CN117624282A - Selective crystallization method of alanyl-L-tyrosine hydrate - Google Patents
Selective crystallization method of alanyl-L-tyrosine hydrate Download PDFInfo
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- 229960004441 tyrosine Drugs 0.000 title claims abstract description 147
- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000010956 selective crystallization Methods 0.000 title claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 120
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 75
- 239000002904 solvent Substances 0.000 claims abstract description 52
- 239000012043 crude product Substances 0.000 claims abstract description 43
- 238000001035 drying Methods 0.000 claims abstract description 42
- 238000001914 filtration Methods 0.000 claims abstract description 38
- 238000003756 stirring Methods 0.000 claims abstract description 36
- 239000000047 product Substances 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 239000007787 solid Substances 0.000 claims description 30
- 238000001816 cooling Methods 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000008213 purified water Substances 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 abstract description 15
- 150000004683 dihydrates Chemical class 0.000 abstract description 13
- 239000013078 crystal Substances 0.000 abstract description 12
- 150000004684 trihydrates Chemical class 0.000 abstract description 12
- 150000004677 hydrates Chemical class 0.000 abstract description 7
- 230000009466 transformation Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000012046 mixed solvent Substances 0.000 abstract description 2
- 230000001376 precipitating effect Effects 0.000 abstract description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- 239000012065 filter cake Substances 0.000 description 20
- 238000004321 preservation Methods 0.000 description 18
- 239000000203 mixture Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000003064 anti-oxidating effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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Abstract
The invention discloses a hydrate selective crystallization method of alanyl-L-tyrosine, belonging to the technical field of organic synthesis. At the appropriate temperature and solvent ratio: dispersing the crude alanyl-L-tyrosine in methanol for crystal transformation to obtain a hydrate-free product; dissolving in water and precipitating to obtain a trihydrate; dispersing in a mixed solvent to obtain a monohydrate or a dihydrate, and adjusting the adding sequence and conditions to obtain the monohydrate or the dihydrate; the solvent is common methanol or ethanol, so flexible adjustment is more needed. The target hydrate can be obtained under the condition of the patent no matter the alanyl-L-tyrosine crude product is a few hydrates, and the repeatability is good. The solvents are common solvents, the conditions are mild, the process mainly comprises stirring, filtering and drying, the waste water can be recycled to recover methanol or ethanol, the operation is simple, and the method is suitable for industrial production. Different crystalline hydrates are suitable for different fields due to different physicochemical properties.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a hydrate selective crystallization method of alanyl-L-tyrosine.
Background
alanyl-L-tyrosine has various biological activities such as antibiosis, antioxidation, blood pressure reduction and the like, so that the alanyl-L-tyrosine is widely applied to various fields such as food, medicine, cosmetics and the like. In the field of foods, alanyl-L-tyrosine can be used as a food additive to increase the nutritional value of foods and improve the mouthfeel; in the field of medicine, alanyl-L-tyrosine can be applied to a plurality of fields of antibiosis, antioxidation, blood pressure reduction and the like; in the field of cosmetics, alanyl-L-tyrosine can be used for research and application in various aspects such as anti-aging, whitening and the like. Meanwhile, alanyl-L-tyrosine can be used as an excellent culture medium raw material.
At present, a number of related documents have been reported in detail about the synthesis of alanyl-L-tyrosine, but few methods have been mentioned about the synthesis of different crystalline hydrates of alanyl-L-tyrosine. Different crystalline hydrates can be better suitable for different fields due to different physicochemical properties. Therefore, the development of a synthetic method for different crystal hydrates of alanyl-L-tyrosine, which is simple to operate, good in reproducibility and suitable for industrial production, is necessary.
Disclosure of Invention
The invention provides a hydrate selective crystallization method of alanyl-L-tyrosine, which takes alanyl-L-tyrosine crude product as an initial raw material to respectively obtain pure anhydrous compound, monohydrate, dihydrate and trihydrate of alanyl-L-tyrosine through different feeding sequences, different solvent ratios, different crystallization temperatures and the like. The technical scheme is as follows:
the embodiment of the invention provides a method for selectively crystallizing alanyl-L-tyrosine hydrate, which comprises the following steps:
preparation of alanyl-L-tyrosine anhydrate (moisture content 0-2%): gradually adding the alanyl-L-tyrosine crude product into the solvent A, stirring for 4-6h at 30-60 ℃, gradually cooling to 10-30 ℃, filtering and drying to obtain the alanyl-L-tyrosine non-hydrate. Wherein the solvent A is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, etc. The mass ratio of the alanyl-L-tyrosine crude product to the solvent A is 1:3-6.
