CN100448842C - Process for synthesizing alpha-(N-methyl-benzyl)-3-hydroxy acetophenone - Google Patents
Process for synthesizing alpha-(N-methyl-benzyl)-3-hydroxy acetophenone Download PDFInfo
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- 238000000034 method Methods 0.000 title abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000005893 bromination reaction Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 15
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010189 synthetic method Methods 0.000 claims abstract description 11
- 238000005576 amination reaction Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 230000031709 bromination Effects 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 7
- OTHYPAMNTUGKDK-UHFFFAOYSA-N (3-acetylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC(C(C)=O)=C1 OTHYPAMNTUGKDK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002699 waste material Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 58
- 239000010410 layer Substances 0.000 claims description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 17
- 238000010521 absorption reaction Methods 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 239000012044 organic layer Substances 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- 239000008213 purified water Substances 0.000 claims description 11
- 238000007664 blowing Methods 0.000 claims description 9
- 235000002639 sodium chloride Nutrition 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 239000000284 extract Substances 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000002912 waste gas Substances 0.000 claims description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 14
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 6
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- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 231100000481 chemical toxicant Toxicity 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000003440 toxic substance Substances 0.000 abstract 1
- 238000011084 recovery Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 229960003328 benzoyl peroxide Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 4
- 230000002939 deleterious effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229960002668 sodium chloride Drugs 0.000 description 3
- LUJMEECXHPYQOF-UHFFFAOYSA-N 3-hydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1 LUJMEECXHPYQOF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- ARKIFHPFTHVKDT-UHFFFAOYSA-N 1-(3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=CC([N+]([O-])=O)=C1 ARKIFHPFTHVKDT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- -1 3-benzoyloxy methyl phenyl Chemical group 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DEOLOLRQXYCZFC-UHFFFAOYSA-N C1=CC=C(C=C1)COC2=CC=CC(=C2)C(=O)C=NO Chemical compound C1=CC=C(C=C1)COC2=CC=CC(=C2)C(=O)C=NO DEOLOLRQXYCZFC-UHFFFAOYSA-N 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 208000011861 acute hypotension Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
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- 238000005984 hydrogenation reaction Methods 0.000 description 1
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- 239000002932 luster Substances 0.000 description 1
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Abstract
The present invention relates to a synthetic method for alpha-(N-methyl-benzyl)-3-hydroxy acetyl benzene, which uses 3-acetoxy acetyl benzene and methyl-benzyl amine as main raw materials, uses single butyl acetate as solvent and is prepared and obtained through bromination, amination and hydrolytic reaction. The present invention has the advantages of simple process and easy procuration of raw materials, the use of inflammable chemical solvent, explosive chemical solvent, toxic chemical solvent, etc. can be prevented in synthesis, and compared with original technology, yield is improved by 5 percent. The present invention has the characteristics of high yield, good purity, low cost, little three waste, friendly environment, etc.
Description
Technical field
The present invention relates to α-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride synthetic method.
Background technology
Phenylephrine hydrochloride, the another name neophryn, it is the adrenomimetic drug medicine, local vascular there is contraction, be mainly used in surgical operation, prolong the toponarcosis time, be the detumescence anti-inflammatory of nasal mucosa hyperemia, suit the medicine to the illness in the boosting and symptom such as heartbeat the is unusual of expansion pupil of ophthalmology and acute hypotension, product all has bigger demand in the field separately.
α-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride is called for short BAH, is the key intermediate of preparation phenylephrine hydrochloride (being neophryn), and following three routes are arranged.
[1] Sergievskaya, S.I.; Ravdel, G.A., Zhurnal Obshchei Khimii (1952), 22 496-502. are main raw material with 3-benzoyloxy methyl phenyl ketone, methyl-benzyl amine etc., make through reactions such as bromination, amination, hydrolysis.Its reaction formula is as follows:
This is reflected in bromination and the amine reaction, use deleterious chloroform and benzene equal solvent.And contain the phenylformic acid that is hydrolyzed in the product, be difficult to remove from product fully, product purity is not high.
