CN115466217B - Method for recycling cyclic acid - Google Patents
Method for recycling cyclic acid Download PDFInfo
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- CN115466217B CN115466217B CN202211174847.2A CN202211174847A CN115466217B CN 115466217 B CN115466217 B CN 115466217B CN 202211174847 A CN202211174847 A CN 202211174847A CN 115466217 B CN115466217 B CN 115466217B
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- 239000002253 acid Substances 0.000 title claims abstract description 217
- 125000004122 cyclic group Chemical group 0.000 title claims abstract description 207
- 238000000034 method Methods 0.000 title claims abstract description 79
- 238000004064 recycling Methods 0.000 title abstract description 11
- 239000012452 mother liquor Substances 0.000 claims abstract description 77
- 239000007787 solid Substances 0.000 claims abstract description 45
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 44
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims abstract description 27
- 239000000920 calcium hydroxide Substances 0.000 claims abstract description 27
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims abstract description 27
- 238000005406 washing Methods 0.000 claims abstract description 26
- 239000010413 mother solution Substances 0.000 claims abstract description 16
- 238000010438 heat treatment Methods 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 7
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims abstract description 6
- 229910001863 barium hydroxide Inorganic materials 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 230000001105 regulatory effect Effects 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 230000002378 acidificating effect Effects 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000292 calcium oxide Substances 0.000 claims abstract description 3
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 59
- 239000002994 raw material Substances 0.000 abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 186
- 238000003756 stirring Methods 0.000 description 52
- 238000001914 filtration Methods 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 36
- 238000002360 preparation method Methods 0.000 description 36
- 239000012065 filter cake Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 25
- 238000001514 detection method Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- 238000001035 drying Methods 0.000 description 18
- 239000005457 ice water Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 13
- 239000011343 solid material Substances 0.000 description 5
- 235000000638 D-biotin Nutrition 0.000 description 4
- 239000011665 D-biotin Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- -1 10% Chemical compound 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229930003756 Vitamin B7 Natural products 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011735 vitamin B7 Substances 0.000 description 3
- 235000011912 vitamin B7 Nutrition 0.000 description 3
- HNNQYHFROJDYHQ-UHFFFAOYSA-N 3-(4-ethylcyclohexyl)propanoic acid 3-(3-ethylcyclopentyl)propanoic acid Chemical compound CCC1CCC(CCC(O)=O)C1.CCC1CCC(CCC(O)=O)CC1 HNNQYHFROJDYHQ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 159000000009 barium salts Chemical class 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical group [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LLIANSAISVOLHR-GBCQHVBFSA-N 5-[(3as,4s,6ar)-2-oxidanylidene-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 LLIANSAISVOLHR-GBCQHVBFSA-N 0.000 description 1
- NKFIBMOQAPEKNZ-UHFFFAOYSA-N 5-amino-1h-indole-2-carboxylic acid Chemical compound NC1=CC=C2NC(C(O)=O)=CC2=C1 NKFIBMOQAPEKNZ-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940068840 d-biotin Drugs 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for recovering cyclic acids. The method comprises the following steps: 1) Regulating the pH of the lithium mother liquor for preparing (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenyl ethyl ] half-ester to convert cyclic acid salt into cyclic acid; 2) Adding calcium hydroxide, barium hydroxide or calcium oxide into the mother solution to enable the pH value of the mother solution to be more than or equal to 8, heating the mother solution, preserving heat, and separating to obtain solid matters; 3) Dissolving the solid substance in an acidic aqueous solution, regulating the pH to be less than or equal to 2, separating, and washing to obtain a crude cyclic acid product; 4) And (3) dissolving the crude cyclic acid product in an organic solvent, adding acid to separate out the cyclic acid, and separating to obtain a cyclic acid finished product. The method for recycling cyclic acid provided by the invention can recycle cyclic acid with high purity, so that the cyclic acid can be recycled as a raw material.
Description
Technical Field
The invention belongs to the technical field of chemical wastewater treatment, and particularly relates to a method for recycling cyclic acid.
