WO2019085983A1 - Procédé de préparation d'un dérivé de benzimidazole à faible teneur en impuretés - Google Patents

Procédé de préparation d'un dérivé de benzimidazole à faible teneur en impuretés Download PDF

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WO2019085983A1
WO2019085983A1 PCT/CN2018/113598 CN2018113598W WO2019085983A1 WO 2019085983 A1 WO2019085983 A1 WO 2019085983A1 CN 2018113598 W CN2018113598 W CN 2018113598W WO 2019085983 A1 WO2019085983 A1 WO 2019085983A1
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solvent
formula
compound
ppm
group
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PCT/CN2018/113598
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雷四军
方祥
刘均均
祁雯雯
韦彦斌
陈永凯
王朝东
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武汉朗来科技发展有限公司
武汉启瑞药业有限公司
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Publication of WO2019085983A1 publication Critical patent/WO2019085983A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of preparation methods of pharmaceutical compounds, in particular to a preparation method of a low impurity content benzimidazole derivative.
  • Hypertension is one of the most common cardiovascular diseases and a major risk factor for the development of congestive heart failure, stroke, coronary heart disease, renal failure, and the incidence and mortality of aortic aneurysms.
  • Antihypertensive drugs play a key role in the treatment and prevention of hypertension. With the deepening of the understanding of the pathogenesis of hypertension, many antihypertensive drugs with better curative effects, such as diuretics, ⁇ -blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors (ACEI, Angiotensin II, an AT1 receptor blocker (ARB, sartan), has been continuously discovered and successfully applied in clinical practice.
  • ACEI angiotensin converting enzyme inhibitors
  • ARB AT1 receptor blocker
  • angiotensin II AT1 receptor blocker antihypertensive drugs began in the 1970s.
  • the first marketed drug for this product was losartan potassium, which was introduced in 1994. Since the drug was marketed in Sweden, Sartans have developed rapidly, and so far valsartan, candesartan cilexetil, irbesartan, eprosartan, tamsartan, telmisartan and olmesartan medoxomil have been exported to the United States.
  • the present invention provides a process for the preparation of a compound of formula I, which comprises dissolving the initial product of the compound of the following formula I with an organic solvent S1, crystallizing and drying to obtain a purified compound of the formula I;
  • the organic solvent S1 may be selected from the group consisting of an ester solvent, an alkane solvent, an ether solvent, a nitrile solvent, an alcohol solvent, a halogenated hydrocarbon solvent, a ketone solvent, two or more;
  • R 1 is selected from H or an unsubstituted or substituted group: an alkyl group, an alkenyl group, an alkyloxy group or an alkenyloxy group;
  • R 2 is selected from the group consisting of unsubstituted or substituted: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl nitrate;
  • the substituent may be selected from one or more R a ;
  • Each R c , R d , R e is the same or different and is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or —CONH 2 ;
  • Each Y 1 is independently selected from a chemical bond, -O-, -S-, or -NH-, alkyl, alkoxy, cycloalkyl, heterocycle which is unsubstituted or optionally substituted by one or more R a Base, aryl, heteroaryl, -(CH 2 CH 2 O) j -;
  • j is selected from an integer of 1 or more, for example, an integer of 1 to 20, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 1 may be selected from H or an unsubstituted or substituted group of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, vinyl, methoxy. Or ethoxylate;
  • R 2 may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl;
  • R a may be selected from
  • R b may be selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -ONO 2 , -alkyl-ONO 2 .
  • the compound of formula I of the invention is selected from the structure:
  • the organic solvent S1 is an anhydrous solvent.
  • the ester solvent may be selected from one of methyl acetate, ethyl acetate, hexyl acetate, and isopropyl acetate, two or more;
  • the alkane solvent may be selected from one, two or more of n-hexane, cyclohexane, pentane, n-heptane;
  • the ether solvent may be selected from the group consisting of diethyl ether, methyl ethyl ether, methyl tert-butyl ether, dipropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, 1,4-two One, two or more of oxyhexacyclohexane and tetrahydrofuran;
  • the nitrile solvent may be selected from one, two or more of acetonitrile, propionitrile, and the like;
  • the alcohol solvent may be selected from one, two or more of monohydric, dihydric or polyhydric alcohols having 1 to 10 carbon atoms, for example, selected from the group consisting of methanol, ethanol, propanol, and isopropanol.
