CN118063369B - Preparation method of doxepin hydrochloride - Google Patents
Preparation method of doxepin hydrochloride Download PDFInfo
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- CN118063369B CN118063369B CN202410465622.5A CN202410465622A CN118063369B CN 118063369 B CN118063369 B CN 118063369B CN 202410465622 A CN202410465622 A CN 202410465622A CN 118063369 B CN118063369 B CN 118063369B
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- MHNSPTUQQIYJOT-SJDTYFKWSA-N Doxepin Hydrochloride Chemical compound Cl.C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 MHNSPTUQQIYJOT-SJDTYFKWSA-N 0.000 title claims abstract description 35
- 229960002861 doxepin hydrochloride Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 75
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 29
- 230000007062 hydrolysis Effects 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000002425 crystallisation Methods 0.000 claims abstract description 21
- 230000008025 crystallization Effects 0.000 claims abstract description 21
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 18
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 10
- 239000012044 organic layer Substances 0.000 claims abstract description 8
- 238000001556 precipitation Methods 0.000 claims abstract description 7
- CLRZIQGKTOQIDR-UHFFFAOYSA-N 2-(1-ethylpyrrolidin-3-yl)-2,2-diphenylacetonitrile Chemical compound C1N(CC)CCC1C(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 CLRZIQGKTOQIDR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010979 pH adjustment Methods 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 238000004821 distillation Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 8
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 230000029936 alkylation Effects 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- RQWLDFSUBLIEAS-UHFFFAOYSA-N BrCCC1C(C(N(C1)CC)=O)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound BrCCC1C(C(N(C1)CC)=O)(C1=CC=CC=C1)C1=CC=CC=C1 RQWLDFSUBLIEAS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 10
- 238000004440 column chromatography Methods 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 4
- 239000003651 drinking water Substances 0.000 description 10
- 235000020188 drinking water Nutrition 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960005426 doxepin Drugs 0.000 description 2
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BQKWGHPTGWFILN-UHFFFAOYSA-N 2-(1-ethylpyrrolidin-3-yl)-2,2-diphenylacetic acid Chemical compound C1N(CC)CCC1C(C(O)=O)(C=1C=CC=CC=1)C1=CC=CC=C1 BQKWGHPTGWFILN-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 210000001011 carotid body Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 108091008690 chemoreceptors Proteins 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- MBGXILHMHYLZJT-UHFFFAOYSA-N doxapram hydrochloride (anhydrous) Chemical group [Cl-].C=1C=CC=CC=1C1(C=2C=CC=CC=2)C(=O)N(CC)CC1CC[NH+]1CCOCC1 MBGXILHMHYLZJT-UHFFFAOYSA-N 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000001767 medulla oblongata Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application provides a preparation method of doxepin hydrochloride, which belongs to the technical field of pharmaceutical chemistry and comprises the following specific steps: s1, adding 2- (1-ethylpyrrolidine-3-yl) -2, 2-diphenylacetonitrile into sulfuric acid, performing two-stage hydrolysis to obtain a compound II, extracting an organic layer with dichloromethane and water, concentrating the organic layer, removing water by DMF (dimethyl formamide) distillation, cooling, crystallizing and filtering to obtain the compound II; s2, placing the compound II obtained in the step S1 in DMF, dropwise adding phosphorus tribromide for heating reaction, and obtaining a compound III through pH adjustment, precipitation and filtration; s3, dissolving the compound III obtained in the step S2 in a reaction solvent, adding sodium carbonate and morpholine for heating reaction, and obtaining the doxepin hydrochloride through salt formation crystallization and filtration. The method simplifies the post-treatment operation of hydrolysis and bromorearrangement process, does not need column chromatography purification of key intermediates, and improves the process production convenience.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of doxepin hydrochloride.
Background
The doxepin hydrochloride is a central nervous system stimulant, and can stimulate carotid body and aortic chemoreceptor reflex excitation medulla oblongata and cardiovascular center at small dose, and has stronger respiratory excitation effect than nikkimei, and large dose of excitation spinal cord and brain stem, but has no influence on cerebral cortex. The chemical name is 1-ethyl-3, 3-diphenyl-4- (2-morpholinoethyl) -2-pyrrolidone hydrochloride, and the structural formula is as follows:
。
CN201910343598.7 discloses a preparation method of doxepin and ketodoxepin, in the first hydrolysis stage, a large amount of hydrobromic acid or concentrated sulfuric acid is adopted to make high-temperature reaction, only small-sized experimental work is completed, in the preparation process, the preparation process also uses chloroform, acetic anhydride and other tube products, in the disclosed method, both hydrolysis and alkylation reactions need chromatographic column purification, the operation is complex, and the method is not suitable for industrial scale-up production. Therefore, the reaction process conditions are controlled, the process production convenience is improved, and the purification process is simplified, so that the method is suitable for the industrial scale-up production requirement.