Background
D-Biotin (D-Biotin) is known as 5- [ (3 aS,4S,6 aR) -2-oxohexahydro-1H-thieno [3,4-D ] imidazol-4-yl ] pentanoic acid, and has the structure shown in formula I:
d-biotin is also called vitamin H, biotin, coenzyme R and vitamin B7, is a water-soluble B-group vitamin and is colorless crystalline powder.
Natural D-biotin is widely found in organs such as kidneys, livers, pancreas, and milk, egg yolk, and yeast of animals. It is an essential substance for the synthesis of vitamin C, an essential substance for the normal metabolism of fats and proteins. Has wide application in the fields of medical treatment, feed, biotechnology and the like.
At present, D-biotin is almost produced by a chemical synthesis method, and industrial production technical routes basically take 1, 3-dibenzyl imidazoline-2-ketone-cis-4, 5-dicarboxylic acid (cyclic acid) as a raw material to produce the D-biotin through the steps of dehydration, reduction, vulcanization, grignard, hydrogenation, debenzylation and the like. Lithium (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester is an intermediate in the production of D-biotin. The cyclic acid is subjected to acidification, dehydration, asymmetric alcoholysis and alkali crystallization and then is centrifuged to obtain half-ester lithium salt; due to process limitations, unreacted cyclic acid salts are present in the centrifuge mother liquor. The reaction of cyclic acid to form 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester lithium of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid results in a yield of 80-90% of half-ester lithium, and the cyclic acid as the cyclic acid salt is present in the mother liquor, which would result in a great waste of cyclic acid as the raw material if not recovered.
Disclosure of Invention
The invention aims to provide a method for recycling cyclic acid, which is used for recycling cyclic acid with high purity.
The invention provides a method for recycling cyclic acid, which comprises the following steps:
1) Regulating the pH of the lithium mother liquor for preparing (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenyl ethyl ] half-ester to convert cyclic acid salt into cyclic acid;
2) Adding calcium hydroxide, barium hydroxide or calcium oxide into the mother solution to enable the pH value of the mother solution to be more than or equal to 8, heating the mother solution, preserving heat, and separating to obtain solid matters;
3) Dissolving the solid substance in an acidic aqueous solution, regulating the pH to be less than or equal to 2, separating, and washing to obtain a crude cyclic acid product;
4) And (3) dissolving the crude cyclic acid product in an organic solvent, adding acid to separate out the cyclic acid, and separating to obtain a cyclic acid finished product.
In some embodiments, in step 1), the pH of the mother liquor is from 2 to 5, preferably from 2 to 4, more preferably from 2 to 3.
In some embodiments, in step 2), the pH of the mother liquor is 8 to 14, preferably 8 to 11, more preferably 9 to 10. The pH value of the mother solution is 9-11, and even 9-10, the mother solution is more favorable for separating calcium naphthenate or barium naphthenate and some impurities out in the form of calcium salt or barium salt, so that the yield of the naphthenic acid is improved, the impurities are removed, and the purity of the naphthenic acid is also improved.
In some embodiments, a solid powder of calcium hydroxide or barium hydroxide, or a slurry of calcium hydroxide or barium hydroxide, preferably a solid powder of calcium hydroxide or barium hydroxide, may be added to the mother liquor.
In some embodiments, in step 2), calcium hydroxide is added to the mother liquor to a pH of 8 or more while heating the mother liquor, followed by incubation and separation to obtain a solid material. In view of the problems of raw material sources, the cost of recovering the cyclic acid and the safety of production, it is preferable to add calcium hydroxide to the mother liquor.
In some embodiments, in step 2), the temperature of the mother liquor after heating is above 80 ℃, preferably 80-95 ℃, more preferably 80-90 ℃. When the mother solution is heated to 80-90 ℃, the recovery of the cyclic acid with high purity is more facilitated.
In some embodiments, in step 2), the incubation time may be 1 hour or more, for example 1.5 hours, 2 hours, or 3 hours.
In some embodiments, the dissolving the solid material in the acidic aqueous solution may be mixing the solid material with water, followed by conditioning with an acid to dissolve the solid material.
