CN110981771A - Preparation method and application of impurity E of suplatast tosilate process - Google Patents

Preparation method and application of impurity E of suplatast tosilate process Download PDF

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CN110981771A
CN110981771A CN201911228762.6A CN201911228762A CN110981771A CN 110981771 A CN110981771 A CN 110981771A CN 201911228762 A CN201911228762 A CN 201911228762A CN 110981771 A CN110981771 A CN 110981771A
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compound
organic solvent
equivalents
impurity
base
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尚光华
陈渝
陈乐旭
谢辉
邓祥林
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Chongqing Liujiang Pharmatech Co ltd
Chongqing Zen Pharmaceutical Co Ltd
Chongqing Zhien Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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Abstract

The invention discloses a preparation method and application of a suplatast tosilate process impurity E, wherein the impurity is a main impurity in a suplatast tosilate raw material medicine. The preparation method disclosed by the invention is low in cost, can be synthesized in a large amount, and provides a reference substance for qualitative and quantitative analysis of the impurities of the suplatast tosilate, so that a foundation is laid for quality research and compaction of the suplatast tosilate raw material medicine and related preparations.

Description

Preparation method and application of impurity E of suplatast tosilate process
Technical Field
The invention belongs to the technical field of drug synthesis, relates to process impurities in a raw material drug production process and preparation thereof, and particularly relates to a preparation method of a suplatast tosilate process impurity.
Background
Asthma is one of the most common chronic diseases in the world today, and most allergic asthma patients have the characteristic feature of overproducing a specific Immunoglobulin (IGE) protein in response to stimulation by a variety of external allergens. Sulfast (Suplatast tosilate) is a selective Th2 cytokine inhibitor developed by pharmaceutical company of Japan Roc (Taiho), marketed in Japan in 1995. The composition can significantly inhibit eosinophil production in bronchial wall, and can be used for treating allergic diseases such as bronchial asthma, atopic dermatitis, and allergic rhinitis.
The chemical name of suplatast tosilate is: (±) - [2- [4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl ] ethyl ] dimethylsulfonium p-toluenesulfonate having a structural formula:
Figure BDA0002302972080000011
the patent US4556737 reports a preparation method thereof, and the synthetic route is as follows;
Figure BDA0002302972080000021
because the impurities are introduced due to the methylation of hydroxyl in the preparation process of the compound 3 to the supreme of the process impurities in the medicine, the use benefit can be reduced, and therefore, the establishment of a corresponding analysis method through the directional preparation of the hydroxyl methylated impurities (E) has important significance for effectively controlling the quality of the bulk drugs and the preparations.
Disclosure of Invention
The research on impurities is an important content of drug research and development, and the safety, effectiveness and quality controllability of drugs are directly influenced throughout the research and development of drugs. In order to provide a related substance reference substance for the quality research of the suplatast tosilate, improve the quality standard of the suplatast tosilate and provide important guidance for safe medication of the suplatast tosilate, the invention researches and synthesizes and confirms the process impurities in the production route of the suplatast tosilate.
The study shows that the suplatast tosilate can generate the following process impurities in the production process:
Figure BDA0002302972080000031
chemical name: (±) - [2- [4- (3-ethoxy-2-methoxypropoxy) phenylcarbamoyl ] ethyl ] dimethylsulfonium p-toluenesulfonate
The production route is as follows:
Figure BDA0002302972080000032
the invention provides a preparation method of a suplatast tosilate process impurity E, which comprises the following steps;
1) general formula (A)
Figure BDA0002302972080000033
Reacting the compound represented by (a) with a strong base and a methylating agent in an organic solvent 1 to obtain a compound (B);
Figure BDA0002302972080000034
2) adding an organic solvent 2 into the step 1) for dissolving, adding palladium-carbon for catalysis, and introducing hydrogen for reduction to obtain a compound (C);
Figure BDA0002302972080000035
3) adding the organic solvent 3 into the step 2) for dissolving, adding organic base or inorganic base, and then dropwise adding 3-methylthio propionyl chloride to obtain a compound (D);
Figure BDA0002302972080000041
4) adding the organic solvent 3 into the step 3), or adding methyl p-toluenesulfonate into the mixture without adding the organic solvent to obtain a compound (E);
Figure BDA0002302972080000042
the preparation method of the invention has the following preferable scheme:
in some examples, the organic solvent 1 in step 1) is a mixed solvent of one or more of N-methylpyrrolidone, N-dimethylformamide, and dichloromethane, preferably N, N-dimethylformamide.
In some examples, the strong base in step 1) is sodium hydroxide, potassium hydroxide, or sodium hydrogen, preferably sodium hydrogen.
In some examples, the methylating agent in step 1) is methyl iodide, dimethyl sulfate, or dimethyl carbonate, preferably methyl iodide.
