CN113773219A - Preparation method of new metoclopramide dichlorine impurity - Google Patents
Preparation method of new metoclopramide dichlorine impurity Download PDFInfo
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- CN113773219A CN113773219A CN202111156167.3A CN202111156167A CN113773219A CN 113773219 A CN113773219 A CN 113773219A CN 202111156167 A CN202111156167 A CN 202111156167A CN 113773219 A CN113773219 A CN 113773219A
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- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960004503 metoclopramide Drugs 0.000 title claims abstract description 43
- 239000012535 impurity Substances 0.000 title claims abstract description 37
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 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 4
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 229910006024 SO2Cl2 Inorganic materials 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- PXJJSXABGXMUSU-UHFFFAOYSA-N disulfur dichloride Chemical compound ClSSCl PXJJSXABGXMUSU-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000010979 pH adjustment Methods 0.000 claims 1
- 239000013558 reference substance Substances 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- YTNLUMMYZOKSNG-UHFFFAOYSA-N 4-amino-3,5-dichloro-2-methoxybenzoic acid Chemical compound COC1=C(Cl)C(N)=C(Cl)C=C1C(O)=O YTNLUMMYZOKSNG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 206010047700 Vomiting Diseases 0.000 description 4
- SEHADVWVUBOTQB-UHFFFAOYSA-N 4-amino-3,5-dichloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide Chemical compound CCN(CC)CCNC(C(C=C(C(N)=C1Cl)Cl)=C1OC)=O SEHADVWVUBOTQB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- YJSYOVSDBWOVAD-UHFFFAOYSA-N methyl 4-acetamido-3,5-dichloro-2-methoxybenzoate Chemical compound COC(=O)C1=CC(Cl)=C(NC(C)=O)C(Cl)=C1OC YJSYOVSDBWOVAD-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000015163 Biliary Tract disease Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- 206010015137 Eructation Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 208000027687 belching Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000003152 motion sickness Diseases 0.000 description 1
- UQKAOOAFEFCDGT-UHFFFAOYSA-N n,n-dimethyloctan-1-amine Chemical compound CCCCCCCCN(C)C UQKAOOAFEFCDGT-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- 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
- C07C227/16—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 not involving the amino or carboxyl groups
-
- 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
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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 discloses a method for preparing a new metoclopramide dichlorine impurity through chlorination reaction, hydrolysis reaction and amidation reaction. The preparation method has the advantages of simple and convenient operation, low cost, high yield and the like, and the purity of the prepared metoclopramide dichlorine impurity is more than 99 percent, and the metoclopramide dichlorine impurity can be used as a reference substance for the quality research of metoclopramide.
Description
Technical Field
The invention relates to the technical field of biological medicines, and in particular relates to a preparation method of a new metoclopramide dichlorine impurity.
Background
Metoclopramide, also known as chlorpromamide, also known as metoclopramide, has a molecular formula of C14H22ClN3O2White to pale yellow crystalline powder with molecular weight of 299.7964 and CAS registry number of 364-62-5, and strong central antiemetic effect.
Metoclopramide can be used for treating emesis caused by brain tumor operation, radiotherapy and chemotherapy of tumor, cerebral trauma sequelae, acute craniocerebral injury, and medicine. Has good curative effect on flatulence dyspepsia, inappetence, belching, nausea and vomiting, and can also be used for vomiting and carsickness (ship) caused by sea-air operation. In addition, metoclopramide can relieve nausea and vomiting reaction during barium meal examination and promote barium agent to pass through; or the medicine is taken before the duodenum is intubated, which is beneficial to smooth intubatton; or for the adjuvant treatment of biliary tract diseases and chronic pancreatitis.
The metoclopramide raw material medicine synthetic route adopted by the applicant is as follows:
unknown impurities are found in the synthesis process, and a brand new impurity is obtained by crystallizing the IM2 material and separating and enriching the mother liquor, as shown in formula I.
