CN112680497A - Method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme - Google Patents
Method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme Download PDFInfo
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- CN112680497A CN112680497A CN202011614247.4A CN202011614247A CN112680497A CN 112680497 A CN112680497 A CN 112680497A CN 202011614247 A CN202011614247 A CN 202011614247A CN 112680497 A CN112680497 A CN 112680497A
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- corey lactone
- cyclopentenol
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- chiral
- biological enzyme
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- 150000002596 lactones Chemical class 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 17
- 102000004190 Enzymes Human genes 0.000 title claims abstract description 10
- 108090000790 Enzymes Proteins 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 title claims abstract description 9
- 229940079593 drug Drugs 0.000 title claims abstract description 8
- 229940127293 prostanoid Drugs 0.000 title claims description 5
- 150000003814 prostanoids Chemical class 0.000 title claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- NWZXFAYYQNFDCA-UHFFFAOYSA-N cyclopenten-1-ol Chemical compound OC1=CCCC1 NWZXFAYYQNFDCA-UHFFFAOYSA-N 0.000 claims abstract description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000010791 quenching Methods 0.000 claims abstract description 4
- 230000000171 quenching effect Effects 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 4
- 238000000746 purification Methods 0.000 claims abstract description 3
- 238000004440 column chromatography Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 3
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 241000282421 Canidae Species 0.000 claims 1
- 150000003180 prostaglandins Chemical class 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 239000006227 byproduct Substances 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000010815 organic waste Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- HECLRDQVFMWTQS-RGOKHQFPSA-N 1755-01-7 Chemical compound C1[C@H]2[C@@H]3CC=C[C@@H]3[C@@H]1C=C2 HECLRDQVFMWTQS-RGOKHQFPSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 238000010478 Prins reaction Methods 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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Abstract
The invention provides a method for splitting prostaglandin drug key intermediate (1S,5R) -Corey lactone by biological enzyme, firstly adding hydrolase into acetonitrile aqueous solution of racemic Corey lactone, stirring at normal temperature, quenching reaction liquid by using water, then extracting by using ethyl acetate, drying and purifying to obtain chiral cyclopentenol; and (3) slowly adding dilute HCl into the ethanol solution of the cyclopentenol, and carrying out post-treatment and purification on a reaction product to obtain the cyclopentenol. The method has the advantages of wide substrate application range, good reaction selectivity, no need of metal catalyst and mild reaction conditions; the synthesized (1S,5R) -Corey lactone can be used for various medicinal functions, compared with the traditional chemical chiral resolution route, the synthetic steps are shortened, meanwhile, the obtained by-products can also be utilized, and the atom utilization rate is increased. The synthetic method has the advantages of cheap and easily-obtained raw materials, short steps, easy acquisition of raw materials, mild reaction conditions and high yield, and chiral resolution is carried out by using the biological enzyme; the (1S,5R) -Corey lactone synthesized by the present invention can be easily converted into various useful synthetic structures.
Description
Technical Field
The invention belongs to the technical field of bio-organic synthesis, relates to a synthesis method of Corey lactone, and particularly relates to a method for splitting a key intermediate (1S,5R) -Corey lactone of a prostaglandin medicament by using biological enzyme.
Background
Prostaglandin (PGs) drugs are widely used for contraception, induction of labor, treatment of asthma, peptic ulcer, hypertension, thrombosis, glaucoma, induction of labor by veterinary drugs, and the like.
Corey lactone is a general intermediate for synthesizing prostaglandin drugs, and at present, dicyclopentadiene is mainly used as a raw material in a general synthesis method, and is subjected to steps of depolymerization, cyclization, dechlorination, resolution, oxidation, Prins reaction, hydrolysis and the like to synthesize the Corey lactone, and then various PGs are further synthesized. The synthetic route is shown in figure 1.