In some embodiments, in step 3), the pH is 0.5 or greater and 2 or less, preferably 0.8 to 2, more preferably 1 to 2, more preferably 0.8 to 1.5, more preferably 1 to 1.5. In the process of separating out the product mainly containing the barium salt or the calcium salt of the cyclic acid, the closer the pH value is to 1, the higher the purity of the obtained cyclic acid finished product is.
In some embodiments, in step 3), the temperature of the water used for the washing is 10 ℃ or less, preferably 5 ℃ or less, greater than 0 ℃. The loss of cyclic acid can be reduced by adopting low-temperature water washing.
In some embodiments, in step 4), the organic solvent is acetone.
In carrying out the present invention, the inventors have found that increasing the amount of organic solvent increases the amount of subsequent acid, increases the cost of recovering the cyclic acid, and also decreases the yield of the cyclic acid. Thus, in some embodiments, the ratio of the crude cyclic acid to the acetone is from 1:2 to 1:5g/mL, preferably from 1:2 to 1:4g/mL, more preferably from 1:2 to 1:3g/mL.
In the process of realizing the invention, the inventor finds that the purity and yield of the finished product of the cyclic acid can be influenced if the amount of the acid is increased in the process of separating out the crude product of the cyclic acid. Thus, in some embodiments, the crude cyclic acid to acid mass to volume ratio is from 1:2 to 1:5g/mL, preferably from 1:3 to 1:5g/mL, more preferably from 1:3 to 1:4g/mL.
In some embodiments, the pH of the lithium mother liquor used to prepare (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester may be adjusted with hydrochloric acid, e.g., 10%, 20%, 30%, 37% hydrochloric acid.
In some embodiments, the means of separation is selected from filtration, pressure filtration, centrifugation, and the like.
In some embodiments, in step 2), after filtration, the solid material obtained is known as a filter cake.
The method for recycling cyclic acid provided by the invention can obtain the cyclic acid with high purity, so that the cyclic acid can be reused as a raw material.
The cyclic acid with the purity higher than 96% can be obtained by the method for recycling cyclic acid provided by the invention, so that the cyclic acid can be reused as a raw material.
The method for recycling the cyclic acid can obtain the cyclic acid with the purity higher than 98 percent, so that the cyclic acid can be directly used for preparing the (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenyl ethyl ] half-ester lithium.
The method for recycling cyclic acid provided by the invention not only can improve the yield of cyclic acid, but also can obtain cyclic acid with high purity, so that the cyclic acid can be recycled as a raw material.
Drawings
FIG. 1 is an HPLC chart of the product cyclic acid prepared in example 1. In the figure, peak 12 is the chromatographic peak of cyclic acid.
Detailed Description
The invention is further illustrated by the following examples, it being understood that the examples of the invention are presented by way of illustration only and not by way of limitation, and that simple modifications of the invention are within the scope of the invention as claimed.
The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Examples
Example 1
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, pH was adjusted to 1, stirring was performed for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 17.89g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 14.86g of cyclic acid solid, the purity of the product was 99.57% and the yield was 97.34%. The results of the product HPLC (high performance liquid chromatography) are shown in FIG. 1 and Table 1. Peak No. 12 in table 1 is the HPLC detection result of cyclic acid.
