CN113801034A - Mosapride impurity compound - Google Patents
Mosapride impurity compound Download PDFInfo
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- CN113801034A CN113801034A CN202010542305.0A CN202010542305A CN113801034A CN 113801034 A CN113801034 A CN 113801034A CN 202010542305 A CN202010542305 A CN 202010542305A CN 113801034 A CN113801034 A CN 113801034A
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- mosapride
- ethoxy
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- 239000012535 impurity Substances 0.000 title claims abstract description 50
- 229960004085 mosapride Drugs 0.000 title claims abstract description 41
- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- QYFOWMNKCFMXOK-UHFFFAOYSA-N ethyl 4-acetamido-5-bromo-2-ethoxybenzoate Chemical compound CCOC(C(C=C(C(NC(C)=O)=C1)Br)=C1OCC)=O QYFOWMNKCFMXOK-UHFFFAOYSA-N 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- JHSPPBBJOLKJDH-UHFFFAOYSA-N [4-[(4-fluorophenyl)methyl]morpholin-2-yl]methanamine Chemical compound C1COC(CN)CN1CC1=CC=C(F)C=C1 JHSPPBBJOLKJDH-UHFFFAOYSA-N 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- -1 N-bromosuccinimide Chemical compound 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- UXMNCPGQOLANOH-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;hydrobromide Chemical compound Br.OC(=O)CC(O)(C(O)=O)CC(O)=O UXMNCPGQOLANOH-UHFFFAOYSA-N 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 239000013558 reference substance Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- XWGYOMHQGQZRLC-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxybenzoic acid Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(O)=O XWGYOMHQGQZRLC-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- PPHBGGPQULUZPZ-UHFFFAOYSA-N ethyl 4-acetamido-2-ethoxybenzoate Chemical compound CCOC(=O)C1=CC=C(NC(C)=O)C=C1OCC PPHBGGPQULUZPZ-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YBTVSGCNBZPRBD-UHFFFAOYSA-N 4-acetamidosalicylic acid Chemical compound CC(=O)NC1=CC=C(C(O)=O)C(O)=C1 YBTVSGCNBZPRBD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 229940124161 5 Hydroxytryptamine 4 receptor agonist Drugs 0.000 description 1
- FVVDKUPCWXUVNP-UHFFFAOYSA-M Aminosalicylate sodium anhydrous Chemical compound [Na+].NC1=CC=C(C([O-])=O)C(O)=C1 FVVDKUPCWXUVNP-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000006203 ethylation Effects 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000007347 radical substitution reaction Methods 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a mosapride impurity compound. The mosapride impurity compound provided by the invention is 2-ethoxy-4-acetamido-5-ethyl bromobenzoate, and the preparation method of the impurity comprises the following steps: adding 2-ethoxy-4-ethyl acetamino benzoate and N-bromosuccinimide (NBS) into an organic solvent, and stirring at controlled temperature to react to obtain 2-ethoxy-4-acetamido-5-ethyl bromobenzoate; meanwhile, the invention further provides a method for preparing the impurity compound VI of the mosapride citrate bromide. The magazine compound provided by the invention can be used as an impurity reference substance for detecting mosapride citrate intermediate, bulk drug and/or preparation in the production process.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a mosapride impurity compound.
Background
Mosapride citrate (mosapride citrate), chemically 2-ethoxy-4-amino-5-chloro-N- [ [4- [ (4-fluorophenyl) -methyl ] morpholin-2-yl ] methyl ] benzamide citrate dihydrate, is a gut prokinetic drug developed by japan pharmaceutical limited and belongs to a selective 5-hydroxytryptamine 4 receptor agonist; the medicine is firstly marketed in Japan in 6 months in 1998, is clinically used for treating digestive tract diseases such as chronic gastritis with burning heat, nausea, vomiting and the like, has the advantages of strong receptor selectivity, small dosage, safety, high efficiency and the like, and has the following structure:
mosapride citrate bulk drug is already on the market, and the preparation method of the bulk drug at present is to respectively synthesize two important side chains of 2-ethoxy-4-amino-5-chlorobenzoic acid and 2-aminomethyl-4- (4-fluorobenzyl) morpholine, and then carry out condensation and salt formation to obtain the mosapride citrate, wherein for the preparation method of the important intermediate 2-ethoxy-4-amino-5-chlorobenzoic acid, Chinese patent application CN101538217 and literature (improvement of the synthesis process of 4-amino-5-chloro-2-ethoxybenzoic acid [ J ]. China medical industry journal, 2003(01):8-9) report that sodium p-aminosalicylate is used as a raw material to react with acetic anhydride to obtain p-acetaminosalicylic acid, and then the p-acetaminosalicylic acid reacts with bromoethane to obtain 2-ethoxy-4-acetaminosalicylic acid ethyl ester benzoate through bisethylation Performing chlorination reaction under the action of N-chlorosuccinimide (NCS) to obtain 2-ethoxy-4-acetamido-5-ethyl chlorobenzoate, and performing alkaline hydrolysis to obtain an intermediate 2-ethoxy-4-amino-5-chlorobenzoic acid, wherein the synthetic route is as follows:
