CN117843473A - Preparation method of levocarnitine impurity - Google Patents
Preparation method of levocarnitine impurity Download PDFInfo
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- CN117843473A CN117843473A CN202311646667.4A CN202311646667A CN117843473A CN 117843473 A CN117843473 A CN 117843473A CN 202311646667 A CN202311646667 A CN 202311646667A CN 117843473 A CN117843473 A CN 117843473A
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract description 27
- 229960001518 levocarnitine Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000012535 impurity Substances 0.000 title claims abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 93
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- TVOMCUWVZVBDBG-UHFFFAOYSA-N 4-chlorobut-2-enoic acid Chemical group OC(=O)C=CCCl TVOMCUWVZVBDBG-UHFFFAOYSA-N 0.000 claims abstract description 13
- AKDAXGMVRMXFOO-UHFFFAOYSA-N 4-chloro-3-hydroxybutanoic acid Chemical compound ClCC(O)CC(O)=O AKDAXGMVRMXFOO-UHFFFAOYSA-N 0.000 claims abstract description 12
- WMRINGSAVOPXTE-UHFFFAOYSA-N methyl 4-chloro-3-hydroxybutanoate Chemical compound COC(=O)CC(O)CCl WMRINGSAVOPXTE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012074 organic phase Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- LHBPNZDUNCZWFL-SCSAIBSYSA-N (3r)-4-chloro-3-hydroxybutanenitrile Chemical compound ClC[C@H](O)CC#N LHBPNZDUNCZWFL-SCSAIBSYSA-N 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012065 filter cake Substances 0.000 claims abstract description 6
- 239000000706 filtrate Substances 0.000 claims abstract description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 13
- 239000003208 petroleum Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000009423 ventilation Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 description 11
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- XENVCRGQTABGKY-ZHACJKMWSA-N chlorohydrin Chemical compound CC#CC#CC#CC#C\C=C\C(Cl)CO XENVCRGQTABGKY-ZHACJKMWSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a levocarnitine impurity, wherein the impurity is 4-chloro-2-butenoic acid, and the preparation method comprises the following steps: putting R-4-chloro-3-hydroxybutyronitrile and methanol into a reaction vessel, introducing hydrogen chloride, tracking the reaction progress by TLC, separating out solids, and washing a filter cake by using ethyl acetate; collecting filtrate and concentrating to obtain 4-chloro-3-hydroxybutyric acid methyl ester; adding methyl 4-chloro-3-hydroxybutyrate and water into a second reaction container, adding sodium hydroxide into the second reaction container, tracking the reaction progress by TLC, adding ethyl acetate, standing for layering, collecting an organic phase, and concentrating to dryness to obtain 4-chloro-3-hydroxybutyrate; adding 4-chloro-3-hydroxybutyric acid, water and sulfuric acid into a three-port container, tracking the reaction progress by TLC, adding ethyl acetate, standing for layering, collecting an organic phase, and concentrating to dryness to obtain 4-chloro-2-butenoic acid.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and in particular relates to a levocarnitine impurity which comprises the following components in percentage by weight: a method for preparing 4-chloro-2-butenoic acid.
Background
Levocarnitine (L-carnitine), also known as L-carnitine, vitamin BT, chemical name: (R) -3-hydroxy-4-trimethylammonio-butyrate, levocarnitine is a substance necessary for metabolism of human body, and has many clinical applications, and has curative effect or auxiliary curative effect on levocarnitine deficiency, cardiovascular disease, hyperlipidemia, dialysis nephropathy, liver cirrhosis, diabetes and the like.
The production method of the levocarnitine mainly comprises a food extraction method, a biosynthesis method and a chemical synthesis method. The food is mainly extracted from meat, and the process is complex, difficult and not suitable for industrial production. The biosynthesis method comprises biological enzyme fermentation and enzyme conversion, and compared with the product synthesized by a chemical method, the levocarnitine synthesized by the biological method has disadvantages of purity, quality stability, process controllability and the like, and the crude drug of the original research company is prepared by chemical synthesis.
There are many literature reports on methods for synthesizing levocarnitine, such as: the method comprises the steps of reacting epichlorohydrin with trimethylamine to obtain racemic chlorohydrin, resolving the racemic chlorohydrin with L-tartaric acid to obtain an S-configuration intermediate (formula E), replacing chloride with sodium cyanide or potassium cyanide to generate nitrile, and finally carrying out acidic hydrolysis to obtain L-carnitine (formula G). The synthesis route one is as follows:
the quality of the levocarnitine bulk drug is studied by adopting the route, and the levocarnitine impurity is generated in the process of researching the quality of the levocarnitine bulk drug: the 4-chloro-2-butenoic acid has great significance for formulating a more scientific and reasonable quality standard of the levocarnitine and guaranteeing the safety of medication.