Wherein, the compound 5 is a racemate, and the pure (1S,5R) configuration is obtained by repeated recrystallization in an organic solvent through a chiral resolving reagent such as phenylethylamine and the like, and the yield is only 15-20%. There are major problems: the chemical resolution efficiency is very low, the (1R,5S) configuration in the resolved mother liquor is not effectively utilized, the total utilization rate of the compound is only about 15 to 20 percent, a large amount of organic waste liquid and waste residue are generated, and the cost is very high. Thus resulting in high cost of the finished prostaglandin drug product.
Disclosure of Invention
1. The technical problem to be solved is as follows:
in the prior art, the resolution efficiency is low, the total utilization rate of the compound is not high (15-20%), a large amount of organic waste liquid and waste residue are generated, and the cost is high.
2. The technical scheme is as follows:
in order to solve the problems, the invention provides a method for separating a key intermediate (1S,5R) -Corey lactone of a prostanoid drug by using biological enzyme, which comprises the following steps: step 1: firstly, adding hydrolase into a water solution of acetonitrile of racemic Corey lactone, stirring for 24-48 hours, quenching a reaction solution by using water, and then extracting, drying, purifying and drying to obtain a mixture; step 2: purifying the mixture obtained in the step 1 by a column chromatography method to obtain an intermediate product chiral cyclopentenol; and step 3: adding the chiral cyclopentenol obtained in the step 2 into an ethanol solution to obtain an ethanol solution of the cyclopentenol; and 4, step 4: adding dilute HCl (dilute hydrochloric acid) into the ethanol solution of the chiral cyclopentenol obtained in the step (3), and reacting for 2-4 hours at normal temperature; extracting, drying, purifying, concentrating under reduced pressure to remove solvent, and purifying by column chromatography to obtain (1S,5R) -Corey lactone.
In the step 1, the mass ratio of the racemic Corey lactone to the hydrolase is 90-110: 1.
the concentration of the racemic Corey lactone in acetonitrile water solution is 0.8-1.2 mol/L.
In step 2, when column chromatography is used for purification, the developing solvent ratio is ethyl acetate: petroleum ether = 1: 3.6-4.4.
In step 3, the concentration of the ethanol solution of the cyclopentenol is 0.8-1.2 mol/L.
The steps 1 to 4 are all carried out at normal temperature.
In step 4, the ratio of chiral cyclopentenol: the molar ratio of HCl is 1: 1.8-2.2.
The molar concentration of HCl is 1M.
3. Has the advantages that:
the synthetic method has the advantages of cheap and easily-obtained raw materials, short steps, easy acquisition of raw materials, mild reaction conditions and high yield, and chiral resolution is carried out by using the biological enzyme; the (1S,5R) -Corey lactone synthesized by the present invention can be easily converted into various useful synthetic structures.
Drawings
FIG. 1 is a synthetic route of the prior art.
FIG. 2 is a schematic diagram of the resolution of the biological enzyme of the present invention.
FIG. 3 is a nuclear magnetic hydrogen spectrum of (1S,5R) -Corey lactone obtained in example 1.
FIG. 4 is a nuclear magnetic hydrogen spectrum of (1S,5R) -Corey lactone obtained in example 1.
Detailed Description
The present invention will be described in detail with reference to examples.
Example 1
As shown in figure 2, the method for separating the key intermediate (1S,5R) -Corey lactone of the prostanoid drug by using the biological enzyme comprises the following steps: firstly, adding hydrolase into a water solution of acetonitrile of racemized Corey lactone, stirring for 24-48 hours at normal temperature, quenching a reaction solution by using water, extracting, drying, purifying to obtain a mixture, and purifying the mixture by using a column chromatography to obtain an intermediate product chiral cyclopentenol; the yield was 38%.
Slowly adding dilute HCl (dilute hydrochloric acid) into an ethanol solution of chiral cyclopentenol, reacting for 2-4 hours at normal temperature, extracting, drying, purifying, concentrating the dried mixture under reduced pressure to remove the solvent, and purifying by column chromatography to obtain the product (1S,5R) -Corey lactone with a yield of 95%.
The molar concentration of HCl is 1M.
