CN113956154A - D-lactic acid-14C, preparation method and application - Google Patents
D-lactic acid-14C, preparation method and application Download PDFInfo
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- CN113956154A CN113956154A CN202111346713.XA CN202111346713A CN113956154A CN 113956154 A CN113956154 A CN 113956154A CN 202111346713 A CN202111346713 A CN 202111346713A CN 113956154 A CN113956154 A CN 113956154A
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- lactic acid
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- JVTAAEKCZFNVCJ-PAMGXOTGSA-N (2R)-2-hydroxy(114C)propanoic acid Chemical compound [14C]([C@H](O)C)(=O)O JVTAAEKCZFNVCJ-PAMGXOTGSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 59
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- QNAYBMKLOCPYGJ-SDZBVLERSA-N alanine-1-14c Chemical compound C[C@H](N)[14C](O)=O QNAYBMKLOCPYGJ-SDZBVLERSA-N 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 N-acetyl-DL-alanine-1-14C Chemical compound 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 11
- QNAYBMKLOCPYGJ-YZRHJBSPSA-N 2-amino(114C)propanoic acid Chemical compound NC(C)[14C](=O)O QNAYBMKLOCPYGJ-YZRHJBSPSA-N 0.000 claims abstract description 10
- 101710150975 N-acyl-L-amino acid amidohydrolase Proteins 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 10
- 229930182843 D-Lactic acid Natural products 0.000 claims abstract description 9
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims abstract description 9
- 229940022769 d- lactic acid Drugs 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- 230000003287 optical effect Effects 0.000 claims description 11
- 238000009987 spinning Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 6
- 235000011152 sodium sulphate Nutrition 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- YBADLXQNJCMBKR-UHFFFAOYSA-N (4-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000010438 heat treatment Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 3
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 235000010288 sodium nitrite Nutrition 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 239000007788 liquid Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000010622 cold drawing Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QNAYBMKLOCPYGJ-HQMMCQRPSA-N N[14CH](C)C(=O)O Chemical compound N[14CH](C)C(=O)O QNAYBMKLOCPYGJ-HQMMCQRPSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of preparation of chemical raw materials, and discloses a preparation method and application of 14C-labeled D-lactic acid. The method comprises the following steps: adding acetic acid and acetic anhydride into DL-alanine-1-14C, and heating to react to obtain N-acetyl-DL-alanine-1-14C; dissolving N-acetyl-DL-alanine-1-14C in water, adding L-aminoacylase at a certain temperature and pH to react to obtain a first batch of L-alanine-1-14C, recovering the filtrate, and repeating the steps to obtain a second batch of L-alanine-1-14C; and combining the two batches of L-alanine-1-14C, and reacting with sodium nitrite to obtain the D-lactic acid-1-14C. The method has the advantages of mild reaction conditions, simple reaction device, convenient operation, high purity and chirality of the obtained product, and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of preparation of chemical raw materials, and particularly relates to a preparation method and application of 14C-labeled D-lactic acid.
Background
The description of the background of the invention pertaining to the related art to which this invention pertains is given for the purpose of illustration and understanding only of the summary of the invention and is not to be construed as an admission that the applicant is explicitly or implicitly admitted to be prior art to the date of filing this application as first filed with this invention.
D-lactic acid is an important chemical raw material and an intermediate, and is widely applied to the industries of medicine, agriculture, food, materials and the like. At present, the main production methods of D-lactic acid comprise a chemical synthesis method, an enzyme catalysis method and a microbial fermentation method, and at present, the microbial fermentation method is mainly adopted, wherein wheat, corn and the like are used as raw materials, starch is saccharified by enzyme, and then the D-lactic acid is obtained by biological fermentation and transformation. However, the limitation of the biological fermentation method is very large, and with the vigorous development of the pharmaceutical and pesticide industries in China, D-lactic acid is required to be used for synthesizing a plurality of intermediates, and the requirement on the optical purity of the D-lactic acid is more than 99%. The current preparation method can not meet the requirement.
Disclosure of Invention
The embodiment of the invention aims to provide a preparation method and application of 14C-labeled D-lactic acid, and aims to overcome the defects in the prior art and provide a method which has the advantages of cheap and easily-obtained reaction raw materials, mild reaction conditions, simple reaction device, convenient operation and product purification and fills the domestic blank. The product of the invention has high optical purity and chemical purity.
