WO2020107913A1 - 化合物或其盐、其制备方法及应用 - Google Patents

化合物或其盐、其制备方法及应用 Download PDF

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WO2020107913A1
WO2020107913A1 PCT/CN2019/097806 CN2019097806W WO2020107913A1 WO 2020107913 A1 WO2020107913 A1 WO 2020107913A1 CN 2019097806 W CN2019097806 W CN 2019097806W WO 2020107913 A1 WO2020107913 A1 WO 2020107913A1
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salt
compound
formula
alkyl
compound represented
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PCT/CN2019/097806
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English (en)
French (fr)
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张保献
胡杰
闫东辉
秦梦芝
曹瑛
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盈科瑞（天津）创新医药研究有限公司
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Publication of WO2020107913A1 publication Critical patent/WO2020107913A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a compound or a salt thereof, and also relates to a preparation method and application of the compound or a salt thereof.
  • COPD Chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • airflow obstruction characterized by airflow obstruction, which can further develop into common chronic diseases such as pulmonary heart disease and respiratory failure.
  • COPD is related to the abnormal inflammatory response of airways and lungs to harmful gases or harmful particles. Its morbidity and mortality are high. The incidence of people over the age of 40 in the world is as high as 9% to 10%.
  • Terbutaline's chemical name is 5-(1-hydroxy-2-tert-butylaminoethyl)benzene-1,3-diphenol, CAS number is 23031-25-6, and its molecular formula is C 12 H 19 NO 3 .
  • Terbutaline is a short-acting ⁇ 2-receptor agonist developed by AstraZeneca for the treatment of COPD. It is a clinically recommended drug for patients with mild to moderate COPD. Compared with other short-acting ⁇ 2-receptor agonists that have been marketed, terbutaline has lower dose-dependent side effects.
  • the structural formula of terbutaline is as follows:
  • the terbutaline compound was first synthesized by Lacco of Sweden.
  • the synthesis method is to use 3,5-dihydroxybenzoic acid as the raw material and react with ethanol to obtain ethyl 3,5-dihydroxybenzoate and 3,5-dihydroxybenzene
  • Ethyl formate reacts with benzyl chloride to protect the hydroxyl group, and then hydrolyzes the reaction product.
  • the hydrolyzed product reacts with thionyl chloride to form an acid chloride.
  • the acid chloride is then condensed with diazomethane, and the condensate is brominated with hydrobromic acid. After that, the bromide is condensed with isobutylamine, then the condensation reaction product is reduced by sodium borohydride, and finally the reduced product is hydrogenated to debenzylate and form a salt with an acid.
  • terbutaline can also be prepared according to the following synthetic route, which uses the compound of formula II as a raw material, and sequentially undergoes benzyl protection reaction, bromination reaction, condensation reaction, reduction reaction, hydrogenation debenzylation React with salt formation to get terbutaline sulfate;
  • synthetic drugs contain impurities, which are mainly caused by by-products generated during the synthesis process or introduced through raw materials or caused by degradation products generated during storage. Because the impurity content of drugs directly affects the efficacy and may cause toxic and side effects, the pharmaceutical industry must monitor the impurity content of drugs to ensure the safety and effectiveness of drugs, and the quality standards of drugs all over the world also regard the purity of the active ingredients And the content of impurities has stricter regulations. Impurities may be introduced at various stages in the synthesis route of terbutaline or its pharmaceutically acceptable salts, therefore, the impurities introduced during the synthesis of terbutaline or its pharmaceutically acceptable salts need to be effectively monitored, To ensure the efficacy and safety of special drug products.
  • the present invention provides a compound or a salt thereof, which is an impurity introduced during the synthesis of terbutaline or a pharmaceutically acceptable salt thereof. Therefore, the compound or a salt thereof can be used as an impurity control substance to monitor terbutaline Or the introduction of impurities during the synthesis of pharmaceutically acceptable salts thereof, thereby ensuring the efficacy and safety of the pharmaceutical product.
  • the present invention provides a preparation method and application of the compound or its salt.
  • the first aspect of the present invention relates to a compound represented by formula I or a salt thereof:
  • R 1 is selected from hydrogen, hydroxyl, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, amino, and mercapto; the substituted C 1-6 alkyl is substituted with one or more halogens C 1-6 alkyl.
  • R 1 is selected from hydrogen, hydroxyl, C 1-4 alkyl, substituted C 1-4 alkyl, halogen, amino, and mercapto; the substituted C 1-4 alkyl
  • the group is a C 1-4 alkyl group substituted with one or more halogens (for example, fluorine, chlorine, bromine, iodine, astatine).
  • R 1 is selected from hydrogen, hydroxyl, C 1-6 alkyl, substituted C 1-6 alkyl, and halogen; the substituted C 1-6 alkyl is substituted by one Or C 1-6 alkyl substituted with multiple halogens (eg, fluorine, chlorine, bromine, iodine, astatine).
  • halogens eg, fluorine, chlorine, bromine, iodine, astatine
  • R 1 is selected from hydrogen, hydroxy, C 1-4 alkyl, substituted C 1-4 alkyl, and halogen; the substituted C 1-4 alkyl is substituted by one Or C 1-4 alkyl substituted with multiple halogens (eg, fluorine, chlorine, bromine, iodine, astatine).
  • halogens eg, fluorine, chlorine, bromine, iodine, astatine
  • R 1 is selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, and halogen; the substituted C 1-6 alkyl is substituted by one or more C 1-6 alkyl substituted with one halogen (for example, fluorine, chlorine, bromine, iodine, astatine).
  • halogen for example, fluorine, chlorine, bromine, iodine, astatine
  • R 1 is selected from hydrogen, C 1-4 alkyl, substituted C 1-4 alkyl, and halogen; the substituted C 1-4 alkyl is substituted by one or more C 1-4 alkyl substituted by halogen (for example, fluorine, chlorine, bromine, iodine, astatine).
  • halogen for example, fluorine, chlorine, bromine, iodine, astatine
  • R 1 is selected from hydrogen, C 1-6 alkyl, and substituted C 1-6 alkyl; the substituted C 1-6 alkyl is substituted by one or more halogens (E.g. fluorine, chlorine, bromine, iodine, astatine) substituted C 1-6 alkyl.
  • halogens E.g. fluorine, chlorine, bromine, iodine, astatine
  • R 1 is selected from hydrogen, C 1-4 alkyl, and substituted C 1-4 alkyl; the substituted C 1-4 alkyl is substituted by one or more halogens (E.g. fluorine, chlorine, bromine, iodine, astatine) substituted C1-4 alkyl.
  • halogens E.g. fluorine, chlorine, bromine, iodine, astatine
  • R 1 is selected from C 1-6 alkane and substituted C 1-6 alkyl; the substituted C 1-6 alkyl is C substituted with one or more halogens 1-6 alkyl;
  • the halogen is selected from fluorine, chlorine, bromine, iodine and astatine (for example from fluorine, chlorine, bromine and iodine).
  • R 1 is selected from C 1-4 alkyl and substituted C 1-4 alkyl; the substituted C 1-4 alkyl is C substituted with one or more halogens 1-4 alkyl;
  • the halogen is selected from fluorine, chlorine, bromine, iodine and astatine (for example from fluorine, chlorine, bromine and iodine).
