CN104402746B - A kind of synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride - Google Patents
A kind of synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride Download PDFInfo
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- XSYRYMGYPBGOPS-UHFFFAOYSA-N 4-amino-3-phenylbutanoic acid;hydrochloride Chemical compound [Cl-].OC(=O)CC(C[NH3+])C1=CC=CC=C1 XSYRYMGYPBGOPS-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 12
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 9
- 235000002639 sodium chloride Nutrition 0.000 claims description 8
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006845 Michael addition reaction Methods 0.000 claims description 6
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- 238000011084 recovery Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000004080 punching Methods 0.000 claims description 4
- 239000004519 grease Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 8
- 230000000977 initiatory effect Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000011017 operating method Methods 0.000 abstract description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 11
- 239000002994 raw material Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011344 liquid material Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- -1 α-phenyl-β-benzoyl-γ-nitro butyric acid Chemical compound 0.000 description 2
- YTJKDXDSAUVHJG-UHFFFAOYSA-N (4-butyl-3-phenylmethoxyphenyl)azanium;chloride Chemical compound [Cl-].CCCCC1=CC=C([NH3+])C=C1OCC1=CC=CC=C1 YTJKDXDSAUVHJG-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000006856 Wolf-Kishner-Huang Minlon reduction reaction Methods 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010514 butyrylation reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- BOTNYLSAWDQNEX-UHFFFAOYSA-N phenoxymethylbenzene Chemical compound C=1C=CC=CC=1COC1=CC=CC=C1 BOTNYLSAWDQNEX-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride, this synthetic method comprises step: after preparing ethyl benzoylacetate, prepare nitrostyrolene and preparing addition compound product through processing to obtain product. This synthetic method has created the complete process of a synthetic 4-Amino-3-phenylbutyric acid hydrochloride, technique is simple, and yield is high, and cost is lower, mainly solve the initiation material price that existing technique uses high, the lengthy and tedious and heavy-polluted problem of production process of operating procedure.
Description
Technical field
The present invention relates to a kind of synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride.
Background technology
The structural formula of 4-Amino-3-phenylbutyric acid hydrochloride is as follows:
At present, disclosed 3-benzyloxy is as follows the synthetic method of-4-butylaniline hydrochloride: with an ammoniaBase phenol is raw material, and through Butyrylation reaction, Fries resets, and obtains 2-bytyry-5-amide-based small phenol:Under the effect of alkali, 2-butyryl-5-amide-based small phenol and the effect of halogenation benzyl generate 2-bytyry-5-butyramideBase benzyl phenyl ether, then hydrolysis obtains 3-benzyloxy-4-bytyry aniline, finally by crossing Huang Min-lon reductionReaction, salify obtains 3-benzyloxy-4-4-butylaniline hydrochloride. The initiation material price that above technique is usedHeight, operating procedure is lengthy and tedious, and production process is polluted large.
Summary of the invention
The invention provides a kind of synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride, mainly solved existingThe initiation material price that technique is used is high, the lengthy and tedious and heavy-polluted problem of production process of operating procedure.
