CN115974813A - Synthetic method of high-purity promethazine hydrochloride - Google Patents
Synthetic method of high-purity promethazine hydrochloride Download PDFInfo
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- CN115974813A CN115974813A CN202211640153.3A CN202211640153A CN115974813A CN 115974813 A CN115974813 A CN 115974813A CN 202211640153 A CN202211640153 A CN 202211640153A CN 115974813 A CN115974813 A CN 115974813A
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- XXPDBLUZJRXNNZ-UHFFFAOYSA-N promethazine hydrochloride Chemical compound Cl.C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 XXPDBLUZJRXNNZ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229960002244 promethazine hydrochloride Drugs 0.000 title claims abstract description 36
- 238000010189 synthetic method Methods 0.000 title claims description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 322
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229960003910 promethazine Drugs 0.000 claims abstract description 27
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 22
- MSUCLKFPHDRRGG-UHFFFAOYSA-N 1-chloro-n,n-dimethylpropan-1-amine Chemical compound CCC(Cl)N(C)C MSUCLKFPHDRRGG-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 21
- NCXUNZWLEYGQAH-UHFFFAOYSA-N 1-(dimethylamino)propan-2-ol Chemical compound CC(O)CN(C)C NCXUNZWLEYGQAH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 19
- 239000007788 liquid Substances 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000001308 synthesis method Methods 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 77
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 69
- 239000000243 solution Substances 0.000 claims description 41
- 238000001816 cooling Methods 0.000 claims description 36
- 238000010438 heat treatment Methods 0.000 claims description 27
- 238000001914 filtration Methods 0.000 claims description 24
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 22
- 239000008213 purified water Substances 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 8
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 7
- 229950000688 phenothiazine Drugs 0.000 claims description 7
- 235000006408 oxalic acid Nutrition 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 abstract description 14
- 239000012535 impurity Substances 0.000 abstract description 13
- 239000000047 product Substances 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 5
- 238000000605 extraction Methods 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- -1 salt ions Chemical class 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 24
- 238000001514 detection method Methods 0.000 description 21
- 239000007791 liquid phase Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 201000003152 motion sickness Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002761 liquid phase assay Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
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- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000002990 phenothiazines Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
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- 208000009056 telangiectasis Diseases 0.000 description 1
Images
Abstract
The invention relates to the technical field of medicine synthesis methods, and particularly relates to a synthesis method of high-purity promethazine hydrochloride. Firstly, synthesizing N, N-dimethyl isopropanolamine; then synthesizing N, N-dimethylamino chloropropane; then synthesizing promethazine oxalate; finally, the synthesis of promethazine hydrochloride. The method has mild reaction conditions, normal-pressure reaction in the whole process, conventional liquid separation in the post-treatment method, no need of high-pressure operation, simple operation and avoidance of the danger of high-pressure reaction by using an autoclave in the conventional synthesis process. The post-synthesis treatment of the N, N-dimethylamino chloropropane is simple, and the product can be obtained by simple alkali adjustment and extraction, so that the trouble that the product contains a large amount of water and is difficult to treat during the conventional normal-pressure reaction post-treatment is avoided; the intermediate product has small molecular weight, is not easy to be layered in water and toluene, increases the concentration of salt ions in a water phase, reduces the surface tension between two phases, uses methanol as an impurity removal solvent, improves the yield and reduces the isomer of the product.
Description
Technical Field
The invention relates to the technical field of medicine synthesis methods, and particularly relates to a synthesis method of high-purity promethazine hydrochloride.
Background
The chemical name of promethazine hydrochloride is: n, N, alpha-trimethyl-10H-phenothiazin-10-ethylamine hydrochloride (C) 17 H 20 N 2 S · HCl), english name: promethazine Hydrochloride, which is white or almost white powder or granule, almost odorless and bitter in taste; it turns blue in air, is very soluble in water, is soluble in ethanol or chloroform, and is almost insoluble in acetone or diethyl ether.
Promethazine hydrochloride is a phenothiazine derivative, also called promimidyl hydrochloride and finasteride, and can competitively block a histamine H1 receptor to generate obvious antihistaminic effect. Can resist telangiectasia caused by histamine, reduce permeability of capillary, and relieve asthma caused by bronchial smooth muscle contraction. Compared with diphenhydramine hydrochloride, the effect is stronger and lasting, and the medicine can easily enter brain tissues. Therefore, the medicine has obvious sedative effect and can strengthen the central inhibition effect of hypnotics, analgesics and narcotics. The choline resistance effect is also stronger, and the effect of preventing and treating the motion sickness is particularly good. It can also be used for treating skin and mucous membrane allergy such as allergic rhinitis, asthma, food allergy, skin scratch mark, carsickness, seasickness and air sickness.
