CN113804805A - Pregabalin intermediate impurity compound II and preparation method thereof - Google Patents
Pregabalin intermediate impurity compound II and preparation method thereof Download PDFInfo
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 25
- 229960001233 pregabalin Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000012535 impurity Substances 0.000 title abstract description 26
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 17
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 16
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 239000004202 carbamide Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 229940117803 phenethylamine Drugs 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 238000003908 quality control method Methods 0.000 claims description 5
- 239000013558 reference substance Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 235000019837 monoammonium phosphate Nutrition 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims 3
- 238000011895 specific detection Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- AYXYPKUFHZROOJ-UHFFFAOYSA-N 3-(azaniumylmethyl)-5-methylhexanoate Chemical compound CC(C)CC(CN)CC(O)=O AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 208000028329 epileptic seizure Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
- C07C273/1863—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety from urea
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a pregabalin intermediate impurity compound II and a preparation method thereof, wherein reaction raw materials are used as solvents, and no organic solvent or catalyst is used in the reaction process.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a pregabalin intermediate impurity compound II and a preparation method thereof.
Background
Pregabalin, english name (Pregabalin), chemical name 3-aminomethyl-5-methylhexanoic acid. The structural formula of pregabalin is shown as follows:
pregabalin is a gamma-aminobutyric acid (GABA) analogue, has a structure and an effect similar to gabapentin, has anti-epilepsy, analgesic and anxiolytic activities, and can be used for the adjuvant treatment of neuralgia of diabetic peripheral neuropathy, postherpetic neuralgia, epileptic seizure, anxiety disorder and the like.
In the process of research and development of medicines, the research and control of impurities are a very critical and indispensable link, and the method has important significance for the research of the impurities in the synthesis reaction of key intermediates. Meanwhile, in the process of detecting the quality of the medicine, high-purity impurities are required to be used as reference substances for controlling the quality of the medicine possibly containing the impurities, so that qualified impurity reference substances are prepared and controlled within a reasonable and safe limit range, and the method has important significance on the quality control and safety of the medicine.
The compound III is a key intermediate compound for preparing pregabalin and is prepared by reacting a compound IV with urea, the compound IV is obtained by treating mother liquor obtained by splitting the compound III and R-phenylethylamine, and a small amount of R-phenylethylamine in the compound IV reacts with urea to form a compound II. The impurity compound II participates in subsequent chemical reaction, new impurities are generated by derivation, and the removal effect of the derived impurities is poor through conventional extraction, washing, alkali adjustment, crystallization and other operation modes, so that the quality of finished products is influenced, therefore, the compound II needs to be controlled in the preparation process of the compound III, and the stable quality of the final products is ensured.
Disclosure of Invention
In one aspect, the present invention provides a method for controlling the quality of pregabalin by controlling the mass content of the compound of formula II in pregabalin or the compound of formula III to be not higher than 0.5%.
In one aspect, the present invention provides the use of a compound of formula II as a standard or control for the quality control of pregabalin for controlling the quality of pregabalin.
In one aspect, the present invention provides a process for the preparation of a compound of formula II, comprising the reaction of:
the reaction does not require the addition of a solvent and/or the addition of a catalyst.
As a preferred technical scheme, the reaction does not need to add a solvent or a catalyst.
As a preferable technical scheme, the phenylethylamine serving as a reaction raw material is used as a solvent in the reaction.
Further, as a preferred technical scheme, the preparation method comprises the following steps: adding urea and phenethylamine into a reaction container, heating for reaction, cooling after the reaction is finished, and filtering to obtain a crude product.
Furthermore, as a preferred technical scheme, the molar ratio of the phenylethylamine to the urea in the reaction is 1: 1.0-1: 10, preferably 1: 2.0-1: 3.
furthermore, as a preferable technical scheme, the reaction temperature of the temperature rise reaction is 90-150 ℃, the reaction time is 0.5-24 h, the reaction temperature is preferably 110-120 ℃, and the reaction time is 3-5 h.
Further, as a preferred technical solution, the preparation method comprises a step of further comprising the following purification steps: and adding an organic solvent into the crude product, heating to dissolve, cooling to crystallize, filtering, and drying to obtain the high-purity impurity compound shown in the formula II.
Further, as a preferred technical scheme, the organic solvent is selected from one of ethyl acetate, isopropyl acetate, methyl formate, ethanol, methanol or acetonitrile, and ethyl acetate is preferred.