In the process of developing new medicines, the impurity content of the medicines directly influences the curative effect and the toxic and side effects of the medicines, so that the control of the impurity limit and the improvement of the purity are very important for ensuring the safety, the effectiveness and the quality controllability of the medicines. Therefore, the invention further develops a preparation method of the new metoclopramide dichlorine impurity so as to realize stricter quality control of the medicine.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of a new metoclopramide dichlorine impurity, wherein the purity of the prepared new metoclopramide dichlorine impurity is more than 99 percent, and the new metoclopramide dichlorine impurity can be used as a reference substance for the quality research of metoclopramide.
The invention provides a preparation method of a new metoclopramide dichlorine impurity shown as a formula I, which is characterized by comprising the following reaction steps:
(1) reacting the compound shown in the formula II with a chlorinated reagent to generate a compound shown in the formula III;
(2) reacting the compound shown in the formula III with an alkaline reagent to generate a compound shown in the formula IV;
(3) and reacting the compound shown in the formula IV with N, N-diethyl ethylenediamine in the presence of CDI to obtain the compound shown in the formula I.
Further, the chlorinating reagent in the step (1) is selected from Cl2、Cl2O、S2Cl2、SO2Cl2One or more of t-BuOCl and NCS, preferably NCS; the molar ratio of the chlorinated reagent to the compound of the formula II is 1: 1-3: 1, preferably 2: 1;
further, optionally, the step (1) further comprises a step of recrystallization with tetrahydrofuran/petroleum ether; the volume ratio of the tetrahydrofuran to the petroleum ether is 5: 10-5: 20, preferably 5: 16;
further, the alkaline reagent in the step (2) is one or more of LiOH, NaOH or KOH, and NaOH is preferred; the molar ratio of the alkaline reagent to the compound of the formula III is 2: 1-4: 1, preferably 2.5: 1-3.5: 1, and more preferably 3.2: 1;
further, optionally, the step (2) further comprises the steps of adjusting pH, adding water for pulping, filtering, adding ethanol/water for recrystallization; the pH adjusting step is to adjust the pH to 4-6 by using hydrochloric acid, preferably to adjust the pH to 5 by using 1M hydrochloric acid;
further, the reaction solvent in the step (3) is one or more of acetonitrile, dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide or N, N-dimethylacetamide, and dichloromethane is preferred;
further, the molar ratio of the CDI, the N, N-diethyl ethylenediamine and the compound shown in the formula IV in the step (3) is 1-1.5: 1, preferably 1:1: 0.9;
further, the reaction temperature of the step (1) is 70-100 ℃, preferably 80-90 ℃, and more preferably 85 ℃;
the reaction temperature in the step (2) is 0 ℃ to the system reflux temperature, and the system reflux temperature is preferably selected;
the reaction temperature in the step (3) is 0 ℃ to the system reflux temperature, wherein the reaction temperature after the CDI is added is preferably 30-40 ℃, and the reaction temperature after the N, N-diethylethylenediamine is added is preferably the system reflux temperature;
the Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The invention discloses a preparation method of a new metoclopramide dichlorine impurity, wherein the purity of the obtained new metoclopramide dichlorine impurity is more than 99%, the new metoclopramide dichlorine impurity can be used as a reference substance for the quality research of metoclopramide, and the preparation method has the advantages of simple operation, low cost, high yield and the like.