The existing promethazine hydrochloride preparation process has the following problems: 1. the epoxypropane and dimethylamine gas are subjected to high-pressure reaction or normal-pressure reaction, and a large amount of water is concentrated during post-treatment, so that the safety coefficient is low, and the operation is complicated; 2. only thionyl chloride is used for chlorination, so that the yield is low and the extraction and emulsification are serious; 3. toluene is used for preparing a salt solvent during the post-treatment, so that the crystallization property is poor, the filtration is difficult, the impurity wrapping is serious, and the isomer content is high.
Disclosure of Invention
The present invention is directed to solve at least one of the problems of the prior art, and therefore, an aspect of the present invention is to provide a method for synthesizing high-purity promethazine hydrochloride, which comprises the following steps:
s1, synthesizing N, N-dimethyl isopropanolamine:
adding toluene into a reaction kettle, adding propylene oxide under the stirring state, cooling, dropwise adding a dimethylamine aqueous solution, keeping the temperature and continuously stirring after dropwise adding, adding a sodium hydroxide solution after the reaction is finished, stirring again, separating liquid, keeping a toluene layer, concentrating a toluene phase under vacuum, adding anhydrous calcium chloride after concentrating, drying, and filtering to obtain a toluene solution of N, N-dimethyl isopropanolamine;
s2, synthesizing N, N-dimethylamino chloropropane:
adding a chlorinating agent and toluene into a reaction kettle, cooling, stirring and dropwise adding the toluene solution of N, N-dimethyl isopropanolamine prepared in the step S1, heating, stirring and reacting, cooling after the reaction is finished, dropwise adding purified water, stirring, standing, separating liquid, retaining a water layer, adding toluene and sodium chloride solid into the water layer again, adjusting the pH by using a sodium hydroxide solution, stirring, separating liquid, retaining the toluene layer, adding anhydrous calcium chloride for drying, and filtering to obtain the toluene solution of N, N-dimethylamino chloropropane;
s3, synthesis of promethazine oxalate:
adding toluene and phenothiazine into a reaction kettle, stirring, adding sodium hydroxide solid, heating, refluxing and dividing water, reducing the temperature after dividing water, dropwise adding a toluene solution of N, N-dimethylamino chloropropane prepared in S2, continuing to reflux, reducing the temperature after reaction, dropwise adding purified water, stirring, dividing the liquid, retaining a toluene layer, washing the toluene layer to be neutral by using hot water, concentrating to be dry, adding a solvent, heating, adding acid to adjust the pH value, keeping the temperature and stirring, cooling, crystallizing, filtering and drying to obtain promethazine oxalate;
s4, synthesis of promethazine hydrochloride:
adding methylbenzene and purified water into a reaction kettle, adding promethazine oxalate prepared in S3 under the stirring state, adjusting pH, separating liquid, retaining a methylbenzene layer, washing the methylbenzene layer, adding activated carbon for decoloring, filtering, concentrating to dry, adding acetone, transferring into a brown bottle, heating, introducing hydrochloric acid gas to adjust pH, stirring, cooling, continuously stirring, filtering, and drying in vacuum to obtain a finished promethazine hydrochloride product.
Preferably, the mass ratio of toluene, propylene oxide, dimethylamine aqueous solution and sodium hydroxide solution in S1 is 3.0-3.5:1.0:2.0-2.2:1.5-1.7; the concentration of the sodium hydroxide solution was 40%.
Preferably, the temperature of the S1 is reduced to below 30 ℃, and a dimethylamine aqueous solution is dripped, and after the dripping, the temperature is kept at 10-30 ℃ and the stirring is continuously carried out for 2-4 h; concentrating toluene phase under 0.08Mpa for 30min, adding anhydrous calcium chloride, and drying for 2 hr.
Preferably, the chlorinating agent in S2 is thionyl chloride.
Preferably, the mass ratio of the thionyl chloride to the toluene solution of the N, N-dimethyl isopropanolamine in the S2 is 0.5-0.55:1.0-1.2:1.0; the concentration of the sodium hydroxide solution was 30%.
Preferably, the temperature of the S2 is reduced to 20-30 ℃, the toluene solution of N, N-dimethyl isopropanolamine is stirred and dripped, after the dripping is finished, the temperature is increased to 45-75 ℃, the stirring reaction is carried out for 2-6 h, after the reaction is finished, the temperature is reduced to below 15 ℃, purified water is dripped, and the stirring is carried out for 30min; adjusting pH to 12-14 with sodium hydroxide, and stirring for 30min; adding anhydrous calcium chloride, and drying for 2 hr.
