CN102295680B - Preparation method of aspartame - Google Patents
Preparation method of aspartame Download PDFInfo
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- CN102295680B CN102295680B CN2011102458472A CN201110245847A CN102295680B CN 102295680 B CN102295680 B CN 102295680B CN 2011102458472 A CN2011102458472 A CN 2011102458472A CN 201110245847 A CN201110245847 A CN 201110245847A CN 102295680 B CN102295680 B CN 102295680B
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- phenylalanine
- aspartyl
- water
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- formyl
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- 108010011485 Aspartame Proteins 0.000 title claims abstract description 44
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 title claims abstract description 44
- 229960003438 aspartame Drugs 0.000 title claims abstract description 44
- 235000010357 aspartame Nutrition 0.000 title claims abstract description 44
- 239000000605 aspartame Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 59
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 22
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims abstract description 20
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims abstract description 20
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 20
- 229960005261 aspartic acid Drugs 0.000 claims abstract description 20
- 235000019253 formic acid Nutrition 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000012452 mother liquor Substances 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 34
- 238000009413 insulation Methods 0.000 claims description 24
- 235000021050 feed intake Nutrition 0.000 claims description 22
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 claims description 19
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 19
- 238000005119 centrifugation Methods 0.000 claims description 17
- 239000012528 membrane Substances 0.000 claims description 17
- 238000005469 granulation Methods 0.000 claims description 10
- 230000003179 granulation Effects 0.000 claims description 10
- 238000012856 packing Methods 0.000 claims description 10
- 238000001728 nano-filtration Methods 0.000 claims description 9
- 238000006386 neutralization reaction Methods 0.000 claims description 9
- 238000013467 fragmentation Methods 0.000 claims description 8
- 238000006062 fragmentation reaction Methods 0.000 claims description 8
- 238000012216 screening Methods 0.000 claims description 8
- -1 granulation Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- AAQFSZFQCXLMNT-ACMTZBLWSA-N (3s)-3-amino-4-[[(2s)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid;hydrochloride Chemical compound Cl.OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 AAQFSZFQCXLMNT-ACMTZBLWSA-N 0.000 abstract 1
- 229940009098 aspartate Drugs 0.000 abstract 1
- 235000019659 mouth feeling Nutrition 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 36
- 238000005516 engineering process Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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- Peptides Or Proteins (AREA)
Abstract
The invention relates to a preparation method of aspartame, which belongs to the technical field of a chemosynthetic method of the aspartame and comprises the following steps of: feeding methanoic acid, acetic anhydride and L-aspartic acid for reaction to prepare N-formoxyl-alpha-L- anhydride aspartate, then adding sodium hydroxide for reaction to prepare N-formoxyl-alpha-L-aspartyl-L-phenylalanine, then adding methanol, hydrochloric acid and water for reaction to prepare alpha-L-aspartyl-L-phenylalanine methyl ester hydrochloride, subsequently adding the water to prepare a wet product of the aspartame, and finally carrying out post-processing to obtain a finished product of the aspartame. Through the aspartame obtained by the preparation method, the problems of insufficient sweetness, poorer mouth feeling, poor product appearance, poor dissolving performance and the like caused by high relative-impurity content and high electrical conductivity are solved.
Description
Technical field
The present invention relates to a kind of preparation method of aspartame, belong to the chemical synthesis technical field of aspartame.
Background technology
Aspartame (Aspartame), chemical name is N-2-L-aspartyl-L-phenylalanine methyl esters, it is a kind of novel synthetic peptide class sweeting agent, sugariness is about sucrose to 200 times, this sweeting agent has been got permission more than 100 countries and regions to use at present, be applied to more than 6000 kind of beverage, in the products such as food and medicine.Aspartame is because its security of generally acknowledging, low-heat Gao Tian, and characteristics such as taste is pure have become the leading product of global high intensity sweetner at present, the consumption rapid growth, global demand is above 30000 tons/year at present.
One of main production method of aspartame is to adopt chemical synthesis, and the chemical synthesis of our domestic employing, because Technology and equipment are backward relatively, factor such as key point control is not strict causes quality product and to compare gap abroad bigger.