in the process of preparing 2-ethoxy-4-acetamido-5-ethyl bromobenzoate, bromide ions generated in the double ethylation process of a main compound 2 can bring the next chlorination reaction, and a free radical substitution reaction is generated in the presence of N-chlorosuccinimide (NCS) to generate a bromo-impurity compound, wherein the structure of the bromo-impurity compound is as follows:
in the process of research and development of new drugs, the quality of drugs is an important standard for measuring the quality of drugs, the quality standard of drugs has strict regulations on the purity of active ingredients of the drugs and the limit of impurities, generally, more than 0.1% of drug impurities should be identified and quantified by a selective method, and for drug research and development personnel, the impurities generated in the efficient impurity synthesis route oriented synthesis process are developed so as to obtain an impurity reference substance, so that the development of quality detection work (such as impurity HPLC positioning, impurity content measurement and the like) of each batch of raw material drugs is also very important work.
The bromo-impurity is similar to the chloro-product 3 in structure, so that the bromo-impurity is difficult to separate in subsequent separation and purification, even the bromo-impurity is difficult to detect by a conventional method, the impurity compound I can continuously participate in subsequent reaction, if the intermediate impurity is not researched and controlled, the subsequent purification is difficult, the quality of the mosapride citrate bulk drug is finally influenced, along with the advance of national drug consistency research work, the preparation method of the impurity compound, namely the mosapride citrate bromo-impurity is determined, a qualified reference substance is provided, and the quality control of the mosapride citrate can be positively influenced.
At present, the preparation method of the mosapride citrate bromo-impurity is not reported in documents, so that the problem to be solved at present is to explore a process route which is low in production cost, simple and convenient to operate and high in yield for the mosapride citrate bromo-impurity.
Disclosure of Invention
The invention aims to provide a mosapride citrate bromo-impurity compound I and a preparation method thereof, wherein the impurity compound can be used as an impurity reference substance in mosapride citrate intermediate and finished product detection standards and is used in quality control links of impurity qualitative and quantitative analysis in the production process of mosapride citrate. The preparation method is novel, the operation is simple, and the purity of the sample is high.
The mosapride bromo-impurity compound shown as the formula I has the following structure:
the invention also provides a preparation method of the mosapride bromo-impurity compound I shown as the formula I, which comprises the following steps:
adding a compound II, namely 2-ethoxy-4-ethyl acetamidobenzoate, and a compound III, namely N-bromosuccinimide (NBS) into an organic solvent, and stirring and reacting at controlled temperature to obtain 2-ethoxy-4-acetamido-5-ethyl bromobenzoate, wherein the route is as follows:
in a preferable scheme, the feeding molar ratio of the compound II to the compound III is 1: 1.0 to 1.8, wherein a ratio of 1: 1.3.
in a preferred scheme, the reaction temperature is 50-80 ℃.
Preferably, the organic solvent is one or a combination of DMF, methanol, ethanol, acetonitrile and tetrahydrofuran, and DMF is particularly preferred.
In a preferred scheme, after the reaction is finished, post-treatment operation is required, specifically: and after the reaction is finished, pouring the reaction solution into ice water, stirring and crystallizing, and filtering, washing and drying the obtained solid to obtain the compound I.
On the other hand, the invention also provides the application of the compound shown in the formula I in detecting the mosapride citrate bulk drug and/or preparation, the impurity VI of the mosapride citrate bromide can be synthesized and detected according to the following route, and the impurity VI can be used for detecting the content of the mosapride citrate bulk drug and/or preparation impurity:
a preparation method of an impurity compound VI of mosapride citrate bromide shown as a formula VI comprises the following steps: adding a compound I, namely 2-ethoxy-4-acetamido-5-bromobenzoate ethyl ester, EDCl and DMAF into dichloromethane, adding triethylamine and 4- (4-fluorobenzyl) -2-aminomethyl morpholine) to generate a compound VI, namely 2-ethoxy-4-acetamido-5-bromo-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide, and then reacting with a citric acid aqueous solution to generate a mosapride citrate bromo impurity VI.
The compounds of formula I may be converted into pharmaceutically acceptable salts, solvates.
