CN105153062A - Preparation method of permitil - Google Patents
Preparation method of permitil Download PDFInfo
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- CN105153062A CN105153062A CN201510650471.1A CN201510650471A CN105153062A CN 105153062 A CN105153062 A CN 105153062A CN 201510650471 A CN201510650471 A CN 201510650471A CN 105153062 A CN105153062 A CN 105153062A
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- reaction
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- toluene
- piperazine
- trifluoromethyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 95
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000007789 gas Substances 0.000 claims abstract description 20
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 129
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 22
- FVBUPJIWGKVQPW-UHFFFAOYSA-N 1-fluorophenazine Chemical compound C1=CC=C2N=C3C(F)=CC=CC3=NC2=C1 FVBUPJIWGKVQPW-UHFFFAOYSA-N 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 19
- 239000003513 alkali Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- PPXLQETZAQHSSL-UHFFFAOYSA-N 2-[4-(3-chloropropyl)piperazin-1-yl]ethanol Chemical compound OCCN1CCN(CCCCl)CC1 PPXLQETZAQHSSL-UHFFFAOYSA-N 0.000 claims description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims description 8
- 239000005864 Sulphur Substances 0.000 claims description 8
- 238000007086 side reaction Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000011084 recovery Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 229960002690 fluphenazine Drugs 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000003672 processing method Methods 0.000 claims description 2
- 235000021050 feed intake Nutrition 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 abstract description 10
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 abstract description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 6
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 4
- MBHNWCYEGXQEIT-UHFFFAOYSA-N Fluphenazine hydrochloride Chemical compound Cl.Cl.C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 MBHNWCYEGXQEIT-UHFFFAOYSA-N 0.000 abstract 2
- RKGYJVASTMCSHZ-UHFFFAOYSA-N 2-(trifluoromethyl)-10H-phenothiazine Chemical compound C1=CC=C2NC3=CC(C(F)(F)F)=CC=C3SC2=C1 RKGYJVASTMCSHZ-UHFFFAOYSA-N 0.000 abstract 1
- -1 and 1 Chemical compound 0.000 abstract 1
- 229960004369 flufenamic acid Drugs 0.000 abstract 1
- 231100000614 poison Toxicity 0.000 abstract 1
- 230000007096 poisonous effect Effects 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 25
- 238000004821 distillation Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 12
- 238000010792 warming Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000003068 static effect Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical group S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012263 liquid product Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 229960002050 hydrofluoric acid Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention discloses a preparation method of permitil. The preparation method is characterized by comprising the following steps: (1) taking flufenamic acid as a starting material, and carrying out decarboxylation and a cyclization reaction to prepare an intermediate 2-trifluoromethyl phenothiazine; (2) taking 1-(2-ethoxyl)piperazine, and 1,3-bromochloropropane as raw materials, carrying out a substitution reaction to prepare an intermediate 1-(3-chloropropyl)-4-(2-ethoxyl)piperazine; (3) carrying out a condensation reaction between the two intermediates to prepare an anatensol base, and salifying the anatensol base with hydrogen chloride gas to prepare the permitil. The preparation method is simple and convenient to operate, and free from risks and poisonous reactions; the prepared permitil is low in cost and high in purity.
Description
Technical field
The present invention relates to the preparation of fluophenazine hydrochloride and intermediate thereof, be specifically related to intermediate 2-trifluoromethyl thiodiphenylamine when preparing, the use of catalyzer iron powder, and in ring-closure reaction process, 0.5 equivalent cyclizing agent feeds intake the+application of recovery raw material process method; During the preparation of intermediate 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine, the utilization of hydrogen chloride gas salify edulcoration purification processing method; During the preparation of fluophenazine hydrochloride, sodium hydroxide mineral alkali fluoric acid agent+refluxing toluene divides the utilization of water conservancy project process.
Background technology
Fluophenazine hydrochloride, chemistry 4-[3-[2-(trifluoromethyl)-10H-thiodiphenylamine-10-base] propyl group]-1-piperazine ethanol dihydrochloride by name, is used as treatment mental disorder medicine clinically.Have side reaction in production reaction process in the past, quality product is not up to standard, increases production cost.
Summary of the invention
The object of the present invention is to provide the preparation method of fluophenazine hydrochloride, with low cost, quality product is high.For achieving the above object, mainly by the following technical solutions:
(1) preparation of 2-trifluoromethyl thiodiphenylamine: added by Tecramine in reaction flask, raised temperature, to 180-190 DEG C, adds the iron powder of 10% weight after material all melts, and stirring reaction about 2 hours, can obtain 3-trifluoromethyl pentanoic through underpressure distillation.3-trifluoromethyl pentanoic, 0.5 equivalent sulphur are added in reaction flask, add catalyst iodine, raised temperature is to 185-190 DEG C, react about 1 hour, can obtain intermediate 2-trifluoromethyl thiodiphenylamine through re crystallization from toluene, in filtrate, excessive unreacted 3-trifluoromethyl pentanoic adopts distillation mode recovery.