Preparation of alanyl-L-tyrosine monohydrate (moisture content 5.5-7.5%): mixing the alanyl-L-tyrosine crude product with water, heating to 60-90 ℃, gradually dropwise adding the solvent B after dissolving, gradually cooling to 10-30 ℃ after dropwise adding, filtering and drying to obtain alanyl-L-tyrosine monohydrate. Wherein the solvent B is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, etc. The mass ratio of the alanyl-L-tyrosine crude product to the water to the solvent B is 1:1.5-4.0:2-6.
Preparation of alanyl-L-tyrosine dihydrate (moisture content 10-14%): gradually adding the alanyl-L-tyrosine crude product into the solvent C, stirring for 4-6h at 30-60 ℃, gradually dropwise adding water, keeping the temperature of 40-60 ℃ until crystalline solid appears in the reaction liquid, gradually cooling to 10-30 ℃, filtering and drying to obtain the alanyl-L-tyrosine dihydrate. Wherein the solvent C is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, etc. The mass ratio of the alanyl-L-tyrosine crude product to the water to the solvent C is 1:3-4:3-6.
Preparation of alanyl-L-tyrosine trihydrate (16.5-18.5%): gradually adding alanyl-L-tyrosine crude product into water, gradually heating to 50-80 ℃, stirring until the alanyl-L-tyrosine crude product is completely dissolved, gradually dropwise adding solvent D, gradually cooling to 0-5 ℃ after the dropwise adding, filtering and drying to obtain alanyl-L-tyrosine trihydrate. Wherein the solvent D is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone or no solvent. The mass ratio of the alanyl-L-tyrosine crude product to the water to the solvent D is 1:4.3-8.0:0-5.
Wherein the crude alanyl-L-tyrosine is selected from alanyl-L-tyrosine anhydrous, alanyl-L-tyrosine monohydrate, alanyl-L-tyrosine dihydrate and/or alanyl-L-tyrosine trihydrate.
Specifically, the crude alanyl-L-tyrosine product in the embodiment of the invention is alanyl-L-tyrosine monohydrate prepared synthetically (which is the existing synthetic method).
Wherein, the drying conditions are as follows: drying under reduced pressure at 50-70deg.C.
Preferably, solvent A is methanol, solvent B is ethanol, solvent C is methanol, and solvent D is no solvent.
Preferably, the water is purified water.
Preferably, the process for preparing alanyl-L-tyrosine anhydrous compound is as follows: gradually adding alanyl-L-tyrosine crude product into methanol, stirring at 50-60deg.C for 4-6 hr, gradually cooling to 10-30deg.C, filtering, and drying at 50-70deg.C under reduced pressure to obtain alanyl-L-tyrosine non-hydrate. Wherein, the mass ratio of the alanyl-L-tyrosine crude product to the methanol is 1:3-6.
Preferably, the process for preparing alanyl-L-tyrosine monohydrate is: mixing the alanyl-L-tyrosine crude product with purified water, heating to 80-85deg.C, dissolving, gradually dripping ethanol, gradually cooling to 10-30deg.C, filtering, and drying under reduced pressure at 50-70deg.C to obtain alanyl-L-tyrosine monohydrate. Wherein, the mass ratio of the alanyl-L-tyrosine crude product to the purified water to the ethanol is 1:1.5-4.0:2-6.
Preferably, the process for preparing alanyl-L-tyrosine dihydrate is: gradually adding alanyl-L-tyrosine crude product into methanol, stirring at 50-60deg.C for 4-6 hr, gradually dripping purified water, maintaining at 50-60deg.C until crystalline solid appears in the reaction solution, gradually cooling to 10-30deg.C, filtering, and drying under reduced pressure at 50-70deg.C to obtain alanyl-L-tyrosine dihydrate. Wherein, the mass ratio of the alanyl-L-tyrosine crude product to the purified water to the methanol is 1:3-4:3-6.