  • the halogenated hydrocarbon solvent may be selected from one of methyl chloride, dichloromethane, chloroform, carbon tetrachloride, monochloroethane, dichloroethane, trichloroethane, two or more.
  • the ketone solvent may be selected from one, two or more of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl cyclohexanone, cyclohexanone, and methyl isobutyl ketone.
  • the ratio of the compound of the formula I to the organic solvent S1 may be 1 g/(3-20) ml, for example 1 g/(5-15) ml.
  • the preparation method may include crystallization under stirring.
  • the crystallization time may be 1-6 hours, such as 2-4 hours, for example 3 hours.
  • a filtration step may be performed after crystallization.
  • the filtered filter cake may be further beaten or recrystallized with an organic solvent S2, filtered, and then subjected to a drying step.
  • the filtered filter cake is further beaten or recrystallized with an organic solvent S2, and after filtration, it is further pulverized and/or sieved, and then subjected to a drying step.
  • the organic solvent S2 independently has the definition of the above organic solvent S1.
  • the total volume ratio of the organic solvent S1 to the organic solvent S2 may be 1:0.5 to 1:1.5, for example 1:1.
  • the sieving may be a sieve of 0.3-1.0 mm, such as a sieve of 0.4-0.6 mm.
  • the preparation method further comprises a drying step.
  • the drying temperature may be from room temperature to 70 ° C, such as from 30 to 65 ° C, such as from 40 to 60 ° C, such as from 50 to 55 ° C.
  • the drying time may be from 2 to 48 hours, such as from 12 to 40 hours, such as from 24 to 36 hours.
  • the drying can also be carried out in a vacuum environment, for example, a vacuum degree ⁇ 500 Pa, such as a vacuum degree ⁇ 200 Pa.
  • the initial product of the compound of formula I includes, but is not limited to, the crude product of the compound of formula I, the unpurified product, or the product which, although purified, has a purity or impurity content to be improved.
  • the compound of formula I-1 is present in an amount of >0.15%, such as > 0.25%, such as about 0.50%:
  • R 2 has the meanings indicated above.
  • the content of the compound of the formula I-1 is lower than the content of the starting product of the compound of the formula I.
  • the molar percentage content of the compound of formula I-1 is ⁇ 0.15%, preferably ⁇ 0.12%, more preferably ⁇ 0.10%.
  • the mole percent content of the compound of formula I-1 is ⁇ 0.05%, such as ⁇ 0.03%, such as ⁇ 0.02%.
  • the content of the genotoxic impurity GTI-001 represented by the formula is ⁇ 15.00 ppm, for example ⁇ 10.00 ppm, for example ⁇ 5.00 ppm, for example ⁇ 1.00 ppm, for example ⁇ 0.50 ppm , for example, ⁇ 0.45 ppm, such as ⁇ 0.30 ppm
  • the present invention also provides the above purified compound of formula I.
  • the invention also provides a composition comprising a compound of formula I and a compound of formula 1-1, wherein the compound of formula I and the compound of formula 1-1 have the definitions set forth above;
  • the molar percentage content of the compound of the formula I-1 is ⁇ 0.15%, preferably ⁇ 0.12%, further preferably ⁇ 0.10%; preferably, the molar percentage content of the compound of the formula I-1 in the composition is ⁇ 0.05 %, for example ⁇ 0.03%, such as ⁇ 0.02%.
  • the content of the genotoxic impurity GTI-001 in the composition is ⁇ 15.00 ppm, such as ⁇ 10.00 ppm, such as ⁇ 5.00 ppm, such as ⁇ 1.00 ppm, such as ⁇ 0.50 ppm, such as ⁇ 0.45 ppm, such as ⁇ 0.30 Ppm.
  • the content of the genotoxic impurity GTI-002 in the composition is ⁇ 15.00 ppm, such as ⁇ 10.00 ppm, such as ⁇ 5.00 ppm, such as ⁇ 1.00 ppm, such as ⁇ 0.50 ppm, such as ⁇ 0.45 ppm, such as ⁇ 0.30 Ppm, preferably ⁇ 0.20 ppm or ⁇ 0.10 ppm.
  • the content of the genotoxic impurity GTI-003 in the composition is ⁇ 15.00 ppm, for example ⁇ 10.00 ppm, such as ⁇ 5.00 ppm, such as ⁇ 1.00 ppm, such as ⁇ 0.50 ppm, such as ⁇ 0.45 ppm, such as ⁇ 0.30 Ppm, preferably ⁇ 0.20 ppm or ⁇ 0.10 ppm.