Table 1 HPLC assay data
Detector A220nm
| Peak number | Retention time | Area of | Area percent | Height | Degree of separation (USP) | Tailing factor |
| 1 | 2.529 | 3202 | 0.023 | 542 | -- | -- |
| 2 | 2.670 | 1652 | 0.012 | 254 | 0.336 | -- |
| 3 | 2.790 | 2061 | 0.015 | 297 | 0.235 | -- |
| 4 | 2.956 | 3148 | 0.022 | 486 | 0.597 | -- |
| 5 | 3.097 | 2506 | 0.018 | 260 | 0.478 | -- |
| 6 | 4.373 | 732 | 0.005 | 73 | 3.895 | -- |
| 7 | 5.360 | 472 | 0.003 | 37 | 3.139 | -- |
| 8 | 5.869 | 13314 | 0.094 | 1255 | 1.613 | 1.208 |
| 9 | 7.433 | 2855 | 0.020 | 297 | 5.923 | -- |
| 10 | 7.755 | 1400 | 0.010 | 105 | 0.953 | -- |
| 11 | 8.325 | 1761 | 0.012 | 166 | 0.913 | -- |
| 12 | 8.766 | 14091866 | 99.566 | 1093392 | 0.752 | 1.040 |
| 13 | 11.303 | 517 | 0.004 | 37 | 6.630 | 1.129 |
| 14 | 12.290 | 5330 | 0.038 | 259 | 2.172 | 1.534 |
| 15 | 13.323 | 394 | 0.003 | 26 | 2.179 | 0.865 |
| 16 | 15.182 | 11293 | 0.080 | 463 | 3.471 | 0.864 |
| 17 | 17.452 | 837 | 0.006 | 41 | 4.100 | 1.006 |
| 18 | 18.606 | 1925 | 0.014 | 84 | 2.052 | 1.117 |
| 19 | 44.314 | 1333 | 0.009 | 28 | 30.727 | -- |
| 20 | 46.412 | 2267 | 0.016 | 47 | 1.899 | 1.212 |
| 21 | 50.728 | 4402 | 0.031 | 77 | 3.223 | 0.944 |
| Totals to | 14153264 | 100.000 | 1098228 |
HPLC detection conditions:
chromatographic column: c (C) 18 Column length 250mm, inner diameter 4.6mm, granularity 5 μm;
mobile phase: mobile phase a is acetonitrile, mobile phase B is potassium dihydrogen phosphate buffer solution (2.72 g potassium dihydrogen phosphate, dissolved in 950mL water, adjusted to pH 2.5 with dilute phosphoric acid, and then added with water to volume to 1000 mL); mobile phase a: mobile phase b=35:65;
flow rate: 1.0mL/min;
detection wavelength: 220nm;
sample injection amount: 20. Mu.L.
Example 2
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The difference between this example and example 1 is that the pH in step (1) was 10. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 10, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water is added to the filter cake, 30mL of 30% industrial hydrochloric acid is added once again, about 70mL of 30% industrial hydrochloric acid is slowly added after stirring for 0.5h, the pH is adjusted to 1, stirring is carried out for 2 h, filtration is carried out, and the filter cake is washed twice by ice water, thus obtaining 17.14g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 14.29g of cyclic acid solid, the purity of the product was 99.02% and the yield was 93.09%.
The HPLC detection conditions in this example were the same as in example 1.
Example 3
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the pH in step (1) was 11. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 11, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, and after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, the pH was adjusted to 1, and after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 16.83g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 14.31g of cyclic acid solid, the purity of the product was 98.82% and the yield was 93.03%.
The HPLC detection conditions in this example were the same as in example 1.
Example 4
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the heating temperature in step (1) is 85 ℃. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 85℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water is added to the filter cake, 30mL of 30% industrial hydrochloric acid is added once again, about 70mL of 30% industrial hydrochloric acid is slowly added after stirring for 0.5h, the pH is adjusted to 1, stirring is carried out for 2 h, filtration is carried out, and the filter cake is washed twice by ice water, thus obtaining 17.05g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 14.17g of cyclic acid solid, the purity of the product was 99.1% and the yield was 92.38%.
The HPLC detection conditions in this example were the same as in example 1.
Example 5
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the heating temperature in step (1) is 90 ℃. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 90℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water is added to the filter cake, 30mL of 30% industrial hydrochloric acid is added once again, about 70mL of 30% industrial hydrochloric acid is slowly added after stirring for 0.5h, the pH is adjusted to 1, stirring is carried out for 2 h, filtration is carried out, and the filter cake is washed twice by ice water, thus obtaining 17.12g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 14.53g of cyclic acid solid, the product was detected by HPLC (high performance liquid chromatography), the purity was 99.11%, and the yield was 94.74%.
The HPLC detection conditions in this example were the same as in example 1.