The existing preparation process of 4-chloro-2-butenoic acid is complex, and the yield is low.
Disclosure of Invention
In order to solve the problems of the prior art, the invention provides a levocarnitine: the preparation method of the 4-chloro-2-butenoic acid has the characteristics of simple preparation, easy operation and higher yield.
In order to achieve the above purpose, the present invention adopts the following technical scheme: the chemical name of the levocarnitine impurity is 4-chloro-2-butenoic acid, and the structural formula is as follows:
the preparation method of the levocarnitine impurity comprises the following steps:
step 1):
adding 1 part by weight of R-4-chloro-3-hydroxybutyronitrile and 8-12 parts by weight of methanol into a reaction vessel, cooling to 0-5 ℃, introducing 0.2-1.2 parts by weight of hydrogen chloride gas, heating to 60-65 ℃ after ventilation is finished, and carrying out reflux reaction for 2.5-3 hours; TLC tracks the reaction progress, and after the reaction is finished, heating is stopped; cooling the reaction system to 10-15 ℃, separating out solids, filtering, and washing a filter cake with ethyl acetate; the filtrate was collected and concentrated to give a first yellow oil: 4-chloro-3-hydroxybutyric acid methyl ester;
step 2):
adding 1 part by weight of 4-chloro-3-hydroxybutyric acid methyl ester and 9-15 parts by weight of water into a second reaction container, cooling to 0-10 ℃, starting stirring, adding 0.2-0.5 part by weight of sodium hydroxide in batches, heating to 20-30 ℃ after the addition is finished, preserving heat for 2 hours, tracking the reaction progress by TLC, and stopping heating after the reaction is finished; adjusting the pH value of the system to 7-8, adding 10-15 parts of ethyl acetate, stirring for 30 minutes, standing, layering, collecting an organic phase, and concentrating to dryness to obtain a second yellow oily matter: 4-chloro-3-hydroxybutyric acid;
step 3):
adding 1 part by weight of 4-chloro-3-hydroxybutyric acid and 12-17 parts by weight of water into a three-port reaction container, dropwise adding 0.6-2 parts by weight of sulfuric acid after stirring and dissolving completely, heating to 50-60 ℃ after the dropwise adding is finished, stirring and reacting for 2-3 hours, tracking the reaction progress by TLC, after the reaction is finished, regulating the pH value to 7-8, adding 11-16 parts by weight of ethyl acetate, stirring for 30 minutes, standing and layering, collecting an organic phase, concentrating to dryness, and obtaining a third yellow oily substance, and passing through a chromatographic column to obtain 4-chloro-2-butenoic acid.
The TLC in each step tracks the reaction progress, and the developing agent is the mixed solution of petroleum ether and ethyl acetate according to the volume ratio: petroleum ether/ethyl acetate=3/1. The concentration of sulfuric acid is 50%.
The beneficial technical effects of the invention are as follows: the method has simple preparation and easy operation, the highest yield of the step 1 can reach 95.3 percent, the highest yield of the step 2 can reach 89.1 percent, and the highest yield of the step 3 can reach 54.1 percent.
Description of the embodiments
Example 1
The preparation method of the levocarnitine impurity comprises the following steps:
step 1): putting 11.9g R-4-chloro-3-hydroxybutyronitrile and 120ml methanol into a 500ml reaction bottle, cooling to 0-5 ℃, introducing 10.95g hydrogen chloride gas, heating to 60-65 ℃ after ventilation is finished, and carrying out reflux reaction for 2.5-3h; TLC followed the reaction progress (developing solvent: petroleum ether/ethyl acetate=3/1), and after the reaction was completed, heating was stopped; cooling the reaction system to 10-15 ℃, precipitating a large amount of solids, filtering, and washing a filter cake with ethyl acetate. The filtrate was collected and concentrated to give 14.5g of yellow oil (methyl 4-chloro-3-hydroxybutyrate) in 95.3% yield.