  • R 1 is selected from methyl, ethyl, propyl, monobromomethyl, dibromomethyl, tribromomethyl, 1-bromoethyl, 2-bromoethyl , 1-bromopropyl, 2-bromopropyl, 3-bromopropyl.
  • R 1 is selected from methyl, ethyl, propyl, monobromomethyl, 1-bromoethyl, 2-bromoethyl, 1-bromopropyl, 2-bromo Propyl, 3-bromopropyl.
  • the compound is selected from:
  • the second aspect of the present invention relates to a method for preparing the compound or salt thereof according to the first aspect of the present invention, which includes the following step (1), optional step (2), optional step (3) and optional Step (4):
  • R 1 is defined as described in the first aspect of the invention.
  • reaction product, liquid phase or first concentrate is subjected to column chromatography, and the eluent is collected.
  • the method further includes the following steps:
  • the concentration temperature is 35°C to 70°C, for example, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C;
  • the second concentrate is a solid.
  • the eluent or second concentrate comprises or is a compound of formula I or a salt thereof as described in the first aspect of the invention.
  • the mass content of the compound of formula I or its salt in the second concentrate is 80%-99.9%, such as 82%, 90%, 95%, 97%, 98%, 99 %.
  • the reaction temperature is 60°C to 120°C, such as 70°C, 80°C, 90°C, 100°C, and 110°C.
  • step (1) the progress of the reaction is monitored by TLC until the reaction is complete.
  • the TLC monitoring reaction process belongs to the conventional technical means in the art.
  • the molar ratio of the compound represented by formula II or its salt to the benzyl halide is 1:(3-10), preferably 1:(3-5) , For example 1:4, 1:6, 1:7, 1:8, 1:9.
  • the chromatography column used is a silica gel chromatography column
  • the filler in the silica gel chromatography column is 100-400 mesh silica gel, such as 200-300 mesh silica gel.
  • the eluent used in the column chromatography is selected from dichloromethane, ethyl acetate, petroleum ether, and methyl tert-butyl ether, preferably ethyl acetate And/or petroleum ether.
  • the gradient elution procedure of column chromatography is: 2-9 column volumes (eg 3, 4, 5, 6, 7, 8 column volumes) Petroleum ether ⁇ 2 to 9 times the column volume (for example, 3, 4, 5, 6, 7, 8 times the column volume) volume ratio is (35 to 65): 1 (for example 40: 1, 50: 1, 60: 1) A mixture of petroleum ether and ethyl acetate ⁇ 6 to 18 column volumes (for example, 8, 10, 12, 13, 15, 17 column volumes), the volume ratio is (10 to 30): 1 (for example, 13: 1, 15:1, 17:1, 20:1, 22:1, 25:1, 27:1, 29:1) petroleum ether and ethyl acetate mixture.
  • Some embodiments of the second aspect of the present invention include one or more of the following (A) to (K):
  • step (1) the benzyl halide is selected from benzyl bromide and benzyl chloride;
  • the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium hydride, preferably potassium carbonate and/or potassium hydroxide;
  • the solvent is selected from absolute ethanol, methanol, toluene, benzene, dimethylformamide and dimethylacetamide, preferably absolute ethanol and/or methanol;
  • step (1) the molar ratio of the compound represented by formula II or its salt to the base is 1: (3 to 10), preferably 1: (3 to 5), for example, 1:4, 1:6 , 1:7, 1:8, 1:9;
  • the mass of the solvent is 5 to 20 times the mass of the compound represented by formula II or a salt thereof, preferably 8 to 15 times, such as 6 times, 7 times, 8 times, 9 Times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times;
  • step (2) the solid-liquid separation method is suction filtration
  • step (3) the method of concentration is concentration under reduced pressure
  • the temperature for concentration under reduced pressure is 35°C to 70°C, for example, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C;
  • step (3) the first concentrate is a solid
  • step (4) the height of the chromatography column used is 280-320mm (for example 290mm, 300mm, 310mm), and the inner diameter is 60-90mm (for example 70mm, 80mm);
  • step (4) collect the eluent according to the TLC detection result
  • step (4) the mass of the packing material in the chromatographic column is 5 to 10 times, for example 6, 7, 8, 9 times, the mass of the reaction product, liquid phase or first concentrate.
  • the method further includes the following steps:
  • step (6) the bromination reaction is performed using bromination reagents and conditions of a conventional bromination reaction.
  • step (6) is specifically: dissolving the eluent or the second concentrate in a mixed solvent to obtain a first solution; and using tetrahydrofuran formulated with tetrabutylammonium tribromide The solution is slowly added to the first solution, and then reacted at room temperature for 1 to 5 hours (for example, 2 hours) to obtain a reaction product; the reaction product is concentrated to obtain a concentrate; then the concentrate is mixed with an ethanol solution, allowed to stand, and collected by filtration solid.
  • the mixed solvent is tetrahydrofuran and anhydrous methanol with a volume ratio of 2:1.
  • the ratio of the eluent or the second concentrate to the mixed solvent is 1: (7-12) (g/ml), for example, 1:9 (g /ml).
  • the mass ratio of tetrabutylammonium tribromide to the eluent or the second concentrate is (1-2):1, for example 1.2:1 1.5:1, 1.8:1.
  • step (6) the concentration is concentrated under reduced pressure
  • the temperature for concentration under reduced pressure is 30°C to 60°C, such as 40°C, 45°C, 50°C, and 55°C.
  • the third aspect of the present invention relates to a method for determining the content of impurities in a substance, including the following steps:
  • the substance is terbutaline or a pharmaceutically acceptable salt thereof, a compound represented by formula III or a salt thereof, or a preparation of terbutaline or a pharmaceutically acceptable salt thereof Raw materials or intermediates of salt;
  • R 2, R 1 is.
  • the intermediate for preparing terbutaline or a pharmaceutically acceptable salt thereof includes a compound represented by formula III or a salt thereof.
  • the compound represented by formula III or a salt thereof in addition to the preparation of terbutaline or a pharmaceutically acceptable salt thereof, may also be a raw material or intermediate for preparing other compounds
  • the process of the compound represented by Formula III or its salt may also be a process of preparing raw materials or intermediates of other compounds.
  • terbutaline or a pharmaceutically acceptable salt thereof a compound represented by formula III or a salt thereof, or a raw material for preparing terbutaline or a pharmaceutically acceptable salt thereof or
  • the impurities in the intermediate include the compound or salt thereof according to the first aspect of the present invention.
  • the fourth aspect of the present invention relates to a method for calibrating the purity of a compound represented by formula I or a salt thereof, including the following steps:
  • R 1 is as defined in the first aspect of the present invention.
  • a liquid chromatograph (such as a high performance liquid chromatograph) is used for the measurement.
  • the operating conditions of liquid chromatography include one or more of the following (a) to (g):
  • the specification of the chromatography column is 5 ⁇ m, 250 ⁇ 4.6 mm;
  • the column temperature is 20°C to 40°C, for example 25°C, 30°C, 35°C;
  • the injection volume is 5-15 ⁇ l, for example 10 ⁇ l;
  • the detector is an ultraviolet detector
  • the detection wavelength is 210nm
  • the mobile phase includes mobile phase A and mobile phase B.