Disclosure of Invention
In order to solve the defects in the prior art, the application provides the preparation method of the doxepin hydrochloride, which simplifies the post-treatment operation of hydrolysis and bromorearrangement process, improves the process production convenience, avoids the column chromatography purification of key intermediates and realizes the industrialized production of the doxepin hydrochloride.
In order to achieve the above object, the present invention adopts the following technique:
the preparation method of the doxepin hydrochloride comprises the following specific steps:
S1, hydrolysis: compound I:2- (1-ethyl-pyrrolidin-3-yl) -2, 2-diphenylacetonitrile was added to sulfuric acid and subjected to two-stage hydrolysis to give compound II:2- (1-ethyl pyrrolidine-3-yl) -2, 2-diphenyl acetic acid, extracting an organic layer by using dichloromethane and water after the reaction is finished, concentrating the organic layer, removing water by using DMF (dimethyl formamide) distillation, cooling, crystallizing and filtering to obtain a compound II, wherein the reaction formula of the obtained compound II is as follows:
s2, bromorearrangement: placing the compound II obtained in the step S1 in DMF, dropwise adding phosphorus tribromide for heating reaction, and obtaining a compound III through pH adjustment, precipitation and filtration: 1-ethyl-4- (2-bromoethyl) -3, 3-diphenylpyrrolidin-2-one, the reaction formula to give compound III is as follows:
s3, alkylation: dissolving the compound III obtained in the step S2 in a reaction solvent, adding sodium carbonate and morpholine for heating reaction, and obtaining the doxepin hydrochloride through salt formation crystallization and filtration, wherein the reaction formula of the doxepin hydrochloride is as follows:
。
Further, in the hydrolysis process of the two stages in the step S1, the feeding mass ratio of sulfuric acid and the compound I in the hydrolysis of the first stage is 2-5:1, the feeding mass ratio of water and the compound I is 1-3.5:1, the reaction temperature is 100-150 ℃, the feeding mass ratio of water and the compound I in the hydrolysis of the second stage is 3-8.5:1, and the reaction temperature is 90-115 ℃.
In the step S1, the volume ratio of dichloromethane to water used for extraction is 1:3.5-10, and the feeding mass ratio of DMF to the compound I is 2-10: 1, adopting DMF distillation to remove water at 80-120 ℃ and crystallization at 10-40 ℃.
Further, in the step S2, the molar feed ratio of phosphorus tribromide to compound II is 1 to 2.5:1, the reaction temperature is 25-85 ℃, and the feeding mass ratio of the reaction solvent DMF to the compound II is 3-10: 1.
In the step S2, the pH is adjusted to 3-6, then precipitation is carried out, and crystallization and filtration are carried out at 10-50 ℃.
Further, in the step S3, the molar feed ratio of sodium carbonate to the compound III is 1 to 3:1, the volume ratio of the reaction solvent to the compound III is 5-15: 1, the molar feed ratio of morpholine to compound III is 1.0-1.5: 1, the reaction temperature of the temperature-rising reaction is 50-80 ℃, and the molar feed ratio of hydrochloric acid to the compound III is 0.9-2.0: 1, the salifying temperature is 30-55 ℃, and the volume ratio of a salifying solvent to a compound III used in salifying crystallization is 3-12: 1.
Further, in step S3, the reaction solvent is one or more of acetonitrile, ethanol, tetrahydrofuran, and DMF.
In step S3, the salifying solvent used in salifying crystallization is one or more of acetone, ethanol, isopropanol and acetonitrile.