Preferably, the process for preparing alanyl-L-tyrosine trihydrate is: gradually adding alanyl-L-tyrosine crude product into purified water, gradually heating to 65-70deg.C, stirring to completely dissolve, gradually cooling to 0-5deg.C, filtering, and drying under reduced pressure at 50-70deg.C to obtain alanyl-L-tyrosine trihydrate. Wherein, the mass ratio of the alanyl-L-tyrosine crude product to the purified water is 1:4.3-8.0.
At the appropriate temperature and solvent ratio: dispersing the crude alanyl-L-tyrosine in methanol for crystal transformation to obtain a hydrate-free product; dissolving in water and precipitating to obtain a trihydrate; dispersing in a mixed solvent to obtain a monohydrate or a dihydrate, and adjusting the adding sequence and conditions to obtain the monohydrate or the dihydrate; the solvent is common methanol or ethanol, and can be flexibly adjusted according to the needs. The target hydrate can be obtained under the condition of the patent no matter the alanyl-L-tyrosine crude product is a few hydrates, and the repeatability is good. The solvents are common solvents (methanol or ethanol), the conditions are mild (the temperature is not very high), the process mainly comprises stirring, filtering and drying, the waste water can be recycled to recycle the methanol or the ethanol (recycling equipment is very mature), the operation is simple, and the method is suitable for industrial production. Particularly under the specific solvent (methanol, ethanol or no solvent), the yield can be ensured, and the pure target hydrate can be ensured. Different crystalline hydrates are suitable for different fields (such as anhydrous compounds with highest alanyl-L-tyrosine content, suitable for being used as chemical raw materials, monohydrate and dihydrate alanyl-L-tyrosine are suitable for being used as culture media, and trihydrate has the best solubility and is suitable for being used as a preparation) due to different physicochemical properties.
Detailed Description
The present invention will be described in further detail below in order to make the objects, technical solutions and advantages of the present invention more apparent.
Preparation of alanyl-L-tyrosine anhydrous compound
1.1 in a 1000ml three-port flask 250g of methanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (dihydrate, moisture 11.1%) was gradually added in portions over about 1 hour. The reaction system is gradually heated to 40-50 ℃, is stirred for 5 hours under heat preservation, is gradually cooled to 15-25 ℃, and is stirred for 1 hour under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white powdery solid 41.56g with a molar yield of 95.0% and water content of 0.3% detected by Karl Fischer method.
1.2 in a 1000ml three-port flask 200g of methanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (monohydrate, moisture 6.3%) was gradually added in portions over 1 hour. The reaction system is gradually heated to 50-60 ℃, is stirred for 6 hours under heat preservation, is gradually cooled to 10-15 ℃ and is stirred for 1 hour under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white powdery solid 45.2g with a molar yield of 96.9% and water content of 0.5% detected by Karl Fischer method.
1.3 in a 1000ml three-port flask 300g of methanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (trihydrate, moisture 16.9%) was gradually added in portions over about 1 hour. The reaction system is gradually heated to 55-65 ℃, is stirred for 4 hours under heat preservation, is gradually cooled to 10-15 ℃, and is stirred for 1 hour under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white powdery solid 38.1g with a molar yield of 92.5% and water content of 0.5% detected by Karl Fischer method.
1.4 in a 1000ml three-port flask 200g of ethanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (monohydrate, moisture 6.3%) was gradually added in portions over 1 hour. The reaction system is gradually heated to 50-60 ℃, is stirred for 6 hours under heat preservation, is gradually cooled to 10-15 ℃ and is stirred for 1 hour under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white powdery solid 44.0g with a molar yield of 94.3% (calculated by anhydrous compound as product) and water content of 2.8% detected by Karl Fischer method.
1.5 in a 1000ml three-port flask 200g of methanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (trihydrate, moisture 16.9%) was gradually added in portions over 1 hour. The reaction system is gradually heated to 40-50 ℃, is stirred for 3 hours under heat preservation, is gradually cooled to 10-15 ℃ and is stirred for 1 hour under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white powdery solid 40.4g with a molar yield of 98.2% (calculated by anhydrous compound as product) and water content of 3.5% detected by Karl Fischer method.
As can be seen from example 1.4, when the alanyl-L-tyrosine anhydrous compound is prepared, ethanol is used as a solvent, and the product contains a small amount of mixed crystals, and methanol is better than ethanol. Through experiments, isopropanol, tetrahydrofuran, acetonitrile and acetone are inferior to ethanol in effect, and detailed description is omitted in this example.