[2]Hukki，Jaakko；Honkanen，Erkki.Acta?Chemica?Scandinavica(1959)，
This method is continued to use above-mentioned method basically, but different on the order of reaction.It is a main raw material with 3-hydroxy acetophenone, methyl-benzyl amine etc., makes through reactions such as bromination, ization, amination, hydrolysis.Its reaction formula is as follows:
The yield of this method product only is 40%, and can't overcome that the impurity phenylformic acid is removed fully and reaction process in use a large amount of solvents.
(3) Sergievskaya, the S.I. method
This method is to be main raw material with 3-nitro-acetophenone, methyl-benzyl amine etc., makes through reactions such as bromination, amination, shortening, diazotization, hydrolysis, and its reaction formula is as follows:
This method reactions steps is long, and side reaction is many, and needs pressurization hydrogenation and diazotization, and the three wastes are many, and also use inflammable, explosive ether in reaction process.Overall yield of reaction is below 18%, and color and luster is dark, and is of poor quality.
Existing synthetic method generally adopts 3-acetoxyl group-bromoacetophenone and N-methylbenzylamine to be synthesized into.3-acetoxyl group-bromoacetophenone character instability, perishable, the 3-acetoxyl group-bromoacetophenone and the yield that are difficult to produce higher degree are low.Known several synthetic method, in different reactions steps, adopted different solvents, comprising chemical feedstockss such as inflammable, explosive, deleterious ether, benzene, chloroforms, so not only increase the weight of recovery operation and to the pressure of environmental influence, and increased production cost.
Summary of the invention:
Deleterious chloroform and benzene equal solvent that the object of the invention exists at prior art, contain the phenylformic acid that is hydrolyzed in the product, be difficult to from product, remove fully, the problem that product purity is not high provides that a kind of technology is easy, cost is low, the three wastes are few, eco-friendly α-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride synthetic method.
α of the present invention-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride synthetic method, be to be main raw material with 3-acetoxy acetophenone and methyl-benzyl amine, with single N-BUTYL ACETATE is solvent, prepare target compound through bromination, amination, hydrolysis reaction, its chemical equation is as follows:
Preparation process is as follows:
A, bromination reaction: in reactor, drop into 300kg N-BUTYL ACETATE and 178kg3-acetoxy acetophenone, make dissolving, control 30 ± 10 ℃ of conditions, drip bromine 160kg, the hydrogen bromide waste gas that produces absorbs to the low cold water absorption unit of level Four and handles with-the vacuum absorption of 0.02MPa, dropwise the back and be incubated half an hour, put to the 1000L pot (in 100kg ice purified water is arranged), leave standstill after the stirring, divide and get organic layer, water layer is with N-BUTYL ACETATE 100kg washing extraction and do three wastes processing, merge organic layer, with 100kg saturated common salt water washing organic layer, carry out altogether 6 times at every turn, promptly get bromination reaction liquid.
B, amination condensation reaction: bromination reaction liquid is transferred in the amination pot, under＞20 ± 5 ℃ of conditions, Dropwise 5 8kg yellow soda ash and 330kg purified water institute obtain solution, drip N-methylbenzylamine 121kg simultaneously, PH is between 5-7 during dropping, after dripping end, insulation reaction 1 hour, promptly add ice purified water 150kg in the condensation pot, leave standstill branch after the stirring and get organic layer, water layer is concentrated with N-BUTYL ACETATE 100kg extraction back and is reclaimed Sodium Bromide, merge organic layer, 100kg washs at every turn with saturated aqueous common salt, carries out altogether three times, promptly gets the liquid of answering of condensation.