Further, the feeding mass ratio of sulfuric acid and the compound I in the first stage hydrolysis is 3.5:1, the feeding mass ratio of water and the compound I is 2:1, the reaction temperature is 120-130 ℃, the feeding mass ratio of water and the compound I in the second stage hydrolysis is 5.5:1, the reaction temperature is 100-105 ℃, the volume ratio of dichloromethane and water used for extraction is 2:10, and the feeding mass ratio of DMF and the compound I is 5: the distilled water removal temperature of the 1 DMF is 100-105 ℃, and the crystallization temperature is 20-25 DEG C
Further, in step S2, the molar feed ratio of phosphorus tribromide to compound II is 1.5:1, the reaction temperature is 60-65 ℃, and the mass ratio of DMF to compound II is 7:1, adjusting the pH value to 5, precipitating, and crystallizing and filtering at 25-30 ℃.
Further, in step S3, the molar feed ratio of sodium carbonate to compound III is 1.5:1, the volume ratio of the reaction solvent to the compound III is 7:1, molar feed ratio of morpholine to compound III is 1.2:1, the reaction temperature of the temperature-rising reaction is 60-65 ℃, and the molar feed ratio of hydrochloric acid to the compound III is 1.2:1, the salifying temperature is 40-45 ℃, and the volume ratio of a salifying solvent to a compound III used in salifying crystallization is 8:1.
Further, the reaction solvent is acetonitrile, and the salifying solvent is acetone.
The invention has the beneficial effects that: the post-treatment operation of hydrolysis and bromorearrangement process is simplified, the process production convenience is improved, the column chromatography purification of key intermediates is avoided, the purity measured by HPLC reaches more than 99.9%, and the industrial production of doxepin hydrochloride is realized.
Drawings
Fig. 1 is an HPLC profile of doxepin hydrochloride in example 1.
Fig. 2 is an HPLC profile of doxepin hydrochloride in example 2.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the following detailed description of the embodiments of the present invention will be given with reference to the accompanying drawings, but the described embodiments of the present invention are some, but not all embodiments of the present invention.
The embodiment of the application provides a preparation method of doxepin hydrochloride, which comprises the following steps of hydrolysis, bromorearrangement and alkylation:
s1, hydrolysis: compound I:2- (1-ethyl-pyrrolidin-3-yl) -2, 2-diphenylacetonitrile was added to sulfuric acid and subjected to two-stage hydrolysis to give compound II: extracting an organic layer of 2- (1-ethylpyrrolidine-3-yl) -2, 2-diphenyl acetic acid with dichloromethane and water after the reaction is finished, concentrating the organic layer, distilling with DMF to remove water, cooling for crystallization, and filtering to obtain a compound II;
Compared with the prior art that a large amount of hydrobromic acid or concentrated sulfuric acid is adopted for high-temperature reaction to carry out hydrolysis, the step carries out cyano hydrolysis in two stages, and the second-stage hydrolysis reaction can be carried out after the reaction temperature is reduced by only adding water to dilute the reaction solution on the basis of the first-stage hydrolysis. By the method, the reaction of the original high-concentration strong acid and the high temperature can be completed under the conditions of dilute acid and low temperature, the occurrence of side reactions and degradation reactions can be reduced, and the post-treatment operation is simplified. And the white crystal compound II can be more conveniently obtained by adopting DMF concentration for water removal and cooling crystallization, the condition that the product after the reaction reported in the patent with the application number of CN201910343598.7 is black viscous oily matter and column chromatography purification is required can be avoided, and the industrial production is more facilitated.
S2, bromorearrangement: placing the compound II obtained in the step S1 in DMF, dropwise adding phosphorus tribromide for heating reaction, and obtaining a compound III through pH adjustment, precipitation and filtration: 1-ethyl-4- (2-bromoethyl) -3, 3-diphenylpyrrolidin-2-one;
the reaction system and the post-treatment process are improved in the step: DMF is adopted as the reaction solvent, so that the use of pipe products such as chloroform, acetic anhydride and the like can be avoided. After the reaction is finished, alkali is directly added into the reaction liquid in a dropwise manner to carry out pH adjustment, so that the yellowish-white compound III can be precipitated, the post-treatment operation is simplified, the residual compound II is effectively removed, and the industrial production is facilitated.
S3, alkylation: dissolving the compound III obtained in the step S2 in a reaction solvent, adding sodium carbonate and morpholine for heating reaction, and obtaining the doxepin hydrochloride through salt formation crystallization and filtration, wherein the reaction formula of the doxepin hydrochloride is as follows:
。
The step optimizes the crystallization solvent, and in the salting-out crystallization process, white doxepin hydrochloride can be separated out under the reflux state without free alkali column chromatography purification, so that the impurity removal efficiency is high, the HPLC purity of the generated doxepin hydrochloride is more than 99.9%, and the yield is more than 80%, thereby being more beneficial to industrial production.
