CN116023285A - Levocarnitine related impurities and preparation method thereof - Google Patents
Levocarnitine related impurities and preparation method thereof Download PDFInfo
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- CN116023285A CN116023285A CN202211383125.8A CN202211383125A CN116023285A CN 116023285 A CN116023285 A CN 116023285A CN 202211383125 A CN202211383125 A CN 202211383125A CN 116023285 A CN116023285 A CN 116023285A
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- levocarnitine
- ethyl
- alkali
- chloroacetoacetate
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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 33
- 229960001518 levocarnitine Drugs 0.000 title claims abstract description 28
- 239000012535 impurity Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims abstract description 32
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 claims abstract description 28
- -1 3-ethoxy-4-trimethylammonio-2-butenoic acid salt Chemical class 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 230000006203 ethylation Effects 0.000 claims abstract description 3
- 238000006200 ethylation reaction Methods 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003729 cation exchange resin Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- NVJBFARDFTXOTO-UHFFFAOYSA-N diethyl sulfite Chemical compound CCOS(=O)OCC NVJBFARDFTXOTO-UHFFFAOYSA-N 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 3
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 claims description 3
- 229940008406 diethyl sulfate Drugs 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 230000001276 controlling effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 abstract 1
- 238000010931 ester hydrolysis Methods 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 18
- 238000000034 method Methods 0.000 description 16
- 239000003480 eluent Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000011033 desalting Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 4
- BJAARRARQJZURR-UHFFFAOYSA-N trimethylazanium;hydroxide Chemical compound O.CN(C)C BJAARRARQJZURR-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 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
- 238000004440 column chromatography Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- WSHVQVCBPLNREW-UHFFFAOYSA-N 4-chloro-3-oxobutanoyl chloride Chemical compound ClCC(=O)CC(Cl)=O WSHVQVCBPLNREW-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 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
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction 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
- 238000012790 confirmation Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- ZAJNMXDBJKCCAT-RXMQYKEDSA-N ethyl (3r)-4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](O)CCl ZAJNMXDBJKCCAT-RXMQYKEDSA-N 0.000 description 1
- ZKGUZFGSTHDYQQ-UHFFFAOYSA-N ethyl 4-chloro-3-ethoxybut-2-enoate Chemical compound CCOC(=O)C=C(CCl)OCC ZKGUZFGSTHDYQQ-UHFFFAOYSA-N 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
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
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- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a 3-ethoxy-4-trimethylammonio-2-butenoic acid salt related to levocarnitine and a preparation method thereof, which mainly comprises the following steps: 1) Under the condition of alkali 1, 4-chloroacetoacetic acid ethyl ester (formula A) reacts with an ethylation reagent when the pH is kept between 7.0 and 9.0; 2) Substitution reaction and ester hydrolysis reaction are carried out under the condition of alkali 2 and trimethylamine to obtain the relevant impurity of the levocarnitine: 3-ethoxy-4-trimethylammonio-2-butenoic acid salt (formula B). Wherein, 3-ethoxy-4-trimethylammonio-2-butenoic acid salt (formula B) is a compound with a brand new structure.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and in particular relates to a levocarnitine related impurity: a method for preparing 3-ethoxy-4-trimethylammonio-2-butenoic acid salt (formula B).
Background
Levocarnitine (L-carnitine), also known as L-carnitine, vitamin BT, chemical name: (R) -3-hydroxy-4-trimethylammonio-butyrate, proprietary Sigma-Tau, italy. 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 diseases, 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:
at present, the medicine industry takes 4-chloroacetoacetic acid ethyl ester as a raw material (formula A), chiral pure (R) -4-chloro-3-hydroxybutyric acid ethyl ester (formula H) is obtained through chemical or biological asymmetric catalytic hydrogenation, the intermediate is subjected to ammoniation and hydrolysis in an aqueous solution of trimethylamine strong base to obtain the levocarnitine (formula G), and a synthesis route II is shown as follows:
we found a new impurity 3-ethoxy-4-trimethylammonium-2-butenoic acid salt (formula B) which was not reported in the literature before in the course of studying the quality of levocarnitine bulk drug using route two:
the discovery is significant for formulating a more scientific and reasonable quality standard of the levocarnitine and guaranteeing the medication safety.