As can be seen from example 1.5, when the alanyl-L-tyrosine anhydrous compound is prepared, if the heat preservation and stirring time is insufficient, mixed crystals are contained in the product, and pure alanyl-L-tyrosine anhydrous compound cannot be obtained.
Preparation of (II) alanyl-L-tyrosine monohydrate
2.1, 125g of water is added into a 1000ml three-port reaction bottle, stirring is started, 50g of alanyl-L-tyrosine crude product (dihydrate, water content 11.1%) is gradually added, the reaction system is gradually heated to 70-75 ℃, and the system is gradually dissolved. 200g of ethanol was gradually added dropwise to the system over about 2 hours, and the mixture was stirred at 70-75℃for 1 hour. The system is gradually cooled to 15-25 ℃, and is stirred for 2h under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white granular solid 42.6g with a molar yield of 90.9% and water content of 7.1% detected by Karl Fischer method.
2.2, 150g of water is added into a 1000ml three-port reaction bottle, stirring is started, 50g of alanyl-L-tyrosine crude product (anhydrous compound, water content is 0.4%) is gradually added, the reaction system is gradually heated to 80-85 ℃, and the system is gradually dissolved. 250g of ethanol is gradually added dropwise into the system, after about 2 hours, the mixture is stirred for 1 hour at 75-80 ℃. The system is gradually cooled to 10-15 ℃, and is stirred for 2h under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white granular solid 50.1g with a molar yield of 93.5% and water content of 6.8% detected by Karl Fischer method.
2.3, 120g of water is added into a 1000ml three-port reaction bottle, stirring is started, 50g of alanyl-L-tyrosine crude product (trihydrate, water content is 16.9%) is gradually added, the reaction system is gradually heated to 65-75 ℃, and the system is gradually dissolved. 260g of ethanol was gradually added dropwise to the system over about 2 hours, and the mixture was stirred at 65-75℃for 1 hour. The system is gradually cooled to 10-20 ℃, and is stirred for 2h under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white granular solid 39.3g with a molar yield of 89.1% and water content of 6.5% detected by Karl Fischer method.
2.4, 125g of water is added into a 1000ml three-port reaction bottle, stirring is started, 50g of alanyl-L-tyrosine crude product (dihydrate, water content 11.1%) is gradually added, the reaction system is gradually heated to 40-50 ℃, the temperature is kept for 1h, and the system is not dissolved. 200g of methanol was gradually added dropwise to the system over about 2 hours, and the mixture was stirred at 70-75℃for 1 hour. The system is gradually cooled to 15-25 ℃, and is stirred for 2h under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white granular solid 43.5g with a molar yield of 92.8% (calculated as monohydrate) and water content of 9.6% detected by Karl Fischer method.
2.5, 220g of water is added into a 1000ml three-port reaction bottle, stirring is started, 50g of alanyl-L-tyrosine crude product (trihydrate, water content is 16.9%) is gradually added, the reaction system is gradually heated to 65-75 ℃, and the system is gradually dissolved. 260g of ethanol was gradually added dropwise to the system over about 2 hours, and the mixture was stirred at 65-75℃for 1 hour. The system is gradually cooled to 10-20 ℃, and is stirred for 2h under heat preservation. Filtering, collecting filter cake, drying under reduced pressure at 60-70deg.C to constant weight to obtain white granular solid 33.22g with a molar yield of 75.3% (calculated as monohydrate) and water content of 8.7% detected by Karl Fischer method.
As can be seen from example 2.4, when alanyl-L-tyrosine monohydrate is prepared, incomplete crystal transformation can be caused if the system is not dissolved and the temperature is insufficient, and part of crude product can keep the original crystal form.
As can be seen from example 2.5, in the preparation of alanyl-L-tyrosine monohydrate, if the amounts of crude product, solvent and water are not in specific proportions, such as excessive water, the problems of lower yield, incomplete crystal transformation and the like can be caused.
