CN103524403A - Preparation method of doxylamine succinate - Google Patents
Preparation method of doxylamine succinate Download PDFInfo
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- CN103524403A CN103524403A CN201310456159.XA CN201310456159A CN103524403A CN 103524403 A CN103524403 A CN 103524403A CN 201310456159 A CN201310456159 A CN 201310456159A CN 103524403 A CN103524403 A CN 103524403A
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- 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
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- C07D213/30—Oxygen atoms
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Abstract
The invention relates to a preparation method of doxylamine succinate. The preparation method comprises the steps as follows: firstly, a Grignard reagent generated by iodobenzene and magnesium reacts with 2-acetylpyridine to generate 2-pyridyl phenyl methyl alcohol, the 2-pyridyl phenyl methyl alcohol is recrystallized to be purified, then the 2-pyridyl phenyl methyl alcohol reacts with sodium amide and 2-dimethylamino chloroethane sequentially, doxylamine is obtained and has a salt forming reaction with succinic acid finally, and the doxylamine succinate is obtained. The preparation method is high in reaction efficiency, lower in cost and applicable to industrial mass production.
Description
Technical field
This area belongs to medical technology and organic synthesis field, is specifically related to a kind of preparation method of antihistaminic doxylamine succinate.
Background technology
Doxylamine succinate (doxylamine succinate), chemical name N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate, No. CAS: 562-10-7, it is a kind of ethanol class antihistamine drug, there is antihistamine effect, cholinolytic effect and significant sedative effect, be applicable to multiple anaphylaxis dermatosis, spring fever, asthmatic bronchitis, allergic rhinitis etc.; Also can by suppressing central nervous system, produce sleepiness for the short of insomnia, its clinical safety is effective.
Patent of invention CN201210587388.0 discloses a kind of preparation method of doxylamine succinate intermediate 2-pyridyl phenylmethylcarbinol, methyl phenyl ketone is dissolved in methyl tertiary butyl ether, add the catalyst reactions such as boron trifluoride, tin tetrachloride to prepare 2-pyridyl phenylmethylcarbinol simultaneously, then use methyl alcohol and the acetone mixed solvent recrystallization of 20 times.This complex operation, quantity of solvent is larger, and cost is higher.
CN102108059A has related to a kind of synthetic method of doxylamine succinate, take 2-acetopyridine as starting raw material, the Grignard reagent generating with bromobenzene and magnesium reacts, prepare 2-pyridyl phenylmethylcarbinol crude product, through aftertreatments such as distillations, obtain product, then 2-pyridyl phenylmethylcarbinol is reacted more than 15 hours with sodium amide and 2-dimethylamino monochloroethane successively, obtain doxylamine.This scheme reaction efficiency is lower, and aftertreatment is complicated, and the fusing point of 2-pyridyl phenylmethylcarbinol is 33～34.5 ℃, and distillation is difficult to guarantee product yield and purity.
The inventor overcomes the deficiencies in the prior art, a kind of preparation method of doxylamine succinate is provided, select the active higher Grignard reagent of iodobenzene preparation, do not needing to add under the condition of the lewis acid catalysts such as boron trifluoride, tin tetrachloride and 2-acetopyridine grignard reaction, aftertreatment is purified by the method for low temperature recrystallization, and 2-pyridyl phenylmethylcarbinol is obtained to the finished product with sodium amide and the reaction of 2-dimethylamino monochloroethane successively.Reaction efficiency of the present invention is high, and aftertreatment is simple, and product yield and purity are higher, and process costs is lower, is applicable to industrialized production.
Summary of the invention
The preparation method who the object of this invention is to provide a kind of antihistaminic doxylamine succinate.
Object of the present invention can reach by following measures: a kind of preparation method of doxylamine succinate, is characterized in that comprising following steps:
Synthetic and the purifying of A, 2-pyridyl phenylmethylcarbinol (IV)
Add reaction in organic solvent to obtain Grignard reagent II in the magnesium of iodobenzene, iodine and activation, Grignard reagent II and 2-acetylpyridine are carried out grignard reaction, through aftertreatment purifying, obtain 2-pyridyl phenylmethylcarbinol (IV).