After confirming its structure by means of analysis such as nuclear magnetism, mass spectrometry, etc., it is presumed that its production is introduced by the related impurity ethyl 4-chloro-3-ethoxybutenoate (formula K) in the starting material ethyl 4-chloroacetoacetate (formula a): industrially, 4-chloro-3-oxobutanoyl chloride (formula I) is produced from diketene as a raw material by introducing chlorine gas into methylene dichloride at a low temperature, and a small amount of alkenyl chloride (formula J) is produced due to an enol tautomerism structure. And reacting the formula I and the formula J with ethanol to obtain the 4-chloroacetoacetic acid ethyl ester (formula A) serving as the initial raw material of the levocarnitine and the impurity formula K. The detection of the 4-chloroacetoacetic acid ethyl ester sold in the domestic market at present shows that the impurity type K content is about 0.1% -0.5%. In the preparation of levocarnitine using scheme II, formula K is further substituted with trimethylamine and hydrolyzed under the action of sodium hydroxide to yield the above-mentioned levocarnitine-related impurity formula B.
The new compound shown in the formula B is not reported in the synthesis.
U.S. patent No. 2016024110 discloses a method for synthesizing a compound of formula K, using ethyl 4-chloroacetoacetate as a starting material to react with triethyl orthoformate for 3 days, followed by column chromatography purification to obtain a ketal intermediate, followed by treatment with phosphorus pentoxide and further column chromatography purification to obtain a compound of formula K in a yield of 46%. The whole process is complex to prepare and the yield is low.
Disclosure of Invention
The invention provides a one-pot method for preparing 3-ethoxy-4-trimethylammonio-2-butenoic acid salt (formula B) related impurities of levocarnitine by taking 4-chloroacetoacetic acid ethyl ester as a raw material, so that the preparation is simple and easy to operate.
In order to achieve the above purpose, the present invention adopts the following technical scheme: 1) Adding 4-chloroacetoacetic acid ethyl ester (formula A), an ethylation reagent and an organic solvent into a reaction bottle, replacing nitrogen, heating to 25-100 ℃, adding alkali 1, adjusting the pH of a reaction system to 7.0-9.0, and reacting for 1-6 hours at a constant temperature; 2) Adding aqueous solution of trimethylamine/alkali 2 into the reaction liquid, controlling the temperature of the reaction system to be 0-10 ℃, naturally heating to 20-25 ℃ after the dropwise addition, reacting for 4-10 hours, concentrating, washing and extracting, regulating pH, eluting by a cation exchange resin column, concentrating and crystallizing to obtain the relevant impurities (formula B) of the levocarnitine. The reaction formula is as follows:
according to the above scheme, the reaction temperature selected in step 1 is 25-100 ℃, preferably 50 ℃.
According to the above scheme, the reaction pH selected in step 1 is 7.0-9.0, preferably 7.5-8.0.
According to the above scheme, the reaction time selected in the step 1 is 1-6 hours, preferably 2-3 hours.
According to the scheme, the selected organic solvent can be one of tetrahydrofuran, acetonitrile, ethanol, N-dimethylformamide, acetone and dimethyl sulfoxide, and the preferred solvent is acetonitrile. The volume amount of the solvent is 5 to 10 times the weight of the ethyl 4-chloroacetoacetate (formula A), and preferably 10 times the weight of the ethyl 4-chloroacetoacetate (formula A).
According to the above scheme, the ethylating reagent can be one of diethyl sulfate, diethyl carbonate, ethyl iodide and diethyl sulfite, and preferably the ethylating reagent is diethyl sulfite. The molar ratio of ethyl 4-chloroacetoacetate (formula A) to the ethylating reagent is 1 to 2 times, preferably 1.2 times.