Summary of the invention
For addressing the above problem, the invention provides a kind of high quality, the preparation method of aspartame cheaply.
For achieving the above object, the technical solution adopted in the present invention is:
A kind of preparation method of aspartame comprises following concrete steps:
1. under 30 ℃ ~ 35 ℃ temperature condition, formic acid, diacetyl oxide, L-aspartic acid are fed intake, mix, wherein the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.3 ~ 0.5:1.2 ~ 1.8:0.8 ~ 1.2, under 45 ℃ ± 1 ℃ temperature condition, carried out insulation reaction 12 hours then, carry out centrifugation again, obtain N-formyl-α-L-aspartic anhydride and mother liquor one.This is anhydridization reaction in the formyl.
2. the N-formyl-α that 1. step is obtained-L-aspartic anhydride, under 0 ℃ ~ 10 ℃ temperature condition, feed intake, mix with L-phenylalanine, water, sodium hydroxide, wherein the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 0.8 ~ 1.2:0.8 ~ 1.2:5 ~ 7:1.8 ~ 2.5, under 3 ℃ ~ 5 ℃ temperature condition, carried out insulation reaction 3 ~ 5 hours then, then between adjust pH to 0.5 ~ 1, carry out the high pressure sheet frame again and separate, obtain N-formyl-2-L-aspartyl-L-phenylalanine and mother liquor two.This is condensation reaction.
3. the N-formyl-2-L-aspartyl-L-phenylalanine that 2. step is obtained, under 55 ℃ ~ 60 ℃ temperature condition, feed intake, mix with methyl alcohol, hydrochloric acid, water, wherein the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 0.8 ~ 1.2:0.1 ~ 0.3:0.5 ~ 1:0.2 ~ 0.6, under 25 ℃ ~ 28 ℃ temperature condition, carried out insulation reaction 168 hours then, carry out centrifugation again, obtain 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and mother liquor three.This is the hydrolysis esterification.
4. the 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride that 3. step is obtained, under 40 ℃ ~ 45 ℃ temperature condition, feed intake with water, mix, wherein the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 0.5 ~ 1.5:15 ~ 20, under 55 ℃ ~ 60 ℃ temperature condition, carried out neutralization reaction 0.5 ~ 1 hour then, then between adjust pH to 4.8 ~ 5.1, wash again, the high pressure sheet frame separates, obtain wet product aspartame and mother liquor four, the product aspartame that will wet is at last carried out fragmentation more successively, mix, granulation, ball blast, oven dry, screening, packing, finished product.This is neutralization reaction.
As the further setting of such scheme, described step 1. in, the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.4 ~ 0.5:1.5 ~ 1.7:0.9 ~ 1.1.
Described step 2. in, the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 0.9 ~ 1.1:0.9 ~ 1.1:5.5 ~ 6.5:2 ~ 2.4.
Described step 3. in, the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 0.9 ~ 1.1:0.2 ~ 0.3:0.6 ~ 0.8:0.4 ~ 0.6.
Described step 4. in, the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 0.8 ~ 1.2:16 ~ 18.
Described step 1. in, the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.425:1.6:1; Step 2. in, the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 1.05:1:6:2.2; Step 3. in, the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 1:0.25:0.75:0.52; Step 4. in, the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 1:17.
Described mother liquor two, mother liquor four all carry out membrane sepn by nanofiltration membrane and reclaim.
Described step 4. in, granulating working procedure adopts wet granulator, specification comprises 80-100 order and 150-200 order.
The preparation method of aspartame of the present invention has following beneficial effect:
1, connects peptide
Adopt water law to connect the peptide method, abandoned institute's use Glacial acetic acid in the original technology, because reaction solvent changes, technology obtains simplifying, equipment and operational requirement are not harsh, the intermediate product yield is brought up to existing technology average yield 96.8% from former technology average yield 94.6%, and the change of reaction solvent makes the mother liquor cost recovery descend 31%.When cost is reduced, also solved the environmental problem that the acetate acid tail gas discharging causes.