The purpose of the embodiment of the invention is realized by the following technical scheme:
a preparation method of D-lactic acid-1-14C is characterized by comprising the following steps:
(1) synthesis of N-acetyl-DL-alanine-1-14C: under the protection of nitrogen, adding acetic acid into DL-alanine-1-14C for dissolving, adding acetic anhydride at the temperature of 100-150 ℃, keeping the temperature for continuous reaction after the addition is finished, and directly distilling to remove acetic acid and acetic anhydride with low boiling point after the reaction is completed to obtain N-acetyl-DL-alanine-1-14C;
(2) synthesis of L-alanine-1-14C: adding water to dissolve the N-acetyl-DL-alanine-1-14C, and adjusting the pH value to 7-9; adding L-aminoacylase at 37-40 deg.C, reacting at the above temperature, adjusting pH to acidity after reaction, filtering with 0.22 μm water film, spin-drying, adjusting isoelectric point, naturally crystallizing, filtering to obtain first batch of L-alanine-1-14C, recovering filtrate, and repeating step (2) to obtain second batch of L-alanine-1-14C;
(3) synthesis of D-lactic acid-1-14C: dissolving two batches of the obtained L-alanine-1-14C in AcOH/H2O ═ 1/4 solution, and dropwise adding NaNO at 0 DEG C2And (3) after the water solution is added, naturally raising the temperature to room temperature for reaction, after the reaction is completed, removing the solvent by spinning, adjusting the pH value to be acidic, extracting by EA, drying the organic phase sodium sulfate, and spinning to obtain the D-lactic acid-1-14C.
Preferably, in the step (1), the feeding molar ratio of the DL-alanine-1-14C, the acetic acid and the acetic anhydride is 1:40-100: 3-8.
Preferably, in the step (1), the acetyl raw material is at least one of acetic anhydride, acetyl chloride or 4-nitrophenyl acetate.
Preferably, in step (2), the pH of the reaction is controlled to be 7-9.
Preferably, in the step (2), the temperature of the reaction is controlled to be 37-40 ℃.
Preferably, in step (2), the L-aminoacylase is at least 1500 units/mg.
Preferably, in step (3), the NaNO is2The concentration of the aqueous solution is 0.5mol/L-2 mol/L.
In a second aspect, the invention provides D-lactic acid-14C, wherein the D-lactic acid-14C is prepared by the preparation method.
Furthermore, the chemical purity of the D-lactic acid-14C is not less than 99 percent, and the optical purity reaches 100 percent.
In a third aspect, the application of D-lactic acid-14C is to use D-lactic acid-14C in the preparation of degradable materials, wherein the D-lactic acid-14C is prepared by the preparation method.
The embodiment of the invention has the following beneficial effects:
the invention avoids using complex or difficult-to-obtain labeled compounds as the starting raw materials, directly uses the commercially available labeled DL-alanine-14C as the starting raw material (potassium cyanide-14C or barium carbonate-14C can also be used for synthesizing DL-alanine-1-14C, the synthesis is very simple), and simplifies the synthetic process of the D-lactic acid-1-14C;
the method has mild reaction conditions and simple reaction device, can obtain the high-purity D-lactic acid-1-14C by adopting the high-activity L-aminoacylase hydrolysis reaction, has only one configuration, has the optical purity of 100 percent, and can be used for the labeled metabolism of medicines and pesticides.
Detailed Description
The present application is further described below with reference to examples.
In the following description, different "one embodiment" or "an embodiment" may not necessarily refer to the same embodiment, in order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art. Various embodiments may be replaced or combined, and other embodiments may be obtained according to the embodiments without creative efforts for those skilled in the art.