Example 1
(1) Hydrolysis: 8.0kg of drinking water and 14.0kg of concentrated sulfuric acid are stirred and mixed uniformly, 4.0kg of compound I is added, and the mixture is heated to 130 ℃ for reaction for 12 hours; slowly adding 21.5kg of drinking water, and controlling the temperature to be 105 ℃ for reaction for 24 hours; cooling to 20+ -5deg.C, adding 40.0kg of drinking water and 7.0kg of dichloromethane, extracting, separating liquid, and discarding water phase. The organic phase was concentrated below 50 ℃ to no distinct droplets. Adding 20.0kg of DMF, heating to 100-105 ℃ for concentrating and removing water, cooling and crystallizing after the concentrated solution is turbid, and filtering to obtain 3.55kg of compound II with the yield of 83.3%.
(2) Bromorearrangement: mixing 18.0kg of DMF and 3.5kg of compound II under stirring, vacuumizing and protecting with nitrogen, dropwise adding 1.89kg of phosphorus tribromide, and reacting for about 1h at the temperature of 60-65 ℃; and adding alkali dropwise into the reaction solution to adjust the pH to about 5. Cooling to 25 ℃, stirring and crystallizing for more than 3 hours, centrifuging, and drying to obtain 3.8kg of compound III, wherein the yield is 90.2%.
(3) Alkylation: 3.8kg of compound III, 21.0kg of acetonitrile, 1.6kg of sodium carbonate and 1.1kg of morpholine are mixed and stirred, and reacted for more than 5 hours at 65 ℃. Cooling to 25+ -5deg.C, adding 19.0kg of drinking water and 11.5kg of ethyl acetate, extracting and separating, washing organic phase with 7.6kg of drinking water, and separating; the organic phase is concentrated at 65 ℃ to obtain a crude product, 25.0kg of acetone is added for dissolution, 1.26kg of concentrated hydrochloric acid is added dropwise to the temperature of 45 ℃ for salifying, crystallization and centrifugation are carried out to obtain 3.8kg of doxepin hydrochloride, the yield is 89.3%, and the HPLC purity is 99.9%.
Example 2
(1) 27.2Kg of drinking water and 48.9kg of concentrated sulfuric acid are stirred and mixed uniformly, 13.58kg of compound I is added, and the mixture is heated to 125+/-5 ℃ for reaction for 10 hours; slowly adding 73.3kg of drinking water, and controlling the temperature to be 100-105 ℃ for reaction for 24 hours; cooling to 20+ -5deg.C, adding 136.0kg of drinking water and 36kg of dichloromethane, extracting, separating liquid, and discarding water phase. The organic phase was concentrated below 50 ℃ to no distinct droplets. 68kg of DMF is added, the temperature is raised to 100-105 ℃ for concentrating and dewatering, and after the concentrated solution is turbid, the temperature is reduced for crystallization and filtration, 12.6kg of compound II is obtained, and the yield is 87.1%.
(2) 84Kg of DMF and 12.0kg of compound II are stirred and mixed, the mixture is vacuumized and protected by nitrogen, 6.5kg of phosphorus tribromide is added dropwise, and the temperature is controlled to be 60-65 ℃ for reaction for about 1h; and adding alkali dropwise into the reaction solution to adjust the pH to about 5. Cooling to 25-30 ℃, stirring and crystallizing for more than 3 hours, centrifuging, and drying to obtain 13.2kg of compound III with the yield of 91.4%.
(3) 13Kg of compound III, 72kg of acetonitrile, 5.5kg of sodium carbonate and 3.6kg of morpholine are mixed and stirred, and the mixture is reacted for more than 5 hours at the temperature of 60-65 ℃. Cooling to 25+/-5 ℃, adding 65kg of drinking water and 39kg of ethyl acetate for extraction and liquid separation, and washing an organic phase with 26kg of drinking water for liquid separation; concentrating the organic phase at 65 ℃ to obtain a crude product, adding 83kg of acetone for dissolution, heating to 40-45 ℃, dropwise adding 4.3kg of concentrated hydrochloric acid to form a salt, crystallizing, and centrifuging to obtain 12.3kg of doxepin hydrochloride, wherein the yield is 84.6%, and the HPLC purity is 100%.