2, separate
In the product if related impurities content height, the specific conductivity height, will cause the taste variation of product, the sugariness deficiency, phenomenons such as outward appearance jaundice, be head it off, we adopt high-efficient washing, filter two-in-one equipment, substitute the mode of traditional centrifugation, adopt repeatedly washing automatically continuously, change original block material washing and be the washing of pulpous state material, after online detection reached inner quality standard, with the contracting of diaphragm type high pressure sheet frame disjoining pressure, solid content was about 80%, guaranteeing under the prerequisite of former yield, in the finished product related substances content from U.S. FCC standard code≤2% drop to≤1%.Specific conductivity drops to 30us/cm from average 100us/cm.
3, granulation
Domestic manufacturer is nearly all with processing 30-60 order macrobead product or powder-like product packing and selling, but like this downstream client caused inconvenience in many uses, increases as dust, and product is mobile poor, and dissolution rate waits slowly.We adopt the wet pulverization granulation, and the technology of ball blast shaping produces the 80-100 order of uniform specification, 150-200 order granulated product, and can adjust size-grade distribution specification, the good fluidity of product according to user's actual needs, dissolution rate is fast, and is non-caked, and packing is used all very convenient.
4, reclaim
We adopt nanofiltration membrane to concentrate and reclaim various materials, substitute original distil process, reduced energy consumption on the one hand significantly, reduced the interpolation of auxiliary materials such as soda acid, and reduced blowdown, on the other hand owing to stopped unfavourable condition such as High Temperature High Pressure, solved the racemization difficult problem that amino acid produces in removal process, the intermediate product rate of recovery improves 7%, and the quality of recovered material is improved simultaneously, and reclamation rate reaches 100%.Quality raising and cost decline to the finished product have very great help.
5, use
Aspartame generally is applied to food service industry, through after our technological improvement, quality product is brought up to the pharmaceutical grade requirement, has begun to promote the use of in medicine, healthcare products, and domestic have the large-scale pharmacy corporation of several families as breathing out the product that medicine six factories, Chengde JINGFUKANG medicine company etc. have adopted us.
The aspartame that makes by the present invention has following basic mechanical design feature:
| Sequence number | Test item | Unit | Standard value | Result data | Individual event is judged |
| 1 | Aspartame content (butt meter) | % | 98.0～102.0 | 99.6 | Meet |
| 2 | Weight loss on drying | % | ≤4.5 | 3.5 | Meet |
| 3 | Specific rotatory power | ° | +14.5～+16.5 | +15.6 | Meet |
| 4 | Ignition residue | % | ≤0.2 | 0.03 | Meet |
| 5 | The pH value | ? | 4.5～6.0 | 5.2 | Meet |
| 6 | Plumbous (pb) | mg/kg | ≤1 | Do not detect | Meet |
| 7 | Arsenic | mg/kg | ≤2 | ﹤0.5 | Meet |
| 8 | Specific conductivity | mg/kg | ≤30 | 25 | Meet |
| 9 | Related substances | % | ≤2.0 | 0.8 | Meet |
Embodiment
The present invention is further illustrated below in conjunction with specific embodiment.
Embodiment 1
A kind of preparation method of aspartame comprises following concrete steps:
1. under 30 ℃ temperature condition, formic acid, diacetyl oxide, L-aspartic acid are fed intake, mix, wherein the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.425:1.6:1, under 45 ℃ temperature condition, carried out insulation reaction 12 hours then, carry out centrifugation again, obtain N-formyl-α-L-aspartic anhydride and mother liquor one;
2. the N-formyl-α that 1. step is obtained-L-aspartic anhydride, under 0 ℃ temperature condition, feed intake, mix with L-phenylalanine, water, sodium hydroxide, wherein the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 1.05:1:6:2.2, under 4 ℃ temperature condition, carried out insulation reaction 3 hours then, follow adjust pH to 0.5, carry out the high pressure sheet frame again and separate, obtain N-formyl-2-L-aspartyl-L-phenylalanine and mother liquor two;
3. the N-formyl-2-L-aspartyl-L-phenylalanine that 2. step is obtained, under 55 ℃ temperature condition, feed intake, mix with methyl alcohol, hydrochloric acid, water, wherein the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 1:0.25:0.75:0.52, under 25 ℃ temperature condition, carried out insulation reaction 168 hours then, carry out centrifugation again, obtain 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and mother liquor three;
4. the 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride that 3. step is obtained, under 40 ℃ temperature condition, feed intake, mix with water, wherein the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 1:17, under 55 ℃ temperature condition, carried out neutralization reaction 1 hour then, follow adjust pH to 4.8, wash again, the high pressure sheet frame separates, obtain wet product aspartame and mother liquor four, the product aspartame that will wet is at last carried out fragmentation, mixing, granulation, ball blast, oven dry, screening, packing, finished product more successively.