Synthesizing of B, doxylamine
Sodium amide, 2-pyridyl phenylmethylcarbinol and dimethylamino monochloroethane back flow reaction in xylene solvent are obtained to doxylamine.
Steps A adds iodine and the iodobenzene solution of magnesium chips, catalytic amount in ether, methyl tertiary butyl ether or tetrahydrofuran (THF), after causing, reaction stirs the lower iodobenzene solution that drips, back flow reaction 10～20 hours, obtain grignard reagent solution, then drip 2-acetylpyridine solution, stirring reaction 1～5h, obtains 2-pyridyl phenylmethylcarbinol (IV) through quencher, precipitation, recrystallization aftertreatment;
The reaction of steps A, the reaction mol ratio of iodobenzene and 2-acetylpyridine is (1.1～4): 1;
Preferably, the reaction mol ratio of iodobenzene and 2-acetylpyridine is (1.4～2.5): 1.
Iodobenzene add step can first drip sub-fraction to be stirred to reaction and to cause after, drip remainder.
In steps A, post-reaction treatment comprises the following steps:
A) with aqueous ammonium chloride solution quencher reaction;
B) the reaction solution separatory after cancellation is retained to organic phase, use organic solvent extraction water, merge organic phase, after washing is dry, desolvation obtains 2-pyridyl phenylmethylcarbinol (IV) crude product;
C) crude product at low temperatures recrystallization obtain 2-pyridyl phenylmethylcarbinol (IV).
In steps A, the process of recrystallization: 2-pyridyl phenylmethylcarbinol (IV) crude product is dissolved to stirring in organic solvent, then carry out recrystallization under≤-15 ℃ of low temperature, obtain the 2-pyridyl phenylmethylcarbinol of 33～34.5 ℃ of fusing points.
The solvent of recrystallization is selected from one or more mixing in ethyl acetate, tetrahydrofuran (THF), toluene, normal hexane, sherwood oil; The preferably normal hexane of 50: 1 and ethyl acetate.
The amount of recrystallization solvent is below 8 times of crude product quality, can make product also stir and well be advisable in solvent.
In step B, by sodium amide solution and 2-pyridyl phenylmethylcarbinol solution hybrid reaction, then drip dimethylamino monochloroethane solution in reaction system, back flow reaction 2～5 hours.
In step B, the reaction mol ratio of 2-pyridyl phenylmethylcarbinol, sodium amide and dimethylamino monochloroethane is 1: (1.1～4): (2～6).
Preferably, in step B, the reaction mol ratio of 2-pyridyl phenylmethylcarbinol, sodium amide and dimethylamino monochloroethane is 1: (1.6～2.5): (4～5).
Doxylamine and succsinic acid are reacted and obtain doxylamine succinate, and preparation method can be with reference to prior art.
Preparation method's reaction efficiency of the present invention is high, and aftertreatment is simple, and product yield and purity are higher, and process costs is lower, is applicable to industrialized production.
Embodiment
Following examples further describe the present invention, and still, these embodiment are only for the present invention is described, rather than limitation of the scope of the invention.
The preparation of embodiment 1 2-pyridyl phenylmethylcarbinol
Magnesium chips after the activation of 13.92g (0.58mol) dilute hydrochloric acid is added in the there-necked flask of 1000ml, add 300ml ether and 1 iodine; Again 114.24g (0.56mo) iodobenzene mixing 100ml ether slowly splashed into 10ml; treat that sorrel becomes faint yellow and starts to reflux; drip remaining iodobenzene, solution is from the faint yellow oyster white that becomes, grizzle again gradually; drip complete stirring and refluxing reaction 15h; 48.20g (0.4mol) 2-acetylpyridine is mixed to 100ml ether and slowly splash in above-mentioned solution, solution becomes yellow from grey, drips and finishes the rear reaction 2～3h that continues; after completion of the reaction, drip the saturated NH of 100ml
4the Cl aqueous solution, limit edged stirs, and drips off rear continuation and stirs 1h, and separatory retains organic phase, and 2 * 300ml extracted with diethyl ether time for water merges organic phase, 2 * 500ml water washing organic phase, anhydrous Na
2sO
4dry, be spin-dried for to obtain oily compound; Add normal hexane: ethyl acetate=50: 1 mixed solvent 100ml is in oily compound, stir 1h, put into refrigerator and cooled and freeze crystallization, after 24h, take out, discard liquid, solid normal hexane: ethyl acetate=50: mixed solvent 3 * 50ml washing of 1, solvent is screwed out and to obtain 86.1g oily compound, and crystallization at-20 ℃, obtains solid 70.8g, the purity that HPLC detects crystal reaches 98.9%, and yield is 89%.MS：200[M+H]