Step 2): adding 15.2g of methyl 4-chloro-3-hydroxybutyrate and 200g of water into a 500ml reaction bottle, cooling to 0-10 ℃, starting stirring, adding 5.0g of sodium hydroxide into the reaction bottle in batches, heating to 20-30 ℃ after the addition is finished, preserving heat for 2 hours, tracking the reaction progress by TLC (developing agent: petroleum ether/ethyl acetate=3/1), and stopping heating after the reaction is finished; the pH of the system was adjusted to 7-8, 200ml of ethyl acetate was added, and after stirring for 30 minutes, the organic phase was collected by standing and layering and concentrated to dryness to give 12.3g of a yellow oil: 4-chloro-3-hydroxybutyric acid was 89.1% yield.
Step 3): in a three-port reaction flask of 250ml, 13.8g of 4-chloro-3-hydroxybutyric acid and 200g of water are added, after stirring and complete dissolution, 24.5ml of sulfuric acid is added into the reaction flask, after the dripping is finished, the temperature is raised to 50-60 ℃, stirring and reaction are carried out for 2-3 hours, TLC tracks the reaction progress (developing agent: petroleum ether/ethyl acetate=3/1), after the reaction is finished, pH value is 7-8, 200ml of ethyl acetate is added, stirring is carried out for 30 minutes, standing and layering are carried out, the organic phase is collected and concentrated to dryness, 12.3g of yellow oily matter is obtained, 6.5g of 4-chloro-2-butenoic acid is obtained through a chromatographic column, and the reaction yield is 54.1%. The concentration of sulfuric acid is 50%.
Example 2
The preparation method of the levocarnitine impurity comprises the following steps:
step 1): putting 11.9g R-4-chloro-3-hydroxybutyronitrile and 120ml methanol into a 500ml reaction bottle, cooling to 0-5 ℃, introducing 7.30g hydrogen chloride gas, heating to 60-65 ℃ after ventilation is finished, and carrying out reflux reaction for 2.5-3h; TLC followed the reaction progress (developing solvent: petroleum ether/ethyl acetate=3/1), and after the reaction was completed, heating was stopped; cooling the reaction system to 10-15 ℃, precipitating a large amount of solids, filtering, and washing a filter cake with ethyl acetate. The filtrate was collected and concentrated to give a yellow oil (methyl 4-chloro-3-hydroxybutyrate) in 92.3% yield.
Step 2): 15.2g of methyl 4-chloro-3-hydroxybutyrate and 140g of water are added into a 500ml reaction bottle, the temperature is reduced to 0-10 ℃, stirring is started, 6.0g of sodium hydroxide (or 60ml of 10% sodium hydroxide solution) is added into the reaction bottle in batches, after the addition is finished, the temperature is increased to 20-30 ℃, the reaction is kept for 2 hours, TLC tracks the reaction progress (developing agent: petroleum ether/ethyl acetate=3/1), and after the reaction is finished, heating is stopped; the pH value of the system is adjusted to 7-8, 200ml of ethyl acetate is added, after stirring for 30 minutes, the organic phase is collected by standing and layering and concentrated to dryness, and a second yellow oily matter is obtained: 4-chloro-3-hydroxybutyric acid was 84.1% yield.
Step 3): in a three-port reaction bottle of 250ml, 13.8g of 4-chloro-3-hydroxybutyric acid and 200g of water are added, 19.6ml of sulfuric acid is added into the reaction bottle after stirring and complete dissolution, the temperature is raised to 50-60 ℃ after the dripping is finished, stirring and reaction are carried out for 2-3 hours, TLC tracks the reaction progress (developing agent: petroleum ether/ethyl acetate=3/1), pH value is between 7 and 8 after the reaction is finished, 200ml of ethyl acetate is added, stirring is carried out for 30 minutes, standing and layering are carried out, the organic phase is collected and concentrated to dryness, thus obtaining a third yellow oil, and the product 4-chloro-2-butenoic acid is obtained after passing through a chromatographic column, and the reaction yield is 46.6%. The concentration of sulfuric acid is 50%.
Example 3
The preparation method of the levocarnitine impurity comprises the following steps:
step 1): putting 11.9g R-4-chloro-3-hydroxybutyronitrile and 120ml methanol into a 500ml reaction bottle, cooling to 0-5 ℃, introducing 3.65g hydrogen chloride gas, heating to 60-65 ℃ after ventilation is finished, and carrying out reflux reaction for 2.5-3h; TLC followed the reaction progress (developing solvent: petroleum ether/ethyl acetate=3/1), and after the reaction was completed, heating was stopped; cooling the reaction system to 10-15 ℃, precipitating a large amount of solids, filtering, and washing a filter cake with ethyl acetate. The filtrate was collected and concentrated to give a yellow oil (methyl 4-chloro-3-hydroxybutyrate) in 81.5% yield.