(2) preparation of intermediate 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 1,3-bromo-chloropropane, toluene add reaction flask, the 1-(2-hydroxyethyl of 32-35 DEG C of dropping 2 times of equivalents in reaction flask) piperazine, dropwise rear 32-35 DEG C of reaction 10 hours, after filtration, the aftertreatment such as hydrogen chloride gas salify removal of impurities can obtain intermediate 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine.
(3) preparation of fluophenazine hydrochloride: the sodium hydroxide of 2-trifluoromethyl thiodiphenylamine, toluene, 1 times of weight is added in reaction flask, be heated to reflux state, the toluene solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine of intermediate 1.2 equivalent is dripped in reaction flask, dropwise rear reaction 8 hours, in whole reaction process, be in reflux water-dividing state always.Fluphenazine alkali can be obtained through aftertreatments such as underpressure distillation after reaction terminates.By the ethanol of anhydrous for Fluphenazine salt based sols 4 times of weight, pass into hydrogen chloride gas wherein, regulate PH=2, after filtration, the operation such as dry can obtain fluophenazine hydrochloride product.
Present invention optimizes its preparation technology, reduce raw materials cost, improve quality product, selected synthetic route is as follows:
In the preparation process of fluophenazine hydrochloride, key intermediate 2-trifluoromethyl thiodiphenylamine is mainly starting raw material with Tecramine, obtains through decarboxylation, cyclization two-step reaction.Tecramine is not suitable for adopting carboxylic acid sodium high temperature decarboxylation under base catalysis condition, and too high temperature can cause Tecramine to decompose.The present invention adopts the method for transition metal-catalyzed decarboxylation, and confirm through experiment, iron powder has good catalytic effect to Tecramine decarboxylic reaction.In ring-closure reaction, in order to reduce the generation of side reaction, adopt the cyclizing agent charging capacity of 0.5 equivalent, excessive unreacted raw material adopts distillation mode to apply mechanically.Experiment proves, adopts this charging technology, does not only waste raw material, and only need simple re crystallization from toluene treatment process just can obtain highly purified 2-trifluoromethyl thiodiphenylamine after the completion of reaction.Adopt excessive 1-(2-hydroxyethyl) piperazine as acid binding agent in intermediate 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine preparation process, the present invention adopts the method for hydrogen chloride gas salify to remove excessive 1-(2-hydroxyethyl) piperazine, decrease the generation of side reaction in next step condensation course, decrease the difficulty of aftertreatment, improve raw material availability.Prepare in the condensation reaction of Fluphenazine, the present invention does not adopt organic acid binding agents such as triethylamine, but adopts sodium hydroxide mineral alkali as acid binding agent.The water tiing up the generation of sour process in order to avoid mineral alkali causes side reaction, and the present invention adopts toluene as reaction solvent, continues reflux water-dividing in reaction process, and the moisture of sour process generation is tied up in removing in time.
The invention has the advantages that: (1) selects low cost, effective iron powder as Tecramine decarboxylic reaction catalyzer; 0.5 equivalent cyclizing agent feeds intake+utilization of recovery raw material process, and decrease the generation of side reaction, only need the simple recrystallization of toluene can obtain highly purified 2-trifluoromethyl thiodiphenylamine.(2) be preparation high-quality intermediate 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine, after the completion of reaction, pass into appropriate hydrogen chloride gas and remove excessive unreacted 1-(2-hydroxyethyl) piperazine, reduce the side reaction of next step condensation reaction, reduce the finished product purifying difficulty.(3) when preparing Fluphenazine alkali, select sodium hydroxide as acid binding agent, divide water conservancy project skill with refluxing toluene, reaction effect is good, compares organic base acid-capture agent environmental protection more simultaneously.
Embodiment
Following type reaction is used for illustrating the present invention, and the simple replacement or improvement etc. done the present invention those skilled in the art all belong within the technical scheme that the present invention protects.
embodiment 1
(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 100g(0.356mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 10g(0.178mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 67.5g, yield about 80%.
By 3-trifluoromethyl pentanoic 60g(0.253mol), sublimed sulphur 8g(0.253mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 3g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 200g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 100g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 29g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 85%(and calculates by sulphur)
(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 79g(0.5mol) 1,3-bromo-chloropropane, 320g toluene add in reaction flask, 130g(1.0mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 95g, yield about 92%.
(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 28g(0.105mol), toluene 140g, granular sodium hydroxide 28g(0.7mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 50g toluene, the dropping process lasts about 1.5 hours of 26g (0.126mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 150g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 100g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor's aqueous phase, wash aqueous phase at twice with 150g toluene.In aqueous phase, add toluene 140g, drip the sodium hydroxide solution of 20% of 62g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor's aqueous phase, retain upper organic phase, organic phase 15g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 33g fluorine and put forth energy to be nearly alkali, yield 72%.
(4) preparation of fluophenazine hydrochloride: 32g alkali is dissolved in 128g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 50g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 36g, yield about 95%.
embodiment 2.
(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 500g(1.78mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 50g(0.89mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 346g, yield about 82%.