Preferably, the solvent in S3 is methanol; the mass ratio of the phenothiazine to the toluene solution of N, N-dimethylamino chloropropane to the methanol is 1.0:4.3-4.7:3.0-4.0.
Preferably, the temperature in the S3 is raised to be higher than 110 ℃, reflux water diversion is carried out for 2 hours, after the water diversion is finished, the temperature is reduced to 95-100 ℃, a toluene solution of N, N-dimethylamino chloropropane is dripped, reflux reaction is carried out for 4 hours continuously, the temperature is reduced to 55-65 ℃ again, purified water is dripped, and stirring is carried out for 30 minutes; adding solvent, heating to 60 deg.C, adding oxalic acid to adjust pH to 3-4, keeping the temperature at 60 deg.C, stirring for 30min, cooling to 15-25 deg.C, and crystallizing for 2h.
Preferably, the mass ratio of toluene, purified water, promethazine oxalate and acetone in S4 is 3.0-4.0:2.0-3.0:1.0:2.5-3.0.
Preferably, ammonia water is used in the S4 to adjust the pH value to 11-12; adding activated carbon into the toluene layer for decoloring for 30min; heating to 35-45 deg.C, introducing hydrochloric acid gas to adjust pH to 3-4, stirring for 1h, cooling to 15 deg.C, stirring for 2h, filtering, and vacuum drying at 55 deg.C for 8h
The invention has the following beneficial effects:
the reaction condition of the first step of the invention is mild, the whole course is carried out at normal pressure, the post-treatment method is conventional liquid separation, high-pressure operation is not needed, the operation is simple, and the danger of high-pressure reaction by using an autoclave in the conventional synthesis process is avoided. The post-synthesis treatment of the N, N-dimethylamino chloropropane is simple, and the product can be obtained by simple alkali adjustment and extraction, so that the trouble that the product contains a large amount of water and is difficult to treat during the conventional normal-pressure reaction post-treatment is avoided; the product obtained in the second step has small molecular weight, is not easy to separate layers in water and toluene, about 10% of the product is dissolved in the water phase each time and is not extracted, the use of sodium chloride is increased, the concentration of salt ions in the water phase is increased, and the surface tension between the two phases is reduced, so that the liquid separation effect is good, the yield is improved, and the yield can be improved by more than 10%; in the third step, methanol is used as an impurity removal solvent for synthesizing the promethazine oxalate, so that the problems of salt caking in toluene, serious impurity wrapping and difficult washing are solved, the high-temperature salification property of the methanol is loose and easy to filter, the impurity removal effect is good, the product purity is further improved, and the product isomers are reduced.
The method has the advantages of cheap and easily-obtained raw materials, less three wastes, environmental protection, no use of heavy metal catalyst, no drug safety risk caused by excessive heavy metal in the finished product, no high-temperature high-pressure reaction, mild reaction conditions, simple required equipment, convenience in operation, good controllability and suitability for large-scale industrial production.
Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a gas phase detection spectrum of N, N-dimethylisopropanolamine prepared in the first step of the example of the present invention;
FIG. 2 is a gas-phase detection spectrum of N, N-dimethylamino chloropropane prepared in step two of the example of the invention;
FIG. 3 is a liquid phase detection chromatogram of promethazine oxalate prepared in step three of the example of the invention;
FIG. 4 is a liquid phase detection chromatogram of promethazine oxalate prepared in step three of the comparative example of the present invention;
FIG. 5 is a liquid phase detection spectrum of promethazine hydrochloride prepared in the example of the present invention;
FIG. 6 is a liquid phase detection spectrum of currently available promethazine hydrochloride.
Detailed Description
In order that the above objects, features and advantages of the present invention can be more clearly understood, a more particular description of the invention, taken in conjunction with the accompanying drawings and detailed description thereof, is provided below. It should be noted that the embodiments and features of the embodiments of the present application may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced otherwise than as specifically described and thus the scope of the present invention is not limited by the specific embodiments disclosed below.