C, acidification reaction: in condensation reaction solution, add 150kg ice purified water and the acid of 100kg cryosel, leave standstill the extraction water layer after the stirring, organic layer is with 100kg frozen water extraction 4 times, and combining water layer extracts diamicton with the 100kg N-BUTYL ACETATE and promptly gets esterifying liquid after once and enter next step.The gained N-BUTYL ACETATE washs to neutrality with alkaline water, and behind anhydrous sodium sulfate drying, under-0.092MPa the condition, N-BUTYL ACETATE is reclaimed in underpressure distillation, icy salt solution cooling gained fraction can reclaim N-BUTYL ACETATE 560kg.
D, hydrolysis reaction: the gained water layer is moved to hydrolysis kettle, feed nitrogen, be warming up to 40-50 ℃, close nitrogen below 2 hours postcooling to 5 of hydrolysis reaction ℃, blowing is centrifugal, promptly gets the BAH crude product.
E, refining: gained BAH raw product is fed in 400kg acetone and the 210kg purified water, places the gac decolouring after-filtration that heats up, filtrate is below 60 ℃ of following reclaim under reduced pressure acetone postcooling to 5 ℃, blowing is centrifugal, dry laggard baking, get product about 210kg, content 〉=99%.
Description of drawings
Fig. 1 is that vacuum absorption of the present invention to the low cold water absorption unit of level Four absorbs processing hydrogen bromide waste gas schema:
Recycling step is: emit after the HBr content on first absorption tower reaches 60% outside the packing and sell. The HBr solution of second absorption tower Be transferred to first absorption tower, the like, average every batch can get about 40% recovery hydrobromic acid 198kg, keep water during absorption Temperature＜20 ℃.
Saturated aqueous common salt in the reaction of the present invention, steams under-0.092MPa the reduced pressure and removes moisture content to surplus to neutral through hcl acidifying During 1/2 volume, be cooled to 5 ℃, blowing is centrifugal, with 20kg saturated common salt water wash it, namely get recovery sodium chloride.
Butyl acetate of the present invention reclaims, and butyl acetate washs to neutrality with alkaline water, with anhydrous sodium sulfate drying, and-0.092MPa Under the condition, decompression distillation recovery of acetic acid butyl ester, brine ice cooling gained fraction can get the recovery of acetic acid butyl ester.
Advantage of the present invention:
(1) initiation material of the present invention has used the 3-acetoxy acetophenone, and having overcome with 3-benzoxy benzoylformaldoxime is raw material The time, always contain impurity benzoic acid defective in the product, improved significantly the purity of product.
(2) used with single solvent in the reaction, eco-friendly solvent butyl acetate, the result simplifies technology, has reduced one-tenth This has improved production environment.
(3) with the sodium chloride in the low cold water absorption plant recovery bromize hydrogen gas of low vacuum level Four and the recovered brine, particularly reclaim During the useless saturated aqueous common salt that produces in the condensation reaction with hcl acidifying to neutral, guaranteed to reclaim reusing of sodium chloride.
(4) behind the bromination reaction, do not extract 3-acetoxyl group-α-bromoacetophenone, directly to contain 3-acetoxyl group-α-bromobenzene second The butyl acetate solution of ketone carries out carrying out condensation reaction with the N-methylbenzylamine; After the condensation reaction, directly with hcl acidifying, water Extract the condensation product that is contained in the butyl acetate solution of anhydrating. Both reduce distillation, the step such as centrifugal, reduced again cost.
(5) choice for use 3-acetoxy acetophenone is initiation material, adopts single organic solvent during reaction, with water as solvent, Fill the N2 total process protective and be hydrolyzed, avoid the generation of accessory substance, simplify creating conditions for the purification condition of BAH. Both made environmental protection Administer simplely, simultaneously reduce cost again the BAH that output is high-quality.
(6) do not use the easily bigger organic solvent of toxic of carcinogenic, easy teratogenesis, easy sudden change such as chloroform, benzene, only have with a kind of Machine solvent (butyl acetate) had both met the policy of China environmental protection with regard to the high yield of output, high-quality crude product thing, and was again practical Ensured the reduction of Material Cost.