According to the above scheme, the selected base 1 can be one of pyridine and DBU, TEA, DIPEA, and is preferable: pyridine. The molar amount of the base 1 is 1 to 2 times, preferably 1.1 times, the molar amount of ethyl 4-chloroacetoacetate (formula A).
According to the scheme, the alkali 2 can be NaOH,KOH、Na 3 PO 4 Preferably NaOH. The molar amount of the base 2 is 1 to 2 times, preferably 1.5 times, the molar amount of ethyl 4-chloroacetoacetate (formula A). The molar amount of trimethylamine selected is 1 to 10 times, preferably 5 times, the molar amount of ethyl 4-chloroacetoacetate (formula A). The volume of water is 5-10 times, preferably 10 times, the weight of ethyl 4-chloroacetoacetate (formula A).
The product synthesized by the invention adopts H 1 NMR and MS are used for structural confirmation, and the patterns are shown in figure 1 and figure 2. The beneficial technical effects of the invention are as follows: the method provided by the invention synthesizes the 3-ethoxy-4-trimethylammonio-2-butenoic acid salt related impurity of the levocarnitine by a one-pot method, and the obtained reference substance can be used for guiding the quality method development of the levocarnitine bulk drug and establishing a more scientific and reasonable quality standard.
Drawings
FIG. 1: nuclear magnetic resonance hydrogen spectrum of 3-ethoxy-4-trimethylammonio-2-butenoic acid salt
Fig. 2: 3-ethoxy-4-trimethylammonio-2-butenoic acid salt mass spectrum
Detailed Description
The invention will now be described in detail with reference to specific examples which will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications could be made by those skilled in the art without departing from the inventive concept. These are all within the scope of the present invention.
Example 1: preparation of 3-ethoxy-4-trimethylammonio-2-butenoic acid salt
Ethyl 4-chloroacetoacetate (16.40 g,0.10 mol) was added to the reaction flask, diethyl sulfite (16.58 g,0.12 mol) and 164mL acetonitrile were added, the mixture was stirred at room temperature, nitrogen was replaced, pyridine (8.70 g, 0.11 mol) was slowly added dropwise at a constant temperature after the reaction solution was warmed to 50 ℃, and the pH of the system was controlled to 7.5 to 8.0 during the dropwise addition. After the addition, the reaction is carried out for 2 to 3 hours at constant temperature. Then cooling to 0-10 ℃, adding sodium hydroxide (6.00 g,0.15 mol) and 164mL of water, slowly dripping 30% trimethylamine water solution (98.52 g,0.50 mol), naturally heating the reaction liquid to 20-25 ℃ after the addition, and stirring for reaction for 4 hours.
After the reaction solution is concentrated under reduced pressure and excess trimethylamine is distilled off at the temperature of 40-45 ℃, 200mL of dichloromethane is added for stirring, standing and liquid separation, and an upper water phase is reserved. The pH of the water phase is regulated to 6.5-7.5 by using 2M HCl, then the cation exchange resin column is eluted for desalting, and the eluent with the pH more than 8 is collected after the water phase is washed by 1% ammonia water until no product flows out. Concentrating the eluent under reduced pressure to dryness at 70-75 ℃, adding 10mL of absolute ethyl alcohol, and stirring at room temperature until the eluent is clear. 100mL of acetone is slowly added dropwise for crystallization, filtration and drying are carried out, and 10.30g of white solid is obtained, the yield is 55%, and the purity is 97.90%.
