CN105481795A - Production process of levodropropizine - Google Patents
Production process of levodropropizine Download PDFInfo
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- CN105481795A CN105481795A CN201511012679.7A CN201511012679A CN105481795A CN 105481795 A CN105481795 A CN 105481795A CN 201511012679 A CN201511012679 A CN 201511012679A CN 105481795 A CN105481795 A CN 105481795A
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- China
- Prior art keywords
- levodropropizine
- crude product
- production technique
- sodium hydroxide
- methylene dichloride
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- PTVWPYVOOKLBCG-ZDUSSCGKSA-N levodropropizine Chemical compound C1CN(C[C@H](O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-ZDUSSCGKSA-N 0.000 title claims abstract description 96
- 229960002265 levodropropizine Drugs 0.000 title claims abstract description 96
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000012043 crude product Substances 0.000 claims abstract description 33
- 239000000047 product Substances 0.000 claims abstract description 20
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000007670 refining Methods 0.000 claims abstract description 7
- SSZWWUDQMAHNAQ-VKHMYHEASA-N (R)-3-chloro-1,2-propanediol Chemical compound OC[C@@H](O)CCl SSZWWUDQMAHNAQ-VKHMYHEASA-N 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000008213 purified water Substances 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 14
- 239000012266 salt solution Substances 0.000 claims description 14
- 238000009413 insulation Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000008367 deionised water Substances 0.000 claims description 11
- 229910021641 deionized water Inorganic materials 0.000 claims description 11
- 239000012044 organic layer Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 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 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 18
- 239000002904 solvent Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- PTVWPYVOOKLBCG-UHFFFAOYSA-N 3-(4-phenyl-1-piperazinyl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000001476 alcoholic effect Effects 0.000 description 5
- 229960004722 dropropizine Drugs 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000012429 reaction media Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000011229 interlayer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XFGDAPQOKJYPQP-UHFFFAOYSA-N 1-chloropropane-1,2-diol Chemical compound CC(O)C(O)Cl XFGDAPQOKJYPQP-UHFFFAOYSA-N 0.000 description 1
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis and in particular relates to a production process of levodropropizine. The production process of levodropropizine comprises the following steps: with water as a medium, reacting N-phenylpiperazine and R-(-)-3-chloro-1,2-propanediol in the presence of a catalyst sodium hydroxide to obtain a crude product of levodropropizine, thereby obtaining a refined product of levodropropizine after refining the crude product. The production process has the advantages of low production cost, high yield, high product quality and environment friendliness.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of production technique of levodropropizine.
Background technology
Levodropropizine chemical name (S)-3-(4-phenyl-peiperazinyl)-1,2-PD, its molecular formula is C
13h
20n
2o
2.Levodropropizine is a kind of chirality antisussive and expectorant agent of Italian Dompe ' FarmS.P.A company exploitation listing in 1988, for the levo form of the non-additive racemize dropropizine of maincenter, its effect is identical with racemize dropropizine, but side effect obviously reduces, almost without the maincenter sedative effect of dropropizine.The site that site of action is relevant to sensibility neuropeptide after the knot of periphery, antitussive effect is strong, length of holding time; Be applicable to dry cough that acute upper respiratory tract infection and acute bronchitis cause and persistent cough.
Current synthesis levodropropizine is mainly two methods: one is method of asymmetric synthesis, with raw material one step of chiral carbon or a few step synthesis levodropropizine.As (R)-3-chloro-1 that the 01st phases in 2007 " Chinese pharmaceutical chemistry magazine " such as Shen great Dong are reported, the synthesis of 2-propylene glycol and levodropropizine, R-(-so that N-phenylpiperazine is raw material and chirality)-3-chloro-1,2-propylene glycol reacts, prepare the levodropropizine of optical purity more than 99%, yield 56.3%.Also having with N.F,USP MANNITOL is in addition that raw material is obtained by reacting levodropropizine through five steps, and the reaction times is longer and total recovery only has 28.4%.This method steps is long, yield is low, causes raw materials cost higher.Two is first synthesize racemic modification dropropizine, splits the levodropropizine obtaining chirality with resolving agent.As auspicious 03 phase in 2002 such as firm grade " University Of Chongqing's journal " reports the synthesis of New Antitussive Drug Levodropropizine, raw material aniline and diethanolamine in acid condition about 220 DEG C cyclizations obtain phenylpiperazine, epoxy chloropropane 10% sulfuric acid open loop becomes 3-chlorine-1,2-propylene glycol; Two kinds of intermediates reflux to obtain racemization dropropizine in ethanol, then split obtained levodropropizine with tartrate.Although this method can obtain the higher levodropropizine of optical purity, yield total recovery only 9.5%.