Furthermore, as a preferable technical scheme, the weight volume ratio g/ml of the crude product to the volume of the organic solvent is 1: 1-1: 5, preferably 1: 3-1: 5.
Furthermore, as a preferable technical scheme, the temperature rise and the dissolution and cleaning temperature are 20-80 ℃, the dissolution and cleaning time is 0.5-15 h, the dissolution and cleaning temperature is preferably 50-60 ℃, and the dissolution and cleaning time is preferably 4-6 h.
The preparation method of the pregabalin intermediate impurity compound of the formula II is free of solvent and catalyst, simple and easy to operate, green and environment-friendly, high in yield and high in purity.
The purity of the pregabalin intermediate impurity compound shown in the formula II prepared by the invention is more than 99%, and the pregabalin intermediate impurity compound can be used as an impurity standard substance or an impurity reference substance in medicine quality control.
The research and control of the impurities of the raw material medicines are the precondition and the key link for ensuring the safety and the quality controllability of the medicines and are the important indexes for evaluating the consistency of the medicines. The invention provides a method for preparing a high-purity and high-yield impurity compound of a pregabalin intermediate with a formula II without a solvent and a catalyst for the first time, provides a reliable reference substance for qualitative and quantitative research on impurities in the research and development and production of pregabalin, and provides a basis and guarantee for the quality research of pregabalin.
Detailed Description
The following specific preparation examples are intended to illustrate the invention in detail, and the examples are intended to be illustrative in more detail only, and not to limit the invention in any way.
The HPLC detection method adopted by the invention is as follows:
1.1 chromatographic conditions
The instrument comprises the following steps: high performance liquid chromatograph equipped with ultraviolet detector
A chromatographic column: supelco Discovery RP amide 150X 4.6mm, 5 μm or equivalent chromatography column
Buffer solution: 2.3g of ammonium dihydrogen phosphate are dissolved in 1000mL of water and the pH is adjusted to 3.5 with phosphoric acid.
Mobile phase A: buffer solution: acetonitrile 800: 200 (% V/V)
Mobile phase B: acetonitrile
Temperature of the chromatographic column: detection wavelength at 30 ℃: 210nm
Flow rate: 1.0mL/min run time: 42min sample size: 20 μ L
Gradiometer:
1.2 preparation of solution
Diluting liquid: mobile phase a blank solution: diluent liquid
Test solution: weighing 100mg of sample, precisely weighing in a 20ml volumetric flask, diluting with diluent (mobile phase A), dissolving, cooling to room temperature, diluting to constant volume, and shaking.
1.3 analytical procedure
And after the system is balanced, injecting a blank solution 1 needle, a resolution solution 1 needle and a sample solution 1 needle, and recording the whole chromatographic process, wherein the resolution between different known impurities in the resolution solution is required to be not less than 1.5.
Example 1
Adding 10.0g of phenethylamine and 10.0g of urea into a reaction bottle, heating to 110 ℃ for reaction, reacting for 4 hours, cooling to room temperature after the reaction is finished, and filtering to obtain 13.8g of white solid; and adding 42ml of ethyl acetate into 13.8g of the white solid, heating to 50 ℃, stirring to dissolve the solid for 4 hours, cooling to room temperature, filtering and drying to obtain 13.3g of an impurity compound shown as a formula II, wherein the purity is 99.91% according to HPLC detection, and the yield is 98.5%.
The nuclear magnetic resonance structural characterization data is shown in the following table 1, and the related HPLC detection spectrum is shown in the figure 1.
TABLE 1
| Cδppm | Type C | Number of C | Hδppm | Peak type | Number of H | Home C/H numbering |
| 23.4 | CH3 | 1 | 1.30 | d | 3 | 9 |
| 48.5 | CH | 1 | 4.70 | m | 1 | 7 |
| 125.8 | CH | 2 | 7.29 | m | 2 | 2,3 |
| 126.4 | CH | 1 | 7.21 | m | 1 | 6 |
| 128.2 | CH | 2 | 7.31 | m | 2 | 4,5 |
| 145.8 | C | 1 | — | — | — | 1 |
| 157.9 | C | 1 | — | — | — | 10 |
| N-H | — | — | 5.43 | s | 2 | 11 |
| N-H | — | — | 6.43 | d | 1 | 8 |
The impurities prepared by the invention are characterized by a nuclear magnetic resonance structure, the structure of a synthesized product is determined to be correct, a nuclear magnetic resonance hydrogen spectrum and a nuclear magnetic resonance carbon spectrum are analyzed, and the compound number is as follows:
example 2
Adding 100.0g of phenethylamine and 120.0g of urea into a reaction bottle, heating to 130 ℃ for reaction, reacting for 3 hours, cooling to room temperature after the reaction is finished, and filtering to obtain 136.1g of white solid; and then 680ml of methanol is added into 136.1g of the white solid, the temperature is raised to 60 ℃, the solution is stirred for 5 hours, the temperature is reduced to room temperature, and the mixture is filtered and dried to obtain 132.8g of the impurity compound shown in the formula II, wherein the HPLC purity is 99.96 percent, and the yield is 98.0 percent.