Example 6
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the pH in step (2) was 2. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, and after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, the pH was adjusted to 2, and after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 16.13g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 13.18g of cyclic acid solid, the purity of the product was 96.14% and the yield was 83.36%.
The HPLC detection conditions in this example were the same as in example 1.
Example 7
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the mass to volume ratio of cyclic acid to acetone in step (3) is 1:3g/mL. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, and after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, the pH was adjusted to 1, and after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 17.71g of crude cyclic acid.
(3) Acetone (1:3 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 12.6g of cyclic acid solid, the purity of the product was 99.04% and the yield was 82.99%.
The HPLC detection conditions in this example were the same as in example 1.
Example 8
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the mass to volume ratio of cyclic acid to acetone in step (3) is 1:4g/mL. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water is added to the filter cake, 30mL of 30% industrial hydrochloric acid is added once again, about 70mL of 30% industrial hydrochloric acid is slowly added after stirring for 0.5h, the pH is adjusted to 1, stirring is carried out for 2 h, filtration is carried out, and the filter cake is washed twice by ice water, thus obtaining 17.95g of crude cyclic acid.
(3) Acetone (1:4 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 10.28g of cyclic acid solid, the purity of the product was 99.28% and the yield was 67.14%.
The HPLC detection conditions in this example were the same as in example 1.
Example 9
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the mass to volume ratio of cyclic acid to acetone in step (3) is 1:5g/mL. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, pH was adjusted to 1, stirring was performed for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 17.89g of crude cyclic acid.
(3) Acetone (1:5 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 9.13g of cyclic acid solid, the purity of the product was 99.01% and the yield was 59.47%.
The HPLC detection conditions in this example were the same as in example 1.
Example 10
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the mass to volume ratio of cyclic acid to hydrochloric acid in step (3) is 1:4g/mL. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, pH was adjusted to 1, after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 17.13g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:4 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing was performed 2 times with pure water, and drying was performed to obtain 13.48g of cyclic acid solid, which was detected by HPLC (high performance liquid chromatography) and had a purity of 97.5% and a yield of 86.47%.
The HPLC detection conditions in this example were the same as in example 1.
Example 11
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the mass to volume ratio of crude cyclic acid to hydrochloric acid in step (3) is 1:5g/mL. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, and after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, the pH was adjusted to 1, and after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 16.93g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:5 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing was performed 2 times with pure water, and drying was performed to obtain 13.25g of cyclic acid solid, the purity of the product was 96.52% and the yield was 84.14%.
The HPLC detection conditions in this example were the same as in example 1.
Example 12
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the pH in step (1) was 8. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 8 while heating to 80℃and heat was maintained for 2 hours, and then filtration was carried out while hot, and washing was carried out twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, and after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, the pH was adjusted to 1, and after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 16.53g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing was performed with pure water for 2 times, and drying was performed to obtain 12.75g of cyclic acid solid, which was detected by HPLC (high performance liquid chromatography) and had a purity of 98.69% and a yield of 82.78%.
The HPLC detection conditions in this example were the same as in example 1.
Comparative example 1
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that in step (2) the solvent is ethanol. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, pH was adjusted to 1, stirring was performed for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 17.02g of crude cyclic acid.
(3) Ethanol (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 9.07g of cyclic acid solid, the purity of which was 89.39% and the yield of which was 53.34%.
The HPLC detection conditions of this comparative example were the same as in example 1.
Comparative example 2
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the heating temperature in step (1) is 75 ℃. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 75℃for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, and after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, the pH was adjusted to 1, and after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 16.95g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 10.07g of cyclic acid solid, the purity of the product was 90.39% and the yield was 59.88%.
The HPLC detection conditions of this comparative example were the same as in example 1.
Comparative example 3
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the pH in step (2) was 3. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, and after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, the pH was adjusted to 3, and after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 15.23g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 9.86g of cyclic acid solid, the product was detected by HPLC (high performance liquid chromatography), the purity was 91.39%, and the yield was 59.28%.
The HPLC detection conditions of this comparative example were the same as in example 1.