Patent CN101239952A discloses a kind of synthesis technique of levodropropizine, is namely medium with alcohol, and phenylpiperazine, the chloro-1.2-propylene glycol of (-)-3-are placed in reactor reflux with suitable catalyzer; Remove alcohol under reduced pressure, resistates adds suitable organic solvent reflux, and filtering inorganic salt while hot, filtrate cooling crystallization, filters to obtain crude product; And with suitable organic solvent recrystallization, thus obtain levodropropizine.Yield can reach 69.0%, and purity can reach 99.8%.In this synthesis technique, although obtain the higher product of liquid phase purity, adopt alcohols to do reaction medium, price is more expensive.In this patent, alkali catalyst such as sodium hydroxide is that solid adds in addition, and alkalescence is unsuitable for reaction too by force, causes yield on the low side.Also have the salt produced in reaction in this patent to remove crystallization again through heat filtering, heat filtering itself is not easy operation, therefore the method complex operation therefore be unsuitable for large-scale commercial production; Alcoholic solvent itself has volatility, and in heat filtering process, to have reached boiling point more volatile for solvent, is unfavorable for solvent recuperation contaminate environment, in addition, alcoholic solvent volatilizees, and greatly, also have alcoholic solvent inflammable, in production process, danger coefficient increases workshop solvent odor when easily causing filtration.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides a kind of production technique of levodropropizine.The method raw materials cost is low, environmentally friendly, and yield is high, product purity is high.
The present invention is realized by following technical scheme:
A production technique for levodropropizine, is characterized in that, comprises the following steps:
Take water as medium, N-phenylpiperazine, R-(-)-3-chlorine-1,2-propylene glycol is obtained by reacting levodropropizine crude product under sodium hydroxide catalyzed, obtains levodropropizine fine work after refining.Adopt water as reaction medium, low price, there is not solvent smell problem rambunctious in easy heat filtering, environmentally friendly.
The production technique of levodropropizine of the present invention, its reaction formula is as follows:
In the production technique of above-mentioned levodropropizine, described sodium hydroxide adds in reaction solution with the form of aqueous sodium hydroxide solution, and in described aqueous sodium hydroxide solution, the weight ratio of sodium hydroxide and deionized water is 1:3-6, is preferably 1:4.Adopt the mode that aqueous sodium hydroxide solution drips, easily control the pH value of reaction, the alkalescence of whole reaction is controlled, local can not alkalescence excessively strong, side reaction is few, is conducive to the yield of raising product.
In the production technique of above-mentioned levodropropizine, described step N-phenylpiperazine, R-(-)-3-chlorine-1,2-propylene glycol amount ratio is 1:0.6-0.8.
In the production technique of above-mentioned levodropropizine, described purification step obtains levodropropizine fine work for adopting methylene dichloride and purified water to carry out purifying to levodropropizine crude product, and the weight ratio of described levodropropizine, methylene dichloride and purified water is 1:2-5:1-3.Adopt methylene dichloride and purified water to carry out purification refine to levodropropizine crude product, the salt produced can be got rid of, make the residue on ignition of levodropropizine fine work lower, meet the regulation of the levodropropizine drug standard in crude product preparation process.
Preferably, the weight ratio of described levodropropizine, methylene dichloride and purified water is 1:3:1.
The production technique of above-mentioned levodropropizine, comprises the following steps:
(S1) preparation of levodropropizine crude product:
15-30 DEG C, under pH=8-12 condition, to N-phenylpiperazine, R-(-)-3-chlorine-1,2-propylene glycol, deionized water dropping aqueous solution of sodium, 0.5h-3h dropwises; Dropwise rear 15-30 DEG C insulation reaction 30min, be then warmed up to 40-60 DEG C of insulation reaction 12-20h; React complete, icy salt solution is cooled to 0-10 DEG C, is separated to obtain levodropropizine crude product;
(S2) levodropropizine crude product refining:
Adopt methylene dichloride and purified water to carry out purifying to levodropropizine crude product and obtain levodropropizine fine work.