Drawings
FIG. 1: mass spectrogram of the new impurity of metoclopramide dichloride, namely the compound of the formula I;
FIG. 2: a hydrogen spectrum of a compound of formula I as a novel impurity of metoclopramide dichloride.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
(1)4- (acetylamino) -3, 5-dichloro-2-methoxybenzoic acid methyl ester (formula III)
A three-necked flask was charged with a compound of formula II (36g,0.14mol), DMF100mL, NCS (37.4g,0.28mol) heated to an internal temperature of 85 ℃ and allowed to react for 5 hours, after which the reaction mixture was poured into ice water, extracted with EA 100mL × 3 times, the combined organic phases were washed with water 100mL × 2 times, separated, dried over anhydrous sodium sulfate, concentrated to give a yellow solid 30.2g, recrystallized from THF/PE 5:16 to give 23.6g of an off-white solid, yield 57.9%, mp: 137 ℃ and 139 ℃, ESI-MS (M/z):291.98[ M + H]+。
(2) 2-methoxy-3, 5-dichloro-4-aminobenzoic acid (formula IV)
To a 250mL four-necked flask, methyl 4- (acetylamino) -3, 5-dichloro-2-methoxybenzoate (formula III) (20.0g, 0.069mol), 20mL of ethanol, 100mL of water, and sodium hydroxide (8.7g, 0.22mol) were added, and the mixture was heated to reflux and reacted for 3 hours. Stopping heating, transferring the reaction solution into a 500mL bottle, stirring, starting dropwise adding 1M hydrochloric acid, adjusting the pH to about 5, cooling to below 12 ℃, stirring for 30min, performing suction filtration, adding 100mL of water into the filter cake again, pulping for 30min at below 20 ℃, performing suction filtration, washing the container and the filter cake with 20mL of water, and drying at 80 ℃ to obtain 15g of crude product, wherein the yield of the crude product is 92.9%.
Adding 242mL of absolute ethyl alcohol and 45mL of water into the solid, heating until the solid is clear, closing the heating, slowly cooling, crystallizing, cooling to below 20 ℃, stirring for 3 hours, carrying out suction filtration, washing a filter cake by using 20mL of 85% ethyl alcohol, and drying at 80 ℃ to obtain 12g of white crystals, wherein the yield is 74.3%, and the HPLC purity is 99.8%. m.p.255 deg.C decomposition, ESI-MS (M/z):258.01[ M + Na [)]+。
(3) N- (2-diethylaminoethyl) -2-methoxy-3, 5-dichloro-4-aminobenzamide (formula I)
To a 250mL three-necked flask were added 2-methoxy-3, 5-dichloro-4-aminobenzoic acid (formula IV) (9.6g,40.85mmol), CDI (7.23g, 44.63mmol), and DCM 100mL, heated to an inner temperature of 35 deg.C, and the reaction was allowed to proceed with incubation for 1.5 hours, followed by addition of N, N-diethylethylenediamine (5.18g, 44.63mmol) and refluxing for 1.5 hours. After-treatment, 100mL of DCM diluted reaction solution was added to the flask, 20mL of water was added, and the organic phase was washed with 20X 3 of water, separated, dried over anhydrous sodium sulfate, and concentrated to give 10.1g of pale yellow oil, yield 74.5%, and HPLC purity 99.8%. ESI-MS (M/z) 334.13[ M + H]+。
1H-NMR(400MHz,DCl3)：δ8.148(s,1H),8.006(s,1H),4.781(s,2H),3.862(s,3H),3.470～ 3.518(m,2H),2.543～2.643(m,6H),1.006～1.042(t,6H)。
Example 2:
(1)4- (acetylamino) -3, 5-dichloro-2-methoxybenzoic acid methyl ester (formula III)
A three-necked flask was charged with a compound of formula II (36g,0.14mol), DMF100mL, t-BuOCl (30.4g,0.28mol) heated to an internal temperature of 85 ℃ and allowed to react for 5 hours, the reaction mixture was poured into ice water, extracted with EA 100mL × 3 times, the combined organic phases were washed with water 100mL × 2 times, separated, dried over anhydrous sodium sulfate, concentrated to give 30.2g of a yellow solid, and recrystallized with THF/PE 5:16 to give 20.1g of an off-white solid, yield 49.3%, mp: 137 ℃ and 139 ℃, ESI-MS (M/z):291.98[ M + H]+。
(2) 2-methoxy-3, 5-dichloro-4-aminobenzoic acid (formula IV)
To a 250mL four-necked flask, methyl 4- (acetylamino) -3, 5-dichloro-2-methoxybenzoate (formula III) (20.0g, 0.069mol), 20mL of ethanol, 100mL of water, and sodium hydroxide (8.7g, 0.22mol) were added, and the mixture was heated to reflux and reacted for 3 hours. Stopping heating, transferring the reaction solution into a 500mL bottle, beginning dropwise adding 1M hydrochloric acid while stirring, adjusting the pH to about 4, cooling to below 12 ℃, stirring for 30min, performing suction filtration, adding 100mL of water again into the filter cake, pulping for 30min below 20 ℃, performing suction filtration, washing the container and the filter cake with 20mL of water, and drying at 80 ℃ to obtain 14g of crude product, wherein the yield of the crude product is 86.7%.