Example one
The method comprises the following steps: synthesis of N, N-dimethylisopropanolamine
Adding 300g of toluene into a 1000ml reaction bottle, adding 100g of propylene oxide while stirring, cooling to below 30 ℃, controlling the temperature to below 30 ℃, dropwise adding 212.85g of dimethylamine aqueous solution, keeping the temperature at 15-25 ℃, stirring for 4h, after the reaction is finished, adding 160g of sodium hydroxide solution (the concentration is 40%), stirring for 30min, standing for liquid separation, keeping a toluene layer, concentrating the toluene phase under the vacuum of 0.08MPa for 30min, after the concentration is finished, adding 20g of anhydrous calcium chloride, drying for 2h, and filtering to obtain the toluene solution of N, N-dimethyl isopropanolamine, increasing the weight of 172.95g, the mass yield of 3763 zxft And the weight of 3763% (calculated by the weight of the toluene phase), wherein the gas phase detection spectrum is shown in figure 1, and the results are shown in the following table 1.
| Retention time | Types of | Peak width (min) | Peak area | Crest planeVolume% | Height | Degree of separation | Name of impurity |
| 2.493 | BB | 1.13 | 378117 | 0.767 | 20094 | Dimethylamine | |
| 7.418 | BV | 1.62 | 48110436 | 97.648 | 7193791 | 19.54 | |
| 11.700 | BV | 0.86 | 747555 | 1.517 | 96391 | 23.13 | Isomers |
| 36.264 | BB | 0.36 | 19203 | 0.039 | 2831 | 133.00 | |
| 40.466 | BV | 0.40 | 14157 | 0.029 | 1562 | 20.25 | |
| Sum of | 49269468 |
TABLE 1 gas phase assay of N, N-dimethylisopropanolamine
Step two: synthesis of N, N-dimethylamino chloropropane
259.00g of thionyl chloride and 520.25g of toluene are added into a 2000ml reaction bottle, the temperature is reduced to 10-30 ℃ by stirring, 472.95gN, N-dimethyl isopropanolamine toluene solution is dropwise added under controlled temperature, the temperature is raised to 60 ℃ and stirring is carried out for 4h after the dropwise addition is finished, the temperature is reduced to below 15 ℃ after the reaction is finished, 518.85g of purified water is dropwise added, the mixture is stirred for 30min, standing and liquid separation is carried out, an aqueous layer is reserved, 520.25g of toluene and 42.23g of sodium chloride solid are added into the aqueous layer again, the pH is adjusted to 12-14 by 30% of sodium hydroxide, the mixture is stirred for 30min, liquid separation is carried out, the toluene layer is reserved, 20g of anhydrous calcium chloride is added, drying is carried out for 2h, and filtration is carried out to obtain a toluene solution of N, N-dimethylamino chloropropane, the weight is increased by 175.75g, the mass yield is 101.62% (calculated by the toluene phase), a gas phase weight increase is shown in figure 2, and the results are shown in the following table 2.
| Retention time | Types of | Peak width (min) | Peak area | Peak area% | Height | Degree of separation | Name of impurity |
| 5.857 | BV | 0.71 | 23266838 | 99.376 | 2105788 | ||
| 7.442 | BB | 0.34 | 12071 | 0.052 | 2042 | 7.10 | |
| 8.566 | VB | 0.50 | 134035 | 0.572 | 19694 | 6.74 | Isomers |
| Sum of | 23412944 |
TABLE 2 gas-phase detection results of N, N-dimethylamino chloropropane
Step three: synthesis of promethazine oxalate
Adding 465g of toluene and 155g of phenothiazine into a 2000ml reaction bottle, stirring, adding 116.25g of sodium hydroxide solid, heating to above 110 ℃, refluxing and water dividing for 2h, cooling to about 100 ℃ after water dividing is finished, dropwise adding 694.6g of toluene solution of N-dimethylamino chloropropane, continuing heating and refluxing for 4h, monitoring the reaction by TLC, cooling to 60 ℃, dropwise adding 465g of purified water, stirring for 30min, separating, reserving toluene layers, washing the toluene layers twice by using hot water, 465g each time, concentrating the toluene layers to be dry after washing is finished, adding 620g of methanol, heating to 60 ℃, adjusting the pH to 3-4 by using 69.82g of oxalic acid, stirring for 30min at 60 ℃, cooling to 15-25 ℃, insulating and crystallizing for 2h, filtering, drying to obtain 203g of promethazine oxalate, the mass yield of 130.97%, wherein a liquid phase detection map is shown in the following table 3.