Comparative example 4
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the mass to volume ratio of cyclic acid to acetone in step (3) is 1:1. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, pH was adjusted to 1, stirring was performed for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 17.68g of crude cyclic acid.
(3) Acetone (1:1 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 12.86g of cyclic acid solid, the purity of the product was 90.52% as measured by HPLC (high performance liquid chromatography), and the yield was 76.58%.
The HPLC detection conditions of this comparative example were the same as in example 1.
Comparative example 5
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The only difference from example 1 is that the mass to volume ratio of crude cyclic acid to hydrochloric acid in step (3) is 1:6. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed, 500mL of a mother liquor for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother liquor theoretically calculated from the yield of the half-ester of lithium) was added, pH was adjusted to 2-3 with hydrochloric acid, calcium hydroxide solid was slowly added, pH was adjusted to 9, and the mixture was heated to 80℃while keeping the temperature for 2 hours, filtered while it was still hot, and washed twice with water.
(2) 300mL of water was added to the filter cake, 30mL of 30% industrial hydrochloric acid was added once more, and after stirring for 0.5h, about 70mL of 30% industrial hydrochloric acid was slowly added, the pH was adjusted to 1, and after stirring for 2 hours, filtration was performed, and the filter cake was washed twice with ice water to obtain 17.96g of crude cyclic acid.
(3) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:6 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing with pure water was performed 2 times, and drying was performed to obtain 10.16g of cyclic acid solid, the purity of the product was 90.37% by HPLC (high performance liquid chromatography) detection, and the yield was 60.41%.
The HPLC detection conditions of this comparative example were the same as in example 1.
Comparative example 6
This example provides a process for the preparation of 1, 3-dibenzylimidazolin-2-one-cis-4, 5-dicarboxylic acid (cyclic acid) from a lithium mother liquor in the preparation of 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid. The difference from example 1 is only that no calcium hydroxide solid is added and the heating temperature is 40-50℃and the incubation is for 1 hour. The method comprises the following specific steps:
(1) A1000 mL three-necked flask was warmed to a temperature of 500mL of a mother solution for preparing 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenylethyl ] half-ester of (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid (15.2 g of cyclic acid was present in five hundred milliliters of mother solution theoretically calculated from the yield of the half-ester of lithium), pH was adjusted to 2-3 with hydrochloric acid, and the flask was heated to 40-50℃for 1 hour to allow the cyclic acid salt in the mother solution to be sufficiently converted into cyclic acid, but crystals could not be precipitated from the cyclic acid due to the presence of an organic amine salt in the mother solution, and the temperature was lowered to 10℃to give 15.23g of a dark brown viscous crude cyclic acid as a precipitate.
(2) Acetone (1:2 g/mL) was added to the crude cyclic acid, after stirring for 2 hours, 30% industrial hydrochloric acid (the ratio of crude cyclic acid to 30% hydrochloric acid is 1:3 g/mL) was added dropwise to the acetone solution of cyclic acid, filtration was completed, washing was performed with pure water for 2 times, and drying was performed to obtain 11.8g of a brown yellow viscous spherical cyclic acid solid, the purity of the product was 60.39% as measured by HPLC (high performance liquid chromatography), and the yield was 46.89%.
The HPLC detection conditions of this comparative example were the same as in example 1.
The experimental conditions of examples 1 to 12 and comparative examples 1 to 6 and the purity and yield of the cyclic acid obtained are shown in Table 2.
TABLE 2 experimental conditions and purity and yield of cyclic acids
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The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.
Claims (24)
1. A method for recovering cyclic acid, the method comprising the steps of:
1) Regulating the pH of the lithium mother liquor for preparing (4S, 5R) -1, 3-dibenzyl-2-keto-4, 5-dicarboxylic acid 5- [ (S) -2-hydroxy-1-methyl-2, 2-diphenyl ethyl ] half-ester to convert cyclic acid salt into cyclic acid;
2) Adding calcium hydroxide, barium hydroxide or calcium oxide into the mother solution to enable the pH value of the mother solution to be more than or equal to 8, heating the mother solution, preserving heat, and separating to obtain solid matters;
3) Dissolving the solid substance in an acidic aqueous solution, regulating the pH to be less than or equal to 2, separating, and washing to obtain a crude cyclic acid product;
4) Dissolving the crude cyclic acid product in an organic solvent, adding acid to separate out cyclic acid, and separating to obtain a cyclic acid finished product;
wherein the cyclic acid is 1, 3-dibenzyl imidazoline-2-ketone-cis-4, 5-dicarboxylic acid.
