nitrogen protection; add sodium amide; stir 15-30 minute, add dimethylamino monochloroethane hydrochloride, 0-5 DEG C is stirred 15-30 minute; slowly be warming up to 140-150 DEG C, return stirring reaction 50min-70min.
3. the preparation method of doxylamine succinate according to claim 2, is characterized in that, the 2-pyridinylphenyl carbinol methine described in step S1 and the mol ratio of sodium amide are 1:(2-5).
4. the preparation method of doxylamine succinate according to claim 2, is characterized in that, the mol ratio of the 2-pyridinylphenyl carbinol methine described in step S1 and dimethylamino monochloroethane hydrochloride is 1:(4-8).
5. the preparation method of doxylamine succinate according to claim 1, it is characterized in that, aftertreatment described in step S1 comprises the following steps: reaction system is cooled to 0-5 DEG C, drip 20-30% ammonium chloride, stir 30 minutes, stratification, discard water layer, add 3-5% dilute hydrochloric acid, abundant mixing, stratification, abandon organic phase, aqueous phase adds 20-30% sodium carbonate, sodium bicarbonate or wet chemical and ethyl acetate or methylene dichloride, stratification after abundant mixing, anhydrous sodium sulfate drying ethyl acetate or dichloromethane layer, suction filtration underpressure distillation removing ethyl acetate or methylene dichloride, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine.
6. the preparation method of doxylamine succinate according to claim 1, it is characterized in that, concrete grammar described in step S2.: by N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine 20-30 DEG C is dissolved in the mixing solutions of a certain proportion of Virahol and ethyl acetate, stir the succsinic acid of molar equivalents such as adding, be warming up to 50-60 DEG C, back flow reaction 0.5-1 hour, slow cooling to 0-5 DEG C, stirring and crystallizing 3-5 hour.
7. the preparation method of doxylamine succinate according to claim 6, is characterized in that, the volume ratio of the Virahol described in step S2 and ethyl acetate mixed solvent is (0.5-2): 1.
8. the preparation method of doxylamine succinate according to claim 1; it is characterized in that; aftertreatment described in step S1 comprises the following steps: suction filtration under nitrogen protection; filter cake is respectively with Virahol and ethyl acetate washing; p > 0.08,45-50 DEG C of drying under reduced pressure 6-8 hour; obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate.
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| CN105510512A (en) * | 2016-01-25 | 2016-04-20 | 南京济群医药科技有限公司 | RT-HPLC detection method for related substances of doxylamine succinate |
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| CN107098851A (en) * | 2016-02-22 | 2017-08-29 | 南京秾康生物科技有限公司 | A kind of preparation method of doxylamine succinate |
| CN106674089A (en) * | 2016-12-22 | 2017-05-17 | 南京济群医药科技股份有限公司 | Doxylamine succinate crystal form S and preparation method thereof |
| CN106674089B (en) * | 2016-12-22 | 2022-01-14 | 南京济群医药科技股份有限公司 | Doxylamine succinate crystal form S and preparation method thereof |
| CN107056685A (en) * | 2017-01-23 | 2017-08-18 | 珠海市海瑞德生物科技有限公司 | A kind of synthetic method of doxylamine succinate |
| CN110498764A (en) * | 2019-09-25 | 2019-11-26 | 深圳沃兰德药业有限公司 | A kind of synthetic method of doxylamine succinate |
| CN110498764B (en) * | 2019-09-25 | 2023-09-08 | 深圳沃兰德药业有限公司 | Synthesis method of doxylamine succinate |
| 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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