Example 2: preparation of 3-ethoxy-4-trimethylammonio-2-butenoic acid salt
Ethyl 4-chloroacetoacetate (8.21 g,0.05 mol) was added to a reaction flask, diethyl carbonate (7.09 g,0.06 mol) was added, 82mL of tetrahydrofuran was added, stirring was performed at room temperature, nitrogen was replaced, and triethylamine (5.56 g,0.055 mol) was slowly added dropwise at a constant temperature after the reaction solution was warmed to 50℃and the pH of the system was controlled to 7.0 to 8.0 during the dropwise addition. After the addition, the reaction is carried out for 2 to 3 hours at constant temperature. Then cooling to 0-10 ℃, adding sodium hydroxide (3.00 g,0.075 mol) and 82mL of water, slowly dripping 30% trimethylamine water solution (49.25 g,0.25 mol), naturally heating the reaction solution to 20-25 ℃ after the addition, and stirring for reaction for 4 hours.
After unreacted trimethylamine is evaporated from the reaction solution by concentrating under reduced pressure at 40-45 ℃, 100mL of ethyl acetate is added for stirring, standing and liquid separation, and a layer of water phase is reserved. The pH of the water phase is regulated to 6.5-7.5 by using 2M HCl, then the cation exchange resin column is eluted for desalting, and the eluent with the pH more than 8 is collected after the water phase is washed by 1% ammonia water until no product flows out. Concentrating the eluent under reduced pressure to dryness at 70-75 ℃, adding 25mL of absolute ethyl alcohol, and stirring at room temperature until the eluent is clear. 50mL of acetone is slowly added dropwise for crystallization, filtration and drying are carried out, so that 3.74g of white solid is obtained, the yield is 40%, and the purity is 93.30%.
Example 3: preparation of 3-ethoxy-4-trimethylammonio-2-butenoic acid salt
Ethyl 4-chloroacetoacetate (32.80 g,0.20 mol) was added to a reaction flask, ethyl iodide (37.43 g,0.24 mol) was added, 328mL of ethanol was added, and the mixture was stirred at room temperature and left to standAfter nitrogen is changed and the temperature of the reaction solution is raised to 50 ℃, DIPEA (28.43 g,0.22 mol) is slowly added dropwise at constant temperature, and the pH of the system is controlled between 7.0 and 8.0 during the dropwise addition process. And after the addition, the reaction is carried out for 2 to 3 hours at constant temperature. Then cooling to 0-10 ℃, adding Na 3 PO 4 (49.18 g,0.30 mol) and 328mL of water, 30% trimethylamine aqueous solution (197.03 g,1.00 mol) were slowly added dropwise, and after the addition, the reaction solution was naturally warmed to 20-25℃and stirred for 4 hours.
After unreacted trimethylamine is distilled off by concentrating the reaction solution under reduced pressure at 40-45 ℃, 400mL of ethyl acetate is added for stirring, standing and liquid separation, and a layer of water phase is reserved. The pH of the water phase is regulated to 6.5-7.5 by using 2M HCl, the cation exchange resin column is eluted, and eluent with the pH of more than 8 is collected after 1% ammonia water washing until no product flows out. Concentrating the eluent under reduced pressure to dryness at 70-75 ℃, adding 100mL of absolute ethyl alcohol, stirring at room temperature until the mixture is clear, slowly dripping 200mL of acetone for crystallization, filtering, and drying to obtain 16.10g of white solid, wherein the yield is 43%, and the purity is 94.60%.
Example 4: preparation of 3-ethoxy-4-trimethylammonio-2-butenoic acid salt
Ethyl 4-chloroacetoacetate (24.60 g,0.15 mol) was added to a reaction flask, diethyl sulfate (27.75 g,0.18 mol) was added, 248 mL of N, N-dimethylformamide was added, stirring was performed at room temperature, nitrogen was replaced, DBU (24.35 g,0.16 mol) was slowly added dropwise at a constant temperature after the reaction solution was warmed to 50℃and the pH of the system was controlled to 7.0 to 7.5 during the dropwise addition. And after the addition, the reaction is carried out for 2 to 3 hours at the temperature. Then cooling to 0-10 ℃, adding sodium hydroxide (8.80 g,0.22 mol) and 246mL of water, slowly dripping 30% trimethylamine water solution (147.77 g,0.75 mol), after the addition, naturally heating the reaction solution to 20-25 ℃, stirring and reacting for 4 hours, and ending the reaction.