  • Mobile phase A is 0.005 to 0.02 mol/l (for example, 0.01 mol/l) potassium dihydrogen phosphate aqueous solution
  • mobile phase B is acetonitrile
  • the pH value of the mobile phase A is 2 to 3, for example 3;
  • the flow rate of the mobile phase is 0.5 to 2 ml/min, for example 1 ml/min;
  • Time(min) Mobile phase A (%V/V) Mobile phase B (%V/V) 0 80 20 5 30 70 50 30 70 51 80 20 60 80 20 .
  • the fifth aspect of the present invention relates to the use of the compound or the salt thereof according to the first aspect of the present invention as an impurity reference substance or to determine the impurity content of a substance.
  • the substance is terbutaline or a pharmaceutically acceptable salt thereof, a compound represented by formula III or a salt thereof, or a preparation of terbutaline or a pharmaceutically acceptable salt thereof Raw materials or intermediates of salt;
  • R 2, R 1 is.
  • the compound or salt thereof according to the first aspect of the present invention is used as an impurity control substance.
  • the intermediate for preparing terbutaline or a pharmaceutically acceptable salt thereof includes a compound represented by formula III or a salt thereof.
  • the compound represented by formula III or a salt thereof in addition to the preparation of terbutaline or a pharmaceutically acceptable salt thereof, may also be a raw material or intermediate for preparing other compounds.
  • the process of the compound represented by Formula III or its salt may also be a process of preparing raw materials or intermediates of other compounds.
  • terbutaline or a pharmaceutically acceptable salt thereof a compound represented by formula III or a salt thereof, or a raw material or intermediate for preparing terbutaline or a pharmaceutically acceptable salt thereof
  • the impurities in the body include the compound or salt thereof according to the first aspect of the present invention.
  • the sixth aspect of the present invention relates to the use of the compound or its salt according to the first aspect of the present invention for calibrating the purity of the compound represented by formula I or its salt;
  • R 1 is defined as described in the first aspect of the present invention.
  • the compound or salt thereof according to the first aspect of the present invention is used as a standard control.
  • the compound represented by formula I or its salt according to the first aspect of the present invention is used to determine the content of impurities in a substance.
  • the substance is terbutaline or a pharmaceutically acceptable salt thereof, a compound represented by formula III or a salt thereof, or a preparation of terbutaline or a pharmaceutically acceptable salt thereof Raw materials or intermediates;
  • R 2, R 1 is.
  • the compound or salt thereof according to the first aspect of the present invention is used as an impurity control substance.
  • the intermediate for preparing terbutaline or a pharmaceutically acceptable salt thereof includes a compound represented by formula III or a salt thereof.
  • impurities of terbutaline or a pharmaceutically acceptable salt thereof, a compound represented by formula III or a salt thereof, or a raw material or intermediate for preparing terbutaline or a pharmaceutically acceptable salt thereof Contains the compound or salt thereof according to the first aspect of the present invention.
  • the compound represented by formula III or a salt thereof may also be a raw material or intermediate for preparing other compounds.
  • the process of a compound or its salt may also be a process of preparing raw materials or intermediates of other compounds.
  • the compound or pharmaceutically acceptable salt thereof according to the first aspect of the present invention is used to calibrate the purity of the compound represented by formula I or its salt;
  • R 1 is defined as described in the first aspect of the present invention.
  • the compound or salt thereof according to the first aspect of the present invention is used as a standard control.
  • Bn represents benzyl or benzyl.
  • the present invention also includes the following aspects 1 to 6:
  • the benzyl halide is benzyl chloride or benzyl bromide.
  • alkyl refers to a linear or branched alkyl group having one or more carbon atoms, such as C 1-6 alkyl, C 1-4 alkyl, C 1 alkyl, C 2 alkyl, C 3 Alkyl, C 4 alkyl, C 5 alkyl. Specific examples include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • salt refers to a salt formed by (1) an acidic functional group (for example, -COOH, -OH, -SO 3 H, etc.) present in a compound of the present invention and an appropriate inorganic or organic cation (base), for example, a compound of the present invention Salts with alkali metals or alkaline earth metals, ammonium salts of the compounds of the invention, and salts of the compounds of the invention with nitrogen-containing organic bases; and (2) basic functional groups present in the compounds of the invention (eg -NH 2 etc.) Salts formed with appropriate inorganic or organic anions (acids), such as salts of compounds of the invention with inorganic acids or organic carboxylic acids; for example sulfates, nitrates, hydrochlorides, acetates, formates, propionic acid Salt, citrate, etc.
  • an acidic functional group for example, -COOH, -OH, -SO 3 H, etc.
  • base for example, a compound of the present invention Salts
  • petroleum ether is a colorless and transparent liquid with odor of kerosene, mainly a mixture of pentane and hexane; petroleum ether is insoluble in water, soluble in absolute ethanol, benzene, chloroform , Oils and other organic solvents; flammable and explosive, can react strongly with oxidants; mainly used as a solvent and grease treatment.
  • benzyl bromide also known as benzyl bromide, is an aromatic compound with a benzene ring replaced by bromomethyl.
  • the CAS number is 100-39-0.
  • benzyl chloride also known as benzyl chloride, is a colorless or yellowish transparent liquid. It is a carcinogen and has a pungent odor. The CAS number is 100-44-7.
  • the compound or its salt of the present invention is an impurity introduced during the synthesis of terbutaline or a pharmaceutically acceptable salt thereof. Taking the compound or its salt as an impurity reference substance, it can be used to monitor terbutaline or its pharmacologically Impurities are introduced during the synthesis of acceptable salts to ensure the efficacy and safety of pharmaceutical products.
  • the method of the present invention can synthesize the compound of formula I or its salt with high purity, which can be used as an impurity reference substance.
  • Example 1 is an MS spectrum of the compound of formula i in Example 1 of the present invention.
  • Example 3 is a HPLC chromatogram of an external standard solution in Example 4 of the present invention.
  • Example 4 is an HPLC chromatogram of a test solution of the first batch of compound of formula iii in Example 4 of the present invention.
  • Example 4 Application in determining the impurity content of the compound of formula iii
  • the high-performance liquid chromatograph is used to detect the external standard solution and the sample solution.
  • the operating conditions are as follows:
  • the chromatographic column is Tnature C18 (specification is 5 ⁇ m, 250 ⁇ 4.6mm); the column temperature is 30°C; the injection volume is 10 ⁇ l; the mobile phase A is 0.01mol/l potassium dihydrogen phosphate aqueous solution (phosphoric acid adjusted pH value 3.0) Mobile phase B is acetonitrile; the flow rate of the mobile phase is 1.0ml/min; the mobile phase gradient elution procedure is shown in Table 1, the elution time is 60min; the detector is an ultraviolet detector; the detection wavelength is 210nm; the retention time of the compound of formula i 29.874min ( ⁇ 1.0min), the retention time of the compound of formula iii is 23.573min ( ⁇ 1.0min);
  • terbutaline sulfate was synthesized.
  • three batches of the compound of formula iii were taken as samples, and their impurities (compound of formula i) were determined according to the aforementioned methods.
  • Figure 3 is the HPLC chromatogram of the external standard solution
  • Figure 4 is the HPLC chromatogram of the first batch of sample solution. The results of the impurity content are shown in Table 2.

