CN115636742B - Recrystallization method - Google Patents
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- CN115636742B CN115636742B CN202211411791.8A CN202211411791A CN115636742B CN 115636742 B CN115636742 B CN 115636742B CN 202211411791 A CN202211411791 A CN 202211411791A CN 115636742 B CN115636742 B CN 115636742B
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- 238000001953 recrystallisation Methods 0.000 title claims abstract description 71
- 238000000034 method Methods 0.000 title claims abstract description 60
- 229940125904 compound 1 Drugs 0.000 claims abstract description 57
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000012043 crude product Substances 0.000 claims abstract description 19
- 239000013078 crystal Substances 0.000 claims abstract description 11
- 239000003208 petroleum Substances 0.000 claims abstract description 8
- 239000012535 impurity Substances 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 4
- 238000004811 liquid chromatography Methods 0.000 claims description 4
- 239000004593 Epoxy Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- URQPUXMZAJAFJW-UHFFFAOYSA-N 2,6-bis(methoxymethoxy)benzaldehyde Chemical compound COCOC1=CC=CC(OCOC)=C1C=O URQPUXMZAJAFJW-UHFFFAOYSA-N 0.000 description 1
- GSHNZOVUGRZEON-UHFFFAOYSA-N 2-hydroxy-6-(methoxymethoxy)benzaldehyde Chemical compound COCOC1=CC=CC(O)=C1C=O GSHNZOVUGRZEON-UHFFFAOYSA-N 0.000 description 1
- FWCVZAQENIZVMY-UHFFFAOYSA-N 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=CC(O)=C1C=O FWCVZAQENIZVMY-UHFFFAOYSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a recrystallization method, and belongs to the field of methods for purifying compounds. The invention provides a recrystallization method for recrystallizing a compound 1, wherein the compound 1 is
Description
Technical Field
The invention relates to a method for purifying a compound, in particular to a recrystallization method.
Background
2-hydroxy-6- (methoxymethoxy) benzaldehyde (i.e., compound 1) is a compound which has been widely used.
Compound 1 was reported as a synthetic intermediate for hemoglobin modulators as reported in paper Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell hepoglobin (ACS med. Chem. Lett.2017,8, 321-326).
As another example, paper The Chirality Conversion Reagent for Amino Acids Based on Salicyl Aldehyde (bull. Korean chem. Soc.2012, vol.33, no. 51715-1718) reports that compound 1 can be used as a synthetic intermediate for chiral conversion reagents for an amino acid.
In the prior art, the synthesis of compound 1 is generally prepared using a process in which 2, 6-bis (methoxymethoxy) benzaldehyde is selectively freed of one methoxymethyl protecting group in an acidic solution.
However, the compound 1 prepared by the above method generally contains various impurities such as a compound from which two methoxymethyl groups are removed, and the impurities are similar to the compound 1 in all aspects, and even after the compound 1 is subjected to post-treatment or purification by a certain method, the product still contains a considerable amount of impurities, and the purity is limited, so that the compound 1 is difficult to prepare into a solid form, usually an oily liquid by a recrystallization method, and the compound 1 in the oily liquid is not stable in a common storage environment and is difficult to store for a long time.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a recrystallization method that can produce a solid compound 1 that is high in purity and storage-stable.
The invention provides a recrystallization method for recrystallizing a compound 1, wherein the compound 1 isHas the characteristics that the method comprises the following steps: and (3) dissolving the crude product of the compound 1 in a recrystallization agent, controlling the temperature to-10 ℃ to 10 ℃, and preserving heat, wherein the recrystallization agent comprises at least one of n-heptane, n-hexane or petroleum ether.
The invention also provides a recrystallization method for recrystallizing the compound 1, wherein the compound 1 isHas the characteristics that the method comprises the following steps: crude compound 1 was taken upDissolving in a recrystallization agent, controlling the temperature to-10 ℃ to 10 ℃, preserving heat, and separating to obtain a compound 1 crystal, wherein the recrystallization agent comprises at least one of n-heptane, n-hexane or petroleum ether.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the crude product of the compound 1 also contains at least one organic impurity, and the total impurity content of the crude product of the compound 1 is less than 15 percent in liquid chromatography analysis.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the crude product of the compound 1 also contains at least one organic impurity, and the maximum single impurity content of the crude product of the compound 1 in liquid chromatography analysis is less than 1.5 percent.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: the recrystallization agent A is selected from any one or more of n-heptane, n-hexane or petroleum ether, and the recrystallization agent B is selected from any one or more of dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, ethylbenzene, diethyl ether, propyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1, 4-epoxyhexacyclic ring, acetone or methyl ethyl ketone.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the recrystallization agent B is selected from any one or more of diethyl ether, propyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1, 4-epoxyhexacyclic ring, acetone or methyl ethyl ketone.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the volume ratio of the recrystallization agent A to the recrystallization agent B is (4-6): 1.