The present invention compares with the method for having reported, this technology have simple process, raw material be easy to get, removed from synthetic use inflammable, The chemical solvent such as explosive, poisonous, the more former technology of yield has exceeded 5 percentage points, have the yield height, purity is good, cost is low, The characteristics such as the three wastes are few, environmental friendliness.
Embodiment
Embodiment
Wet crude product charging capacity (single pot)
N-BUTYL ACETATE: 300kg (one barrel) nitrogen: 3 bottles
3-acetoxy acetophenone: 178kg
Bromine: 160kg
Yellow soda ash: 58kg
N-methylbenzylamine: 121kg N-BUTYL ACETATE: 300kg
Hydrochloric acid: 100kg
Sodium-chlor: 300kg
1, in the 500L reactor, drops into 300kg N-BUTYL ACETATE and 178kg3-acetoxy acetophenone, stirred 15 minutes, under 20 ℃, drip the bromine 160kg of suction header tank in advance in interior temperature.Reclaim bromize hydrogen gas with the low cold water absorption unit of rough vacuum level Four, drip and finish, be incubated 5 minutes, be cooled to 20 ℃, be discharged to 1000L reactor (100kg0 ℃ water is wherein arranged), blowing finishes, continue to stir 5 minutes, left standstill 30 minutes, tell lower aqueous layer, water layer with the extraction of 100kg salt acid recovery N-BUTYL ACETATE once, abandon water layer, merge organic layer, use 100kg saturated sodium-chloride salt water washing 6 times at every turn, abandon water layer, get bromination reaction liquid.
2, washings is evacuated in other the 1000L reactor, under 15-25 ℃, Dropwise 5 8kg yellow soda ash adds the solution and the 121kgN-methylbenzylamine of 330kg water, control reaction solution PH=6.5 carries out, after dripping end, interior temperature 15-25 ℃ is incubated 1 hour down, adds purified water 150kg, stirred 5 minutes, left standstill 30 minutes, and told lower aqueous layer, water layer focuses on after extracting with the 100kg N-BUTYL ACETATE, merge organic layer, must condensation reaction solution after carrying out 3 times altogether with the washing of 100kg saturated nacl aqueous solution at every turn.
3, place frozen water 150kg and cryosel acid 100kg in organic layer, stir and left standstill 30 minutes after 15 minutes, divide and take off a layer water layer, organic layer is with 100kg frozen water washing 4 times, and combining water layer washs once with the 100kg N-BUTYL ACETATE, to remove impurity.Sour water is transferred in the hydrolyzer, and logical nitrogen is warming up to 45 ℃ after 10 minutes, is incubated 2 hours postcooling to 3 and ℃ closes nitrogen, and blowing is centrifugal, and crude product 280kg must wet.
4, the 280kg crude product is fed in the acetone soln of 410kg and 210kg, places gac 10kg, be warming up to 55 ℃, insulation decolouring 1 hour is filtered, and filtrate is reclaim under reduced pressure acetone under-0.05MPa condition, in temperature stop to reclaim acetone to 59 ℃, close vacuum, cooling reaction solution to 3 ℃, blowing is centrifugal, get wet finished product 240kg, get finished product 209kg after drying, content is 99.31%, count to such an extent that reclaim acetone 330kg, can overlap and be used in down during batch materials makes with extra care.