  • the preparation process optionally further comprises the step of reacting a compound of formula II with a potassium salt reagent to give the primary product of the compound of formula I:
  • R 1 and R 2 have the definitions described above.
  • the potassium salt agent is selected from a mixture of one or more of an organic acid potassium salt and a mineral acid potassium salt.
  • the potassium salt of an organic acid is selected from the group consisting of potassium hydrogen phthalate, potassium acetate, potassium formate, potassium di-tert-butyl phosphate, dipotassium glycyrrhizinate, potassium 2-ethylhexanoate, potassium ethyl xanthate, and sorbus Potassium acid, potassium phthalimide, potassium maleimide, potassium oxalate, potassium silicate, potassium citrate, potassium malate, potassium gluconate, potassium lactate, potassium tartrate, potassium salicylate, rich a mixture of one or more of potassium maleate, potassium stearate, and potassium laurate;
  • the potassium salt of the inorganic acid is selected from the group consisting of potassium nitrate, potassium sulfate, potassium sulfite, potassium bromate, potassium hydrogencarbonate, potassium thiocyanate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and potassium hydrogen phthalate. Or a mixture of multiples.
  • the potassium olefinate is selected from potassium octoate of C 3 or higher, preferably potassium octoate of C 3-26 , such as potassium acrylate, potassium crotonate, potassium octadecanoate or the like.
  • the reaction is preferably carried out in an organic solvent, for example, in a halogenated hydrocarbon solvent, and the halogenated hydrocarbon solvent may be selected from the group consisting of dichloromethane, chloroform, and carbon tetrachloride. One, two or more.
  • the potassium salt reagent does not need to be dissolved beforehand, and of course, it may be dissolved in the solvent in advance.
  • some potassium salt reagents are stored in a solvent because they are unstable or dangerous, and the potassium salt reagents stored in the solvent can be directly used at this time.
  • the molar ratio of K in the compound of Formula II to the potassium salt reagent is from about 1:0.3 to 3, more preferably from about 1:0.9 to about 2, and most preferably from about 1:0.95 to about 1.5.
  • the compound of formula II is first placed in a solvent and then the potassium salt reagent is added.
  • the temperature may be between room temperature and the reflux temperature of the solvent; further preferably, after the potassium salt reagent is added, the temperature may be between 5 and 25 ° C, for example 10-20 °C.
  • the product may be dissolved in the solution or may be directly precipitated from the solution.
  • the product is directly precipitated from the solution, after the reaction, it is filtered and dried to give the initial product of the compound of formula I.
  • it is cooled prior to filtration and has a cooling temperature of from about -50 ° C to about 30 ° C, more preferably from about -10 ° C to about 10 ° C, most preferably from about 0 ° C to about 5 ° C.
  • the solvent in the solution is removed to obtain the initial product of the compound of the formula I or an anti-solvent is added to the solution, filtered and dried to obtain the formula I.
  • the method of removing the solvent is, for example, spin drying or the like.
  • it is cooled prior to filtration and has a cooling temperature of from about -50 ° C to about 30 ° C, preferably from about -10 ° C to about 10 ° C, most preferably from about 0 ° C to about 5 ° C.
  • the anti-solvent is selected from the group consisting of a reagent in which the solubility is inferior to the selected solvent, such as methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, and different Propyl ether, diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, n-hexane, cyclohexane, pentane, n-heptane, benzene, toluene, xylene a mixture of one or more of them.
  • a reagent in which the solubility is inferior to the selected solvent such as methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-buty
  • the invention also provides a process for the preparation of a compound of formula II as described above, comprising the steps of:
  • the solvent A may be selected from one of organic solvents such as an alcohol solvent, a nitrile solvent, an ester solvent, a ketone solvent, two or more; or, when the organic When the solvent is miscible with water, the solvent A may be a mixed solution of the organic solvent and water;
  • the solvent B may be selected from one, two or more selected from the group consisting of a ketone solvent, an ether solvent, a nitrile solvent, an ester solvent, a halogenated hydrocarbon solvent, and the like; preferably a ketone solvent or an ester solvent.
  • a ketone solvent or an ester solvent One, two or more of a halogenated hydrocarbon solvent;
  • the ketone solvent, ether solvent, nitrile solvent, ester solvent, halogenated hydrocarbon solvent has the definitions described above.