By 3-trifluoromethyl pentanoic 300g(1.265mol), sublimed sulphur 40g(1.265mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 15g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 1000g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 1000g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 147g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 86%(and calculates by sulphur)
(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 395g(2.5mol) 1,3-bromo-chloropropane, 1600g toluene add in reaction flask, 650g(5.0mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 470g, yield about 91%.
(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 140g(0.525mol), toluene 700g, granular sodium hydroxide 140g(3.5mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 300g toluene, the dropping process lasts about 1.5 hours of 130g (0.63mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 750g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 500g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor's aqueous phase, wash aqueous phase at twice with 750g toluene.In aqueous phase, add toluene 720g, drip the sodium hydroxide solution of 20% of 310g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor's aqueous phase, retain upper organic phase, organic phase 75g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 168g fluorine and put forth energy to be nearly alkali, yield 73%.
(4) preparation of fluophenazine hydrochloride: 160g alkali is dissolved in 640g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 300g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 182g, yield about 96%.
embodiment 3.
(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 1000g(3.56mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 100g(1.78mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 1029g, yield about 82%.
By 3-trifluoromethyl pentanoic 600g(2.53mol), sublimed sulphur 80g(2.53mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 30g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 2000g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 1000g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 294g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 86%(and calculates by sulphur)
(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 790g(5mol) 1,3-bromo-chloropropane, 3200g toluene add in reaction flask, 1300g(10mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 940g, yield about 91%.
(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 280g(1.05mol), toluene 1400g, granular sodium hydroxide 280g(7mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 500g toluene, the dropping process lasts about 1.5 hours of 260g (1.26mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 1500g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 1000g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor's aqueous phase, wash aqueous phase at twice with 1500g toluene.In aqueous phase, add toluene 1400g, drip the sodium hydroxide solution of 20% of 620g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor's aqueous phase, retain upper organic phase, organic phase 150g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 344g fluorine and put forth energy to be nearly alkali, yield 75%.
(4) preparation of fluophenazine hydrochloride: 320g alkali is dissolved in 1280g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 500g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 364g, yield about 96%.
Claims (5)
1. a preparation method for fluophenazine hydrochloride, is characterized in that the method is carried out as follows:
(1) when preparing intermediate 2-trifluoromethyl thiodiphenylamine, decarboxylic reaction adopts iron powder as catalyzer; Ring-closure reaction adopts the sulphur cyclizing agent of 0.5 equivalent to feed intake and to apply mechanically with raw materials recovery, can obtain highly purified intermediate with toluene as aftertreatment recrystallisation solvent;
(2) when preparing intermediate 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine, complete 1-(2-hydroxyethyl) piperazine of excessive unreacted adopts the mode of appropriate hydrogen chloride gas salify to be removed;
(3) when preparing Fluphenazine alkali, the acid binding agent of condensation reaction adopts cheap sodium hydroxide, adopts toluene to make reaction solvent, and reaction process adopts the mode of reflux water-dividing to reduce the generation of side reaction.
2. according to the preparation method of a kind of fluophenazine hydrochloride described in claim 1, it is characterized in that the preparation process of 2-trifluoromethyl thiodiphenylamine, is that catalyzer carries out decarboxylic reaction with iron powder; Adopt 0.5 equivalent cyclizing agent to feed intake the+processing method of recovery raw material in ring-closure reaction process, aftertreatment only needs the simple recrystallization of toluene can obtain highly purified 2-trifluoromethyl thiodiphenylamine.
3. according to the preparation method of a kind of fluophenazine hydrochloride described in claim 1, it is characterized in that the preparation process of intermediate 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine, remove the complete 1-of unreacted (2-hydroxyethyl) piperazine raw material in the mode of hydrogen chloride gas salify.
4. according to the preparation method of a kind of fluophenazine hydrochloride described in claim 1, it is characterized in that the preparation process of fluophenazine hydrochloride, with sodium hydroxide mineral alkali for acid binding agent, simultaneously with refluxing toluene dividing method for water removing system moisture, reduce the generation of side reaction.
5., according to the preparation method of a kind of fluophenazine hydrochloride described in claim 1, it is characterized in that preparation method's chemical equation of fluophenazine hydrochloride:
。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB833473A (en) * | 1955-03-19 | |||
| GB829246A (en) * | 1957-05-13 | 1960-03-02 | Smith Kline French Lab | Improvements in or relating to new perfluoroalkyl-phenothiazine derivatives |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB833473A (en) * | 1955-03-19 | |||
| GB829246A (en) * | 1957-05-13 | 1960-03-02 | Smith Kline French Lab | Improvements in or relating to new perfluoroalkyl-phenothiazine derivatives |
Non-Patent Citations (4)
| Title |
|---|
| HARRY L. YALE等: "10-(3-Dimethylaminopropyl)-2-(Trifluoromethyl)-phenothiazine Hydrochloride (VESPRIN) and Related Compounds. Ⅰ", 《J. AM. CHEM. SOC.》 * |
| 沈阳红星制药厂: "精神药物——盐酸氟奋乃静工艺简介", 《医药工业》 * |
| 韩长日等: "《药物制造技术》", 31 March 2000 * |
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