Step 2): 15.2g of methyl 4-chloro-3-hydroxybutyrate and 160g of water are added into a 500ml reaction bottle, the temperature is reduced to 0-10 ℃, stirring is started, 4.0g of sodium hydroxide (or 40ml of 10% sodium hydroxide solution) is added into the reaction bottle in batches, after the addition is finished, the temperature is increased to 20-30 ℃, the reaction is kept for 2 hours, TLC tracks the reaction progress (developing agent: petroleum ether/ethyl acetate=3/1), and after the reaction is finished, heating is stopped; the pH value of the system is adjusted to 7-8, 200ml of ethyl acetate is added, after stirring for 30 minutes, the organic phase is collected by standing and layering and concentrated to dryness, and a second yellow oily matter is obtained: 4-chloro-3-hydroxybutyric acid, the reaction yield was 81.1%.
Step 3): in a three-port reaction bottle of 250ml, 13.8g of 4-chloro-3-hydroxybutyric acid and 200g of water are added, after stirring and complete dissolution, 9.8g of sulfuric acid is added into the reaction bottle, after the dripping is finished, the temperature is raised to 50-60 ℃, stirring and reaction are carried out for 2-3 hours, TLC tracks the reaction progress (developing agent: petroleum ether/ethyl acetate=3/1), after the reaction is finished, pH value is 7-8, 200ml of ethyl acetate is added, stirring is carried out for 30 minutes, standing and layering are carried out, the organic phase is collected and concentrated to dryness, thus obtaining a third yellow oil, and the product 4-chloro-2-butenoic acid is obtained through a chromatographic column, and the reaction yield is 43.3%. The concentration of sulfuric acid is 50%.
Claims (4)
1. A preparation method of a levocarnitine impurity, wherein the chemical name of the levocarnitine impurity is 4-chloro-2-butenoic acid, and the structural formula is as follows:
2. the preparation method comprises the following steps:
1) Adding 1 part by weight of R-4-chloro-3-hydroxybutyronitrile and 8-12 parts by weight of methanol into a reaction vessel, cooling to 0-5 ℃, introducing 0.2-1.2 parts by weight of hydrogen chloride gas, heating to 60-65 ℃ after ventilation is finished, and carrying out reflux reaction for 2.5-3 hours; TLC tracks the reaction progress, and after the reaction is finished, heating is stopped; cooling the reaction system to 10-15 ℃, separating out solids, filtering, and washing a filter cake with ethyl acetate; the filtrate was collected and concentrated to give a first yellow oil: 4-chloro-3-hydroxybutyric acid methyl ester;
2) Adding 1 part by weight of 4-chloro-3-hydroxybutyric acid methyl ester and 9-15 parts by weight of water into a second reaction container, cooling to 0-10 ℃, starting stirring, adding 0.2-0.5 part by weight of sodium hydroxide in batches, heating to 20-30 ℃ after the addition is finished, preserving heat for 2 hours, tracking the reaction progress by TLC, and stopping heating after the reaction is finished; adjusting the pH value of the system to 7-8, adding 10-15 parts of ethyl acetate, stirring for 30 minutes, standing, layering, collecting an organic phase, and concentrating to dryness to obtain a second yellow oily matter: 4-chloro-3-hydroxybutyric acid;
3) Adding 1 part by weight of 4-chloro-3-hydroxybutyric acid and 12-17 parts by weight of water into a three-port reaction container, dropwise adding 0.6-2 parts by weight of sulfuric acid after stirring and dissolving completely, heating to 50-60 ℃ after the dropwise adding is finished, stirring and reacting for 2-3 hours, tracking the reaction progress by TLC, after the reaction is finished, regulating the pH value to 7-8, adding 11-16 parts by weight of ethyl acetate, stirring for 30 minutes, standing and layering, collecting an organic phase, concentrating to dryness, and obtaining a third yellow oily substance, and passing through a chromatographic column to obtain 4-chloro-2-butenoic acid.
3. The method of manufacturing according to claim 1, characterized in that: the TLC in each step tracks the reaction progress, and the developing agent is the mixed solution of petroleum ether and ethyl acetate according to the volume ratio: petroleum ether/ethyl acetate=3/1.
4. The method of manufacturing according to claim 1, characterized in that: the concentration of sulfuric acid is 50%.
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| CN202311646667.4A CN117843473A (en) | 2023-12-04 | 2023-12-04 | Preparation method of levocarnitine impurity |
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| CN202311646667.4A CN117843473A (en) | 2023-12-04 | 2023-12-04 | Preparation method of levocarnitine impurity |
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