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Abstract

本发明公开了式Ⅰ所示的化合物或其盐，其中，R 1选自氢、羟基、C 1-6烷基、取代的C 1-6烷基、卤素、氨基和巯基；所述取代的C 1-6烷基是被一个或多个卤素取代。本发明化合物或其盐可作为杂质对照品用于监控特布他林或其药学上可接受盐的合成过程中的杂质引入，从而确保药物产品的药效和安全性。

Description

化合物或其盐、其制备方法及应用 技术领域
本发明属于医药技术领域，具体涉及一种化合物或其盐，还涉及该化合物或其盐的制备方法及应用。
背景技术
慢性阻塞性肺疾病(COPD)是具有气流阻塞特征的慢性支气管炎和/或肺气肿疾病，它可进一步发展为肺心病、呼吸衰竭等常见慢性疾病。COPD与气道和肺脏对有害气体或有害颗粒的异常炎症反应有关，其致残率和病死率高，全球40岁以上人群的发病率高达9％～10％。
特布他林的化学名称为5-(1-羟基-2-叔丁基氨基乙基)苯-1,3-二酚，CAS号为23031-25-6，分子式为C 12H 19NO 3。特布他林是由阿斯利康公司研发的用于治疗COPD的短效β2-受体激动剂，是轻、中度COPD患者的临床推荐用药。相较其它已上市的短效β2-受体激动剂，特布他林具有更低的剂量依赖性副作用。特布他林的结构式如下：
Figure PCTCN2019097806-appb-000001
特布他林化合物最早由瑞典拉科公司合成，合成方法是以3,5-二羟基苯甲酸为原料，与乙醇反应得到3,5-二羟基苯甲酸乙酯，3,5-二羟基苯甲酸乙酯与氯化苄反应以保护羟基，继而对反应产物水解，水解产物与氯化亚砜发生氯代反应生成酰氯，酰氯再与重氮甲烷缩合，将缩合物通过氢溴酸溴代，之后将溴代物与异丁胺缩合，然后通过硼氢化钠还原缩合反应产物，最后将还原产物氢化脱苄、与酸成盐。
除上述合成方法之外，通常还可按照如下的合成路线制备特布他林，其以式II化合物为原料，依次经过苄基保护反应、溴代反应、缩合反应、还原反应、氢化脱苄反应和成盐反应，得到特布他林硫酸盐；
Figure PCTCN2019097806-appb-000002
通常，合成药物中会含有杂质，其主要由合成过程中产生的副产物导致或者经由原辅料引入或者由贮存过程中产生的降解物导致。由于药物的杂质含量直接影响药效并可能导致毒副作用，因此，医药行业必须对药物的杂质含量加以监控，以确保药物的安全和有效性，世界各国的药物质量标准也都对有效成分的纯度和杂质含量有较为严格的规定。由于特布他林或其药学上可接受盐的合成路线中的各阶段都可能引入杂质，因此，需要对特布他林或其药学上可接受盐的合成过程中引入的杂质进行有效监控，以确保特药物产品的药效和安全性。
发明内容
本发明提供了一种化合物或其盐，其为合成特布他林或其药学上可接受盐的过程中引入的杂质，因此，该化合物或其盐可作为杂质对照品来监控特布他林或其药学上可接受盐的合成过程中的杂质引入，从而确保药物产品的药效和安全性。在此基础上，本发明提供了该化合物或其盐的制备方法及应用。
本发明第一方面涉及式Ⅰ所示的化合物或其盐：
Figure PCTCN2019097806-appb-000003
其中，R 1选自氢、羟基、C 1-6烷基、取代的C 1-6烷基、卤素、氨基和巯基；所述取代的C 1-6烷基是被一个或多个卤素取代的C 1-6烷基。
本发明第一方面的一些实施方式中，R 1选自氢、羟基、C 1-4烷基、取代的C 1-4烷基、卤素、氨基和巯基；所述取代的C 1-4烷基是被一个或多个卤素(例如氟、氯、溴、碘、砹)取代的C 1-4烷基。
本发明第一方面的一些实施方式中，R 1选自氢、羟基、C 1-6烷基、取代的C 1-6烷基和卤素；所述取代的C 1-6烷基是被一个或多个卤素(例如氟、氯、溴、碘、砹)取代的C 1-6烷基。
本发明第一方面的一些实施方式中，R 1选自氢、羟基、C 1-4烷基、取代的C 1-4烷基和卤素；所述取代的C 1-4烷基是被一个或多个卤素(例如氟、氯、溴、碘、砹)取代的C 1-4烷基。
本发明第一方面的一些实施方式中，R 1选自氢、C 1-6烷基、取代的C 1-6烷基和卤素；所述取代的C 1-6烷基是被一个或多个卤素(例如氟、氯、溴、碘、砹)取代的C 1-6烷基。
本发明第一方面的一些实施方式中，R 1选自氢、C 1-4烷基、取代的C 1-4烷基和卤素；所述取代的C 1-4烷基是被一个或多个卤素(例如氟、氯、溴、碘、砹)取代的C 1-4烷基。
本发明第一方面的一些实施方式中，R 1选自氢、C 1-6烷基和取代的C 1-6烷基；所述取代的C 1-6烷基是被一个或多个卤素(例如氟、氯、溴、碘、砹)取代的C 1-6烷基。
本发明第一方面的一些实施方式中，R 1选自氢、C 1-4烷基和取代的C 1-4烷基；所述取代的C 1-4烷基是被一个或多个卤素(例如氟、氯、溴、碘、砹)取代的C 1-4烷基。
本发明第一方面的一些实施方式中，R 1选自C 1-6烷和取代的C 1-6烷基；所述取代的C 1-6烷基是被一个或多个卤素取代的C 1-6烷基；
优选地，所述卤素选自氟、氯、溴、碘和砹(例如选自氟、氯、溴和碘)。
本发明第一方面的一些实施方式中，R 1选自C 1-4烷和取代的C 1-4烷基；所述取代的C 1-4烷基是被一个或多个卤素取代的C 1-4烷基；
优选地，所述卤素选自氟、氯、溴、碘和砹(例如选自氟、氯、溴和碘)。
本发明第一方面的一些实施方式中，R 1选自甲基、乙基、丙基、一溴甲基、二溴甲基、三溴甲基、1-溴乙基、2-溴乙基、1-溴丙基、2-溴丙基、3-溴丙基。
本发明第一方面的一些实施方式中，R 1选自甲基、乙基、丙基、一溴甲基、1-溴乙基、2-溴乙基、1-溴丙基、2-溴丙基、3-溴丙基。
本发明第一方面的一些实施方式中，所述的化合物选自：
Figure PCTCN2019097806-appb-000004
本发明第二方面涉及一种制备本发明第一方面所述化合物或其盐的方法，包括如下的步骤(1)、可选的步骤(2)、可选的步骤(3)和可选的步骤(4)：
(1)将式Ⅱ所示的化合物或其盐、卤化苄以及碱在溶剂中反应，得到反应产物；
Figure PCTCN2019097806-appb-000005
其中，R 1的定义为本发明第一方面中所述；
(2)将反应产物固液分离，得到液相物；
(3)将反应产物或液相物浓缩，得到第一浓缩物；
(4)将反应产物、液相物或者第一浓缩物进行柱层析处理，收集洗脱液。
本发明第二方面的一些实施方式中，所述方法还包括如下步骤：
(5)将洗脱液浓缩，得到第二浓缩物；
优选地，浓缩的温度为35℃～70℃，例如40℃、45℃、50℃、55℃、60℃、65℃；
优选地，第二浓缩物为固体。
本发明第二方面的一些实施方式中，洗脱液或者第二浓缩物包含或者为本发明第一方面所述的式Ⅰ化合物或其盐。
本发明第二方面的一些实施方式中，式Ⅰ化合物或其盐在第二浓缩物中的质量含量为80％～99.9％，例如82％、90％、95％、97％、98％、99％。
本发明第二方面的一些实施方式中，步骤(1)中，反应的温度为60℃～120℃，例如70℃、80℃、90℃、100℃、110℃。