Concrete technical solution of the present invention is as follows:
The synthetic method of this 4-Amino-3-phenylbutyric acid hydrochloride comprises the following steps:
1] prepare ethyl benzoylacetate
Under the condition lower than 15 DEG C, it is that 99% ethyl acetoacetate stirs that Xiang Shuizhong adds mass concentration,When stirring, adding mass concentration is that 40% sodium hydroxide solution and mass concentration are 99% chlorobenzoyl chloride and make anti-Answer the pH of system to maintain between 9～11; The mass ratio of described water and ethyl acetoacetate is 1:0.2～0.3,Ethyl acetoacetate and chlorobenzoyl chloride are identical in quality;
After having reacted, reaction system is warming up to 50～60 DEG C and leaves standstill 4～5h;
After having left standstill, reaction system is cooled to below 25 DEG C, adds saturated aqueous common salt to stir 10～30h,After completing, stirring carries out separatory processing, grease washing, and anhydrous sodium sulfate drying, obtains benzoyl acetic acidEthyl ester; The mass ratio of described ethyl acetoacetate and saturated aqueous common salt is 1:0.3～0.5;
2] prepare nitrostyrolene
2.1] get nitromethane, benzaldehyde, NaOH and methyl alcohol and react 2～4h under 0 DEG C of environment, reactionAfter completing, add water, hydrochloric acid, centrifugal treating obtains yellow nitrostyrolene finished product; Described nitromethane, benzeneThe mass ratio of formaldehyde, NaOH and methyl alcohol is 1:1.6～2.0:3.1～3.4:6.3～6.6, nitromethane withThe mass ratio of water is 1:1.5～1.7, and water and hydrochloric acid are identical in quality;
2.2] getting nitrostyrolene and toluene, ethyl benzoylacetate, the triethylamine that step 2.1 makes refluxesReaction 3～5h, concentration and recovery toluene, concentrate adds the cooling placement crystallization of methyl alcohol, obtains Michael addition and producesThing α-phenyl-β-benzoyl-γ-nitro ethyl butyrate; Described nitrostyrolene and toluene, benzoyl secondThe mass ratio of acetoacetic ester, triethylamine is 1:4～6:1.5～2:0.1～0.3;
3] prepare addition compound product
By step 2 prepare α-phenyl-β-benzoyl-γ-nitro ethyl butyrate of gained and methyl alcohol withThe mass ratio of 1:4～6 carries out the pressurize processing of 10～30min under dry hyperbaric environment, and pressure is1.3～1.8MPa; Pressurize completes in backward dry hyperbaric environment and passes into 4.0MPa hydrogen punching row 2～4 times, rushesAfter drained one-tenth, stir and be warming up to 38～42 DEG C and carry out hydrogenation reaction 6～8h, after completing, leave standstill 1～2h, leave standstillAfter completing, concentrated methyl alcohol is to small size crystallization, centrifugal crude product;
4] stir after being warming up to 90～100 DEG C and drip dense salt prepare the crude product of gained and purified water through step 3Acid, controls and dropwises for 30-60 minute, controls reacting system PH value in 1-2 left and right, after being added dropwise to completeContinue to stir 1～2h, after having stirred, be cooled to 30 DEG C of following centrifugal discharges, centrifugal rear mother liquid obtained concentratingCollect, 80～90 DEG C of recovered under reduced pressure hydrochloric acid of temperature control, treat material thickness, be cooled to 30 DEG C following centrifugalDischarging, to gained material by the absolute ethyl alcohol fine work that is recrystallized to obtain.
Above-mentioned steps 1] in, lower than adding ethyl acetoacetate to stir specifically in water under the condition of 15 DEG CBy ice bath mode in reactor by water management lower than 15 DEG C, then add ethyl acetoacetate.
Above-mentioned steps 1] in, the concentration that adds sodium hydroxide solution when stirring is that 40%, PH maintains 10.
The invention has the advantages that:
The present invention has created the complete process of a synthetic 4-Amino-3-phenylbutyric acid hydrochloride, and technique is simple,Yield is high, and cost is lower.
Brief description of the drawings
Fig. 1 is the liquid phase detection figure in example 1 of the present invention;
Fig. 2 is the liquid phase detection figure in example 2 of the present invention;
Fig. 3 is the liquid phase detection figure in example 3 of the present invention.
Detailed description of the invention
Synthesis technique is as follows:
Example one
1] in 1000L reactor, add 250kg water, ice bath temperature control is lower than 15 DEG C, then to reactionIn still, add ethyl acetoacetate 70kg, vigorous stirring is also controlled temperature and is no more than 15 DEG C; Stir and drip simultaneously40% sodium hydroxide solution and the 70kg mass concentration 99% chlorobenzoyl chloride solution that add mass concentration and be, make anti-The system ph of answering maintains 10 left and right. After being added dropwise to complete, under 55 DEG C of conditions, leave standstill 4-5h; Then be cooled toAt 25 DEG C, add saturated aqueous common salt 100kg, slowly stir after 10～30 hours and carry out separatory processing, oilyThing washing, anhydrous sodium sulfate drying, obtains ethyl benzoylacetate.
2.1] get nitromethane 62kg and benzaldehyde 110kg methyl alcohol 400kg and join the 1000L of step 1In reactor and be cooled to 0 DEG C, and then add the sodium hydroxide solution 200kg of concentration 40%, after addingReact three hours, adding water with mass concentration is the each 100kg of 37% concentrated hydrochloric acid, and then centrifugal treating obtains yellow nitreBase styrene finished product;
2.2] get dry nitrostyrolene 50kg, toluene 250kg, ethyl benzoylacetate 80kg, three secondAmine 10kg, puts in 500L reactor back flow reaction four hours, and concentration and recovery toluene obtains concentrate,In concentrate, add 95% methyl alcohol 50kg, and cooling placement crystallization, Michael addition adducts α-phenyl obtained-β-benzoyl-γ-nitro ethyl butyrate.