| Retention time | Type (B) | Peak width (min) | Peak area | Peak area% | Height | Degree of separation | Name of impurity |
| 0.926 | BBA | 0.44 | 149.153 | 0.507 | 34.950 | Oxalic acid | |
| 27.348 | BB | 11.55 | 28901.844 | 98.300 | 400.776 | 38.64 | |
| 44.755 | BB | 4.89 | 25.695 | 0.883 | 3.675 | 11.35 | Isomers |
| 55.144 | BB | 6.70 | 90.162 | 0.307 | 0.469 | 2.91 | |
| Sum of | 29400.854 |
TABLE 3 liquid-phase detection of promethazine oxalate synthesis using methanol as solvent
Step four: synthesis of promethazine hydrochloride
Adding 710.5g of toluene and 507.5g of purified water into a 2000ml reaction bottle, adding 203g of promethazine oxalate under stirring, adjusting the pH to 11-12 by using 70.00g of ammonia water, heating to 60 ℃, stirring for 30min, separating, retaining a toluene layer, washing the toluene layer with water, decoloring, filtering, concentrating to be dry, adding 609g of acetone, transferring to a 2000ml brown bottle, heating to 35-45 ℃, introducing hydrochloric acid gas to adjust the pH to 3-4, stirring for 1h, cooling to 15 ℃, continuing stirring for 2h, filtering, vacuum drying at 55 ℃ for 8h to obtain 130.47g of promethazine hydrochloride, wherein the HPLC purity is 99.95%, the isomer is 0.05%, and the liquid phase detection spectrum is shown in figure 5, and the results are shown in the following table 4.
| Retention time | Types of | Peak width (min) | Peak area | Peak area% | Height | Degree of separation | Name of impurity |
| 10.604 | BV | 1.09 | 4.238 | 0.012 | 0.156 | Impurity A | |
| 25.269 | BB | 11.40 | 34820.709 | 99.939 | 536.070 | 15.96 | Promethazine |
| 41.788 | BB | 2.84 | 16.936 | 0.049 | 0.262 | 11.54 | Isomers |
| Sum of | 34841.883 |
TABLE 4 promethazine hydrochloride liquid phase assay results
Example two
The method comprises the following steps: synthesis of N, N-dimethyl isopropanolamine
Adding 350g of toluene into a 1000ml reaction bottle, adding 100g of propylene oxide under stirring, cooling to below 30 ℃, controlling the temperature to below 30 ℃, dropwise adding 220g of dimethylamine aqueous solution, finishing dropwise adding, keeping the temperature at 15-25 ℃, stirring for 4h, finishing the reaction, adding 150g of sodium hydroxide solution (the concentration is 40%), stirring for 30min, standing, separating, retaining a toluene layer, concentrating the toluene phase under the vacuum of 0.08MPa for 30min, finishing concentration, adding 25g of anhydrous calcium chloride, drying for 2h, filtering to obtain the toluene solution of N, N-dimethyl isopropanolamine, increasing the weight by 165.33g, obtaining the mass yield by 165.33% (calculated by the weight increase of the toluene phase), and detecting the map by gas phase as shown in figure 1.
Step two: synthesis of N, N-dimethylamino chloropropane
Adding 255.90g of thionyl chloride and 558.40g of toluene into a 2000ml reaction bottle, stirring and cooling to 10-30 ℃, dropwise adding 465.33gN, N-dimethyl isopropanolamine toluene solution under controlled temperature, heating to 60 ℃, stirring and reacting for 4h, cooling to below 15 ℃, dropwise adding 518.85g of purified water, stirring for 30min, standing and separating, retaining an aqueous layer, adding 496g of toluene and 41.37g of sodium chloride solid into the aqueous layer again, adjusting the pH to 12-14 by using 30% of sodium hydroxide, stirring for 30min, separating, retaining the toluene layer, adding 25g of anhydrous calcium chloride, drying for 2h, filtering to obtain a toluene solution of N, N-dimethylamino chloropropane, increasing the weight by 180.45g, obtaining the mass yield of 109.12% (calculated by the weight gain of the toluene phase), and obtaining a gas phase detection map as shown in figure 2.
Step three: synthesis of promethazine oxalate
Adding 450g of toluene and 150g of phenothiazine into a 2000ml reaction bottle, stirring, adding 112.5g of sodium hydroxide solid, heating to above 110 ℃, refluxing and water-dividing for 6h, cooling to about 100 ℃, dropwise adding 676.45gN, N-dimethylamino chloropropane toluene solution, continuing heating and refluxing for 4h, monitoring the reaction by TLC, cooling to 60 ℃, dropwise adding 450g of purified water, stirring for 30min, separating, keeping the toluene layer, washing the toluene layer twice by hot water, each time for 450g, concentrating the toluene layer to be dry after washing is finished, adding 600g of methanol, heating to 60 ℃, adjusting the pH to 3-4 by 67.56g of oxalic acid, keeping the temperature for 60 ℃, stirring for 30min, cooling to 15-25 ℃, keeping the temperature and crystallizing for 2h, filtering, drying to obtain 210g of promethazine oxalate, the mass yield of 140%, and detecting the liquid phase pattern as shown in figure 3.