in the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the recrystallization agent is n-hexane and tetrahydrofuran with the volume ratio of (4-6): 1.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the recrystallization agent is n-heptane and the volume ratio of 1, 4-dioxane is (4-6): 1.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the recrystallization agent is n-heptane and acetone with the volume ratio of (4-6): 1.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the mass volume ratio of the crude product of the compound 1 to the recrystallization agent is 1g: (6.5-8) mL.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein the heat preservation time is more than 0.5h, preferably 0.5-5h.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: the method comprises the following steps of: adding a recrystallization agent into the crude product containing the compound 1, heating to 30-50 ℃ to enable the crude product to be fully dissolved in the recrystallization agent, controlling the temperature to-10 ℃, preserving heat for more than 0.5 hours, preferably controlling the temperature to-5-0 ℃, preserving heat for 3-5 hours, filtering, and drying to obtain the crystal of the compound 1.
In the method for recrystallization provided by the invention, the method can also have the following characteristics: wherein, the preparation method of the crude product of the compound 1 has the following reaction formula:
the method comprises the following reaction steps:
dissolving the compound 2 in a solvent, adding hydrochloric acid aqueous solution, heating to 25-50 ℃, keeping the temperature, stirring and reacting for 3-12 h to obtain a reaction solution, purifying the reaction solution to obtain a crude product of the compound 1,
the purification method comprises distillation, rectification, column chromatography, thin plate chromatography, pulping, extraction, centrifugation, freeze-drying and filtration.
Effects and effects of the invention
According to the recrystallization method of the present invention, the crude compound is recrystallized using a recrystallization agent containing at least one of n-heptane, n-hexane or petroleum ether, so that the present invention can produce crystals of compound 1 in high purity in high yield.
Detailed Description
The present invention will be described in detail with reference to the following examples, so that the technical means, the creation characteristics, the achievement of the purpose and the effect achieved by the present invention are easily understood.
In the examples below, each chemical reagent is commercially available unless otherwise indicated.
In the examples described below, both saturated saline and saturated aqueous sodium bicarbonate were prepared at 25℃under standard atmospheric pressure.
In the examples below, the meanings of total and individual impurities are as follows:
total impurities: refers to the ratio of the sum of the peak areas of the respective correlation peaks except the HPLC main peak and the solvent blank to the sum of the peak areas of the respective correlation peaks except the solvent blank.
Maximum single impurity: the ratio of the peak area of the single correlation peak having the largest peak area except the main peak of HPLC and the solvent blank to the sum of the peak areas of the respective correlation peaks except the solvent blank.
In the following examples, the detection conditions of the high performance liquid chromatography are shown in table 1 unless otherwise indicated.
TABLE 1 high performance liquid chromatography detection conditions table
Example 1 ]
Preparation of crude Compound 1
The present example provides a process for preparing an acidic solution containing compound 1, the reaction equation being as follows:
the specific reaction steps are as follows:
dissolving 500g of compound 2 in 3000mL of dichloromethane, dropwise adding 44.8g of 36wt% hydrochloric acid aqueous solution at a temperature controlled between 20 ℃ and 30 ℃, heating to 30 ℃ after the dropwise adding is finished, and carrying out heat preservation and stirring for 6 hours to obtain a reaction solution;
2500mL of saturated saline solution is added to the reaction solution for washing once, the organic phase is taken out, 3000mL of saturated sodium bicarbonate aqueous solution is used for washing once, the organic phase is taken out, anhydrous sodium sulfate is added for drying for 12 hours, the concentration is carried out under reduced pressure, the solvent is removed, 378g of crude product of the compound 1 is obtained, and the yield is 93.9%.
The crude compound 1 prepared in this example has a content of 95.9%, a maximum of 0.89% single impurity and a total impurity of 4.1% as determined by HPLC conditions in Table 1.
Example 2 ]
Method for purifying compound 1
Column chromatography is carried out on 20g of crude compound 1, wherein the chromatographic liquid is petroleum ether/ethyl acetate=10:1-6:1 (volume ratio), and 18.9g of purified compound 1 is obtained as yellow oily liquid.
The purified compound 1 prepared in this example contained 96.6% of the maximum single impurity of 0.31% and 3.4% of the total impurities as measured by high performance liquid chromatography conditions in table 1.
Example 3 ]
Recrystallization method
This example provides a process for recrystallizing a crude compound 1 comprising the steps of:
48mL of 1, 4-dioxane and 240mL of n-heptane were added to 40g of the crude compound 1 prepared by the method described in example 1, the temperature was raised to 30℃and stirring was sufficient to dissolve compound 1, the temperature was lowered to-8℃and stirring was performed for 4 hours with heat preservation, the solid was filtered and taken out, and the solid was rinsed with 50mL of n-heptane and dried at 40℃to obtain 36.8g of crystals of compound 1, the yield of which was 92.0%.
The purity of compound 1 in the crystals of compound 1 prepared in this example was 99.7% and the maximum single impurity was 0.09% as measured by high performance liquid chromatography conditions shown in table 1.