FIG. 2 is a nuclear magnetic hydrogen spectrum of (1S,5R) -Corey lactone obtained in example 1; FIG. 3 is a nuclear magnetic carbon spectrum of (1S,5R) -Corey lactone obtained in example 1. From FIGS. 1 and 2, it can be confirmed that the product was (1S,5R) -Corey lactone.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (8)
1. A method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme comprises the following steps: step 1: firstly, adding hydrolase into a water solution of acetonitrile of racemic Corey lactone, stirring for 24-48 hours, quenching a reaction solution by using water, and then extracting, drying, purifying and drying to obtain a mixture; step 2: purifying the mixture obtained in the step 1 by a column chromatography method to obtain an intermediate product chiral cyclopentenol; and step 3: adding the chiral cyclopentenol obtained in the step 2 into an ethanol solution to obtain an ethanol solution of the cyclopentenol; and 4, step 4: adding dilute HCl into the ethanol solution of the chiral cyclopentenol obtained in the step (3), and reacting for 2-4 hours at normal temperature; extracting, drying, purifying, concentrating under reduced pressure to remove solvent, and purifying by column chromatography to obtain (1S,5R) -Corey lactone.
2. The method of claim 1, wherein: in the step 1, the mass ratio of the racemic Corey lactone to the hydrolase is 90-110: 1.
3. the method of claim 1, wherein: the concentration of the racemic Corey lactone in acetonitrile water solution is 0.8-1.2 mol/L.
4. The method of claim 1, wherein: in step 2, when column chromatography is used for purification, the developing solvent ratio is ethyl acetate: petroleum ether = 1: 3.6-4.4.
5. The method of claim 1, wherein: in step 3, the concentration of the ethanol solution of the cyclopentenol is 0.8-1.2 mol/L.
6. The method of any one of claims 1-5, wherein: the steps 1 to 4 are all carried out at normal temperature.
7. The method of any one of claims 1-5, wherein: in step 4, the ratio of chiral cyclopentenol: the molar ratio of HCl is 1: 1.8-2.2.
8. A method for searching foxes, in accordance with claim 7, characterized by: the molar concentration of HCl is 1M.
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| CN202011614247.4A CN112680497A (en) | 2020-12-31 | 2020-12-31 | Method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114921507A (en) * | 2022-05-30 | 2022-08-19 | 南京工业大学 | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-ene-3-one |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5219743A (en) * | 1991-02-27 | 1993-06-15 | Nissan Chemical Industries, Ltd. | Method for optical resolution of corey lactone diols |
| WO2010083722A1 (en) * | 2009-01-20 | 2010-07-29 | 中国药科大学 | A process for one-pot synthesis of corey lactone |
| CN109161577A (en) * | 2018-09-26 | 2019-01-08 | 厦门欧瑞捷生物科技有限公司 | A kind of left-handed Corey lactone diol intermediates, preparation method and its medicinal application |
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2020
- 2020-12-31 CN CN202011614247.4A patent/CN112680497A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5219743A (en) * | 1991-02-27 | 1993-06-15 | Nissan Chemical Industries, Ltd. | Method for optical resolution of corey lactone diols |
| WO2010083722A1 (en) * | 2009-01-20 | 2010-07-29 | 中国药科大学 | A process for one-pot synthesis of corey lactone |
| CN109161577A (en) * | 2018-09-26 | 2019-01-08 | 厦门欧瑞捷生物科技有限公司 | A kind of left-handed Corey lactone diol intermediates, preparation method and its medicinal application |
Non-Patent Citations (1)
| Title |
|---|
| 齐创宇等: "前列腺素关键中间体———手性Corey Lactone 的合成研究进展", 合成化学, vol. 14, no. 6, pages 539 - 545 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114921507A (en) * | 2022-05-30 | 2022-08-19 | 南京工业大学 | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-ene-3-one |
| CN114921507B (en) * | 2022-05-30 | 2024-01-30 | 南京工业大学 | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-en-3-one |
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Application publication date: 20210420 |