Above-mentioned, mother liquor two, mother liquor four all carry out membrane sepn by nanofiltration membrane and reclaim.Step 4. in, granulating working procedure adopts wet granulator, specification comprises 80-100 order and 150-200 order.
Embodiment 2
A kind of preparation method of aspartame comprises following concrete steps:
1. under 35 ℃ temperature condition, formic acid, diacetyl oxide, L-aspartic acid are fed intake, mix, wherein the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.3:1.2:0.8, under 44 ℃ temperature condition, carried out insulation reaction 12 hours then, carry out centrifugation again, obtain N-formyl-α-L-aspartic anhydride and mother liquor one;
2. the N-formyl-α that 1. step is obtained-L-aspartic anhydride, under 2 ℃ temperature condition, feed intake, mix with L-phenylalanine, water, sodium hydroxide, wherein the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 0.8:0.8:5:1.8, under 3 ℃ temperature condition, carried out insulation reaction 4 hours then, follow adjust pH to 0.8, carry out the high pressure sheet frame again and separate, obtain N-formyl-2-L-aspartyl-L-phenylalanine and mother liquor two;
3. the N-formyl-2-L-aspartyl-L-phenylalanine that 2. step is obtained, under 58 ℃ temperature condition, feed intake, mix with methyl alcohol, hydrochloric acid, water, wherein the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 0.8:0.1:0.5:0.2, under 26 ℃ temperature condition, carried out insulation reaction 168 hours then, carry out centrifugation again, obtain 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and mother liquor three;
4. the 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride that 3. step is obtained, under 42 ℃ temperature condition, feed intake, mix with water, wherein the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 0.5:15, under 58 ℃ temperature condition, carried out neutralization reaction 0.5 hour then, follow adjust pH to 5.1, wash again, the high pressure sheet frame separates, obtain wet product aspartame and mother liquor four, the product aspartame that will wet is at last carried out fragmentation, mixing, granulation, ball blast, oven dry, screening, packing, finished product more successively.
Above-mentioned, mother liquor two, mother liquor four all carry out membrane sepn by nanofiltration membrane and reclaim.Step 4. in, granulating working procedure adopts wet granulator, specification comprises 80-100 order and 150-200 order.
Embodiment 3
A kind of preparation method of aspartame comprises following concrete steps:
1. under 32 ℃ temperature condition, formic acid, diacetyl oxide, L-aspartic acid are fed intake, mix, wherein the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.4:1.5:0.9, under 46 ℃ temperature condition, carried out insulation reaction 12 hours then, carry out centrifugation again, obtain N-formyl-α-L-aspartic anhydride and mother liquor one;
2. the N-formyl-α that 1. step is obtained-L-aspartic anhydride, under 5 ℃ temperature condition, feed intake, mix with L-phenylalanine, water, sodium hydroxide, wherein the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 0.9:0.9:5.5:2, under 5 ℃ temperature condition, carried out insulation reaction 5 hours then, follow adjust pH to 1, carry out the high pressure sheet frame again and separate, obtain N-formyl-2-L-aspartyl-L-phenylalanine and mother liquor two;
3. the N-formyl-2-L-aspartyl-L-phenylalanine that 2. step is obtained, under 60 ℃ temperature condition, feed intake, mix with methyl alcohol, hydrochloric acid, water, wherein the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 0.9:0.2:0.6:0.4, under 28 ℃ temperature condition, carried out insulation reaction 168 hours then, carry out centrifugation again, obtain 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and mother liquor three;
4. the 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride that 3. step is obtained, under 45 ℃ temperature condition, feed intake, mix with water, wherein the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 0.8:16, under 60 ℃ temperature condition, carried out neutralization reaction 0.8 hour then, follow adjust pH to 5.0, wash again, the high pressure sheet frame separates, obtain wet product aspartame and mother liquor four, the product aspartame that will wet is at last carried out fragmentation, mixing, granulation, ball blast, oven dry, screening, packing, finished product more successively.