Example 4 ]
Screening of recrystallization agents
This example was conducted by screening the recrystallization agent and the amount thereof based on example 3, and the conditions were the same as example 3 except for the conditions listed in the following table.
The screening results are shown in Table 2.
TABLE 2 screening of recrystallization agents
As shown in Table 3, various recrystallization agents can be recrystallized to obtain crystals of the compound 1, wherein the combination of n-heptane/1, 4-dioxane, n-heptane/acetone and n-hexane/tetrahydrofuran can be optimized in terms of both yield and purity. However, if n-heptane/t-butanol is used as the recrystallization agent, the recrystallization cannot be successfully performed.
Effects and effects of the examples
According to the recrystallization method according to the above examples, since a recrystallization agent comprising at least one of n-heptane, n-hexane or petroleum ether is used, the technical solution provided in the above examples enables to obtain crystals of compound 1 with high purity.
Further, since a recrystallization agent combination of n-heptane/1, 4-dioxane, n-heptane/acetone or n-hexane/tetrahydrofuran is used, the technical scheme provided in the above examples not only enables the production of compound 1 crystals in high yield, but also ensures that the purity of compound 1 crystals is 99% or more and the single impurity is less than 0.2%.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (8)
1. A recrystallization method is used for recrystallizing crude product of a compound 1, wherein the compound 1 isThe method is characterized by comprising the following steps of:
dissolving the crude product of the compound 1 in a recrystallization agent, controlling the temperature to-10 ℃ to 10 ℃, preserving the heat, separating to obtain a compound 1 crystal,
wherein the recrystallization agent consists of recrystallization A and recrystallization B,
the recrystallization agent A is selected from any one or more of n-heptane, n-hexane or petroleum ether, and the recrystallization agent B is selected from any one or more of dichloromethane, chloroform, benzene, toluene, tetrahydrofuran, 1, 4-epoxy hexacyclic ring or acetone.
2. The method of recrystallization according to claim 1, wherein:
wherein the crude product of the compound 1 also contains at least one organic impurity, and the total impurity content of the crude product of the compound 1 is less than 15 percent in liquid chromatography analysis.
3. The method of recrystallization according to claim 1, wherein:
wherein the crude product of the compound 1 also contains at least one organic impurity, and the maximum single impurity content of the crude product of the compound 1 in liquid chromatography analysis is less than 1.5 percent.
4. The method of recrystallization according to claim 1, wherein:
wherein the volume ratio of the recrystallization agent A to the recrystallization agent B is (4-6): 1.
5. the method of recrystallization according to claim 1, wherein:
wherein the recrystallization agent is n-hexane and tetrahydrofuran with the volume ratio of (4-6): 1.
6. The method of recrystallization according to claim 1, wherein:
wherein the recrystallization agent is n-heptane and the volume ratio of 1, 4-dioxane is (4-6): 1.
7. The method of recrystallization according to claim 1, wherein:
wherein the recrystallization agent is n-heptane and acetone with the volume ratio of (4-6): 1.
8. The method of recrystallization according to claim 1, wherein:
wherein the mass volume ratio of the crude product of the compound 1 to the recrystallization agent is 1g: (6.5-8) mL.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4535183A (en) * | 1980-12-18 | 1985-08-13 | Burroughs Wellcome Co. | Pharmaceutical compounds, preparation, use and intermediates therefor and their preparation |
| CN104540835A (en) * | 2012-04-26 | 2015-04-22 | 百时美施贵宝公司 | Imidazothiadiazole derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
| CN105431147A (en) * | 2014-02-07 | 2016-03-23 | 全球血液疗法股份有限公司 | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
| CN113272290A (en) * | 2018-12-21 | 2021-08-17 | 晶体制药独资有限公司 | Process and intermediates for synthesis of vortiotropium |
-
2022
- 2022-11-11 CN CN202211411791.8A patent/CN115636742B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4535183A (en) * | 1980-12-18 | 1985-08-13 | Burroughs Wellcome Co. | Pharmaceutical compounds, preparation, use and intermediates therefor and their preparation |
| CN104540835A (en) * | 2012-04-26 | 2015-04-22 | 百时美施贵宝公司 | Imidazothiadiazole derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
| CN105431147A (en) * | 2014-02-07 | 2016-03-23 | 全球血液疗法股份有限公司 | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
| CN113272290A (en) * | 2018-12-21 | 2021-08-17 | 晶体制药独资有限公司 | Process and intermediates for synthesis of vortiotropium |
Non-Patent Citations (2)
| Title |
|---|
| Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin;Metcalf, Brian等;ACS Medicinal Chemistry Letters;第8卷(第3期);321-326 * |
| Pearson, Emma L.等.Controlling cis/trans-selectivity in intramolecular Diels-Alder reactions of benzo-tethered, ester linked 1,3,9-decatrienes.Organic & Biomolecular Chemistry.2007,第6卷(第3期),513-522. * |
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