2. The method according to claim 1, wherein in step 1), the pH of the mother liquor is 2-5.
3. The method according to claim 1, wherein in step 1), the pH of the mother liquor is 2-4.
4. The method according to claim 1, wherein in step 1), the pH of the mother liquor is 2-3.
5. The method according to claim 1, characterized in that in step 2) the pH of the mother liquor is 8-14.
6. The method according to claim 1, characterized in that in step 2) the pH of the mother liquor is 8-11.
7. The method according to claim 1, characterized in that in step 2) the pH of the mother liquor is 9-11.
8. The method according to claim 1, wherein in step 2), calcium hydroxide is added to the mother liquor to a pH of 8 or more while heating the mother liquor, and then the mother liquor is kept warm and separated to obtain a solid substance.
9. The method according to claim 1, wherein in step 2), the temperature of the mother liquor after heating is 80 ℃ or higher.
10. The method according to claim 1, characterized in that in step 2) the temperature of the mother liquor after heating is 80-95 ℃.
11. The method according to claim 1, characterized in that in step 2) the temperature of the mother liquor after heating is 80-90 ℃.
12. The method according to claim 1, wherein in step 3), the pH is 0.5 or more and 2 or less.
13. The method according to claim 1, wherein in step 3), the pH is 0.8-2.
14. The method according to claim 1, wherein in step 3), the pH is 1-2.
15. The method according to claim 1, wherein in step 3), the pH is 1-1.5.
16. The method according to claim 1, wherein in step 3), the temperature of the water used for the washing is 10 ℃ or lower.
17. The method according to claim 1, wherein in step 3), the temperature of the water used for the washing is 5 ℃ or lower and more than 0 ℃.
18. The method according to claim 1, wherein in step 4), the organic solvent is acetone.
19. The method of claim 18, wherein the mass to volume ratio of crude cyclic acid to acetone is 1:2-1:5g/mL.
20. The method of claim 18, wherein the mass to volume ratio of crude cyclic acid to acetone is 1:2-1:4g/mL.
21. The method of claim 18, wherein the mass to volume ratio of crude cyclic acid to acetone is 1:2-1:3g/mL.
22. The method of claim 1, wherein the mass to volume ratio of crude cyclic acid to acid is 1:2 to 1:5g/mL.
23. The method of claim 1, wherein the mass to volume ratio of crude cyclic acid to acid is 1:3 to 1:5g/mL.
24. The method of claim 1, wherein the mass to volume ratio of crude cyclic acid to acid is 1:3 to 1:4g/mL.
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| CN1768063A (en) * | 2003-04-22 | 2006-05-03 | 帝斯曼知识产权资产管理有限公司 | The Stereoselective synthesizing process of lactone |
| CN109251207A (en) * | 2018-09-29 | 2019-01-22 | 江西天新药业股份有限公司 | The method of stereoselective syntheses asymmetric lactone |
| CN114634515A (en) * | 2022-02-25 | 2022-06-17 | 复旦大学 | Stereoselective synthesis method of (3aS,6aR) -lactone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1768063A (en) * | 2003-04-22 | 2006-05-03 | 帝斯曼知识产权资产管理有限公司 | The Stereoselective synthesizing process of lactone |
| CN109251207A (en) * | 2018-09-29 | 2019-01-22 | 江西天新药业股份有限公司 | The method of stereoselective syntheses asymmetric lactone |
| CN114634515A (en) * | 2022-02-25 | 2022-06-17 | 复旦大学 | Stereoselective synthesis method of (3aS,6aR) -lactone |
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