Preferably, in the production technique of above-mentioned levodropropizine, in described step S1, aqueous sodium hydroxide solution time for adding is 1.5h.
Preferably, in the production technique of above-mentioned levodropropizine, in described step S1,40-60 DEG C of insulation reaction time is 12h.
The production technique of above-mentioned levodropropizine, detailed step is:
(S1) levodropropizine crude product is prepared:
By N-phenylpiperazine, R-(-)-3-chloro-1,2-propylene glycol, deionized water be the rear dropping of suction reactor cooling 20% sodium hydroxide solution respectively, temperature of reaction 15-30 DEG C, pH=8-12 is controlled during dropping, 0.5-3h dropwises, dropwise rear insulated and stirred 30min, then be warmed up to 40-60 DEG C of insulation reaction 12-20h, then icy salt solution is cooled to 0-10 DEG C and gets rid of and expect to obtain levodropropizine crude product;
(S2) levodropropizine crude product refining:
Methylene dichloride, purified water, levodropropizine crude product are dropped into clean reactor rising temperature for dissolving, the weight ratio of levodropropizine, methylene dichloride and purified water is 1:2-5:1-3, leave standstill after stirring 1h and treat layering in 0.5 hour, organic layer is filled in another clean reactor through accurate filter, and icy salt solution is cooled to 0-10 DEG C and is separated to obtain levodropropizine wet product; Wet product is put into baking oven pallet temperature control 35-40 DEG C and is dried material 4-5 hour, and 50 DEG C are dried material 10 hours, and 60 DEG C are dried material 8 hours, obtain levodropropizine fine work.
The production technique of levodropropizine of the present invention has carried out producing amplifying, and is suitable for pilot scale and scale operation levodropropizine, can obtains the guaranteed product of steady quality.Have that production cost is low, yield is high, quality product is high, environment amenable advantage.
Beneficial effect of the present invention is:
(1) production technique of levodropropizine of the present invention uses water to do reaction medium, and do reaction medium relative to employing alcohol, water low price, reduces raw materials cost.In technique disclosed in patent CN101239952A, need heat filtering to remove inorganic salt in crude product sepn process, alcoholic solvent has volatility, and in heat filtering process, during filtration, workshop solvent odor is large, and alcoholic solvent is inflammable in addition, and in production process, danger is larger.And adopting water to do reaction medium, inorganic salt are soluble in water and there is not the problem of solvent smell large bad control when filtering, environmentally friendly, reduce environmental protection pressure, and production danger is less.
(2) in the process preparing levodropropizine, adopt sodium hydroxide as catalyzer, if directly add sodium hydrate solid, dissolve and easily cause local alkalescence to be unsuitable for reaction too by force instantaneously, cause yield on the low side.And the production technique of levodropropizine of the present invention adopts aqueous sodium hydroxide solution to drip mode catalyzed reaction, and strict control pH, control milder, side reaction is few, and the crude product purity obtained is high, and yield is high.
(3) adopt methylene dichloride and purified water to carry out recrystallization purifying, the residue in product can be reduced during purified water dissolve inorganic salts crystallization, make residue on ignition content in product reach drug standard requirement, improve the quality of product.
(4) adopt the production technique of levodropropizine of the present invention to prepare levodropropizine, there is yield high, the advantage that product purity is high.This production technique yield can reach 77.9-83.4%, and liquid phase purity can reach more than 99.9%, specific optical rotation about-33 °, and residue on ignition is qualified.Products obtained therefrom steady quality, is suitable for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is further described, so that those skilled in the art more understands the present invention, but does not therefore limit the present invention.