Step four: synthesis of promethazine hydrochloride
630g of toluene and 525g of purified water are added into a 2000ml reaction bottle, 210g of promethazine oxalate is added under stirring, the pH is adjusted to 11-12 by using 78.00g of ammonia water, the temperature is increased to 60 ℃, the mixture is stirred for 30min, liquid separation is carried out, a toluene layer is kept, the toluene layer is washed by water and decolored, filtered and concentrated to be dry, 609g of acetone is added, the mixture is transferred into a 2000ml brown bottle, the temperature is increased to 35-45 ℃, hydrochloric acid gas is introduced to adjust the pH to 3-4, the mixture is stirred for 1h, the temperature is reduced to 15 ℃, the mixture is continuously stirred for 2h, filtered, vacuum drying is carried out at 55 ℃ for 8h, and then promethazine hydrochloride 130.47g is obtained, and the liquid phase detection spectrum is shown in figure 5.
Comparative example
The method comprises the following steps: synthesis of N, N-dimethyl isopropanolamine
Adding 350g of toluene into a 1000ml reaction bottle, adding 100g of propylene oxide under stirring, cooling to below 30 ℃, controlling the temperature to below 30 ℃, dropwise adding 220g of dimethylamine aqueous solution, finishing dropwise adding, keeping the temperature at 15-25 ℃, stirring for 4h, finishing the reaction, adding 150g of sodium hydroxide solution (the concentration is 40%), stirring for 30min, standing, separating, retaining a toluene layer, concentrating the toluene phase under the vacuum of 0.08MPa for 30min, finishing concentration, adding 25g of anhydrous calcium chloride, drying for 2h, filtering to obtain the toluene solution of N, N-dimethyl isopropanolamine, increasing the weight by 165.33g, obtaining the mass yield by 165.33% (calculated by the weight increase of the toluene phase), and detecting the map by gas phase as shown in figure 1.
Step two: synthesis of N, N-dimethylamino chloropropane
Adding 255.90g of thionyl chloride and 558.40g of toluene into a 2000ml reaction bottle, stirring and cooling to 10-30 ℃, dropwise adding 465.33gN, N-dimethyl isopropanolamine toluene solution under controlled temperature, heating to 60 ℃, stirring and reacting for 4h, cooling to below 15 ℃, dropwise adding 518.85g of purified water, stirring for 30min, standing and separating, retaining an aqueous layer, adding 496g of toluene and 41.37g of sodium chloride solid into the aqueous layer again, adjusting the pH to 12-14 by using 30% of sodium hydroxide, stirring for 30min, separating, retaining the toluene layer, adding 25g of anhydrous calcium chloride, drying for 2h, filtering to obtain a toluene solution of N, N-dimethylamino chloropropane, increasing the weight by 180.45g, obtaining the mass yield of 109.12% (calculated by the weight gain of the toluene phase), and obtaining a gas phase detection map as shown in figure 2.
Step three: synthesis of promethazine oxalate
Adding 450g of toluene and 150g of phenothiazine into a 2000ml reaction bottle, stirring, adding 112.5g of sodium hydroxide solid, heating to above 110 ℃, refluxing and water-dividing for 6h, cooling to about 100 ℃, dropwise adding 676.45gN, N-dimethylamino chloropropane toluene solution, continuing heating and refluxing for 4h, monitoring the completion of the TLC reaction, cooling to 60 ℃, dropwise adding 450g of purified water, stirring for 30min, separating, keeping the toluene layer, washing the toluene layer twice with hot water, 450g each time, after washing, adding 600g of purified water, heating to 60 ℃, adjusting the pH to 3-4 with 67.56g of oxalic acid, keeping the temperature for 60 ℃, stirring for 30min, cooling to 15-25 ℃, keeping the temperature and crystallizing for 2h, filtering, drying to obtain 210g of promethazine oxalate, the mass yield of 140%, and the liquid phase detection pattern is shown in the figure 4, wherein the results are shown in the following table 5.
| Retention time | Type (B) | Peak width (min) | Peak area | Peak area% | Height | Degree of separation | Name of impurity |
| 11.087 | VB | 1.28 | 16.944 | 0.053 | 0.669 | ||
| 21.027 | VB | 1.76 | 20.092 | 0.063 | 0.534 | 12.17 | |
| 26.766 | BB | 12.62 | 30460.046 | 95.228 | 444.515 | 5.24 | |
| 42.671 | BB | 5.20 | 1489.446 | 4.656 | 22.412 | 11.00 | Isomers |
| Sum of | 31986.528 |
TABLE 5 liquid-phase detection of promethazine oxalate synthesis using toluene as solvent
Step four: synthesis of promethazine hydrochloride
630g of toluene and 525g of purified water are added into a 2000ml reaction bottle, 210g of promethazine oxalate is added under stirring, the pH is adjusted to 11-12 by using 78.00g of ammonia water, the temperature is increased to 60 ℃, the mixture is stirred for 30min, liquid separation is carried out, a toluene layer is kept, the toluene layer is washed by water and decolored, filtered and concentrated to be dry, 609g of acetone is added, the mixture is transferred into a 2000ml brown bottle, the temperature is increased to 35-45 ℃, hydrochloric acid gas is introduced to adjust the pH to 3-4, the mixture is stirred for 1h, the temperature is reduced to 15 ℃, the mixture is continuously stirred for 2h, filtered, vacuum drying is carried out at 55 ℃ for 8h, and then promethazine hydrochloride 130.47g is obtained, and the liquid phase detection spectrum is shown in figure 5.