Above-mentioned, mother liquor two, mother liquor four all carry out membrane sepn by nanofiltration membrane and reclaim.Step 4. in, granulating working procedure adopts wet granulator, specification comprises 80-100 order and 150-200 order.
Embodiment 4
A kind of preparation method of aspartame comprises following concrete steps:
1. under 33 ℃ temperature condition, formic acid, diacetyl oxide, L-aspartic acid are fed intake, mix, wherein the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.5:1.7:1.1, under 45 ℃ temperature condition, carried out insulation reaction 12 hours then, carry out centrifugation again, obtain N-formyl-α-L-aspartic anhydride and mother liquor one;
2. the N-formyl-α that 1. step is obtained-L-aspartic anhydride, under 8 ℃ temperature condition, feed intake, mix with L-phenylalanine, water, sodium hydroxide, wherein the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 1.1:1.1:6.5:2.4, under 4 ℃ temperature condition, carried out insulation reaction 4 hours then, follow adjust pH to 0.6, carry out the high pressure sheet frame again and separate, obtain N-formyl-2-L-aspartyl-L-phenylalanine and mother liquor two;
3. the N-formyl-2-L-aspartyl-L-phenylalanine that 2. step is obtained, under 57 ℃ temperature condition, feed intake, mix with methyl alcohol, hydrochloric acid, water, wherein the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 1.1:0.3:0.8:0.6, under 27 ℃ temperature condition, carried out insulation reaction 168 hours then, carry out centrifugation again, obtain 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and mother liquor three;
4. the 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride that 3. step is obtained, under 41 ℃ temperature condition, feed intake, mix with water, wherein the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 1.2:18, under 57 ℃ temperature condition, carried out neutralization reaction 0.6 hour then, follow adjust pH to 4.9, wash again, the high pressure sheet frame separates, obtain wet product aspartame and mother liquor four, the product aspartame that will wet is at last carried out fragmentation, mixing, granulation, ball blast, oven dry, screening, packing, finished product more successively.
Above-mentioned, mother liquor two, mother liquor four all carry out membrane sepn by nanofiltration membrane and reclaim.Step 4. in, granulating working procedure adopts wet granulator, specification comprises 80-100 order and 150-200 order.
Embodiment 5
A kind of preparation method of aspartame comprises following concrete steps:
1. under 34 ℃ temperature condition, formic acid, diacetyl oxide, L-aspartic acid are fed intake, mix, wherein the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.5:1.8:1.2, under 45 ℃ temperature condition, carried out insulation reaction 12 hours then, carry out centrifugation again, obtain N-formyl-α-L-aspartic anhydride and mother liquor one;
2. the N-formyl-α that 1. step is obtained-L-aspartic anhydride, under 10 ℃ temperature condition, feed intake, mix with L-phenylalanine, water, sodium hydroxide, wherein the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 1.2:1.2:7:2.5, under 5 ℃ temperature condition, carried out insulation reaction 3 hours then, follow adjust pH to 0.7, carry out the high pressure sheet frame again and separate, obtain N-formyl-2-L-aspartyl-L-phenylalanine and mother liquor two;
3. the N-formyl-2-L-aspartyl-L-phenylalanine that 2. step is obtained, under 56 ℃ temperature condition, feed intake, mix with methyl alcohol, hydrochloric acid, water, wherein the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 1.2:0.3:1:0.6, under 28 ℃ temperature condition, carried out insulation reaction 168 hours then, carry out centrifugation again, obtain 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and mother liquor three;
4. the 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride that 3. step is obtained, under 43 ℃ temperature condition, feed intake, mix with water, wherein the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 1.5:20, under 56 ℃ temperature condition, carried out neutralization reaction 0.7 hour then, follow adjust pH to 5.0, wash again, the high pressure sheet frame separates, obtain wet product aspartame and mother liquor four, the product aspartame that will wet is at last carried out fragmentation, mixing, granulation, ball blast, oven dry, screening, packing, finished product more successively.