Comparative examples
50G of 2- (1-ethylpyrrolidine-3-yl) -2, 2-diphenylacetonitrile is added into 350 ml of 85% sulfuric acid, the reaction solution is heated to 130 ℃ for 4 hours, the system gradually becomes clear solution, then the reaction is continued to be heated to 150 ℃ for 44 hours, the system becomes black, and no precipitation exists after cooling and standing, so that the solution cannot be separated. After addition of dichloromethane extract and separation, the aqueous phase was discarded, and the oil layer was collected, washed 3 times with 500 ml of water each time. The organic phase was dried over anhydrous sodium sulfate, and then filtered and dried to give a crude product as a black oil. Purification by column chromatography gave 36 g of solid compound II in about 65% yield.
32 G of compound II is dissolved in 800 ml of chloroform, 82.4 g of phosphorus tribromide is added under ice bath, then the temperature is raised to 85 ℃ for reaction for 12 hours, the reaction solution is concentrated to dryness under reduced pressure, and then 33 g of compound III is obtained after recrystallization and purification by methanol, and the yield is about 85%.
10.4 G of morphine was dissolved in 300 ml of N, N-dimethylacetamide, 4.8 mg of 60% sodium hydroxide was added under ice bath, then, after 30 minutes of reaction at room temperature, 30 g of compound III was added, and after 8 hours of reaction at 65 ℃, the reaction solution was poured into 1500 ml of ice water, extracted 3 times with 1500 ml of ethyl acetate, and after the organic phase was combined, washed with 1500 ml of saturated saline water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. Column chromatography of the crude product gave doxepin, dissolving the free product in diethyl ether, adding a ethereal solution of hydrogen chloride to ph=1, then stirring for 30 minutes under ice bath, and suction filtration of the precipitated solid gave doxepin hydrochloride 23.8 g in about 71% yield.
The present invention makes comparative analysis on the yields of doxepin hydrochloride in the above examples and comparative examples, and the results are shown in the following table:
| Example 1 | Example 2 | Comparative examples |
| 90.2% | 84.6% | 71% |
The comparison shows that the yield of the doxepin hydrochloride synthesized by the method is relatively high, and the purities of the example 1 and the example 2 reach 99.9 percent and 100 percent respectively by referring to the figures 1 and 2, so that the method is suitable for industrial production. Meanwhile, the method simplifies the post-treatment operation of hydrolysis and bromorearrangement process, can improve the process production convenience, does not need column chromatography purification of key intermediates, enhances the production safety, reduces the environmental pollution, and makes the synthesis method of the doxepin hydrochloride more suitable for industrial production compared with the existing synthesis method.
The foregoing description of the preferred embodiments of the invention is merely exemplary and is not intended to be exhaustive or limiting of the invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention.
Claims (8)
1. The preparation method of the doxepin hydrochloride is characterized by comprising the following specific steps:
S1, hydrolysis: compound I:2- (1-ethyl-pyrrolidin-3-yl) -2, 2-diphenylacetonitrile was added to sulfuric acid and subjected to two-stage hydrolysis to give compound II:2- (1-ethyl pyrrolidine-3-yl) -2, 2-diphenyl acetic acid, extracting an organic layer by using dichloromethane and water after the reaction is finished, concentrating the organic layer, removing water by using DMF (dimethyl formamide) distillation, cooling, crystallizing and filtering to obtain a compound II, wherein the reaction formula of the obtained compound II is as follows:
；
s2, bromorearrangement: placing the compound II obtained in the step S1 in DMF, dropwise adding phosphorus tribromide for heating reaction, and obtaining a compound III through pH adjustment, precipitation and filtration: 1-ethyl-4- (2-bromoethyl) -3, 3-diphenylpyrrolidin-2-one, the reaction formula to give compound III is as follows:
；
S3, alkylation: dissolving the compound III obtained in the step S2 in a reaction solvent, adding sodium carbonate and morpholine for heating reaction, and obtaining the doxepin hydrochloride through salt formation crystallization and filtration, wherein the reaction formula of the doxepin hydrochloride is as follows:
；
In the hydrolysis process of the two stages in the step S1, the feeding mass ratio of sulfuric acid and the compound I in the hydrolysis of the first stage is 2-5:1, the feeding mass ratio of water and the compound I is 1-3.5:1, the reaction temperature is 100-150 ℃, the feeding mass ratio of water and the compound I in the hydrolysis of the second stage is 3-8.5:1, and the reaction temperature is 90-115 ℃;
in the step S2, the pH is regulated to 3-6, then precipitation is carried out, and crystallization and filtration are carried out at 10-50 ℃.