3] prepare addition compound product
In dry high-pressure reactor, the ratio that is 1:5 according to raw material and methyl alcohol ratio successively adds MichaelAddition compound product α-phenyl-β-benzoyl-γ-nitro ethyl butyrate adds the thunder of raw material weight 5% simultaneouslyBuddhist nun's Raney nickel, then uses nitrogen 1.5Mpa pressurize 15 minutes; After pressurize completes, adopt hydrogen punching row 3Inferior, rush after drained one-tenth after under 38～42 DEG C of conditions, logical 7 hours hydrogenation of 4.0Mpa hydrogen reaction complete, quietPut 1 hour, 350 order press filtration dischargings obtain the about 700kg of liquid material, centralized collection catalyst, and concentrated methyl alcohol is extremelySmall size crystallization, the centrifugal crude product that obtains.
4] synthetic 4-Amino-3-phenylbutyric acid hydrochloride
The crude product of preparing through step 3 and purified water are added in clean reactor. Stir material and be warming up to 90～100 DEG C, reach that to start to drip mass concentration after temperature conditions be 37% hydrochloric acid, be added dropwise to complete rear stirring 1Hour, after having stirred, be cooled to 30 DEG C of following approximately 480～500kg of centrifugal discharge. To the mother of centrifugal gainedLiquid centralized collection, specifically recovered under reduced pressure hydrochloric acid under 80～90 DEG C of conditions, after material thickness, coolingTo 30 DEG C and centrifugal discharge; Centrifugal discharge products therefrom is adopted to the absolute ethyl alcohol fine work that is recrystallized to obtain.
Example two
1] in 2000L reactor, add water 500kg ice bath temperature control lower than 15 DEG C, add acetoacetateEthyl ester 140kg, vigorous stirring, dripping mass concentration is 40% NaOH, controls temperature and is no more than 15DEG C, start to drip mass concentration is the rate of addition that 99% chlorobenzoyl chloride 140kg controls the two simultaneously, makesReaction system ph maintains 10 left and right ethyl acetate, drips off and under 55 DEG C of conditions, leaves standstill 4-5h. Then existAt 25 DEG C, add saturated aqueous common salt 200kg, slowly stir and spend the night, react separatory, oily 20 hoursThing washing, anhydrous sodium sulfate drying. Obtain ethyl benzoylacetate.
2.1] nitromethane 124kg and benzaldehyde 220kg methyl alcohol 800kg join in 2000L reactor and fallTemperature is to 0 degree, and adding mass concentration is 40% NaOH 200kg, adds rear reaction three hours, adds water200kg, adds 200 kilograms of hydrochloric acid, centrifugal yellow nitrostyrolene finished product.
2.2] dry nitrostyrolene 100kg, toluene 500kg, ethyl benzoylacetate 160kg, three secondAmine 24kg, puts in 1000L reactor back flow reaction four hours, concentration and recovery toluene, and concentrate addsEnter the cooling placement crystallization of methyl alcohol, obtain Michael addition adducts α-phenyl-β-benzoyl-γ-nitro butyric acid secondEster.
3] prepare addition compound product
In dry high-pressure reactor, the ratio that is 1:5 according to raw material and methyl alcohol ratio successively adds raw material,Add the palladium-carbon catalyst of raw material weight 1%, with nitrogen 1.5Mpa pressurize 15 minutes. Pressurize is finished, hydrogenPunching row 3 times, logical hydrogen 4.0Mpa, 38～42 DEG C of hydrogenation reactions 7 hours. Hydrogenation is finished, and leaves standstill 1 littleTime, 350 order press filtration dischargings obtain the about 700kg of liquid material. Centralized collection catalyst, concentrated methyl alcohol is to small sizeCrystallization, the centrifugal crude product that obtains.