Adding 242mL of absolute ethyl alcohol and 45mL of water into the solid, heating until the solid is clear, closing the heating, slowly cooling, crystallizing, cooling to below 20 ℃, stirring for 3 hours, carrying out suction filtration, washing a filter cake by using 20mL of 85% ethyl alcohol, and drying at 80 ℃ to obtain 11g of white crystals, wherein the yield is 68.1%, and the HPLC purity is 99.6%. m.p.255 deg.C decomposition, ESI-MS (M/z):258.01[ M + Na [)]+。
(3) N- (2-diethylaminoethyl) -2-methoxy-3, 5-dichloro-4-aminobenzamide (formula I)
To a 250mL three-necked flask were added 2-methoxy-3, 5-dichloro-4-aminobenzoic acid (formula IV) (9.6g,40.85mmol), CDI (7.23g, 44.63mmol), and DCM 100mL, heated to an inner temperature of 35 deg.C, and the reaction was allowed to proceed with incubation for 1.5 hours, followed by addition of N, N-diethylethylenediamine (5.18g, 44.63mmol) and refluxing for 1.5 hours. After-treatment, 100mL of DCM diluted reaction solution was added to the flask, and 20mL of water was added, and the organic phase was washed with 20X 3 of water, separated, dried over anhydrous sodium sulfate, and concentrated to give 10g of pale yellow oil, yield 73.7%, and HPLC purity 99.5%. ESI-MS (M/z) 334.13[ M + H]+. The nuclear magnetic data are shown in example 1.
Example 3:
(1)4- (acetylamino) -3, 5-dichloro-2-methoxybenzoic acid methyl ester (formula III)
A three-necked flask was charged with the compound of formula II (36g,0.14mol), DMF100mL, NCS (37.4g,0.28mol), heated to an internal temperature of 85 ℃ and allowed to react for 5 hours while maintaining the temperature, the reaction mixture was poured into ice water, extracted with EA 100 mL. times.3 times, the combined organic phases were washed with water 100 mL. times.2 times, separated, dried over anhydrous sodium sulfate, concentrated to give a yellow solid 30.2g,recrystallization from THF/PE 5:20 gave 21.3g of an off-white solid in 52.3% yield, mp: 137 ℃ and 139 ℃, ESI-MS (M/z):291.98[ M + H]+。
(2) 2-methoxy-3, 5-dichloro-4-aminobenzoic acid (formula IV)
To a 250mL four-necked flask, methyl 4- (acetylamino) -3, 5-dichloro-2-methoxybenzoate (formula III) (20.0g, 0.069mol), 20mL of ethanol, 100mL of water, and sodium hydroxide (8.7g, 0.22mol) were added, and the mixture was heated to reflux and reacted for 3 hours. Stopping heating, transferring the reaction solution into a 500mL bottle, stirring, starting dropwise adding 1M hydrochloric acid, adjusting the pH to about 5, cooling to below 12 ℃, stirring for 30min, performing suction filtration, adding 100mL of water into the filter cake again, pulping for 30min at below 20 ℃, performing suction filtration, washing the container and the filter cake with 20mL of water, and drying at 80 ℃ to obtain 15.1g of crude product, wherein the yield of the crude product is 93.5%.