本发明第二方面的一些实施方式中，步骤(1)中，通过TLC监测反应进程至反应完全。其中，TLC监测反应进程属于本领域常规技术手段。
本发明第二方面的一些实施方式中，步骤(1)中，式Ⅱ所示的化合物或其盐与卤化苄的摩尔比为1:(3～10)，优选为1:(3～5)，例如1:4、1:6、1:7、1:8、1:9。
本发明第二方面的一些实施方式中，步骤(4)中，使用的层析柱为硅胶层析柱；
优选地，硅胶层析柱内的填料为100～400目硅胶，例如200～300目硅胶。
本发明第二方面的一些实施方式中，步骤(4)中，柱层析使用的洗脱剂选自二氯甲烷、乙酸乙酯、石油醚和甲基叔丁基醚，优选为乙酸乙酯和/或石油醚。
本发明第二方面的一些实施方式中，步骤(4)中，柱层析的梯度洗脱程序为：2～9倍柱体积(例如3、4、5、6、7、8倍柱体积)的石油醚→2～9倍柱体积(例如3、4、5、6、7、8倍柱体积)的体积比为(35～65):1(例如40:1、50:1、60:1)的石油醚和乙酸乙酯混合液→6～18倍柱体积(例如8、10、12、13、15、17倍柱体积)的体积比为(10～30):1(例如13:1、15:1、17:1、20:1、22:1、25:1、27:1、29:1)的石油醚和乙酸乙酯混合液。
本发明第二方面的一些实施方式中，包括如下(A)至(K)中的一项或多项：
(A)步骤(1)中，所述卤化苄选自溴化苄和氯化苄；
(B)步骤(1)中，所述碱选自碳酸钠、碳酸钾、氢氧化钠、氢氧化钾和氢化钠，优选为碳酸钾和/或氢氧化钾；
(C)步骤(1)中，所述溶剂选自无水乙醇、甲醇、甲苯、苯、二甲基甲酰胺和二甲基乙酰胺，优选为无水乙醇和/或甲醇；
(D)步骤(1)中，式Ⅱ所示的化合物或其盐与碱的摩尔比为1:(3～10)，优选为1:(3～5)，例如1:4、1:6、1:7、1:8、1:9；
(E)步骤(1)中，所述溶剂的质量为式Ⅱ所示的化合物或其盐的质量的5～20倍，优选为8～15倍，例如6倍、7倍、8倍、9倍、10倍、11倍、12倍、13倍、14倍、15倍、16倍、17倍、18倍、19倍、20倍；
(F)步骤(2)中，固液分离的方式为抽滤；
(G)步骤(3)中，浓缩的方式为减压浓缩；
优选地，减压浓缩的温度为35℃～70℃，例如40℃、45℃、50℃、55℃、60℃、65℃；
(H)步骤(3)中，第一浓缩物为固体；
(I)步骤(4)中，使用的层析柱的高度为280～320mm(例如290mm、300mm、310mm)、内径为60～90mm(例如70mm、80mm)；
(J)步骤(4)中，根据TLC检测结果收集洗脱液；
(K)步骤(4)中，层析柱中填料的质量为反应产物、液相物或者第一浓缩物的 质量的5～10倍，例如6、7、8、9倍。
本发明第二方面的一些实施方式中，所述方法还包括如下步骤：
(6)将洗脱液或第二浓缩物进行溴代反应。
本发明第二方面的一些实施方式中，步骤(6)中，所述溴代反应采用常规溴代反应的溴代试剂和条件进行。
本发明第二方面的一些实施方式中，步骤(6)具体为：将洗脱液或第二浓缩物溶解于混合溶剂中，得到第一溶液；将用四丁基三溴化铵配制的四氢呋喃溶液缓慢加入第一溶液中，再在室温下反应1至5小时(例如2小时)，得到反应产物；将反应产物浓缩，得到浓缩物；然后将浓缩物与乙醇溶液混合，静置，过滤收集固体。
本发明第二方面的一些实施方式中，步骤(6)中，混合溶剂为体积比为2:1的四氢呋喃和无水甲醇。
本发明第二方面的一些实施方式中，步骤(6)中，洗脱液或第二浓缩物与混合溶剂的比例为1:(7～12)(g/ml)，例如1:9(g/ml)。
本发明第二方面的一些实施方式中，步骤(6)中，四丁基三溴化铵与洗脱液或第二浓缩物的质量比为(1～2):1，例如1.2:1、1.5:1、1.8:1。
本发明第二方面的一些实施方式中，步骤(6)中，浓缩为减压浓缩；
优选地，减压浓缩的温度为30℃～60℃，例如40℃、45℃、50℃、55℃。
本发明第三方面涉及一种测定物质中杂质含量的方法，包括如下步骤：
提供本发明第一方面所述的化合物或其盐，将其作为杂质对照品；
检测物质中的杂质含量。
本发明第三方面的一些实施方式中，所述物质为特布他林或其药学上可接受的盐、式Ⅲ所示的化合物或其盐、或者制备特布他林或其药学上可接受的盐的原料或中间体；
Figure PCTCN2019097806-appb-000006
其中，R 2的定义与本发明第一方面中R 1的定义相同。
本发明第三方面的一些实施方式中，制备特布他林或其药学上可接受的盐的中间体包括式Ⅲ所示的化合物或其盐。
本发明第三方面的一些实施方式中，除了制备特布他林或其药学上可接受的盐之外，式Ⅲ所示的化合物或其盐也可以是制备其它化合物的原料或中间体，制备式Ⅲ所示的化合物或其盐的过程也可以是制备其它化合物的原料或中间体的过程。
本发明第三方面的一些实施方式中，特布他林或其药学上可接受的盐、式Ⅲ所示的化合物或其盐、或者制备特布他林或其药学上可接受盐的原料或中间体中的杂质包含本发明第一方面所述的化合物或其盐。
本发明第四方面涉及一种标定式Ⅰ所示化合物或其盐的纯度的方法，包括如下步骤：
提供本发明第一方面所述的化合物或其盐，将其作为标准对照品；
标定式Ⅰ所示化合物或其盐的纯度；
Figure PCTCN2019097806-appb-000007
其中，R 1的定义如本发明第一方面中所述。
本发明第三或四方面的一些实施方式中，采用液相色谱仪(例如高效液相色谱仪)进行测定。
本发明第三或四方面的一些实施方式中，液相色谱的操作条件包括如下(a)至(g)中的一项或多项：
(a)色谱柱为Tnature C18；
优选地，色谱柱的规格为5μm，250×4.6mm；
(b)柱温为20℃～40℃，例如25℃、30℃、35℃；
(c)进样量为5～15μl，例如10μl；
(d)检测器为紫外检测器；
优选地，检测波长为210nm；
(e)流动相包括流动相A和流动相B，流动相A为0.005～0.02mol/l(例如0.01mol/l)的磷酸二氢钾水溶液，流动相B为乙腈；
优选地，流动相A的pH值为2～3，例如3；
(f)流动相的流速为0.5～2ml/min，例如1ml/min；
(g)流动相的洗脱程序如下表所示：
时间(min) 流动相A(％V/V) 流动相B(％V/V)
0 80 20
5 30 70
50 30 70
51 80 20
60 80 20
。
本发明第五方面涉及本发明第一方面所述的化合物或其盐作为杂质对照品的用途或在测定物质的杂质含量中的用途。
本发明第五方面的一些实施方式中，所述物质为特布他林或其药学上可接受的盐、式Ⅲ所示的化合物或其盐、或者制备特布他林或其药学上可接受盐的原料或中间体；
Figure PCTCN2019097806-appb-000008
其中，R 2的定义与本发明第一方面中R 1的定义相同。
本发明第五方面的一些实施方式中，本发明第一方面所述的化合物或其盐作为杂质对照品使用。
本发明第五方面的一些实施方式中，制备特布他林或其药学上可接受盐的中间体包括式Ⅲ所示的化合物或其盐。
本发明第五方面的一些实施方式中，除了制备特布他林或其药学上可接受的盐之外，式Ⅲ所示的化合物或其盐也可以是制备其它化合物的原料或中间体，制备式Ⅲ所示的化合物或其盐的过程也可以是制备其它化合物的原料或中间体的过程。