Preparation of (III) alanyl-L-tyrosine dihydrate
3.1 in a 1000ml three-port flask 200g of methanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (monohydrate, moisture 6.3%) was gradually added in portions over 1 hour. The reaction system is gradually heated to 40-50 ℃, and is stirred for 5h under heat preservation. 180g of water was gradually added dropwise to the reaction system, and the mixture was stirred at 40-50℃until a crystalline solid appeared. Then gradually cooling to 20-30 ℃, preserving heat and stirring for 2h. Filtering, collecting filter cake, drying under reduced pressure at 50-60deg.C to constant weight to obtain white sandy solid 49.9g, and detecting water content by Karl Fischer method at 93.6% molar yield.
3.2 in a 1000ml three-port flask 250g of methanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (anhydrous compound, moisture 0.4%) was gradually added in portions over 1 hour. The reaction system is gradually heated to 50-60 ℃, and is stirred for 4 hours while maintaining the temperature. 200g of water was gradually added dropwise to the reaction system, and the mixture was stirred at 50 to 60℃to give a crystalline solid. Then gradually cooling to 10-15 ℃, preserving heat and stirring for 2h. Filtering, collecting filter cake, drying under reduced pressure at 50-60deg.C to constant weight to obtain white sandy solid 54.5g with a molar yield of 95.4%, and water content of 12.5% detected by Karl Fischer method.
3.3 in a 1000ml three-port flask 235g of methanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (trihydrate, moisture 16.9%) was gradually added in portions over about 1 hour. The reaction system is gradually heated to 45-55 ℃, and is kept warm and stirred for 5h. 150g of water was gradually added dropwise to the reaction system, and the mixture was stirred at 50 to 60℃to give a crystalline solid. Then gradually cooling to 15-25 ℃, preserving heat and stirring for 2h. Filtering, collecting filter cake, drying under reduced pressure at 50-60deg.C to constant weight to obtain white sandy solid 42.9g with molar yield of 91.2%, and detecting water content of 12.3% by Karl Fischer method.
3.4 in a 1000ml three-port flask 200g of ethanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (monohydrate, moisture 6.3%) was gradually added in portions over 1 hour. The reaction system is gradually heated to 40-50 ℃, and is stirred for 5h under heat preservation. 180g of water was gradually added dropwise to the reaction system, and the mixture was stirred at 50-60℃to give a crystalline solid. Then gradually cooling to 20-30 ℃, preserving heat and stirring for 2h. Filtering, collecting filter cake, drying under reduced pressure at 50-60deg.C to constant weight to obtain white sandy solid 51.1g with a molar yield of 95.8% (calculated as dihydrate), and detecting water content by Karl Fischer method of 15.3%.
3.5 in a 1000ml three-port flask 200g of methanol was added, stirring was started, and 50g of crude alanyl-L-tyrosine (monohydrate, moisture 6.3%) was gradually added in portions over 1 hour. The reaction system is gradually heated to 50-60 ℃, and is stirred for 3 hours while maintaining the temperature. 125g of water was gradually added dropwise to the reaction system, and the mixture was stirred at 40-50℃to give a crystalline solid. Then gradually cooling to 20-30 ℃, preserving heat and stirring for 2h. Filtering, collecting filter cake, drying under reduced pressure at 50-60deg.C to constant weight to obtain white sandy solid 49.3g with a molar yield of 92.5% (calculated as dihydrate), and measuring water content by Karl Fischer method of 9.5%.
As can be seen from example 3.4, when the alanyl-L-tyrosine anhydrous compound is prepared, ethanol is used as a solvent, and mixed crystals are contained in the product (part of the trihydrate is judged to be generated), and methanol is better than ethanol. Through experiments, isopropanol, tetrahydrofuran, acetonitrile and acetone are inferior to ethanol in effect, and detailed description is omitted in this example.
As can be seen from example 3.5, when alanyl-L-tyrosine dihydrate is prepared, mixed crystals (containing alanyl-L-tyrosine monohydrate) occur if the amounts of crude product, solvent and water are not in the specific proportions and the incubation and stirring times are insufficient, e.g., the amount of water is too small.
In addition, in the preparation of alanyl-L-tyrosine dihydrate, if no solids are present, the temperature is reduced and the precipitated product is a mixture of part of the dihydrate and the trihydrate.
Preparation of alanyl-L-tyrosine trihydrate
4.1, 250g of water and 50g of crude alanyl-L-tyrosine (anhydrous compound, water content 0.4%) are added into a 500ml three-port reaction bottle, the temperature is gradually increased to 70-75 ℃, and the system is gradually dissolved. After the system is completely dissolved, the temperature is gradually reduced to 0-5 ℃ and the temperature is kept for 2 hours. Filtering, collecting filter cake, drying under reduced pressure at 65-70deg.C to constant weight to obtain white crystalline solid 55.3g with a molar yield of 91.1% and water content of 17.3% detected by Karl Fischer method.