Embodiment 1
1, the aqueous sodium hydroxide solution of 20% is prepared:
By in deionized water suction 1000 liters of reactors of 416 kilograms, add 104 kilograms of sodium hydroxide under whipped state, after dissolving, reactor interlayer passes into recirculated water to be down to room temperature for subsequent use;
2, levodropropizine crude product is prepared:
After checking that 3000 liters of reactors are clean, then successively by N-phenylpiperazine 400 kilograms of (GC:95%), R-(-)-3-chloro-1,2-propylene glycol 288 kilograms, deionized water 1280 kilograms squeeze into reactor, pass into salt solution and be cooled to 16 DEG C, start to drip 20% alkali lye, temperature still controls at 15-30 DEG C, pays close attention to and control pH=8-12 during dropping, within 1.5 hours, dropwises.Dropwise rear closedown salt solution valve, in 20 DEG C of insulated and stirred 30 minutes, be then warmed up to 42 DEG C of insulation reaction 12h; After insulation reaction terminates, pass into icy salt solution and be cooled to less than 10 DEG C, get rid of and expect to obtain off-white color solid and levodropropizine crude product 535 kilograms;
3, levodropropizine is refined:
By 3000 liters of clean to the methylene dichloride of 1605 kilograms, the purified water suction of 535 kilograms reactors, under whipped state, then drop into the levodropropizine crude product of 535 kilograms.Be warming up to 40 DEG C after feeding intake, stirring and refluxing is dissolved; Stirring and dissolving 1h, closes and stirs standing 0.5 hour, carry out layering subsequently; Separate organic layer to squeeze in another clean reactor through accurate filter.Open and stir, pass into icy salt solution and be cooled to 0 DEG C of stirring and crystallizing 4h, centrifugal drying material obtains wet product 506 kilograms; Filter cake is put into baking oven pallet temperature control 35-40 DEG C and is dried material 4-5 hour, and temperature adjustment 50 DEG C dries material 10 hours, then temperature adjustment 60 DEG C dries material 8 hours, and rewinding obtains levodropropizine fine work 442 kilograms.Molar yield 80.1%.The liquid phase purity of testing product is 99.966%, and specific optical rotation is-32.8 °, residue on ignition 0.02%.
Embodiment 2
1, the aqueous sodium hydroxide solution of 20% is prepared:
By in deionized water suction 1000 liters of reactors of 416 kilograms, add 104 kilograms of sodium hydroxide under whipped state, after dissolving, reactor interlayer passes into recirculated water to be down to room temperature for subsequent use;
2, levodropropizine crude product is prepared:
After checking that 3000 liters of reactors are clean, then successively by N-phenylpiperazine 400 kilograms of (GC:95%), R-(-)-3-chloro-1,2-propylene glycol 288 kilograms, deionized water 1280 kilograms squeeze into reactor, pass into salt solution and be cooled to 18 DEG C, start to drip 20% alkali lye, temperature still controls at 15-30 DEG C, pays close attention to and control pH=9-11 during dropping, within about 1 hour 20 minutes, dropwises.Dropwise rear closedown salt solution valve, continue at 22 DEG C of insulated and stirred 30 minutes, be then warmed up to 43 DEG C of insulation reaction 12h; After insulation reaction terminates, pass into icy salt solution and be cooled to less than 10 DEG C, get rid of and expect to obtain off-white color solid and levodropropizine crude product 538 kilograms.
3, levodropropizine is refined:
By 3000 liters of clean to the methylene dichloride of 1614 kilograms, the purified water suction of 538 kilograms reactors, under whipped state, then drop into the levodropropizine crude product of 538 kilograms.Be warming up to 40 DEG C after feeding intake, stirring and refluxing is dissolved; Close after stirring and dissolving 1h and stir power supply, leave standstill 0.5 hour, carry out layering subsequently; Separate organic layer to squeeze in another clean reactor through accurate filter.Open and stir, pass into icy salt solution and be cooled to less than 5 DEG C stirring and crystallizing 4h, centrifugal drying material obtains wet product 512 kilograms.The filter cake of 512 kilograms is put into baking oven pallet temperature control 35-40 DEG C and dry material 4-5 hour, temperature adjustment 50 DEG C dries material 10 hours, then temperature adjustment 60 DEG C dries material 8 hours, and rewinding obtains levodropropizine fine work 445 kilograms.Molar yield 80.6%.The liquid phase purity of testing product can be 99.958%, and specific optical rotation is-33.1 °, residue on ignition 0.03%.
Claims (10)
1. a production technique for levodropropizine, is characterized in that, comprises the following steps:
Take water as medium, N-phenylpiperazine, R-(-)-3-chlorine-1,2-propylene glycol is obtained by reacting levodropropizine crude product under sodium hydroxide catalyzed, obtains levodropropizine fine work after refining.