Comparing the liquid phase detection spectrogram 3 of the embodiment of the invention with the liquid phase detection spectrogram 4 of the comparative example, the solvent synthesized by using methanol as promethazine oxalate has great improvement on related substances and isomers compared with the solvent using toluene as solvent, and the isomers meet the standard under the condition of not synthesizing promethazine tetrahydrochloride.
The liquid phase detection spectrum of the currently commercially available promethazine hydrochloride is shown in fig. 6, and the results are shown in table 6 below.
| Retention time | Types of | Peak width (min) | Peak area | Peak area% | Height | Degree of separation | Name of impurity |
| 2.614 | BB | 0.23 | 6.826 | 0.039 | 1.633 | Impurity D | |
| 11.706 | BV | 1.27 | 4.326 | 0.025 | 0.122 | 17.44 | Impurity A |
| 27.940 | BB | 13.97 | 17618.451 | 99.826 | 241.915 | 14.61 | Promethazine |
| 45.501 | VB | 3.02 | 19.505 | 0.111 | 0.265 | 10.77 | Isomers |
| Sum of | 17649.108 |
TABLE 6 liquid phase assay results for promethazine hydrochloride available on the market
Compared with the promethazine hydrochloride liquid phase detection chart 5 prepared by the embodiment of the invention, the promethazine hydrochloride isomer prepared by the invention has lower content and the purity can reach more than 99.9 percent.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and it is obvious to those skilled in the art that various modifications and variations can be made in the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthetic method of high-purity promethazine hydrochloride is characterized by comprising the following steps: the synthesis method comprises the following specific steps:
s1, synthesizing N, N-dimethyl isopropanolamine:
adding toluene into a reaction kettle, adding propylene oxide under the stirring state, cooling, dropwise adding a dimethylamine aqueous solution, keeping the temperature and continuously stirring after dropwise adding, adding a sodium hydroxide solution after the reaction is finished, stirring again, separating liquid, keeping a toluene layer, concentrating a toluene phase under vacuum, adding anhydrous calcium chloride after concentrating, drying, and filtering to obtain a toluene solution of N, N-dimethyl isopropanolamine;
s2, synthesizing N, N-dimethylamino chloropropane:
adding a chlorinating agent and toluene into a reaction kettle, cooling, stirring and dripping the toluene solution of the N, N-dimethyl isopropanolamine prepared in the step S1, after finishing dripping, heating, stirring and reacting, after finishing reacting, cooling, dripping purified water, stirring, standing, separating liquid, reserving a water layer, adding toluene and sodium chloride solid into the water layer again, adjusting the pH value by using a sodium hydroxide solution, stirring, separating liquid, reserving the toluene layer, adding anhydrous calcium chloride, drying, and filtering to prepare the toluene solution of the N, N-dimethylamino chloropropane;
s3, synthesis of promethazine oxalate:
adding toluene and phenothiazine into a reaction kettle, stirring, adding sodium hydroxide solid, heating, refluxing and dividing water, reducing the temperature after dividing water, dropwise adding a toluene solution of N, N-dimethylamino chloropropane prepared in S2, continuing to reflux, reducing the temperature after reaction, dropwise adding purified water, stirring, dividing the liquid, retaining a toluene layer, washing the toluene layer to be neutral by using hot water, concentrating to be dry, adding a solvent, heating, adding acid to adjust the pH value, keeping the temperature and stirring, cooling, crystallizing, filtering and drying to obtain promethazine oxalate;
s4, synthesis of promethazine hydrochloride:
adding methylbenzene and purified water into a reaction kettle, adding promethazine oxalate prepared in S3 under the stirring state, adjusting pH, separating liquid, retaining a methylbenzene layer, washing the methylbenzene layer, adding activated carbon for decoloring, filtering, concentrating to dry, adding acetone, transferring into a brown bottle, heating, introducing hydrochloric acid gas to adjust pH, stirring, cooling, continuously stirring, filtering, and drying in vacuum to obtain a finished promethazine hydrochloride product.