+。
1H-NMR：(400MHz，CDCl
3)δ1.97(3H，s，CH
3)，7.18～7.37(5H，m)，7.50～7.55(2H，m)，7.66(1H，dt)，8.56(1H，m)。
The preparation of embodiment 2 2-pyridyl phenylmethylcarbinols
Magnesium chips after the activation of 13.92g (0.58mol) dilute hydrochloric acid is added in the there-necked flask of 1000ml, adds 300ml methyl tertiary butyl ether and 1 iodine; Again 114.24g (0.56mo) iodobenzene mixing 100ml methyl tertiary butyl ether slowly splashed into 10ml; treat that sorrel becomes faint yellow and starts to reflux; drip remaining iodobenzene; solution is from the faint yellow oyster white that becomes; gradually grizzle again; drip complete stirring and refluxing reaction 10h; 48.20g (0.4mol) 2-acetylpyridine is mixed to 100ml methyl tertiary butyl ether slowly to be splashed in above-mentioned solution; solution becomes yellow from grey; drip and finish the rear reaction 2～3h that continues; after completion of the reaction, drip the saturated NH of 100ml
4the Cl aqueous solution, limit edged stirs, and drips off rear continuation and stirs 1h, and separatory retains organic phase, and 2 * 300ml extracted with diethyl ether time for water merges organic phase, 2 * 500ml water washing organic phase, anhydrous Na
2sO
4dry, be spin-dried for to obtain oily compound; Add sherwood oil: tetrahydrofuran (THF)=50: 1 mixed solvent 80ml is in oily compound, stir 1h, put into refrigerator and cooled and freeze crystallization, after 24h, take out, discard liquid, solid sherwood oil: tetrahydrofuran (THF)=50: mixed solvent 3 * 50ml washing of 1, solvent is screwed out and to obtain 72g oily compound, and crystallization at-25 ℃, obtains solid 67.5g, the purity that HPLC detects crystal reaches 98.9%, and yield is 85%.MS：200[M+H]
+。
The preparation of embodiment 3 2-pyridyl phenylmethylcarbinols
Magnesium chips after the activation of 7.2g (0.30mol) dilute hydrochloric acid is added in the there-necked flask of 1000ml, add 100ml tetrahydrofuran (THF) and 1 iodine; Again 50.0g (0.25mo) iodobenzene mixing 50ml tetrahydrofuran (THF) slowly splashed into 10ml, treat that sorrel becomes faint yellow and starts to reflux, drip remaining iodobenzene, solution is from the faint yellow oyster white that becomes, gradually grizzle again, drips complete stirring and refluxing reaction 8h; 12.1g (0.1mol) 2-acetylpyridine is mixed to 50ml tetrahydrofuran (THF) and slowly splash in above-mentioned solution, solution becomes yellow from grey, drips and finishes the rear reaction 2～3h that continues; After completion of the reaction, drip the saturated NH of 100ml
4the Cl aqueous solution, limit edged stirs, and drips off rear continuation and stirs 1h, and separatory retains organic phase, and 2 * 200ml tetrahydrofuran (THF) extraction time for water, merges organic phase, 2 * 300ml water washing organic phase, anhydrous Na
2sO
4dry, be spin-dried for to obtain oily compound; Column chromatography is removed unnecessary iodobenzene, and solvent is screwed out and to obtain 17.5g oily compound, and crystallization at-15 ℃, obtains solid 12g, and the purity that HPLC detects crystal reaches 99.5%, and yield is 60%.MS：200[M+H]
+。
The preparation of embodiment 4 2-pyridyl phenylmethylcarbinols
Magnesium chips after the activation of 9.6g (0.40mol) dilute hydrochloric acid is added in the there-necked flask of 1000ml, add 100ml ether and 1 iodine; Again 80.4g (0.4mo) iodobenzene mixing 50ml ether slowly splashed into 10ml, treat that sorrel becomes faint yellow and starts to reflux, drip remaining iodobenzene, solution is from the faint yellow oyster white that becomes, gradually grizzle again, drips complete stirring and refluxing reaction 15h, 12.1g (0.1mol) 2-acetylpyridine is mixed to 50ml ether and slowly splash in above-mentioned solution, solution becomes yellow from grey, drips and finishes the rear reaction 2～3h that continues; After completion of the reaction, drip the saturated NH of 100ml
4the Cl aqueous solution, limit edged stirs, and drips off rear continuation and stirs 1h, and separatory retains organic phase, and 2 * 300ml extracted with diethyl ether time for water merges organic phase, 2 * 500ml water washing organic phase, anhydrous Na
2sO
4dry, be spin-dried for to obtain oily compound; Column chromatography is removed unnecessary iodobenzene, and solvent is screwed out and to obtain 18.0g oily compound, and crystallization at-18 ℃, obtains solid 11.7g, and yield is 65%.