The reaction for preparing the D-lactic acid-14C of the invention is as follows:
specifically, the preparation method of the D-lactic acid-14C is characterized by comprising the following steps:
synthesis of N-acetyl-DL-alanine-1-14C: under the protection of nitrogen, adding acetic acid into DL-alanine-1-14C for dissolving, adding acetic anhydride at the temperature of 100-150 ℃, keeping the temperature for continuous reaction after the addition is finished, and directly distilling to remove acetic acid and acetic anhydride with low boiling point after the reaction is completed to obtain N-acetyl-DL-alanine-1-14C;
synthesis of L-alanine-1-14C: adding water to dissolve the N-acetyl-DL-alanine-1-14C, and adjusting the pH value to 7-9; adding L-aminoacylase at 37-40 deg.C, reacting at the above temperature, adjusting pH to acidity after reaction, filtering with 0.22 μm water film, spin-drying, adjusting isoelectric point, naturally crystallizing, filtering to obtain first batch of L-alanine-1-14C, recovering filtrate, and repeating step (2) to obtain second batch of L-alanine-1-14C;
synthesis of D-lactic acid-1-14C: dissolving two batches of the obtained L-alanine-1-14C in AcOH/H2O ═ 1/4 solution, and dropwise adding NaNO at 0 DEG C2And (3) after the water solution is added, naturally raising the temperature to room temperature for reaction, after the reaction is completed, removing the solvent by spinning, adjusting the pH value to be acidic, extracting by EA, drying the organic phase sodium sulfate, and spinning to obtain the D-lactic acid-1-14C.
Example 1
Synthesis of N-acetyl-DL-alanine-1-14C: a150 ml single-mouth bottle is connected with a bisection tube, a condenser tube and a tee joint, and is blown hot, pulled cold by an oil pump and protected by nitrogen. Adding DL-alanine-1-14C (1.0g,10.98mmol,1.0eq), pumping for 5min under nitrogen protection, adding acetic acid 50ml, heating to 120 deg.C, reacting for 5min, adding acetic anhydride (6.72g,65.87mmol,6.0eq), and reacting for 5h at 120 deg.C. TLC shows that the reaction is complete, acetic acid and acetic anhydride are dried by spinning at 40-60 ℃, a water tape is added for 3 times, the reaction is dried by spinning, and an oil pump is used for pulling at 60 ℃ for 1h, so that 1.34g N-acetyl-DL-alanine-1-14C (yellow viscous liquid, yield 91.5%) is obtained.
Synthesis of L-alanine-1-14C: in a 150ml single-neck flask, N-acetyl-DL-alanine-1-14C (1.34g,10.07mmol,1.0eq) was added and then the mixture was dissolved in water. The reaction mixture was adjusted to pH 7.88 with 10% LiOH, reacted at 37 ℃ and reacted with L-aminoacylase at 37 ℃ for 48 hours. The reaction was stopped, 1MHCl was added to adjust pH to 4.0,22 μm water membrane filtration was performed 2 times, spin-dried, isoelectric point was adjusted, refrigerator was left overnight at 4 deg.C, filtration was performed, the filter cake was washed with 4 deg.C ethanol, and the filter cake was pulled dry to give 105mg L-alanine-1-14C (white solid). The filtrate was spin-dried to give a yellow viscous liquid. The filtrate was spin-dried and the previous procedure was repeated to give 102mg of L-alanine-1-14C (white solid). Combine together to give 207mg of L-alanine-1-14C (yield 22.6%). The chemical purity is 99 percent, and the optical purity reaches 100 percent.
Synthesis of D-lactic acid-1-14C: 25ml single-mouth bottle and nitrogen protection. Adding L-alanine-1-14C (207mg,2.27mmol,1.0eq), dissolving with 10ml of AcOH/H2O ═ 1/4 (ultrasonic), adding 2MNaNO dropwise at 5 deg.C2Aqueous solution (314mg,4.54mmol,2.0eq) (dropwise addition for about 35min), reaction at 10 ℃ for 13h, reaction at 25 ℃ for 4h, TLC has been essentially reversedAnd finishing. The water was dried to a viscous solid at 35-40 ℃, adjusted to pH 2 with 1MHCl, extracted several times with aqueous EA (TLC monitored for complete extraction), dried over sodium sulfate and dried to yield 169 mgD-lactic acid-1-14C (colorless liquid, 81% yield). The chemical purity is 99 percent, and the optical purity reaches 100 percent.