2. The method for synthesizing high-purity promethazine hydrochloride according to claim 1, wherein: the mass ratio of toluene, propylene oxide, dimethylamine aqueous solution and sodium hydroxide solution in S1 is 3.0-3.5:1.0:2.0-2.2:1.5-1.7; the concentration of the sodium hydroxide solution was 40%.
3. The method for synthesizing high-purity promethazine hydrochloride according to claim 1 or 2, wherein: cooling the temperature in the S1 to below 30 ℃, dropwise adding a dimethylamine aqueous solution, keeping the temperature at 10-30 ℃ after the dropwise adding is finished, and continuously stirring for 2-4 h; concentrating the toluene phase under 0.08Mpa for 30min, adding anhydrous calcium chloride, and drying for 2 hr.
4. The method for synthesizing high-purity promethazine hydrochloride according to claim 1, wherein the method comprises the following steps: and the chlorinating agent in the S2 is thionyl chloride.
5. The method for synthesizing high-purity promethazine hydrochloride according to claim 2, wherein: the mass ratio of the thionyl chloride to the toluene solution of N, N-dimethylisopropanolamine in the S2 is 0.5-0.55:1.0-1.2:1.0; the concentration of the sodium hydroxide solution was 30%.
6. The method for synthesizing high-purity promethazine hydrochloride according to claim 1 or 5, wherein: cooling to 20-30 ℃ in S2, stirring and dropwise adding a toluene solution of N, N-dimethyl isopropanolamine, heating to 45-75 ℃ after dropwise adding, stirring and reacting for 2-6 h, cooling to below 15 ℃ after the reaction is finished, dropwise adding purified water, and stirring for 30min; adjusting pH to 12-14 with sodium hydroxide, and stirring for 30min; adding anhydrous calcium chloride, and drying for 2 hr.
7. The method for synthesizing high-purity promethazine hydrochloride according to claim 1, wherein: the solvent in the S3 is methanol; the mass ratio of the toluene solution of phenothiazine and N, N-dimethylamino chloropropane to the methanol is 1.0:4.3-4.7:3.0-4.0.
8. The method for synthesizing high-purity promethazine hydrochloride according to claim 1 or 7, wherein the method comprises the following steps: heating to above 110 ℃ in the S3, refluxing and dividing water for 2h, cooling to 95-100 ℃ after water division is finished, dropwise adding a toluene solution of N, N-dimethylamino chloropropane, continuously refluxing and reacting for 4h, cooling to 55-65 ℃ again, dropwise adding purified water, and stirring for 30min; adding solvent, heating to 60 deg.C, adding oxalic acid to adjust pH to 3-4, keeping the temperature at 60 deg.C, stirring for 30min, cooling to 15-25 deg.C, and crystallizing for 2h.
9. The method for synthesizing high-purity promethazine hydrochloride according to claim 1, wherein: the mass ratio of toluene, purified water, promethazine oxalate and acetone in S4 is 3.0-4.0:2.0-3.0:1.0:2.5-3.0.
10. The method for synthesizing high-purity promethazine hydrochloride according to claim 1 or 9, wherein: in the S4, ammonia water is used for adjusting the PH value to 11-12; adding activated carbon into the toluene layer for decoloring for 30min; heating to 35-45 deg.C, introducing hydrochloric acid gas to adjust pH to 3-4, stirring for 1h, cooling to 15 deg.C, stirring for 2h, filtering, and vacuum drying at 55 deg.C for 8h.
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| CN104387338A (en) * | 2014-11-26 | 2015-03-04 | 千辉药业（安徽）有限责任公司 | Preparation method of promethazine hydrochloride |
| CN104610194A (en) * | 2014-10-30 | 2015-05-13 | 江苏宝众宝达药业有限公司 | Method for recovering promethazine oxalate from mother solution of hydrochloric acid |
| CN113292513A (en) * | 2021-05-25 | 2021-08-24 | 常州康普药业有限公司 | Preparation method of high-purity promethazine hydrochloride |
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| CN104610194A (en) * | 2014-10-30 | 2015-05-13 | 江苏宝众宝达药业有限公司 | Method for recovering promethazine oxalate from mother solution of hydrochloric acid |
| CN104387338A (en) * | 2014-11-26 | 2015-03-04 | 千辉药业（安徽）有限责任公司 | Preparation method of promethazine hydrochloride |
| CN113292513A (en) * | 2021-05-25 | 2021-08-24 | 常州康普药业有限公司 | Preparation method of high-purity promethazine hydrochloride |
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