本发明第五方面的一些实施方式中，特布他林或其药学上可接受盐、式Ⅲ所示的化合物或其盐、或者制备特布他林或其药学上可接受盐的原料或中间体的杂质中包含本发明第一方面所述的化合物或其盐。
本发明第六方面涉及本发明第一方面所述的化合物或其盐在标定式Ⅰ所示化合物或其盐的纯度中的用途；
Figure PCTCN2019097806-appb-000009
其中，R 1的定义如本发明第一方面所述。
本发明第六方面的一些实施方式中，本发明第一方面所述的化合物或其的盐作为标准对照品使用。
本发明第一方面所述的式Ⅰ所示的化合物或其盐，其用于测定物质中的杂质含量。
本发明第一方面的一些实施方式中，所述物质为特布他林或其药学上可接受盐、式Ⅲ所示的化合物或其盐、或者制备特布他林或其药学上可接受盐的原料或中间体；
Figure PCTCN2019097806-appb-000010
其中，R 2的定义与本发明第一方面中R 1的定义相同。
本发明一些实施方式中，本发明第一方面所述的化合物或其盐作为杂质对照品使用。
本发明一些实施方式中，制备特布他林或其药学上可接受盐的中间体包括式Ⅲ所示的化合物或其盐。
本发明一些实施方式中，特布他林或其药学上可接受盐、式Ⅲ所示的化合物或其盐、或者制备特布他林或其药学上可接受盐的原料或中间体的杂质中包含本发明第一方面所述的化合物或其盐。
本发明一些实施方式中，除了特布他林或其药学上可接受的盐之外，式Ⅲ所示的化合物或其盐也可以是制备其它化合物的原料或中间体，制备式Ⅲ所示的化合物或其盐的过程也可以是制备其它化合物的原料或中间体的过程。
本发明第一方面所述的化合物或其药学上可接受的盐，其用于标定式Ⅰ所示化合物或其盐的纯度；
Figure PCTCN2019097806-appb-000011
其中，R 1的定义如本发明第一方面所述。
本发明一些实施方式中，本发明第一方面所述的化合物或其盐作为标准对照品使用。
本发明中，“Bn”代表苯甲基或苄基。
本发明还包括如下的第1至6方面：
1、一种具有式i结构式的化合物，
Figure PCTCN2019097806-appb-000012
2、第1方面所述式i化合物的制备方法，其中，所述式i化合物式由式Ⅱ化合物与卤化苄反应制备而成，
Figure PCTCN2019097806-appb-000013
3、第2方面所述式i化合物的制备方法中，所述卤化苄为氯化苄或溴化苄。
4、第1方面所述式i化合物作为式iii化合物原料或者中间体药物合成工艺中杂质检测的对照品的应用，
Figure PCTCN2019097806-appb-000014
5、一种用于测定式iii化合物原料杂质含量的方法，采用高压液相色谱法分析，其中，第1方面所述式i化合物作为对照品。
6、一种含有本发明第1方面所述式i化合物的式iii化合物，其中，式iii化合物中式i化合物的含量百分比不高于1.0％。
本发明中，如无特别说明，其中：
术语“烷基”是指具有一个或多个碳原子的直链或支链烷基，例如C 1-6烷基、C 1-4烷基、C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
术语“氨基”结构式为-NH 2。
术语“巯基”结构式为-SH。
术语“盐”是指，(1)本发明化合物中存在的酸性官能团(例如-COOH、-OH、-SO 3H等)与适当的无机或者有机阳离子(碱)形成的盐，例如本发明化合物与碱金属或碱土金属形成的盐、本发明化合物的铵盐，和本发明化合物与含氮有机碱形成的盐；以及(2)本发明化合物中存在的碱性官能团(例如-NH 2等)与适当的无机或者有机阴离子(酸)形成的盐，例如本发明化合物与无机酸或有机羧酸形成的盐；例如硫酸盐、硝酸盐、盐酸盐、乙酸盐、甲酸盐、丙酸盐、柠檬酸盐等。
术语“石油醚”CAS号为8032-32-4；石油醚是无色透明液体，有煤油气味，主要为戊烷和己烷的混合物；石油醚不溶于水，溶于无水乙醇、苯、氯仿、油类等多数有机溶剂；易燃易爆，与氧化剂可强烈反应；主要用作溶剂和油脂处理。
术语“溴化苄”又称苄基溴，是一种苯环被溴甲基取代的芳香化合物，CAS号为100-39-0。
术语“氯化苄”又称苄基氯，是一种无色或微黄色的透明液体，属致癌物质，具有刺激性气味，CAS号为100-44-7。
本发明至少取得了如下的有益效果：
1、本发明化合物或其盐为合成特布他林或其药学上可接受盐的过程中引入的杂质，以该化合物或其盐作为杂质对照品，可用于监控特布他林或其药学上可接受盐的合成过程中的杂质引入，从而确保药物产品的药效和安全性。
2、本发明方法能合成出高纯度的式Ⅰ化合物或其盐，可用于作为杂质对照品使用。
附图说明
此处所说明的附图用来提供对本发明的进一步理解，构成本申请的一部分，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1为本发明实施例1中式i化合物的MS图谱；
图2为本发明实施例1中式i化合物的HNMR图谱；
图3为本发明实施例4中的外标溶液的HPLC色谱图；
图4为本发明实施例4中第一批次式iii化合物的供试品溶液的HPLC色谱图。
具体实施方式
下面将结合实施例对本发明的实施方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。以下对至少一个示例性实施例的描述实际上仅仅是说明性的，决不作为对本发明及其应用或使用的任何限制。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：1-(2-苄基-3,5-双(苄氧基)苯基)乙酮(式i化合物)的制备
Figure PCTCN2019097806-appb-000015
(1)将20g式Ⅱ化合物加入500ml单口瓶中，依次加入200ml乙醇、72g碳酸钾粉末和55g氯化苄，在80℃下搅拌反应，TLC检测反应完全后，降温抽滤，将滤液45℃减压浓缩 至干，得到浓缩物，纯度为86.6％(W/W)。
(2)取步骤(1)制得的15g浓缩物溶于50ml二氯甲烷中，加入25g的200-300目的硅胶拌样；使用100g的200-300目硅胶装柱，柱子高度为300mm，内径为70mm；先用500ml(约5倍柱体积)石油醚洗脱，再用500ml(约5倍柱体积)的体积比50:1的石油醚:乙酸乙酯洗脱，最后用1L(约10倍柱体积)的体积比20:1的石油醚:乙酸乙酯洗脱，TLC检测收集样品，将样品在45℃下减压浓缩至干，得到白色固体(式i化合物)，纯度为98.5％(W/W)。
结构确证如下：
MS图谱见图1：ES Ⅰ-MS(m/z):[M+H] +＝423.63；分子式：C 29H 26O 3；
HNMR图谱见图2： 1HNMR(600MHz,DMSO-d 6)δ7.48(d,J＝7.2Hz,2H),7.42(t,J＝7.5Hz,2H),7.38–7.34(m,1H),7.34–7.26(m,3H),7.25–7.17(m,4H),7.14–7.10(m,1H),7.04(d,J＝7.6Hz,2H),6.99(t,J＝1.7Hz,1H),6.93(d,J＝2.8Hz,1H),5.13(d,J＝28.4Hz,4H),4.05(s,2H),2.43(s,3H).