At 40-45 ℃, after the unreacted trimethylamine is evaporated by concentrating the reaction liquid under reduced pressure, 300mL of tertiary methyl ether is added, and the mixture is stirred, kept stand and separated to keep a layer of water phase. The pH of the water phase is regulated to 6.5-7.5 by using 2M HCl, then the cation exchange resin column is eluted for desalting, and the eluent with the pH more than 8 is collected after the water phase is washed by 1% ammonia water until no product flows out. Concentrating the eluent under reduced pressure to dryness at 70-75 ℃, adding 75mL of absolute ethyl alcohol, stirring at room temperature until the mixture is clear, slowly dripping 150mL of acetone for crystallization, filtering, and drying to obtain 13.20g of white solid, wherein the yield is 47%, and the purity is 95.50%.
Example 5: preparation of 3-ethoxy-4-trimethylammonio-2-butenoic acid salt
Ethyl 4-chloroacetoacetate (16.40 g,0.10 mol) was added to the reaction flask, diethyl sulfite (16.58 g,0.12 mol) was added, 164mL of dimethyl sulfoxide was added, stirring was performed at room temperature, nitrogen was replaced, pyridine (15.82 g,0.20 mol) was slowly added dropwise at a constant temperature after the reaction solution was warmed to 100 ℃, and the pH of the system was controlled to 8.5 to 90 during the dropwise. And after the addition, the reaction is carried out for 5 to 6 hours at constant temperature. Then cooling to 0-10 ℃, adding sodium hydroxide (8.00 g,0.20 mol) and 82mL of water, slowly dripping 30% trimethylamine water solution (19.70 g,0.10 mol), naturally heating the reaction liquid to 20-25 ℃ after the addition, and stirring for reaction for 4 hours.
At 40-45 ℃, after unreacted trimethylamine is evaporated by decompressing and concentrating the reaction solution, 200mL of dichloromethane is added for stirring, standing and separating, and the upper water phase is reserved. The pH of the water phase is regulated to 6.5-7.5 by using 2M HCl, then the cation exchange resin column is eluted for desalting, and the eluent with the pH more than 8 is collected after the water phase is washed by 1% ammonia water until no product flows out. Concentrating the eluent under reduced pressure to dryness at 70-75 ℃, adding 50mL of absolute ethyl alcohol, stirring at room temperature until the mixture is clear, slowly dripping 100mL of acetone for crystallization, filtering, and drying to obtain 5.99g of white solid, wherein the yield is 32%, and the purity is 92.30%.
Example 6: preparation of 3-ethoxy-4-trimethylammonio-2-butenoic acid salt
Ethyl 4-chloroacetoacetate (32.80 g,0.20 mol) was added to the reaction flask, ethyl iodide (37.43 g,0.24 mol) was added, 164mL of acetone was added, stirring was performed at room temperature, nitrogen was replaced, pyridine (17.40 g,0.22 mol) was slowly added dropwise at a constant temperature after the reaction solution was warmed to 25 ℃, and the pH of the system was controlled to 7.0 to 7.5 during the dropwise addition. After the addition, the reaction is carried out for 2 to 3 hours at a constant temperature. Then cooling to 0-10 ℃, adding Na 3 PO 4 (49.18 g,0.30 mol), 164mL of water was added, and a 30% aqueous trimethylamine solution (78.81 g,0.40 mol) was slowly added dropwise, after the addition was completed, the reaction mixture was naturally warmed to 20 to 25℃and stirred for 4 hours, and the reaction was completed.