Claims (4)
1, a kind of α-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride synthetic method, be to be main raw material with 3-acetoxy acetophenone and methyl-benzyl amine, with single N-BUTYL ACETATE is solvent, prepare target compound through bromination, amination, hydrolysis reaction, its chemical equation is as follows:
Preparation process is as follows:
A, bromination reaction: in reactor, drop into 300kg N-BUTYL ACETATE and 178kg3-acetoxy acetophenone, make dissolving, be controlled at 30 ± 10 ℃ of conditions, drip bromine 160kg, the hydrogen bromide waste gas that produces absorbs to the low cold water absorption unit of level Four and handles with-the vacuum absorption of 0.02MPa, dropwise the back and be incubated half an hour, put to the 1000L pot of the interior 100kg of having ice purified water, leave standstill after the stirring, divide and get organic layer, water layer is with N-BUTYL ACETATE 100kg washing extraction and do three wastes processing, merge organic layer, with 100kg saturated common salt water washing organic layer, carry out altogether 6 times at every turn, promptly get bromination reaction liquid;
B, amination condensation reaction: bromination reaction liquid is transferred in the amination pot, under＞20 ± 5 ℃ of conditions, Dropwise 5 8kg yellow soda ash and 330kg solution that purified water is joined, drip N-methylbenzylamine 121kg simultaneously, PH is between 5-7 during dropping, after dripping end, insulation reaction 1 hour promptly adds ice purified water 150kg in the condensation pot, leave standstill after the stirring, divide and get organic layer, water layer is concentrated with N-BUTYL ACETATE 100kg extraction back and is reclaimed Sodium Bromide, merges organic layer, and 100kg washs at every turn with saturated aqueous common salt, carry out altogether three times, promptly get the reaction solution of condensation;
C, acidification reaction: in condensation reaction solution, add 150kg ice purified water and the acid of 100kg cryosel, leave standstill the extraction water layer after the stirring, organic layer extracts 4 times with the 100kg frozen water, and combining water layer extracts diamicton with the 100kg N-BUTYL ACETATE and promptly gets esterifying liquid after once and enter next step;
D, hydrolysis reaction: the gained water layer is moved to hydrolysis kettle, feed nitrogen, be warming up to 40-50 ℃, close nitrogen below 2 hours postcooling to 5 of hydrolysis reaction ℃, blowing is centrifugal, promptly gets α-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride crude product;
E, refining: gained α-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride raw product is fed in 400kg acetone and the 210kg purified water, place gac intensification decolouring after-filtration, filtrate is below 60 ℃ of following reclaim under reduced pressure acetone postcooling to 5 ℃, blowing is centrifugal, dry laggard baking, get product.
2, α according to claim 1-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride synthetic method, it is characterized in that the described low cold water absorption unit of rough vacuum level Four of using reclaims bromize hydrogen gas, the HBr content on first absorption tower is reached after 60% and is emitted; The HBr solution on second absorption tower is transferred to first absorption tower, and the like, keep water temperature＜20 ℃ during absorption.
3, α according to claim 1-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride synthetic method, it is characterized in that the saturated aqueous common salt that described bromination reaction is used reclaims, extremely neutral through hcl acidifying, when steaming is extremely surplused 1/2 volume except that moisture content under the-0.092MPa reduced pressure, be cooled to 5 ℃, blowing is centrifugal, with 20kg saturated common salt water wash it, reclaim sodium-chlor.
4, according to the described α of claim 1-(N-methyl-N-benzamido group)-3-hydroxy acetophenone hydrochloride synthetic method, it is characterized in that described N-BUTYL ACETATE reclaims, N-BUTYL ACETATE washs to neutrality with alkaline water, with anhydrous sodium sulfate drying, under-0.092MPa the condition, N-BUTYL ACETATE is reclaimed in underpressure distillation, and icy salt solution cooling gained fraction can reclaim N-BUTYL ACETATE.
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| CNB2006100517761A CN100448842C (en) | 2006-06-02 | 2006-06-02 | Process for synthesizing alpha-(N-methyl-benzyl)-3-hydroxy acetophenone |
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| CN102050749B (en) * | 2010-11-19 | 2013-11-06 | 湖北欣瑞特医药科技有限公司 | Preparation and refining method of alpha-(N-benzyl-N-methyl amino)-m-hydroxyacetophenone hydrochloride |
| CN104356013A (en) * | 2014-11-18 | 2015-02-18 | 浙江海翔药业股份有限公司 | Preparation method of alpha-(N-methyl-N-benzylamino)-3-hydroxyacetophenone hydrochloride |
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| CN1336909A (en) * | 1999-01-21 | 2002-02-20 | 贝林格尔英格海姆法玛公司 | Method for producing L-phenylephrine hydrochloride |
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