4.2 in a 500ml three-port flask 300g of water and 50g of crude alanyl-L-tyrosine (monohydrate, moisture 6.3%) are added, the temperature is gradually raised to 60-65℃and the system is gradually dissolved. After the system is completely dissolved, the temperature is gradually reduced to 0-5 ℃ and the temperature is kept for 2 hours. Filtering, collecting filter cake, drying under reduced pressure at 65-70deg.C to constant weight to obtain white crystalline solid 50.5g with a molar yield of 89.2% and water content of 18.7% detected by Karl Fischer method.
4.3 in a 500ml three-port flask, 275g of water and 50g of crude alanyl-L-tyrosine (dihydrate, moisture 11.1%) were added, and the temperature was gradually raised to 55-65℃and the system gradually dissolved. After the system is completely dissolved, the temperature is gradually reduced to 0-5 ℃ and the temperature is kept for 2 hours. Filtering, collecting filter cake, drying under reduced pressure at 65-70deg.C to constant weight to obtain white crystalline solid 47.0g with molar yield 88.5% and water content 17.5% detected by Karl Fischer method.
4.4 adding 450g of water and 50g of crude alanyl-L-tyrosine (anhydrous compound, water content 0.4%) into a 500ml three-port reaction bottle, gradually heating to 50-60 ℃ and gradually dissolving the system. After the system is completely dissolved, the temperature is gradually reduced to 0-5 ℃ and the temperature is kept for 2 hours. Filtering, collecting filter cake, drying under reduced pressure at 65-70deg.C to constant weight to obtain white crystalline solid 45.7g with a molar yield of 75.3% and water content of 17.2% detected by Karl Fischer method.
4.5, 300g of water and 50g of crude alanyl-L-tyrosine (monohydrate, water content 6.3%) are added into a 500ml three-port reaction bottle, the temperature is gradually increased to 50-60 ℃, the system is not dissolved, 300g of methanol is gradually added dropwise, the temperature is gradually reduced to 0-5 ℃ after the dropwise addition, and the temperature is kept for 2 hours. Filtering, collecting filter cake, drying under reduced pressure at 65-70deg.C to constant weight to obtain white crystalline solid with 53.0g and molar yield of 93.5% (calculated by using product as trihydrate), and detecting moisture content by Karl Fischer method to 16.3%.
As can be seen from example 4.4, in the preparation of alanyl-L-tyrosine trihydrate, if the crude product and water are not used in a particular ratio, for example, the water is used in an excessive amount; the crystal transformation effect meets the requirement, but the yield is lower.
As can be seen from example 4.5, in the preparation of alanyl-L-tyrosine trihydrate, if the crude product, water and solvent are not used in the particular proportions and the system is not clear, for example, more than a specified amount of organic solvent is added; the product contains mixed crystals.
The foregoing description of the exemplary embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (9)
1. A process for the selective crystallization of a hydrate of alanyl-L-tyrosine, said process comprising:
preparation of alanyl-L-tyrosine anhydrate: gradually adding a crude alanyl-L-tyrosine into a solvent A, stirring for 4-6 hours at 30-60 ℃, gradually cooling to 10-30 ℃, filtering and drying to obtain the alanyl-L-tyrosine anhydrous compound, wherein the solvent A is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or acetone, and the mass ratio of the crude alanyl-L-tyrosine to the solvent A is 1:3-6;
preparation of alanyl-L-tyrosine monohydrate: mixing and heating the alanyl-L-tyrosine crude product and water to 60-90 ℃, gradually dropwise adding a solvent B after dissolving, gradually cooling to 10-30 ℃ after dropwise adding, filtering and drying to obtain alanyl-L-tyrosine monohydrate, wherein the solvent B is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or acetone, and the mass ratio of the alanyl-L-tyrosine crude product to the water to the solvent B is 1:1.5-4.0:2-6;
preparation of alanyl-L-tyrosine dihydrate: gradually adding alanyl-L-tyrosine crude product into a solvent C, stirring for 4-6h at 30-60 ℃, gradually dropwise adding water, keeping the temperature of 40-60 ℃ until crystalline solid appears in the reaction liquid, gradually cooling to 10-30 ℃, filtering and drying to obtain alanyl-L-tyrosine dihydrate, wherein the solvent C is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or acetone, and the mass ratio of the alanyl-L-tyrosine crude product, water to the solvent C is 1:3-4:3-6;
preparation of alanyl-L-tyrosine trihydrate: gradually adding a crude alanyl-L-tyrosine product into water, gradually heating to 50-80 ℃, stirring until the crude alanyl-L-tyrosine product is completely dissolved, gradually dropwise adding a solvent D, gradually cooling to 0-5 ℃ after the completion of the dropwise adding, filtering and drying to obtain the alanyl-L-tyrosine trihydrate, wherein the solvent D is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone or no solvent, and the mass ratio of the crude alanyl-L-tyrosine product to the water to the solvent D is 1:4.3-8.0:0-5;
the crude alanyl-L-tyrosine is selected from alanyl-L-tyrosine anhydrous, alanyl-L-tyrosine monohydrate, alanyl-L-tyrosine dihydrate and/or alanyl-L-tyrosine trihydrate.