After unreacted trimethylamine is distilled off by concentrating the reaction solution under reduced pressure at 40-45 ℃, 400mL of n-heptane is added, and the mixture is stirred, kept stand and separated to keep a layer of water phase. The pH of the water phase is regulated to 6.5-7.5 by using 2M HCl, then the cation exchange resin column is eluted for desalting, and the eluent with the pH more than 8 is collected after the water phase is washed by 1% ammonia water until no product flows out. Concentrating the eluent under reduced pressure to dryness at 70-75 ℃, adding 100mL of absolute ethyl alcohol, stirring at room temperature until the mixture is clear, slowly dripping 200mL of acetone for crystallization, filtering, and drying to obtain 9.73g of white solid, wherein the yield is 26%, and the purity is 90.10%.
Claims (6)
1. A levocarnitine-related impurity, chemically designated as 3-ethoxy-4-trimethylammonio-2-butenoic acid salt (formula B), having the structural formula:
2. the process for preparing levocarnitine-related impurity (formula B) according to claim 1, comprising the steps of: 1) Adding 4-chloroacetoacetic acid ethyl ester (formula A), an ethylation reagent and an organic solvent into a reaction bottle, replacing nitrogen, heating to 25-100 ℃, adding alkali 1, adjusting the pH of a reaction system to 7.0-9.0, and reacting for 1-6 hours at a constant temperature; 2) Adding aqueous solution of trimethylamine/alkali 2 into the reaction liquid, controlling the temperature of the reaction system to be 0-10 ℃, naturally heating to 20-25 ℃ after the dropwise addition, reacting for 4-10 hours, concentrating, washing and extracting, regulating pH, eluting by a cation exchange resin column, concentrating and crystallizing to obtain the relevant impurities (formula B) of the levocarnitine. The synthetic route is as follows:
3. the process for preparing levocarnitine-related impurity (formula B) according to claim 2, characterized in that: the organic solvent used in step 1 may be one of tetrahydrofuran, acetonitrile, ethanol, N-dimethylformamide, acetone, and dimethyl sulfoxide. The volume amount of the solvent is 5-10 times of the weight of the ethyl 4-chloroacetoacetate (formula A).
4. The process for preparing levocarnitine-related impurity (formula B) according to claim 2, characterized in that: the ethylating reagent used in step 1 may be one of diethyl sulfate, diethyl carbonate, ethyl iodide and diethyl sulfite. The mol dosage of the ethylating reagent is 1-2 times of that of the ethyl 4-chloroacetoacetate (formula A).
5. The process for preparing levocarnitine-related impurity (formula B) according to claim 2, characterized in that: the alkali used in the step 1 can be one of pyridine and DBU, TEA, DIPEA, and the 1 molar amount of the alkali is 1 to 2 times that of the ethyl 4-chloroacetoacetate (formula A).
6. The process for preparing levocarnitine-related impurity (formula B) according to claim 2, characterized in that: the base 2 used in step 2 may be NaOH, KOH, na 3 PO 4 The molar amount of the alkali 2 is 1-2 times that of the ethyl 4-chloroacetoacetate (formula A). The molar usage of trimethylamine is 1-10 times of that of 4-chloroacetoacetic acid ethyl ester (formula A). The volume usage of water is 5-10 times of the weight of 4-chloroacetoacetic acid ethyl ester (formula A).
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| CN104030934A (en) * | 2014-07-04 | 2014-09-10 | 东北制药集团股份有限公司 | Preparation method of L-carnitine compound |
| CN115057791A (en) * | 2022-07-01 | 2022-09-16 | 安徽普利药业有限公司 | Industrial preparation method of levocarnitine |
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| CN104030934A (en) * | 2014-07-04 | 2014-09-10 | 东北制药集团股份有限公司 | Preparation method of L-carnitine compound |
| CN115057791A (en) * | 2022-07-01 | 2022-09-16 | 安徽普利药业有限公司 | Industrial preparation method of levocarnitine |
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| CN116655481A (en) * | 2023-06-14 | 2023-08-29 | 海南卓科制药有限公司 | Industrial synthesis method of levocarnitine |
| CN116655481B (en) * | 2023-06-14 | 2023-11-28 | 海南卓科制药有限公司 | Industrial synthesis method of levocarnitine |
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