4] synthetic 4-Amino-3-phenylbutyric acid hydrochloride
To in the crude product of preparing through step 3 and the clean reactor of purified water, add. Stirring intensification material to 90～100 DEG C, start to drip mass concentration and be 37% concentrated hydrochloric acid hydrochloric acid, drip to finish and stir 1 hour, be cooled to30 DEG C of following approximately 480～500kg of centrifugal discharge. Mother liquor centralized collection after centrifugal, temperature control 80～90DEG C recovered under reduced pressure hydrochloric acid, treats material thickness, is cooled to 30 DEG C of centrifugal discharges. Absolute ethyl alcohol is recrystallized smartlyProduct.
Example three
1] in 3000L reactor, add water 750kg ice bath temperature control lower than 15 DEG C, add acetoacetateEthyl ester 210kg, vigorous stirring, dripping mass concentration is 40% NaOH, controls temperature and is no more than 15DEG C, start to drip mass concentration is the rate of addition that 99% chlorobenzoyl chloride 210kg controls the two simultaneously,Make reaction system ph maintain 10 left and right ethyl acetate, drip off and under 55 DEG C of conditions, leave standstill 4-5h. ThenAt 25 DEG C, add saturated aqueous common salt 300kg, slowly stir and spend the night, react separatory, oil 20 hoursThe washing of shape thing, anhydrous sodium sulfate drying. Obtain ethyl benzoylacetate.
2.1] nitromethane 186kg and benzaldehyde 360kg methyl alcohol 1200kg join in 3000L reactorBe cooled to 0 degree, adding mass concentration is 40% NaOH 200kg, adds rear reaction three hours, adds water300kg, adds 300 kilograms of concentrated hydrochloric acids, centrifugal yellow nitrostyrolene finished product.
2.2] dry nitrostyrolene 150kg, toluene 900kg, ethyl benzoylacetate 255kg, three secondAmine 45kg, puts in 200L reactor back flow reaction four hours, concentration and recovery toluene, and concentrate addsThe cooling placement crystallization of methyl alcohol, obtains Michael addition adducts α-phenyl-β-benzoyl-γ-nitro butyric acid secondEster.
3] preparing addition compound product in dry high-pressure reactor, is 1:5 according to raw material and methyl alcohol ratio successivelyRatio added raw material, adds the palladium-carbon catalyst of raw material weight 1%, with nitrogen 1.5Mpa pressurize 15 minutes.Pressurize is finished, hydrogen punching row 3 times, and logical hydrogen 4.0Mpa, 38～42 DEG C of hydrogenation reactions 7 hours. HydrogenationFinish, leave standstill 1 hour, 350 order press filtration dischargings obtain the about 700kg of liquid material. Centralized collection catalyst, concentratedMethyl alcohol is to small size crystallization, centrifugal crude product.
4] synthetic 4-Amino-3-phenylbutyric acid hydrochloride
To in the crude product of preparing through step 3 and the clean reactor of purified water, add. Stirring intensification material to 90～100 DEG C, start to drip hydrochloric acid, drip to finish and stir 1 hour, be cooled to 30 DEG C of following centrifugal discharges approximately 480～500kg. Mother liquor centralized collection after centrifugal, 80～90 DEG C of recovered under reduced pressure hydrochloric acid of temperature control, treat that material is stickyThick, the 30 DEG C of centrifugal discharges of lowering the temperature. The absolute ethyl alcohol fine work that is recrystallized to obtain.