  • the organic solvent miscible with water may be selected from, for example, one, two or more of an alcohol solvent, a nitrile solvent, a ketone solvent.
  • the mass percentage of the organic solvent in the mixed solution may be 50 to 99%, for example, 60 to 95%, such as 70 to 95%, as an example, It may be an aqueous alcohol solution having a mass percentage of 75%, 80% or 95%, such as an aqueous ethanol solution.
  • the volume ratio of the mass of the mixture containing the compound of the formula II in step 1) to the solvent A (Kg: L) may be 1: (2 to 6.5), for example, 1: (3.5 to 4.5). , such as 1:4.
  • the beating temperature may be from 5 to 65 ° C, for example from 10 to 60 ° C, for example from 30 to 60 ° C, for example from 40 to 60 ° C, such as from 55 to 60 ° C.
  • the beating time may be 1 to 5 hours, such as 2 to 3 hours.
  • the compound of formula II can be selected from the following compounds:
  • R 2 has the meanings indicated above.
  • the compound of the formula II' in the mixture containing the compound of the formula II in the step 1), may have a molar content of 3% or more, such as 3.5% or more, for example, 4 to 5%.
  • the molar content of the compound of the formula II' may be 0.5% or less, preferably less than 0.5%.
  • the preparation method according to the present invention wherein the mixture containing the compound of the formula II in the step 1) can be obtained by the preparation method described in the application examples, which are described in the application No. 201310042669.2 (publication number CN103709154A) and the application number 201410010180.1 (publication number CN104774196A).
  • the preparation process according to the invention wherein the mixture containing the compound of the formula II in the step 1) is obtained by the following method:
  • R 1 and R 2 have the definitions described above;
  • L is a leaving group such as Cl, Br or II.
  • the azilsartan and the compound of formula 4 are reacted in the presence of a base and an organic solvent;
  • the base may be an organic base, an inorganic base or a mixture thereof, such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, triethylamine.
  • potassium carbonate sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, triethylamine.
  • pyridine piperidine
  • the organic solvent may be any solvent capable of dissolving the reaction substrate, such as N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP);
  • DMF N,N-dimethylformamide
  • NMP N-methylpyrrolidone
  • the reaction temperature is 35 to 60 ° C, such as 40 to 42 ° C;
  • the reaction time may be 2 to 48 hours, such as 12 to 36 hours, for example, 24 hours;
  • the mixture containing the compound of formula II is an oil
  • the organic phase is washed with water or an aqueous solution of sodium chloride, such as a saturated aqueous solution of sodium chloride, dried, and evaporated to give a mixture containing a compound of formula II.
  • an organic solvent such as an ester solvent
  • an aqueous solution of sodium chloride such as a saturated aqueous solution of sodium chloride
  • the mixture can be obtained by the following method:
  • the azilsartan and the compound of the formula 4 are reacted in the presence of a base and an organic solvent at 40 to 42 ° C for 24 hours, the temperature is lowered, water is added, and the mixture is extracted with ethyl acetate. The organic phase is combined, washed with a saturated aqueous solution of sodium chloride and dried. Evaporation of the solvent gave an oil containing the compound of formula II.
  • a mixture containing a compound of formula II which may be in the form of an oil, may be prepared by a method prior to column chromatography as described in Example 13 of Patent Application No. 201410010180.1.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a purified compound of formula I, and optionally in the presence or absence of a pharmaceutically acceptable excipient, such as a carrier and/or excipient.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a composition comprising a compound of formula I and formula I-1, and optionally in the presence or absence of a pharmaceutically acceptable excipient, such as a carrier and/or Shape agent.
  • the pharmaceutical composition of the present invention can be formulated into powders for oral administration, tablets, (including various coated tablets, sustained release or controlled release tablets), troches, capsules (including soft capsules and hard capsules), Granules, pills, dispersible powders, aqueous or oily suspensions, aqueous or oily solutions, emulsions, elixirs, syrups, etc.; powders or liquid aerosols suitable for inhalation; creams suitable for topical application Agent, ointment, gel, aqueous or oily solution, aqueous or oily suspension, etc.; sterile aqueous or oily injection or frozen for intravenous, subcutaneous or intramuscular injection suitable for parenteral administration Dry powder injections, suppositories, etc.