Example 3
Adding 2.0kg of phenethylamine and 2.2kg of urea into a reaction kettle, heating to 120 ℃ for reaction, reacting for 5 hours, cooling to room temperature after the reaction is finished, and filtering to obtain 2.73kg of white solid; and adding 11L of acetonitrile into the 2.73kg of white solid, heating to 55 ℃, stirring for 3h, cooling to room temperature, filtering and drying to obtain 2.67kg of an impurity compound shown as the formula II, wherein the purity of HPLC (high performance liquid chromatography) is 99.91 percent, and the yield is 98.7 percent.
Claims (15)
1. A method for controlling the quality of pregabalin, which is characterized in that the mass content of the compound shown in the formula II in pregabalin is controlled to be not higher than 0.5 percent,
2. the method for controlling the quality of pregabalin according to claim 1, characterized in that the mass content of the compound of formula II in the compound of formula III is controlled to be not higher than 0.5%,
3. a method for controlling the quality of pregabalin, which is characterized in that the mass content of the compound shown in the formula II in the compound shown in the formula III is controlled to be not higher than 0.5%.
4. The use of the compound of formula II in the quality control of pregabalin, characterized in that the compound of formula II is used as a standard or reference substance for the quality control of pregabalin.
5. A process for the preparation of a compound of formula II, said process comprising the following reaction:
characterized in that the reaction is carried out without the addition of a solvent and/or without the addition of a catalyst.
6. The process for the preparation of the compound of formula II according to claim 5, characterized in that the reaction is carried out without addition of solvent and without addition of catalyst.
7. The method for preparing the compound of formula II according to claim 5, wherein the reaction is performed using phenethylamine as a solvent.
8. A process for the preparation of a compound of formula II according to any one of claims 5 to 7, characterized in that it comprises the following steps: adding urea and phenethylamine into a reaction container, heating for reaction, cooling after the reaction is finished, and filtering to obtain a crude product.
9. A process for the preparation of a compound of formula II according to claim 8, characterized in that the process further comprises the following purification steps: adding an organic solvent into the crude product, heating to dissolve, cooling to crystallize, filtering, and drying to obtain the high-purity compound of the formula II.
10. The process for preparing the compound of formula II according to claim 8, wherein the molar ratio of phenethylamine to urea in the reaction is 1: 1-1: 10, preferably 1: 2-1: 3.
11. the process for preparing the compound of formula II according to claim 8, wherein the temperature-raising reaction is carried out at a reaction temperature of 90 ℃ to 150 ℃ for 0.5h to 24h, preferably at a reaction temperature of 110 ℃ to 120 ℃ for 3h to 5 h.
12. Process for the preparation of a compound of formula II according to claim 9, characterized in that the organic solvent is selected from one of ethyl acetate, isopropyl acetate, methyl formate, ethanol, methanol or acetonitrile, preferably ethyl acetate.
13. The method for preparing the compound of formula II according to claim 9, wherein the weight/volume ratio g/ml of the crude product to the volume of the organic solvent is 1:1 to 1:5, preferably 1:3 to 1: 5.
14. The process for preparing the compound of formula II according to claim 9, wherein the temperature-raising and the time for the elution are 20 ℃ to 80 ℃ and 0.5h to 15h, preferably 50 ℃ to 60 ℃ and 4h to 6 h.
15. The detection method of the compound shown in the formula II is characterized in that the specific detection conditions are as follows: buffer solution: 2.3g of ammonium dihydrogen phosphate is dissolved in 1000mL of water, and the pH value is adjusted to 3.5 by phosphoric acid; mobile phase A: buffer solution: acetonitrile 800: 200 (% V/V); mobile phase B-acetonitrile; detection wavelength: 210 nm; temperature of the chromatographic column: 30 ℃, flow rate: 1.0 mL/min; sample introduction amount: 20 μ L, gradient elution, elution gradient program as follows:
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| CN116554062A (en) | 2023-08-08 |
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