Claims (3)
1. a synthetic method for 4-Amino-3-phenylbutyric acid hydrochloride, is characterized in that, comprises the following steps:
1] prepare ethyl benzoylacetate
Under the condition lower than 15 DEG C, Xiang Shuizhong adds ethyl acetoacetate to stir, and adds sodium hydroxide solution and chlorobenzoyl chloride and the pH of reaction system is maintained between 9～11 when stirring; The mass ratio of described water and ethyl acetoacetate is 1:0.2～0.3, and ethyl acetoacetate and chlorobenzoyl chloride are identical in quality;
After having reacted, reaction system is warming up to 50～60 DEG C and leaves standstill 4～5h;
After having left standstill, reaction system is cooled to below 25 DEG C, adds saturated aqueous common salt to stir 10～30h, after having stirred, carry out separatory processing, grease washing, anhydrous sodium sulfate drying, obtains ethyl benzoylacetate; The mass ratio of described ethyl acetoacetate and saturated aqueous common salt is 1:0.3～0.5;
2] prepare nitrostyrolene
2.1] get nitromethane, benzaldehyde, NaOH and methyl alcohol and react 2～4h under 0 DEG C of environment, add water, hydrochloric acid after having reacted, centrifugal treating obtains yellow nitrostyrolene finished product; The mass ratio of described nitromethane, benzaldehyde, NaOH and methyl alcohol is 1:1.6～2.0:3.1～3.4:6.3～6.6, and the mass ratio of nitromethane and water is 1:1.5～1.7, and water and hydrochloric acid are identical in quality;
2.2] get nitrostyrolene that step 2.1 makes and toluene, ethyl benzoylacetate, triethylamine back flow reaction 3～5h, concentration and recovery toluene, concentrate adds the cooling placement crystallization of methyl alcohol, obtains Michael addition adducts α-phenyl-β-benzoyl-γ-nitro ethyl butyrate; The mass ratio of described nitrostyrolene and toluene, ethyl benzoylacetate, triethylamine is 1:4～6:1.5～2:0.1～0.3;
3] prepare addition compound product
α-phenyl-β-benzoyl-γ-nitro ethyl butyrate and the methyl alcohol of being prepared by step 2 to gained carry out the pressurize processing of 10～30min under dry hyperbaric environment with the mass ratio of 1:4～6, pressure is 1.3～1.8MPa; Pressurize completes and in backward dry hyperbaric environment, passes into 4.0MPa hydrogen punching row 2～4 times, rushes to stir after drained one-tenth to be warming up to 38～42 DEG C and carry out hydrogenation reaction 6～8h, leaves standstill 1～2h after completing, and has left standstill rear concentrated methyl alcohol to small size crystallization, centrifugal must crude product;
4] stir after being warming up to 90～100 DEG C and drip hydrochloric acid prepare the crude product of gained and purified water through step 3, be added dropwise to complete rear continuation and stir 1～2h, after completing, stirring is cooled to 30 DEG C of following centrifugal discharges, centrifugal rear mother liquid obtained centralized collection, 80～90 DEG C of recovered under reduced pressure hydrochloric acid of temperature control, treat material thickness, be cooled to 30 DEG C of following centrifugal discharges, to gained material by the absolute ethyl alcohol fine work that is recrystallized to obtain.
2. the synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride according to claim 1, it is characterized in that, described step 1] in, lower than under the condition of 15 DEG C to add in water ethyl acetoacetate stir specifically by ice bath mode in reactor by water management lower than 15 DEG C, then add ethyl acetoacetate.
3. the synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride according to claim 2, is characterized in that, described step 1] in, the concentration that adds sodium hydroxide solution when stirring is that 40%, pH maintains 10.
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| CN105153006A (en) * | 2015-10-08 | 2015-12-16 | 常州强达宝成化工有限公司 | Synthetic method for 4-phenyl-2-pyrrolidone |
| CN107188808A (en) * | 2017-05-22 | 2017-09-22 | 江苏斯威森生物医药工程研究中心有限公司 | A kind of synthetic method of the phenylbutyric acid hydrochloride of 4 amino 3 |
| CN107903175A (en) * | 2017-10-27 | 2018-04-13 | 浙江闰土研究院有限公司 | The preparation method of ethyl benzoylacetate |
| CN109096157A (en) * | 2018-09-28 | 2018-12-28 | 湖南文理学院 | A kind of synthetic method of (E)-alkenyl sulfone compound |
| CN109369591A (en) * | 2018-11-29 | 2019-02-22 | 陕西嘉禾生物科技股份有限公司 | A kind of synthetic method of diosmetin |
| CN111393312A (en) * | 2020-03-11 | 2020-07-10 | 福建科宏生物工程股份有限公司 | Preparation method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride by one-pot method and product prepared by same |
| CN116554029B (en) * | 2023-05-12 | 2024-03-29 | 河北民族师范学院 | A kind of synthesis method of aromatic formyl ethyl acetate |
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| GB1385846A (en) * | 1973-05-18 | 1975-03-05 | Le G Venny Ped I Im A I Gertse | Chlorohydrate of beta-phenyl-ypsilon-amino butyric acid and process for producing same |
| CN101033195A (en) * | 2007-04-17 | 2007-09-12 | 安徽省郎溪县科联实业有限公司 | Method of preparing 4-amino-3-phenyl butyric hydrochloride |
| CN102115450A (en) * | 2009-12-30 | 2011-07-06 | 上海新浦化工厂有限公司 | Preparation method for 4-amino-3-phenylbutyric acid |
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