The invention has the technical effects that:
1. provides a high-purity mosapride bromo-impurity I which can be used as an impurity reference substance and used for detecting a mosapride citrate intermediate, a raw material medicine and/or a preparation in the production process.
2. The method for efficiently preparing the mosapride bromo-impurity compound I and the mosapride bromo-impurity compound VI by using the mosapride bromo-impurity compound I is provided, the whole synthetic method is short in route, simple in operation steps, high in reaction yield and high in product purity.
Drawings
FIG. 1: HPLC profile of compound I.
FIG. 2: HPLC profile of compound 3, retention time of compound I was 15.833 min.
FIG. 3: HPLC profile of compound VI.
FIG. 4: the HPLC profile of mosapride citrate, the retention time of compound VI is 22.142 minutes.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Characterization of the novel Compounds
High resolution mass spectrum of compound I: ESI-HRMS: M/z 330.0263[ M + H ]]+；1H-NMR(500MHz,(CD3)2SO)δ10.01(s,1H),8.09(s,1H),7.15(s,1H),4.20(q,J＝7.31，2H),4.11(q,J＝6.25,2H),2.09(s,3H),1.37(t,J＝6.54,3H),1.28(t,J＝9.31,3H),13C-NMR(125MHz,(CD3)2SO)δ169.31,164.64,157.66,144.25,134.81,114.73,112.01,107.16,65.12,61.35,24.44,15.17,14.52.
High resolution mass spectrum of compound IV: ESI-HRMS: M/z 466.4000[ M + H ]]+；1H-NMR(500MHz,(CD3)2SO)δ8.05(t，J＝5.25,2H),7.86(s,1H)，7.35(dd,J＝5.73,8.40,2H),7.14(t,J＝8.83,2H),6.47(s,1H),5.88(s,1H),4.04(q,J＝6.89,2H),3.82(d,J＝10.33,1H),3.57(m,4H),3.41(m,1H),3.24(m,1H),2.71(m,6H),2.19(m,1H),2.00(t,J＝10.73,1H),1.37(t,J＝6.91,3H)；13C-NMR(125MHz,(CD3)2SO)δ175.04,171.43,171.43,163.58,162.81,157.38,149.79,134.90,132.70,131.31,131.23,115.22,110.74,98.48,98.30,73.76,72.42,65.60,64.50,60.96,55.09,52.09,43.05,43.05,41.57,14.50.
The detection method comprises the following steps:
detection methods for compounds 3 and I: chromatography column an Ascentis Express C18 column (150 × 4.6mm, 3.0 μm), mobile phase a [ phosphoric acid: water (1 ml: 100ml) ]: b (acetonitrile) ═ 80: 20; the column temperature was 25 ℃, the wavelength was 210nm, and the flow rate was 1.0 ml/min;
detection of mosapride and compound VI: chromatography column an Ascentis Express C18 column (4.6 mm. times.150 mm,5.0 μm); mobile phase a [ sodium citrate: water: dilute hydrochloric acid (8 g: 800 ml: 1ml) ]: b (acetonitrile) ═ 70: 30, of a nitrogen-containing gas; the column temperature is 40 ℃; the detection wavelength is 274 nm; the flow rate was 1.0 ml/min.
Example 1
Adding 2-ethoxy-4-acetamino benzoic acid ethyl ester (25.13g, 0.1mol) and NBS (23.14g, 0.13mol) into DMF (120mL), heating at 70 ℃, preserving heat for reaction for 3h, pouring the reaction liquid into ice water after the detection reaction is finished, stirring for crystallization, filtering, washing a filter cake with water (50mL multiplied by 2), and drying to obtain a white solid ethyl 2-ethoxy-4-acetamido-5-bromobenzoate, wherein the yield is 98.7%, and the purity is 99.95%.
Example 2
Adding 2-ethoxy-4-acetamino benzoic acid ethyl ester (25.13g, 0.1mol) and NBS (17.80g, 0.1mol) into methanol (120mL), heating at 50 ℃ for reaction for 3h, pouring the reaction liquid into ice water after the detection reaction is finished, stirring for crystallization, filtering, washing a filter cake with water (50mL multiplied by 2), and drying to obtain a white solid ethyl 2-ethoxy-4-acetamido-5-bromobenzoate, wherein the yield is 94.2% and the purity is 99.85%.
Example 3
Adding 2-ethoxy-4-acetamino benzoic acid ethyl ester (25.13g, 0.1mol) and NBS (32.04g, 0.18mol) into acetonitrile (120mL), heating to 80 ℃, preserving heat for reaction for 3h, pouring the reaction liquid into ice water after the detection reaction is finished, stirring for crystallization, filtering, washing a filter cake with water (50mL multiplied by 2), and drying to obtain a white solid ethyl 2-ethoxy-4-acetamido-5-bromobenzoate, wherein the yield is 93.4% and the purity is 99.76%.