Above-mentioned, mother liquor two, mother liquor four all carry out membrane sepn by nanofiltration membrane and reclaim.Step 4. in, granulating working procedure adopts wet granulator, specification comprises 80-100 order and 150-200 order.
Embodiment 6
A kind of preparation method of aspartame comprises following concrete steps:
1. under 30 ℃ temperature condition, formic acid, diacetyl oxide, L-aspartic acid are fed intake, mix, wherein the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is 0.45:1.6:1, under 45 ℃ temperature condition, carried out insulation reaction 12 hours then, carry out centrifugation again, obtain N-formyl-α-L-aspartic anhydride and mother liquor one;
2. the N-formyl-α that 1. step is obtained-L-aspartic anhydride, under 6 ℃ temperature condition, feed intake, mix with L-phenylalanine, water, sodium hydroxide, wherein the weight ratio between N-formyl-α-L-aspartic anhydride, L-phenylalanine, water, the sodium hydroxide is 1:1:6:2.1, under 4 ℃ temperature condition, carried out insulation reaction 5 hours then, follow adjust pH to 1, carry out the high pressure sheet frame again and separate, obtain N-formyl-2-L-aspartyl-L-phenylalanine and mother liquor two;
3. the N-formyl-2-L-aspartyl-L-phenylalanine that 2. step is obtained, under 56 ℃ temperature condition, feed intake, mix with methyl alcohol, hydrochloric acid, water, wherein the weight ratio between N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, the water is 1:0.25:0.7:0.5, under 26 ℃ temperature condition, carried out insulation reaction 168 hours then, carry out centrifugation again, obtain 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and mother liquor three;
4. the 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride that 3. step is obtained, under 40 ℃ temperature condition, feed intake, mix with water, wherein the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 1:18, under 58 ℃ temperature condition, carried out neutralization reaction 1 hour then, follow adjust pH to 5.0, wash again, the high pressure sheet frame separates, obtain wet product aspartame and mother liquor four, the product aspartame that will wet is at last carried out fragmentation, mixing, granulation, ball blast, oven dry, screening, packing, finished product more successively.
Above-mentioned, mother liquor two, mother liquor four all carry out membrane sepn by nanofiltration membrane and reclaim.Step 4. in, granulating working procedure adopts wet granulator, specification comprises 80-100 order and 150-200 order.
Above-described embodiment only is used for explaining inventive concept of the present invention, but not to the restriction of rights protection of the present invention, allly utilizes this design that the present invention is carried out the change of unsubstantiality, all should fall into protection scope of the present invention.