Example 2
Synthesis of N-acetyl-DL-alanine-1-14C: a250 ml single-mouth bottle is connected with a bisection tube, a condenser tube and a tee joint, hot blowing is carried out, an oil pump is used for cold drawing, and nitrogen protection is carried out. Adding DL-alanine-1-14C (1.95g,21.46mmol,1.0eq), pumping for 5min under nitrogen protection, adding acetic acid 100ml, heating to 130 deg.C, reacting for 5min, adding acetic anhydride (10.96g,107.3mmol,5.0eq), and reacting for 5h at 130 deg.C. TLC shows that the reaction is complete, acetic acid and acetic anhydride are dried by spinning at 40-60 ℃, a water tape is added for 3 times, the reaction is dried by spinning, and an oil pump is used for pulling at 60 ℃ for 1h to obtain 2.63g N-acetyl-DL-alanine-1-14C (yellow viscous liquid, yield 92.3%).
Synthesis of L-alanine-1-14C: a250 ml single-neck flask was charged with N-acetyl-DL alanine-1-14C (2.63g,19.76mmol,1.0eq) and then water-dissolved. The reaction mixture was adjusted to pH 8.3 with 10% LiOH (about 3 hours), and reacted at 39 ℃ with L-aminoacylase added thereto at 39 ℃ for 48 hours. Stopping reaction, adding 1MHCl to adjust pH to 4.0.22 micron water film, filtering for 2 times, spin-drying, adjusting isoelectric point, standing overnight at 4 deg.C in refrigerator, filtering, washing filter cake with 4 deg.C ethanol, and drying to obtain 194mg L-alanine-1-14C (white solid). The filtrate was spin-dried to give a yellow viscous liquid. The filtrate was spin-dried and the previous steps were repeated to give 244mg of L-alanine-1-14C (white solid). Combine them together to give 438mg of L-alanine-1-14C (yield 24.3%). The chemical purity is 99 percent, and the optical purity reaches 100 percent.
Synthesis of D-lactic acid-1-14C: 50ml single-mouth bottle and nitrogen protection. Adding L-alanine-1-14C (438mg,4.81mmol,1.0eq), adding 20ml AcOH/H2O ═ 1/4, dissolving (ultrasonic), adding 1MNaNO dropwise at 0 deg.C2Aqueous solution (664mg,9.62mmol,2.0eq) (dropwise addition for about 45min), reaction at 10 ℃ for 13h, at 25 ℃ for 4h, TLC had substantially completed. Spin-dry the water to a viscous solid at 35-40 ℃, add 1MHCl to adjust pH to 2, extract aqueous EA multiple times (TLC monitored extraction completed), dry organic sodium sulfate, and spin-dry to give 375 mgD-lactic acid-1-14C (colorless liquid, yield 85%). Chemical purity99 percent and the optical purity reaches 100 percent.
Example 3
Synthesis of N-acetyl-DL-alanine-1-14C: a250 ml single-mouth bottle is connected with a bisection tube, a condenser tube and a tee joint, hot blowing is carried out, an oil pump is used for cold drawing, and nitrogen protection is carried out. Adding DL-alanine-1-14C (2.5g,28.06mmol,1.0eq), pumping for 5min under nitrogen protection, adding acetic acid 100ml, heating to 140 deg.C, reacting for 5min, adding acetic anhydride (20.05g,196.4mmol,7.0eq), and reacting for 5h at 140 deg.C. TLC shows that the reaction is complete, acetic acid and acetic anhydride are dried in a rotary manner at 40-60 ℃, a water hose is added for 3 times, the reaction is dried in a rotary manner, and an oil pump is used for pulling at 60 ℃ for 1h to obtain 3.55g N-acetyl-DL-alanine-1-14C (yellow viscous liquid, yield 95%).
Synthesis of L-alanine-1-14C: a250 ml single-neck flask was charged with N-acetyl-DL alanine-1-14C (3.55g,26.67mmol,1.0eq) and then water-dissolved. The reaction mixture was adjusted to pH 8.0 with 10% LiOH (about 3 hours), and reacted at 39 ℃ with L-aminoacylase added thereto at 39 ℃ for 48 hours. Stopping reaction, adding 1MHCl to adjust pH to 4.0.22 μm, filtering with water film for 2 times, spin-drying, adjusting isoelectric point, standing overnight at 4 deg.C in refrigerator, filtering, washing filter cake with 4 deg.C ethanol, and drying to obtain 300mg L-alanine-1-14C (white solid). The filtrate was spin-dried to give a yellow viscous liquid. The filtrate was spin-dried and the previous steps were repeated to give 310mg of L-alanine-1-14C (white solid). Combine together to give 610mg of L-alanine-1-14C (yield 25.1%). The chemical purity is 99 percent, and the optical purity reaches 100 percent.