实施例2：1-(2-苄基-3,5-双(苄氧基)苯基)乙酮(式i化合物)的制备
Figure PCTCN2019097806-appb-000016
(1)将20g式Ⅱ化合物加入500ml单口瓶中，依次加入200ml甲醇、60g氢氧化钠粉末、55g氯化苄，在60℃下搅拌反应，TLC检测反应完全后，降温抽滤，将滤液45℃减压浓缩至干，得到浓缩物，纯度72.3％(W/W)。
(2)取步骤(1)制得的15g浓缩物溶于50ml二氯甲烷中，加入25g的200-300目的硅胶拌样；使用100g的200-300目硅胶装柱，柱子高度为300mm，内径为70mm；先用500ml(约5倍柱体积)石油醚洗脱，再用500ml(约5倍柱体积)的体积比50:1的石油醚:乙酸乙酯洗脱，最后用1L(约10倍柱体积)的体积比20:1的石油醚:乙酸乙酯洗脱，TLC检测收集样品，将样品在30℃下减压浓缩至干，得到白色固体(式i化合物)，纯度为80.5％(W/W)。
结构确证如下：
MS：ES Ⅰ-MS(m/z):[M+H] +＝423.63；分子式：C 29H 26O 3；
1HNMR(600MHz,DMSO-d 6)δ7.48(d,J＝7.2Hz,2H),7.42(t,J＝7.5Hz,2H),7.38–7.34(m,1H),7.34–7.26(m,3H),7.25–7.17(m,4H),7.14–7.10(m,1H),7.04(d,J＝7.6 Hz,2H),6.99(t,J＝1.7Hz,1H),6.93(d,J＝2.8Hz,1H),5.13(d,J＝28.4Hz,4H),4.05(s,2H),2.43(s,3H).
实施例3：1-(2-溴化苄基-3,5-双(苄氧基)苯基)乙酮(式i’化合物)的制备
Figure PCTCN2019097806-appb-000017
将0.5g式i化合物加入50ml单口瓶中，依次加入3ml四氢呋喃、1.5ml无水甲醇，在室温下搅拌溶解，得到溶液1。将0.6g四丁基三溴化铵溶于1.5ml四氢呋喃中，然后缓慢滴加到溶液1中，滴加完毕后在室温下反应2h，TLC检测反应完全后，将反应产物在45℃减压浓缩至干，得浓缩物。在搅拌条件下向浓缩物中加入2.5ml 95％(W/W)乙醇溶液，搅拌均匀之后静置，过滤的析出固体，得到白色固体(式i’化合物)，纯度为81.6％(W/W)。
实施例4：在测定式iii化合物的杂质含量中的应用
Figure PCTCN2019097806-appb-000018
(1)准确称量10mg实施例1制备的白色固体置于10ml量瓶中，加乙腈溶解并稀释至刻度，摇匀，作为供试品溶液；精密量取供试品溶液1mL置于100mL量瓶中，加乙腈至刻度并摇匀，作为外标溶液。其中，外标溶液中式i化合物的浓度为0.00985mg/ml。
(2)称取约10mg制备的式iii化合物置于10ml量瓶中，加乙腈溶解并稀释至刻度，摇匀，作为样品溶液。
(3)采用高效液相色谱仪检测外标溶液和样品溶液，其操作条件如下：
色谱柱为Tnature C18(规格为5μm，250×4.6mm)；柱温为30℃；进样量为10μl；流动相A为0.01mol/l磷酸二氢钾水溶液(磷酸调节pH值为3.0)，流动相B为乙腈；流动相的流速为1.0ml/min；流动相梯度洗脱程序见表1，洗脱时间为60min；检测器为紫外检测器；检测波长为210nm；式i化合物的保留时间为29.874min(±1.0min)，式iii化合物的保留时间为23.573min(±1.0min)；
表1
时间(min) 流动相A(％V/V) 流动相B(％V/V)
0 80 20
5 30 70
50 30 70
51 80 20
60 80 20
(4)根据检测结果计算出制备式iii化合物中的杂质(式i化合物)含量。
按照下述路线合成硫酸特布他林，在第一步取三个批次生成的式iii化合物作为样品，按照前述方法分别测定它们的杂质(式i化合物)含量。
Figure PCTCN2019097806-appb-000019
图3为外标溶液的HPLC色谱图，图4为第一批次的样品溶液的HPLC色谱图，杂质含量的结果如表2所示。
表2
批次 式i化合物的保留时间 杂质含量(W/W)
1 30.040 0.45％
2 30.047 0.36％
3 30.035 0.52％
由表2可知，以本发明式i化合物为外标物，能准确测定制备硫酸特布他林的中间体中的杂质(式i化合物)含量。
最后应当说明的是：以上实施例仅用以说明本发明的技术方案而非对其限制；尽管参照较佳实施例对本发明进行了详细的说明，所属领域的普通技术人员应当理解：依然可以对本发明的具体实施方式进行修改或者对部分技术特征进行等同替换；而不脱离本发明技术方案的精神，其均应涵盖在本发明请求保护的技术方案范围当中。

Claims (19)

  1. 式Ⅰ所示的化合物或其盐：
    Figure PCTCN2019097806-appb-100001
    其中，R 1选自氢、羟基、C 1-6烷基、取代的C 1-6烷基、卤素、氨基和巯基；所述取代的C 1-6烷基是被一个或多个卤素取代的C 1-6烷基。
  2. 根据权利要求1所述的化合物或其盐，其中，R 1选自C 1-6烷基和取代的C 1-6烷基；所述取代的C 1-6烷基是被一个或多个卤素取代的C 1-6烷基；
    优选地，所述卤素选自氟、氯、溴、碘和砹。
  3. 根据权利要求1所述的化合物或其盐，其中，所述化合物选自：
    Figure PCTCN2019097806-appb-100002
  4. 一种制备权利要求1至3中任一项所述化合物或其盐的方法，包括如下的步骤(1)、可选的步骤(2)、可选的步骤(3)和可选的步骤(4)：
    (1)将式Ⅱ所示的化合物或其盐、卤化苄以及碱在溶剂中反应，得到反应产物；
    Figure PCTCN2019097806-appb-100003
    其中，R 1的定义如权利要求1至3任一项中所述；
    (2)将反应产物固液分离，得到液相物；
    (3)将反应产物或液相物浓缩，得到第一浓缩物；
    (4)将反应产物、液相物或者第一浓缩物进行柱层析处理，收集洗脱液；
    可选地，所述方法还包括如下步骤：
    (5)将洗脱液浓缩，得到第二浓缩物。
  5. 根据权利要求4所述的方法，其中，步骤(1)中，反应的温度为60℃～120℃。