In some examples, the reaction temperature in step 1) is from 0 ℃ to 50 ℃, preferably from 20 ℃ to 30 DEG C
In some examples, the organic solvent 2 in step 2) is methanol, ethanol, ethyl acetate, or tetrahydrofuran, preferably methanol or ethanol.
In some examples, the catalyst in step 2) is palladium on carbon, and the amount is 5 to 10 percent (mol ratio).
In some examples, the reaction temperature in step 2) is 0 to 50 ℃, preferably 20 to 30 ℃.
In some examples, the organic solvent 3 in step 3) is dichloromethane, tetrahydrofuran, toluene, acetone, or acetonitrile, preferably dichloromethane.
In some examples, the organic base in step 3) is one or more of pyridine, triethylamine, and N, N-diisopropylethylamine; the inorganic base is one or more of potassium carbonate, sodium hydroxide and potassium hydroxide, the organic base is preferably triethylamine, and the inorganic base is preferably potassium carbonate. The amount of the organic base is 1 to 10 equivalents (based on the compound (C)), preferably 1.1 to 1.5 equivalents; the amount of the inorganic base is 1 to 10 equivalents (based on the compound (C)), preferably 2 to 4 equivalents.
In some examples, the reaction temperature in step 3) is from-10 to 50 deg.C, preferably from 0 to 10 deg.C
In some examples, the organic solvent 4 in step 4) is acetone, butanone, dichloromethane, or acetonitrile, preferably without solvent.
In some examples, the amount of methyl p-toluenesulfonate used in step 4) is from 1.0 to 5.0 equivalents (based on compound (D), preferably from 1.2 to 1.5 equivalents.
In some examples, the reaction temperature in step 4) is 0 to 50 ℃, preferably 30 to 40 ℃.
The invention provides an application of a suplatast tosilate process impurity (E) as a reference substance for quality research of a bulk drug and a preparation.
The invention provides a preparation method of a suplatast tosilate process impurity (E), which can be used for preparing a large amount of the suplatast tosilate process impurity (E) and can be used as a reference substance for quality research of raw material medicines and compound preparations.
Drawings
FIG. 1 shows the LC-MS spectrum of impurity (E);
FIG. 2 shows the impurity (E)1An HNRM map;
Detailed Description
Embodiments of the present invention will be specifically described below by way of examples of the present invention.
Formula (A)
Figure BDA0002302972080000061
The compounds shown can be prepared by j.med.chem.1998,41,33303336 or equivalent methods.
Example 1
Synthesis of Compound (B)
Adding 10.0g of the compound (A) and 50mL of N, N-dimethylformamide into a 100mL three-necked flask, stirring and dissolving, adding 3.36g of sodium hydrogen in batches, controlling the temperature to be 20-30 ℃, then dropwise adding 17.75g of methyl iodide, reacting at room temperature for 2 hours after dropwise adding, adding 10mL of ethanol for quenching, filtering, washing a filter cake with 10mL of ethanol, extracting the filter cake with 50mL of dichloromethane, then washing with tap water twice, separating an organic phase, and concentrating under reduced pressure to obtain a yellow oily compound (B).
Synthesis of Compound (C)
Adding 9.00g of the compound (B) and 90mL of ethanol into a three-necked flask, stirring and dissolving, adding 0.90g of 10% palladium carbon, introducing hydrogen, reacting at room temperature overnight, filtering, washing a filter cake twice with 10mL of ethanol each time, combining filtrates, concentrating and drying at 45 ℃ under reduced pressure, and purifying by column chromatography to obtain 6.28g of a light yellow oily compound (C).
Synthesis of Compound (D)
Adding 6.0g of compound (C), 4.14g of triethylamine and 42mL of dichloromethane into a three-necked bottle, cooling to 0-5 ℃, dropwise adding a mixed solution of 3-methylthiopropionyl chloride and 14.5mL of dichloromethane at 0-5 ℃, controlling the dropwise adding temperature to be 0-5 ℃, finishing dropwise adding, reacting at 0-5 ℃ for 2 hours, adding 2mol/L hydrochloric acid for washing once, washing the organic phase twice with tap water, washing 15mL of the organic phase twice each time, separating the organic phase, adding 9.0g of anhydrous sodium sulfate for drying, filtering, concentrating the filtrate, and purifying by column chromatography to obtain a light yellow oily compound (D).
Synthesis of Compound (E)
Adding 3.03g of the compound (D) and 9.0mL of acetone into a 100mL three-necked bottle, adding 3.59g of methyl p-toluenesulfonate, heating to 25-35 ℃, reacting for 48 hours, cooling to 0 ℃, crystallizing, filtering, and drying to obtain 4.28g of off-white solid. Agilent 1260HPLC-6120MS, LC-MS (ESI source, positive ion mode) shows the charge-to-mass ratio M/z [ M + H ] of impurity (E)]+Is 342.2, and is consistent with the theoretical molecular weight (see the impurity E mass spectrum in the attached figure 1 in detail); bruker Avance 600MHz NMR spectrometer,1H-NMR (600Mz, DMSO-d6) δ:10.09(s,1H), 7.47-7.49 (d, J ═ 9.0Hz,4H),7.10-7.12(d, J ═ 7.8Hz,2H), 6.90-6.92(d, J ═ 8.4Hz,2H), 4.00-4.02(m,1H), 3.92-3.95(m,1H), 3.60-3.63(m,1H), 3.44-3.54 (m,6H),3.37(s,3H), 2.91-2.92(m,8H), 2.29(s,3H), 1.09-1.12 (t, J ═ 7.2Hz) (see fig. 2 for impurity E hydrogen spectrum for details).
Impurity E was detected as a single spot by TLC (developing solvent dichloromethane: methanol: acetic acid: 10:0.8(v: v: v); uv developed).
Finally, it is noted that the above-mentioned embodiments illustrate rather than limit the invention, and that, while the invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (6)