Claims (3)
1. the preparation method of an aspartame is characterized in that comprising following concrete steps:
1. under 30 ℃～35 ℃ temperature condition, formic acid, diacetyl oxide, L-aspartic acid are fed intake, mix, wherein the weight ratio between formic acid, diacetyl oxide, the L-aspartic acid is that the weight ratio between 0.3:1.2:0.8 or formic acid, diacetyl oxide, the L-aspartic acid is 0.5:1.7:1.1, under 45 ℃ ± 1 ℃ temperature condition, carried out insulation reaction 12 hours then, carry out centrifugation again, obtain N-formyl-α-L-aspartic anhydride and mother liquor one;
2. the N-formyl-α that 1. step is obtained-L-aspartic anhydride, under 0 ℃～10 ℃ temperature condition with the L-phenylalanine, water, sodium hydroxide feeds intake, mix, N-formyl-α-L-aspartic anhydride wherein, the L-phenylalanine, water, weight ratio between the sodium hydroxide is 0.8:0.8:5:1.8 or N-formyl-α-L-aspartic anhydride, the L-phenylalanine, water, weight ratio between the sodium hydroxide is 1.1:1.1:6.5:2.4, under 3 ℃～5 ℃ temperature condition, carried out insulation reaction 3～5 hours then, then between adjust pH to 0.5～1, carry out the high pressure sheet frame again and separate, obtain N-formyl-2-L-aspartyl-L-phenylalanine and mother liquor two;
3. the N-formyl-2-L-aspartyl-L-phenylalanine that 2. step is obtained, under 55 ℃～60 ℃ temperature condition, with methyl alcohol, hydrochloric acid, water feeds intake, mix, N-formyl-2-L-aspartyl-L-phenylalanine wherein, methyl alcohol, hydrochloric acid, weight ratio between the water is 0.8:0.1:0.5:0.2 or N-formyl-2-L-aspartyl-L-phenylalanine, methyl alcohol, hydrochloric acid, weight ratio between the water is 1.1:0.3:0.8:0.6, under 25 ℃～28 ℃ temperature condition, carried out insulation reaction 168 hours then, carry out centrifugation again, obtain 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and mother liquor three;
4. the 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride that 3. step is obtained, under 40 ℃～45 ℃ temperature condition, feed intake with water, mix, wherein the weight ratio between 2-L-aspartyl-L-phenylalanine methyl ester hydrochloride and the water is 0.5～1.5:15～20, under 55 ℃～60 ℃ temperature condition, carried out neutralization reaction 0.5～1 hour then, then between adjust pH to 4.8～5.1, wash again, the high pressure sheet frame separates, obtain wet product aspartame and mother liquor four, the product aspartame that will wet is at last carried out fragmentation more successively, mix, granulation, ball blast, oven dry, screening, packing, finished product.
2. the preparation method of aspartame according to claim 1, it is characterized in that: described mother liquor two, mother liquor four all carry out membrane sepn by nanofiltration membrane and reclaim.
3. the preparation method of aspartame according to claim 1 is characterized in that: described step 4. in, granulating working procedure adopts wet granulator, specification comprises 80-100 order and 150-200 order.
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| CN102816204A (en) * | 2012-08-13 | 2012-12-12 | 南通市常海食品添加剂有限公司 | Preparation process of aspartame |
| CN103626842A (en) * | 2012-08-21 | 2014-03-12 | 常州光辉生物科技有限公司 | Water phase condensation method for production of aspartame |
| CN103626843B (en) * | 2012-08-21 | 2015-10-28 | 常州光辉生物科技有限公司 | Impurity control method in a kind of aspartame production |
| CN103626841B (en) * | 2012-08-21 | 2016-01-20 | 常州光辉生物科技有限公司 | In a kind of aspartame and crystallization method |
| CN103626840A (en) * | 2012-08-21 | 2014-03-12 | 常州光辉生物科技有限公司 | Preparation method for aspartame from raw materials containing chiral isomer |
| CN104109089B (en) * | 2014-07-18 | 2016-03-02 | 江苏维多股份有限公司 | One reclaims methyl acetate method from aspartame factory effluent |
| CN105315329A (en) * | 2014-08-04 | 2016-02-10 | 南京集美新型材料研发有限公司 | Condensation method in production process of N-alpha-L-aspartyl-L-phenylalanine 1-methyl ester |
| CN104788539A (en) * | 2015-03-27 | 2015-07-22 | 江苏汉光生物工程有限公司 | Preparing process for aspartame |
| CN106967153A (en) * | 2017-05-22 | 2017-07-21 | 孟州市华兴生物化工有限责任公司 | A kind of preparation method of Aspartame |
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| BE1007425A3 (en) * | 1993-08-30 | 1995-06-13 | Holland Sweetener Co | Method and apparatus for the recovery of raw materials in the cooking aspartame. |
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