MS：200[M+H]
+
1H-NMR：(400MHz，CDCl
3)δ1.97(3H，s，CH
3)，7.18～7.37(5H，m)，7.50～7.55(2H，m)，7.66(1H，dt)，8.56(1H，m)。
Synthesizing of embodiment 5 doxylamines
The sodium amide of 16g (0.4mol) and 100mL dimethylbenzene are added in the there-necked flask of 1000mL, be heated to 140 ℃; The dimethylbenzene of the 2-pyridyl phenylmethylcarbinol mixing 250mL of 50g (0.25mol) is splashed into above-mentioned reaction system, and back flow reaction 5h with this understanding; 108g (1.0mol) dimethylamino monochloroethane mixing 200mLl xylene solution is slowly splashed into reaction system, back flow reaction 3～4h.Question response finishes, and drips the saturated NH of 100mL
4the Cl aqueous solution, stirs 0.5h, then adds water 400mL, adjusts pH value to 2～3, and reject organic phase retains water, and the ethyl acetate extraction of 100mL for water * 2, discards organic phase; Water is adjusted pH value to 5～6, adds, and the extraction of 2 * 200mL ethyl acetate, discards organic phase, and this step can be removed most of unreacted 2-pyridyl phenylmethylcarbinol and a part of impurity; Water is adjusted pH value to 9～10, adds the extraction of 2 * 200ml ethyl acetate, retains organic phase, and organic phase is dried, is spin-dried for, and obtains the thick product of oily; The thick product of oily is crossed to post with silica gel mixed sample, adopts gradient elution: normal hexane: ethyl acetate=10: 1, normal hexane: ethyl acetate=2: 1, methylene dichloride: methyl alcohol=100: 1, methylene dichloride: methyl alcohol=20: 1.Collect elutriant and be spin-dried for to obtain 44g doxylamine, yield is that 65%, HPLC detection purity is 99%.
Synthesizing of embodiment 6 doxylamines
The sodium amide of 11g (0.275mol) and 100mL dimethylbenzene are added in the there-necked flask of 1000mL, be heated to 140 ℃; The dimethylbenzene of the 2-pyridyl phenylmethylcarbinol mixing 250mL of 50g (0.25mol) is splashed into above-mentioned reaction system, and back flow reaction 5h with this understanding; 108g (1.0mol) dimethylamino monochloroethane mixing 200mL xylene solution is slowly splashed into reaction system, back flow reaction 3.5h.Question response finishes, and drips the saturated NH of 100mL
4the Cl aqueous solution, stirs 0.5h, then adds water 400mL, adjusts pH value to 2～3, and reject organic phase retains water, and the ethyl acetate extraction of 100mL for water * 2, discards organic phase; Water is adjusted pH value to 5～6, adds the extraction of 2 * 200mL ethyl acetate, discards organic phase, and this step can be removed most of unreacted 2-pyridyl phenylmethylcarbinol and a part of impurity; Water is adjusted pH value to 9～10, adds the extraction of 2 * 200ml ethyl acetate, retains organic phase, and organic phase is dried, is spin-dried for, and obtains the thick product of oily; The thick product of oily is crossed to post with silica gel mixed sample, adopt gradient elution: normal hexane: ethyl acetate=10: 1, normal hexane: ethyl acetate=2: 1, methylene dichloride: methyl alcohol=100: 1, methylene dichloride: methyl alcohol=20: 1.Collect elutriant and be spin-dried for to obtain 35g doxylamine, yield is that 51%, HPLC detection purity is 99%.