2. The process for preparing doxepin hydrochloride according to claim 1, wherein in step S1, the volume ratio of dichloromethane to water used for extraction is 1: 3.5-10, wherein the mass ratio of DMF to the compound I is 2-10: the distilled water removal temperature of the DMF is 80-120 ℃ and the crystallization temperature is 10-40 ℃.
3. The method for preparing doxepin hydrochloride according to claim 1, wherein in step S2, the molar ratio of phosphorus tribromide to compound II is 1-2.5: 1, the reaction temperature is 25-85 ℃, and the feeding mass ratio of the reaction solvent DMF to the compound II is 3-10: 1.
4. The method for preparing doxepin hydrochloride according to claim 1, wherein in step S3, the molar feed ratio of sodium carbonate to compound III is 1-3: 1, the volume ratio of the reaction solvent to the compound III is 5-15: 1, the molar feed ratio of morpholine to compound III is 1.0-1.5: 1, the reaction temperature of the heating reaction is 50-80 ℃, and the molar feed ratio of hydrochloric acid added during salification to the compound III is 0.9-2.0: 1, the salifying temperature is 30-55 ℃, and the volume ratio of a salifying solvent to a compound III used in salifying crystallization is 3-12: 1.
5. The method for preparing doxepin hydrochloride according to claim 2, wherein the mass ratio of sulfuric acid to compound I in the first stage hydrolysis is 3.5:1, the mass ratio of water to compound I is 2:1, the reaction temperature is 120 ℃ to 130 ℃, the mass ratio of water to compound I in the second stage hydrolysis is 5.5:1, the reaction temperature is 100 ℃ to 105 ℃, the volume of dichloromethane to water used in extraction is 2:10, and the mass ratio of DMF to compound I is 5: the distilled water removal temperature of the DMF is 100-105 ℃ and the crystallization temperature is 20-25 ℃.
6. The process for the preparation of doxepin hydrochloride according to claim 4, wherein in step S2, the molar ratio of phosphorus tribromide to compound II is 1.5:1, the reaction temperature is 60-65 ℃, and the mass ratio of DMF to compound II is 7:1, adjusting the pH value to 5, precipitating, and crystallizing and filtering at 25-30 ℃.
7. The process for the preparation of doxepin hydrochloride according to claim 4, wherein in step S3, the molar ratio of sodium carbonate to compound III is 1.5:1, the volume ratio of the reaction solvent to the compound III is 7:1, molar feed ratio of morpholine to compound III is 1.2:1, the reaction temperature of the heating reaction is 60-65 ℃, and the molar feed ratio of the added hydrochloric acid to the compound III during salification is 1.2:1, the salifying temperature is 40-45 ℃, and the volume ratio of a salifying solvent to a compound III used in salifying crystallization is 8:1.
8. The process for preparing doxepin hydrochloride as claimed in claim 7, wherein the reaction solvent is acetonitrile and the salt-forming solvent is acetone.
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| US3192210A (en) * | 1961-12-04 | 1965-06-29 | Robins Co Inc A H | 4-(omega-substituted alkyl)-3, 3-disubstituted-1-substituted-2-pyrrolidinones and 4-(omega-substituted alkyl)-3, 3-disubstituted-1-substituted-2-thionpyrrolidinones |
| US3192221A (en) * | 1961-12-04 | 1965-06-29 | Robins Co Inc A H | 4-(omega-substituted alkyl)-3, 3-disubstituted-1-substituted-2-pyrrolidinones and 4-(omega-substituted alkyl)-3, 3-disubstituted-1-substituted-2-thionpyrrolidinones and production thereof |
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| Carl D.Lunsford，等.4-(β-Substituted ethyl)-3,3-diphenyl-2- pyrrolidinones. A new series of CNS stimulants.《Journal of Medicinal Chemistry》.1964,302-310. * |
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