2. The method for selectively crystallizing an alanyl-L-tyrosine hydrate as claimed in claim 1, wherein said alanyl-L-tyrosine crude product is a synthetically prepared alanyl-L-tyrosine monohydrate.
3. The method for selectively crystallizing an alanyl-L-tyrosine hydrate as claimed in claim 1, wherein the drying conditions are as follows: drying under reduced pressure at 50-70deg.C.
4. The method for selectively crystallizing an alanyl-L-tyrosine hydrate as claimed in claim 1, wherein the solvent a is methanol, the solvent B is ethanol, the solvent C is methanol, and the solvent D is a non-solvent.
5. The method for selectively crystallizing an alanyl-L-tyrosine hydrate as claimed in claim 1, wherein said water is purified water.
6. The method for selectively crystallizing an alanyl-L-tyrosine hydrate as claimed in claim 1, wherein the process for preparing an alanyl-L-tyrosine non-hydrate comprises:
gradually adding alanyl-L-tyrosine crude product into methanol, stirring at 50-60deg.C for 4-6 hr, gradually cooling to 10-30deg.C, filtering, and drying at 50-70deg.C under reduced pressure to obtain alanyl-L-tyrosine anhydrous compound; the mass ratio of the alanyl-L-tyrosine crude product to the methanol is 1:3-6.
7. The method for selectively crystallizing an alanyl-L-tyrosine hydrate as claimed in claim 1, wherein the process for preparing the alanyl-L-tyrosine monohydrate is as follows:
mixing the alanyl-L-tyrosine crude product with purified water, heating to 80-85deg.C, dissolving, gradually dropwise adding ethanol, gradually cooling to 10-30deg.C, filtering, and drying under reduced pressure at 50-70deg.C to obtain alanyl-L-tyrosine monohydrate; the mass ratio of the alanyl-L-tyrosine crude product to the purified water to the ethanol is 1:1.5-4.0:2-6.
8. The method for selectively crystallizing an alanyl-L-tyrosine hydrate as claimed in claim 1, wherein the process for preparing alanyl-L-tyrosine dihydrate is as follows:
gradually adding alanyl-L-tyrosine crude product into methanol, stirring at 50-60deg.C for 4-6 hr, gradually dripping purified water, maintaining the temperature at 50-60deg.C until crystalline solid appears in the reaction solution, gradually cooling to 10-30deg.C, filtering, and drying under reduced pressure at 50-70deg.C to obtain alanyl-L-tyrosine dihydrate; the mass ratio of the alanyl-L-tyrosine crude product to the purified water to the methanol is 1:3-4:3-6.
9. The method for selectively crystallizing an alanyl-L-tyrosine hydrate as claimed in claim 1, wherein the process for preparing the alanyl-L-tyrosine trihydrate is as follows:
gradually adding alanyl-L-tyrosine crude product into purified water, gradually heating to 65-70deg.C, stirring to completely dissolve, gradually cooling to 0-5deg.C, filtering, and drying under reduced pressure at 50-70deg.C to obtain alanyl-L-tyrosine trihydrate; the mass ratio of the alanyl-L-tyrosine crude product to the purified water is 1:4.3-8.0.
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