Synthesizing of embodiment 7 doxylamines
The sodium amide of 25g (0.625mol) and 100mL dimethylbenzene are added in the there-necked flask of 1000mL, be heated to 140 ℃; The dimethylbenzene of the 2-pyridyl phenylmethylcarbinol mixing 250mL of 50g (0.25mol) is splashed into above-mentioned reaction system, and back flow reaction 5h with this understanding; 162g (1.5mol) dimethylamino monochloroethane mixing 200mL xylene solution is slowly splashed into reaction system, back flow reaction 2.5h.Question response finishes, and drips the saturated NH of 100mL
4the Cl aqueous solution, stirs 0.5h, then adds water 400mL, adjusts pH value to 2～3, and reject organic phase retains water, and the ethyl acetate extraction of 100mL for water * 2, discards organic phase; Water is adjusted pH value to 5～6, adds the extraction of 2 * 200mL ethyl acetate, discards organic phase, and this step can be removed most of unreacted 2-pyridyl phenylmethylcarbinol and a part of impurity; Water is adjusted pH value to 9～10, adds the extraction of 2 * 200ml ethyl acetate, retains organic phase, and organic phase is dried, is spin-dried for, and obtains the thick product of oily; The thick product of oily is crossed to post with silica gel mixed sample, adopt gradient elution: normal hexane: ethyl acetate=10: 1, normal hexane: ethyl acetate=2: 1, methylene dichloride: methyl alcohol=100: 1, methylene dichloride: methyl alcohol=20: 1.Collect elutriant and be spin-dried for to obtain 46g doxylamine, yield is that 68%, HPLC detection purity is 99%.
MS：271[M+H]
+
1H-NMR：(400MHz，CDCl
3)：δ1.97(3H，s，CH
3)，2.27(6H，m)，2.59(2H，m)，3.42(2H，m)，7.10(1H，m)，7.18(1H，m)，7.27(2H，m)，7.41(2H，m)，7.59～7.61(2H，m)，8.56(1H，m)。
Synthesizing of embodiment 8 doxylamines
The sodium amide of 40g (1mol) and 100mL dimethylbenzene are added in the there-necked flask of 1000mL, be heated to 140 ℃; The dimethylbenzene of the 2-pyridyl phenylmethylcarbinol mixing 250mL of 50g (0.25mol) is splashed into above-mentioned reaction system, and back flow reaction 5h with this understanding; 54g (0.5mol) dimethylamino monochloroethane mixing 200mL xylene solution is slowly splashed into reaction system, back flow reaction 3.5h.Question response finishes, and drips the saturated NH of 100mL
4the Cl aqueous solution, stirs 0.5h, then adds water 400mL, adjusts pH value to 2～3, and reject organic phase retains water, and the ethyl acetate extraction of 100mL for water * 2, discards organic phase; Water is adjusted pH value to 5～6, adds the extraction of 2 * 200mL ethyl acetate, discards organic phase, and this step can be removed most of unreacted 2-pyridyl phenylmethylcarbinol and a part of impurity; Water is adjusted pH value to 9～10, adds the extraction of 2 * 200ml ethyl acetate, retains organic phase, and organic phase is dried, is spin-dried for, and obtains the thick product of oily; The thick product of oily is crossed to post with silica gel mixed sample, adopt gradient elution: normal hexane: ethyl acetate=10: 1, normal hexane: ethyl acetate=2: 1, methylene dichloride: methyl alcohol=100: 1, methylene dichloride: methyl alcohol=20: 1.Collect elutriant and be spin-dried for to obtain 51g doxylamine, yield is that 75%, HPLC detection purity is 99%.