Synthesis of D-lactic acid-1-14C: 50ml single-mouth bottle and nitrogen protection. Adding L-alanine-1-14C (610mg,6.70mmol,1.0eq), adding 25ml AcOH/H2O ═ 1/4 for dissolution (ultrasonic), adding 1.5M NaNO dropwise at 1 deg.C2Aqueous solution (925mg,13.4mmol,2.0eq) (dropwise addition for about 60min), after which reaction was completed at 10 ℃ for 13h, at 25 ℃ for 4h, after which TLC had been substantially completed. Spin-drying the water at 35-40 deg.C to obtain viscous solid, adding 1MHCl to adjust pH to 2, extracting with aqueous phase EA for multiple times (TLC for complete extraction), drying with organic phase sodium sulfate, and spin-drying to obtain 543 mgD-lactic acid-1-14C (colorless liquid, yield 88%). The chemical purity is 99 percent, and the optical purity reaches 100 percent.
It should be noted that the above embodiments can be freely combined as necessary. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for preparing 14C-labeled D-lactic acid, which is characterized by comprising the following steps:
(1) under the protection of nitrogen, adding acetic anhydride at the temperature of 100-150 ℃ after dissolving DL-alanine-1-14C in acetic acid, keeping the temperature for continuous reaction after adding, and removing acetic acid and acetic anhydride after complete reaction to obtain N-acetyl-DL-alanine-1-14C;
(2) adding water to dissolve the N-acetyl-DL-alanine-1-14C, and adjusting the pH value to 7-9; adding L-aminoacylase at 37-40 deg.C, maintaining the temperature for reaction, adjusting pH to acidity after reaction, filtering with 0.22 μm water film, spin-drying, adjusting isoelectric point, naturally crystallizing, filtering to obtain a first batch of L-alanine-1-14C, recovering the filtrate, and repeating step (2) to obtain a second batch of L-alanine-1-14C;
(3) two batches of the obtained L-alanine-1-14C were treated with AcOH/H2Dissolving in solution of O-1/4, and dripping NaNO at 0 deg.C2And (3) after the water solution is added, naturally raising the temperature to room temperature for reaction, after the reaction is completed, removing the solvent by spinning, adjusting the pH value to be acidic, extracting by EA, drying the organic phase sodium sulfate, and spinning to obtain the D-lactic acid-1-14C.
2. The method for preparing D-lactic acid-1-14C according to claim 1, wherein in step (1), the molar ratio of the DL-alanine-1-14C, acetic acid and acetic anhydride is 1:40-100: 3-8.
3. The method for preparing D-lactic acid-1-14C according to claim 1, wherein in step (1), the acetyl starting material is at least one of acetic anhydride, acetyl chloride and 4-nitrophenyl acetate.
4. The method for producing D-lactic acid-1-14C according to claim 1, wherein the pH of the reaction in the step (2) is controlled to 7 to 9.
5. The method for producing D-lactic acid-1-14C according to claim 1, wherein the reaction temperature in the step (2) is controlled to be 37-40 ℃.
6. The method of claim 1, wherein the L-aminoacylase is at least 1500units/mg in step (2).
7. The method for producing D-lactic acid-1-14C according to claim 1, wherein in the step (3), the NaNO is added2The concentration of the aqueous solution is 0.5mol/L-2 mol/L.
8. D-lactic acid-14C, wherein the D-lactic acid-14C is produced by the production method according to any one of claims 1 to 7.
9. The D-lactic acid-14C according to claim 8, wherein the chemical purity of D-lactic acid-14C is not less than 99% and the optical purity is up to 100%.
10. Use of D-lactic acid-14C, characterized in that D-lactic acid-14C is used in the preparation of degradable materials, said D-lactic acid-14C being prepared by the preparation method according to any one of claims 1 to 7.
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