1. The preparation method of the methylsufilast process impurity compound shown as the formula (E) comprises the following steps:
Figure FDA0002302972070000011
1) general formula (A)
Figure FDA0002302972070000012
Reacting the compound with strong base and methylating agent in organic solvent 1 to obtain compound (B);
2) adding the compound (B) prepared in the step 1) into an organic solvent 2 for dissolving, adding palladium-carbon for catalysis, and introducing hydrogen for reduction to obtain a compound (C);
Figure FDA0002302972070000013
3) adding the compound (C) prepared in the step 2) into an organic solvent 3 for dissolving, adding an organic base or an inorganic base, and then dropwise adding 3-methylthiopropionyl chloride to obtain a compound (D);
Figure FDA0002302972070000014
4) adding the compound (D) prepared in the step 3) into an organic solvent 4, or adding methyl p-toluenesulfonate into the mixture, so as to obtain an impurity compound (E) of the methylsulfonilast process.
2. The method according to claim 1, wherein the organic solvent 1 in step 1) is a mixed solvent of one or more of N-methylpyrrolidone, N-dimethylformamide, and dichloromethane, preferably N, N-dimethylformamide; the strong base is sodium hydroxide, potassium hydroxide or sodium hydrogen, preferably sodium hydrogen; the methylating agent is methyl iodide, dimethyl sulfate or dimethyl carbonate, and is preferably methyl iodide; the reaction temperature is 0-50 ℃, and preferably 20-30 ℃.
3. The method according to claim 1, wherein the organic solvent 2 in step 2) is methanol, ethanol, ethyl acetate, or tetrahydrofuran, preferably methanol or ethanol; the catalyst is palladium carbon, and the dosage is 5 to 10 percent (molar ratio); the reaction temperature is 0-50 ℃, and preferably 20-30 ℃.
4. The method according to claim 1, wherein the organic solvent 3 in step 3) is dichloromethane, tetrahydrofuran, toluene, acetone, or acetonitrile, preferably dichloromethane; the organic base is one or more of pyridine, triethylamine and N, N-diisopropylethylamine, and the inorganic base is one or more of potassium carbonate, sodium hydroxide and potassium hydroxide; the organic base is preferably triethylamine, and the inorganic base is preferably potassium carbonate; the amount of the organic base is 1 to 10 equivalents, preferably 1.1 to 1.5 equivalents; the using amount of the inorganic base is 1-10 equivalents, preferably 2-4 equivalents; the reaction temperature is-10 to 50 ℃, and preferably 0 to 10 ℃.
5. The process according to claim 1, wherein the organic solvent 4 in step 4) is acetone, butanone, dichloromethane, or acetonitrile, preferably without solvent; the dosage of the methyl p-toluenesulfonate is 1.0 to 5.0 equivalents, preferably 1.2 to 1.5 equivalents; the reaction temperature is 0-50 ℃, and preferably 30-40 ℃.
6. The use of the process impurity E as claimed in claim 1 as a reference substance for the quality study of the bulk drug of suplatast tosilate and its compound preparations.
CN201911228762.6A 2019-12-04 2019-12-04 Preparation method and application of impurity E of suplatast tosilate process Pending CN110981771A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112552220A (en) * 2020-12-17 2021-03-26 植恩生物技术股份有限公司 Preparation method of suplatast tosilate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6353011B1 (en) * 1999-03-08 2002-03-05 University Of Mississippi 1,2-dithiolane derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6353011B1 (en) * 1999-03-08 2002-03-05 University Of Mississippi 1,2-dithiolane derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RUI TAMURA，等: "Ideal enantiomeric resolution (preferential enrichment) by recrystallization of a racemic compound (part 6): hydrogen bonding mode in the crystal structure", 《ENANTIOMER》 *
YUKIO TADA，等: "Synthesis and Antiallergic Activity of Dimethyl-2-(phenylcarbamoyl)ethylsulfonium p-Toluenesulfonate Derivatives", 《J. MED. CHEM.》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112552220A (en) * 2020-12-17 2021-03-26 植恩生物技术股份有限公司 Preparation method of suplatast tosilate
CN112552220B (en) * 2020-12-17 2022-12-02 植恩生物技术股份有限公司 Preparation method of suplatast tosilate

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Address after: No.1-6, standard workshop, Jinfeng biomedical industrial park, 28 Gaoxin Avenue, Jiulongpo District, Chongqing 400021

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Application publication date: 20200410