MS：271[M+H]
+
Synthesizing of embodiment 9 doxylamine succinates
The succsinic acid of the doxylamine of 40.50g (0.15mol) and 17.7g (0.15mol) is added in the flask of 250ml, add the acetone of 130ml, reflux, to dissolution of solid, continues to stir 1h; Acetone is steamed and adds 80ml isopropyl ether again, and ultrasonic 10min, removes the isopropyl ether on upper strata, and be spin-dried for and add 80ml acetone, stirring and crystallizing at 0 ℃, suction filtration obtains thick product.By acetone recrystallization secondary for thick product (thick product 1g: acetone 1.2ml), yield 80%, purity is 99.88%, it is 0.07% that maximum is singly mixed
MS：271[M+H]
+
1H-NMR：(400MHz，CDCl
3)：δ1.97(3H，s，CH
3)，2.55(4H，s)，2.81(6H，s)，3.18(4H，s)，3.64(2H，m)，7.10(1H，m)7.18(1H，m)，7.27(4H，s)，7.41(2H，m)，7.59～7.61(2H，m)，8.56(1H，m)。
Claims (7)
1. the western quick preparation method of succsinic acid Duola, is characterized in that comprising following steps:
A.2-pyridyl phenylmethylcarbinol (IV) synthesizes and purifying
Add reaction in organic solvent to obtain Grignard reagent II in the magnesium of iodobenzene, iodine and activation, Grignard reagent II and 2-acetylpyridine are carried out grignard reaction, through quencher, precipitation, recrystallization aftertreatment, obtain 2-pyridyl phenylmethylcarbinol (IV);
B. western quick the synthesizing of Duola
Sodium amide, 2-pyridyl phenylmethylcarbinol and dimethylamino monochloroethane back flow reaction in xylene solvent are obtained to Duola western quick.
2. Duola's Westminster system Preparation Method according to claim 1 is characterized in that: steps A adds iodine and the iodobenzene solution of magnesium chips, catalytic amount in ether, methyl tertiary butyl ether or tetrahydrofuran (THF); after causing, reaction stirs the lower iodobenzene solution that drips; back flow reaction 10～20 hours; obtain grignard reagent solution; then drip 2-acetylpyridine solution; stirring reaction 1～5h, aftertreatment obtains 2-pyridyl phenylmethylcarbinol (IV).
3. Duola's Westminster system Preparation Method according to claim 2 is characterized in that the reaction mol ratio of iodobenzene and 2-acetylpyridine is (1.1～4): 1, preferably (1.4～2.5): 1.
4. method according to claim 1 and 2, is characterized in that described aftertreatment comprises the following steps:
A) with aqueous ammonium chloride solution quencher reaction;
B) the reaction solution separatory after cancellation is retained to organic phase, use organic solvent extraction water, merge organic phase, after washing is dry, desolvation obtains 2-pyridyl phenylmethylcarbinol (IV) oily matter crude product;
C) crude product recrystallization obtains 2-pyridyl phenylmethylcarbinol (IV).
5. method according to claim 4, it is characterized in that: 2-pyridyl phenylmethylcarbinol (IV) crude product dissolves stirring in organic solvent, then under≤-15 ℃ of low temperature, carry out recrystallization, obtain the 2-pyridyl phenylmethylcarbinol of 33～34.5 ℃ of fusing points.
6. method according to claim 1 or 5, is characterized in that the solvent of recrystallization is selected from one or more mixing in ethyl acetate, tetrahydrofuran (THF), toluene, normal hexane, sherwood oil; Preferred normal hexane and ethyl acetate mixed solvent.
Ylmethyl methanol solution hybrid reaction, drips dimethylamino monochloroethane solution in reaction system, back flow reaction.
7. method according to claim 4, the reaction mol ratio that is characterised in that 2-pyridyl phenylmethylcarbinol, sodium amide and dimethylamino monochloroethane is 1:(1.1～4): (2～6), preferably 1:(1.6～2.5): (4～5).
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| CN105218433A (en) * | 2015-10-22 | 2016-01-06 | 南京济群医药科技有限公司 | A kind of doxylamine succinate new crystal and its preparation method and application |
| CN105237467A (en) * | 2015-09-23 | 2016-01-13 | 南京济群医药科技有限公司 | 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 |
| 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 |
| 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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| CN105001149A (en) * | 2015-07-22 | 2015-10-28 | 南京济群医药科技有限公司 | Method for preparing 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as intermediate of doxylamine succinate |
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| CN105218433A (en) * | 2015-10-22 | 2016-01-06 | 南京济群医药科技有限公司 | A kind of doxylamine succinate new crystal and its preparation method and application |
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| 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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