Example 4
Adding 2-ethoxy-4-acetamino benzoic acid ethyl ester (25.13g, 0.1mol) and NBS (35.60g, 0.2mol) into ethanol (120mL), heating at 45 ℃, preserving heat for reaction for 3h, pouring the reaction liquid into ice water after the detection reaction is finished, stirring for crystallization, filtering, washing a filter cake with water (50mL multiplied by 2), and drying to obtain a white solid ethyl 2-ethoxy-4-acetamido-5-bromobenzoate, wherein the yield is 87.7% and the purity is 99.68%.
Preparation of bromo impurity VI
Putting 2-ethoxy-4-acetamido-5-bromobenzoate ethyl (20.73g, 0.063mol), EDCI (14.49g, 0.0756mol) and DMAF (9.24g, 0.0756mol) into a reaction bottle containing dichloromethane (250ml), keeping the temperature for reaction for 1h, cooling to-10 ℃ to-5 ℃, adding triethylamine (9.11g, 0.09mol), adding 4- (4-fluorobenzyl) -2-aminomethyl morpholine (23.41g, 0.09mol) after dripping, stirring for reaction, transferring the reaction liquid into purified water after the reaction is finished, cooling to 0-5 ℃ for crystallization, washing a filter cake by suction filtration with water (100ml), and drying at 45 ℃ under reduced pressure to obtain a white solid 4-acetamido-5-bromo-2-ethoxy-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide, the yield was 98.6% and the HPLC purity was 99.92%.
Putting 4-acetamido-5-bromo-2-ethoxy-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide (20.00g38.0mmol) into a reaction bottle containing a methanol (200ml) solvent, heating, refluxing, dissolving, cooling to 50 ℃, adding a citric acid (15.96g, 76.0mmol) aqueous solution, carrying out heat preservation reaction, cooling to 0-5 ℃ after the reaction is finished, crystallizing, carrying out suction filtration, washing a filter cake with water (50ml multiplied by 2), drying at 45 ℃ under reduced pressure for 8h to obtain the mosapride citrate related substance VI, wherein the yield is 98.7%, and the HPLC purity is 99.96%.
Claims (9)
1. A mosapride impurity compound shown as a formula I has a structure shown as follows:
2. a process for the preparation of mosapride impurity compound I according to claim 1, comprising the steps of: adding a compound II, namely 2-ethoxy-4-ethyl acetamidobenzoate, and a compound III, namely N-bromosuccinimide, into an organic solvent, and stirring and reacting at a controlled temperature to obtain 2-ethoxy-4-acetamido-5-ethyl bromobenzoate, wherein the route is as follows:
3. the method according to claim 2, wherein the molar ratio of compound II to compound III is 1: 1.0 to 1.8.
4. The method of claim 2, wherein the organic solvent is one or a combination of DMF, methanol, ethanol, acetonitrile, tetrahydrofuran.
5. The method of claim 2, wherein the reaction temperature is 50 ℃ to 80 ℃.
6. The use of a compound of formula I as defined in claim 1, and salts or solvates thereof for the detection of mosapride citrate intermediates, drug substances and/or formulations.
7. The use of the compound of formula I as defined in claim 1 in the preparation of a mosapride citrate bromo-impurity, wherein mosapride citrate bromo-impurity VI can be synthesized by the following route for detecting the content of mosapride citrate bulk drug and/or preparation bromo-impurity:
8. the use of compound I according to claim 7 for the preparation of the impurity moxapride citrate bromide, wherein the preparation process comprises the steps of: adding a compound I, namely 2-ethoxy-4-acetamido-5-bromobenzoate ethyl ester, EDCl and DMAF into dichloromethane, adding triethylamine and 4- (4-fluorobenzyl) -2-aminomethyl morpholine) to react to generate 2-ethoxy-4-acetamido-5-bromo-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide, and then reacting with a citric acid aqueous solution to generate a mosapride citrate bromo impurity VI.
9. A pharmaceutically acceptable salt, solvate of a compound of formula I according to claim 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108341788A (en) * | 2018-02-09 | 2018-07-31 | 鲁南制药集团股份有限公司 | A kind of mosapride citrate intermediate and purposes |
Non-Patent Citations (1)
| Title |
|---|
| 张理星;臧超;夏明军;高佃台;张贵民;: "枸橼酸莫沙必利的合成工艺", 中国医药工业杂志, no. 11, pages 1578 - 1581 * |
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