Adding 242mL of absolute ethyl alcohol and 45mL of water into the solid, heating until the solid is clear, closing the heating, slowly cooling, crystallizing, cooling to below 20 ℃, stirring for 3 hours, carrying out suction filtration, washing a filter cake by using 20mL of 85% ethyl alcohol, and drying at 80 ℃ to obtain 12g of white crystals, wherein the yield is 74.3%, and the HPLC purity is 99.8%. m.p.255 deg.C decomposition, ESI-MS (M/z):258.01[ M + Na [)]+。
(3) N- (2-diethylaminoethyl) -2-methoxy-3, 5-dichloro-4-aminobenzamide (formula I)
To a 250mL three-necked flask were added 2-methoxy-3, 5-dichloro-4-aminobenzoic acid (formula IV) (9.6g,40.85mmol), TsCl (8.51g, 44.63mmol), and DCM 100mL, heated to an inner temperature of 35 deg.C, and the reaction was allowed to proceed with incubation for 1.5 h, followed by addition of N, N-diethylethylenediamine (5.18g, 44.63mmol) and refluxing for 1.5 h. After-treatment 100mL of DCM diluted reaction solution was added to the flask, 20mL of water was added, and the organic phase was washed with 20X 3 of water, separated, dried over anhydrous sodium sulfate, and concentrated to give 8g of pale yellow oil with a yield of 59% and an HPLC purity of 99.0%. ESI-MS (M/z) 334.13[ M + H]+. The nuclear magnetic data are shown in example 1.
Example 4: detection of new metoclopramide dichlorine impurity
The sample solution is precisely weighed and taken as metoclopramide raw material with the weight of about 10mg, and is put into a10 ml measuring flask, and methanol is added: 10ml of water (1:2) was dissolved and diluted to the scale, and shaken up to obtain a sample solution.
Control solution the sample solution was measured precisely and diluted quantitatively with mobile phase to give a solution containing about 1. mu.g of sample per 1ml as a control solution.
Chromatographic conditions the column was Welch Xtimate-C8(5 μm, 4.6X 250 mm); 0.050mol/L potassium dihydrogen phosphate solution (0.2 ml N, N-dimethyl octylamine is added, and the pH value is adjusted to 4.0 by phosphoric acid) is taken as a mobile phase A, and acetonitrile is taken as a mobile phase B; the flow rate is 1 ml/min; the detection wavelength is 275 nm; the column temperature was 35 ℃ and elution was carried out in a linear gradient as shown in Table 1.
The applicability of the system requires that the theoretical plate number is not less than 4000 calculated according to a metoclopramide peak.
The determination method comprises precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram until the retention time of main component chromatogram peak is 2 times.
TABLE 1 gradient elution procedure for related substances
| Time (min) | A(％) | B(％) |
| 0 | 92 | 8 |
| 10 | 92 | 8 |
| 15 | 90 | 10 |
| 40 | 70 | 30 |
| 45 | 70 | 30 |
| 46 | 92 | 8 |
| 55 | 92 | 8 |
TABLE 2 relative retention times and limits of the New Methoxychloropramine Dichloro impurity
Under the chromatographic conditions, the relative retention time shown by the new metoclopramide dichlorine impurity is 1.1, and the metoclopramide dichlorine impurity can be effectively separated from the metoclopramide bulk drug. The establishment of the impurity analysis method provides an effective means for monitoring the content of related substances of metoclopramide, and is more favorable for ensuring the product quality of metoclopramide and the medication safety of patients.
Test example:
the TA97, TA98, TA100 and TA102 are taken as test strains, and the new metoclopramide dichlorine impurity is taken as a sample to carry out a plate doping test, and the result shows that the mutation-causing ratio MR value is 2.1, and the impurity can be judged to be positive in mutation-causing by dose-response relation.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A preparation method of a new metoclopramide dichlorine impurity is characterized by comprising the following reaction steps:
(1) reacting the compound shown in the formula II with a chlorinated reagent to generate a compound shown in the formula III;
(2) reacting the compound shown in the formula III with an alkaline reagent to generate a compound shown in the formula IV;
(3) and reacting the compound shown in the formula IV with N, N-diethyl ethylenediamine in the presence of CDI to obtain the compound shown in the formula I.