2. the production technique of levodropropizine according to claim 1, is characterized in that, described sodium hydroxide adds in reaction solution with the form of aqueous sodium hydroxide solution, and in described aqueous sodium hydroxide solution, the weight ratio of sodium hydroxide and deionized water is 1:3-6.
3. the production technique of levodropropizine according to claim 2, is characterized in that, in described aqueous sodium hydroxide solution, the weight ratio of sodium hydroxide and deionized water is 1:4.
4. the production technique of levodropropizine according to claim 1, is characterized in that, described step N-phenylpiperazine, R-(-)-3-chlorine-1,2-propylene glycol amount ratio is 1:0.6-0.8.
5. the production technique of levodropropizine according to claim 1, it is characterized in that, described purification step obtains levodropropizine fine work for adopting methylene dichloride and purified water to carry out purifying to levodropropizine crude product, and the weight ratio of described levodropropizine, methylene dichloride and purified water is 1:2-5:1-3.
6. the production technique of levodropropizine according to claim 5, is characterized in that, the weight ratio of described levodropropizine, methylene dichloride and purified water is 1:3:1.
7. the production technique of levodropropizine according to claim 1, is characterized in that, comprises the following steps:
(S1) preparation of levodropropizine crude product:
15-30 DEG C, under pH=8-12 condition, to N-phenylpiperazine, R-(-)-3-chlorine-1,2-propylene glycol, deionized water dropping aqueous solution of sodium, 0.5h-3h dropwises; Dropwise rear 15-30 DEG C insulation reaction 30min, be then warmed up to 40-60 DEG C of insulation reaction 12-20h; React complete, icy salt solution is cooled to 0-10 DEG C, is separated to obtain levodropropizine crude product;
(S2) levodropropizine crude product refining:
Adopt methylene dichloride and purified water to carry out purifying to levodropropizine crude product and obtain levodropropizine fine work.
8. the production technique of levodropropizine according to claim 7, is characterized in that, in described step S1, aqueous sodium hydroxide solution time for adding is 1.5h.
9. the production technique of levodropropizine according to claim 7, is characterized in that, in described step S1,40-60 DEG C of insulation reaction time is 12h.
10. the production technique of levodropropizine according to claim 7, is characterized in that, detailed step is:
(S1) levodropropizine crude product is prepared:
By N-phenylpiperazine, R-(-)-3-chloro-1,2-propylene glycol, deionized water be the rear dropping of suction reactor cooling 20% sodium hydroxide solution respectively, temperature of reaction 15-30 DEG C, pH=8-12 is controlled during dropping, 0.5-3h dropwises, dropwise rear insulated and stirred 30min, then be warmed up to 40-60 DEG C of insulation reaction 12-20h, then icy salt solution is cooled to 0-10 DEG C and gets rid of and expect to obtain levodropropizine crude product;
(S2) levodropropizine crude product refining:
Methylene dichloride, purified water, levodropropizine crude product are dropped into clean reactor rising temperature for dissolving, the weight ratio of levodropropizine, methylene dichloride and purified water is 1:2-5:1-3,0.5 little layered is left standstill after stirring 1h, organic layer is filled in another clean reactor through accurate filter, and icy salt solution is cooled to 0-10 DEG C and is separated to obtain levodropropizine wet product; Wet product is put into baking oven pallet temperature control 35-40 DEG C and is dried material 4-5 hour, and 50 DEG C are dried material 10 hours, and 60 DEG C are dried material 8 hours, obtain levodropropizine fine work.
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| EP0575776A2 (en) * | 1992-06-24 | 1993-12-29 | BIDACHEM S.p.A. | A process for the preparation of enantiomers of dropropizine |
| CN101239952A (en) * | 2008-03-13 | 2008-08-13 | 湖南九典制药有限公司 | Technique for synthesizing levodropropizine |
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| EP0575776A2 (en) * | 1992-06-24 | 1993-12-29 | BIDACHEM S.p.A. | A process for the preparation of enantiomers of dropropizine |
| CN101239952A (en) * | 2008-03-13 | 2008-08-13 | 湖南九典制药有限公司 | Technique for synthesizing levodropropizine |
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