  6. 根据权利要求4所述的方法，其中，步骤(1)中，式Ⅱ所示的化合物或其盐与卤化苄的摩尔比为1:(3～10)，优选为1:(3～5)。
  7. 根据权利要求4所述的方法，其中，步骤(4)中，使用的层析柱为硅胶层析柱；
    优选地，硅胶层析柱内的填料为100～400目硅胶；
  8. 根据权利要求4所述的方法，其中，步骤(4)中，柱层析使用的洗脱剂选自二氯甲烷、乙酸乙酯、石油醚和甲基叔丁基醚，优选为乙酸乙酯和/或石油醚。
  9. 根据权利要求8所述的方法，其中，步骤(4)中，柱层析的梯度洗脱程序为：2～9倍柱体积的石油醚→2～9倍柱体积的体积比为(35～65):1的石油醚和乙酸乙酯的混合液→6～18倍柱体积的体积比为(10～30):1的石油醚和乙酸乙酯的混合液。
  10. 根据权利要求4所述的方法，其特征在于如下(A)至(K)中的一项或多项：
    (A)步骤(1)中，所述卤化苄选自溴化苄和氯化苄；
    (B)步骤(1)中，所述碱选自碳酸钠、碳酸钾、氢氧化钠、氢氧化钾和氢化钠，优选为碳酸钾和/或氢氧化钾；
    (C)步骤(1)中，所述溶剂选自无水乙醇、甲醇、甲苯、苯、二甲基甲酰胺和二甲基乙酰胺，优选为无水乙醇和/或甲醇；
    (D)步骤(1)中，式Ⅱ所示的化合物或其盐与碱的摩尔比为1:(3～10)，优选为1:(3～5)；
    (E)步骤(1)中，所述溶剂的质量为式Ⅱ所示的化合物或其盐的质量的5～20倍，优选为8～15倍；
    (F)步骤(2)中，固液分离的方式为抽滤；
    (G)步骤(3)中，浓缩的方式为减压浓缩；
    (H)步骤(3)中，第一浓缩物为固体；
    (I)步骤(4)中，使用的层析柱的高度为280～320mm、内径为60～90mm；
    (J)步骤(4)中，根据TLC检测结果收集洗脱液；
    (K)步骤(4)中，层析柱中填料的质量为反应产物、液相物或者第一浓缩物的质量的5～12倍。
  11. 一种测定物质中杂质含量的方法，包括如下步骤：
    提供权利要求1至3中任一项所述的化合物或其盐，将其作为杂质对照品；
    检测物质中的杂质含量；
    优选地，所述物质为特布他林或其药学上可接受的盐、式Ⅲ所示的化合物或其盐、或者制备特布他林或其药学上可接受盐的原料或中间体；
    Figure PCTCN2019097806-appb-100004
    R 2的定义与权利要求1至3任一项中R 1的定义相同。
  12. 一种标定式Ⅰ所示化合物或其盐的纯度的方法，包括如下步骤：
    提供权利要求1至3中任一项所述的化合物或其盐，将其作为标准对照品；
    标定式Ⅰ所示化合物或其盐的纯度；
    Figure PCTCN2019097806-appb-100005
    其中，R 1的定义如权利要求1至3中任一项所述。
  13. 根据权利要求11或12所述的方法，其中，采用液相色谱仪(例如高效液相色谱仪)进行测定。
  14. 根据权利要求13所述的方法，其中，液相色谱的操作条件包括如下(a)至(g)中的一项或多项：
    (a)色谱柱为Tnature C18；
    优选地，色谱柱的规格为5μm，250*4.6mm；
    (b)柱温为20℃～40℃；
    (c)进样量为5～15μl；
    (d)检测器为紫外检测器；
    优选地，检测波长为210nm；
    (e)流动相包括流动相A和流动相B，流动相A为0.005～0.02mol/l的磷酸二氢钾水溶液，流动相B为乙腈；
    优选地，流动相A的pH值为2～3；
    (f)流动相的流速为0.5～2ml/min；
    (g)流动相的洗脱程序如下表所示：
    时间(min) 流动相A(％V/V) 流动相B(％V/V) 0 80 20 5 30 70 50 30 70 51 80 20 60 80 20
    。
  15. 根据权利要求11所述的方法，其中，制备特布他林或其药学上可接受盐的中间体包括式Ⅲ所示的化合物或其盐。
  16. 权利要求1至3中任一项所述的化合物或其盐作为杂质对照品的用途或者在测定物质的杂质含量中的用途；
    优选地，所述物质为特布他林或其药学上可接受的盐、式Ⅲ所示的化合物或其盐、或者制备特布他林或其药学上可接受盐的原料或中间体；
    Figure PCTCN2019097806-appb-100006
    其中，R 2的定义与权利要求1至3任一项中R 1的定义相同；
    更优选地，制备特布他林或其药学上可接受盐的中间体包括式Ⅲ所示的化合物或其盐。
  17. 权利要求1至3中任一项所述的化合物或其盐在标定式Ⅰ所示化合物或其盐的纯度中的用途；
    Figure PCTCN2019097806-appb-100007
    其中，R 1的定义如权利要求1至3中任一项所述；
    优选地，权利要求1至3中任一项所述的化合物或其盐作为标准对照品使用。
  18. 权利要求1至3中任一项所述的化合物或其盐，用于测定物质中的杂质含量；
    优选地，所述物质为式Ⅲ所示的化合物或其盐、特布他林或其药学上可接受的盐、或者制备特布他林或其药学上可接受盐的原料或中间体，
    Figure PCTCN2019097806-appb-100008
    其中，R 2的定义与权利要求1至3任一项中R 1的定义相同；
    优选地，权利要求1至3中任一项所述的化合物或其盐作为杂质对照品使用；
    优选地，制备特布他林或其药学上可接受盐的中间体包括式Ⅲ所示的化合物或其盐。
  19. 权利要求1至3中任一项所述的化合物或其盐，用于标定式Ⅰ所示化合物或 其盐的纯度；
    Figure PCTCN2019097806-appb-100009
    其中，R 1的定义如权利要求1至3中任一项所述；
    优选地，权利要求1至3中任一项所述的化合物或其盐作为标准对照品使用。
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CN111499528B (zh) * 2020-04-28 2023-06-20 成都瑞特恩科技有限公司 硫酸特布他林中间体及其制备方法和利用其制备硫酸特布他林的方法

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