2. The method for preparing metoclopramide bischloro new impurity as claimed in claim 1, wherein said chlorinating agent in step (1) is selected from the group consisting of Cl2、Cl2O、S2Cl2、SO2Cl2One or more of t-BuOCl and NCS; the molar ratio of the chlorinated reagent to the compound of the formula II is 1: 1-3: 1.
3. The method for preparing metoclopramide bischloro new impurity according to claim 2, wherein said chlorinating agent in step (1) is selected from the group consisting of NCS; the molar ratio of the chlorinating reagent to the compound of formula II is 2: 1.
4. The method for preparing metoclopramide bischloro new impurity as claimed in claim 1, wherein optionally, said step (1) further comprises the step of recrystallization with tetrahydrofuran/petroleum ether; the volume ratio of the tetrahydrofuran to the petroleum ether is 5: 10-5: 20.
5. The method for preparing metoclopramide dichlorine new impurity as claimed in claim 1, wherein the alkaline reagent in step (2) is one or more of LiOH, NaOH or KOH; the molar ratio of the alkaline reagent to the compound of the formula III is 2: 1-4: 1.
6. The method for preparing metoclopramide bischloro new impurity as claimed in claim 1, wherein said step (2) further comprises the steps of pH adjustment, pulping with water, filtering, and recrystallization with ethanol/water.
7. The method for preparing a new impurity metoclopramide dichloride as claimed in claim 6, wherein the pH is adjusted to 4-6.
8. The method for preparing metoclopramide dichlorine new impurity as claimed in claim 1, wherein the reaction solvent in step (3) is one or more of acetonitrile, dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide or N, N-dimethylacetamide.
9. The method for preparing new metoclopramide dichlorine impurities as claimed in claim 1, wherein the molar ratio of CDI, N-diethylethylenediamine and the compound of formula IV in step (3) is 1-1.5: 1.
10. The method for preparing metoclopramide dichlorine new impurity as claimed in claim 1, wherein the reaction temperature of the step (1) is 70-100 ℃; the reaction temperature in the step (2) is 0 ℃ to the reflux temperature of the system; the reaction temperature of the step (3) is 0 ℃ to the reflux temperature of the system.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4413497Y1 (en) * | 1966-11-10 | 1969-06-05 | ||
| DE4131276A1 (en) * | 1990-09-28 | 1992-04-02 | Kali Chemie Pharma Gmbh | New metoclopramide salt compsns. with no additives - for use in treatment of vomiting, nausea and in regulation of gastrointestinal motility |
| CN1849320A (en) * | 2003-09-09 | 2006-10-18 | 阿利茨默治疗学有限公司 | Process for the preparation of renzapride and intermediates thereof |
-
2021
- 2021-09-30 CN CN202111156167.3A patent/CN113773219A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4413497Y1 (en) * | 1966-11-10 | 1969-06-05 | ||
| DE4131276A1 (en) * | 1990-09-28 | 1992-04-02 | Kali Chemie Pharma Gmbh | New metoclopramide salt compsns. with no additives - for use in treatment of vomiting, nausea and in regulation of gastrointestinal motility |
| CN1849320A (en) * | 2003-09-09 | 2006-10-18 | 阿利茨默治疗学有限公司 | Process for the preparation of renzapride and intermediates thereof |
Non-Patent Citations (4)
| Title |
|---|
| CHARLOTTE G. JØRGENSEN等: "Discovery of Benzamide Analogues as a Novel Class of 5-HT3 Receptor Agonists", 《CHEMMEDCHEM》, vol. 6, 18 January 2011 (2011-01-18), pages 1 - 20 * |
| G. JAMET等: "SYNTHESIS OF D3-METOCLOPRAMIM", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICAL》, no. 3, pages 245 - 256 * |
| 原友志等: "琥珀酸普卡必利的合成", 《中国医药工业杂志》, vol. 43, no. 1, 31 December 2012 (2012-12-31), pages 5 * |
| 田兰等: "HPLC法测定盐酸甲氧氯普胺注射液的含量及有关物质", 《药物分析杂志》, vol. 29, no. 06, pages 1031 - 1035 * |
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