  • Pharmaceutically acceptable carriers include, but are not limited to, excipients, lubricants, binders, disintegrants, water soluble polymers, inorganic salts, solvents, dissolution aids, suspending agents, isotonic agents, buffers, preservatives Agents, antioxidants, colorants, sweeteners, sour agents, foaming agents and flavoring agents, and the like.
  • the pharmaceutical composition of the present invention may further comprise other active ingredients, such as other active ingredients for preventing and/or treating hypertension, such as calcium ion antagonists (dihydropyridines, aralkylamines, phenylthiazide). Leather and triphenyl piperazine).
  • Suitable amounts of the purified compound of formula I and various pharmaceutically acceptable carriers and/or other active ingredients in the pharmaceutical compositions can be determined by those skilled in the art according to conventional methods.
  • the term "effective amount” or “therapeutically effective amount” refers to an amount of a compound of the invention sufficient to achieve the intended application, including but not limited to, the treatment of a disease as defined below.
  • the therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, etc. It is readily determined by one of ordinary skill in the art.
  • the particular dosage will vary depending on the particular compound selected, the dosage regimen upon which it is administered, whether it is administered in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system carried.
  • the invention provides the use of a purified compound of formula I or a pharmaceutical composition of the invention in the preparation of an angiotensin II receptor antagonist, or in the preparation for prophylaxis and/or treatment Use in drugs for hypertension, chronic heart failure, and diabetic nephropathy.
  • the invention further provides the use of a purified compound of formula I or a pharmaceutical composition of the invention as an angiotensin II receptor antagonist.
  • the invention further provides the use of a purified compound of formula I or a pharmaceutical composition according to the invention for the prevention and/or treatment of hypertension, chronic heart failure, diabetic nephropathy.
  • the invention also provides a method of purity analysis of a compound of formula I, comprising high performance liquid chromatography using one or more of the following conditions:
  • Detection wavelength 275 ⁇ 285nm, such as 280nm;
  • the gradient elution mobile phase is as follows:
  • Mobile phase A an aqueous solution containing ammonium hexafluorophosphate and phosphoric acid, for example, an aqueous solution containing 10-30 mM ammonium hexafluorophosphate and 0.15-0.35% phosphoric acid (v/v);
  • Mobile phase B a nitrile solvent such as acetonitrile
  • the gradient elution is carried out as follows:
  • a diluent may be used as needed; for example, the diluent may be a mixed solution of acetonitrile or methanol.
  • the volume ratio of acetonitrile to methanol in the mixed solution is (6-8): (2-4).
  • the diluent may also contain phosphoric acid and/or water.
  • the diluent may further contain phosphoric acid and/or water
  • the volume ratio of acetonitrile, methanol, water, phosphoric acid may be (48-50): (20-22): (34-32): (0.05-0.15) ), for example, 49:21:30:0.1.
  • the present invention also provides a mobile phase A comprising ammonium hexafluorophosphate.
  • the mobile phase A is an aqueous solution containing ammonium hexafluorophosphate
  • the mobile phase A comprises a mixture of ammonium hexafluorophosphate, phosphoric acid and water;
  • the mobile phase A is an aqueous solution containing ammonium hexafluorophosphate and phosphoric acid, for example, an aqueous solution containing 10-30 mM ammonium hexafluorophosphate and 0.15-0.35% phosphoric acid (v/v);
  • the mobile phase A is preferably a high performance liquid chromatography mobile phase which can be used to purify the compound of formula I;
  • the mobile phase A can be used in combination with the mobile phase B described above for the above purposes;
  • mobile phase A and mobile phase B can be mixed;
  • one or more of the high performance liquid chromatography conditions and/or gradient elution conditions described above may be employed.
  • the invention also provides the use of ammonium hexafluorophosphate for the purification of a compound of formula I.
  • alkyl is understood to preferably denote a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably a C1-10 alkyl group.
  • C 1-10 alkyl is understood to preferably denote a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like, or isomers thereof.
  • the group has 1, 2, 3, 4, 5, 6, carbon atoms ("C 1-6 alkyl”), such as methyl, ethyl, propyl, butyl, isopropyl , isobutyl, sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms ("C 1-3 alkyl”), such as methyl, ethyl, n-propyl Base or isopropyl.
  • C 1-6 alkyl such as methyl, ethyl, propyl, butyl, isopropyl , isobutyl, sec-butyl, tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl Base or isopropyl.
  • alkenyl is understood to preferably denote a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2 to 40 carbon atoms, preferably "C 2-10 alkenyl".
  • C 2-10 alkenyl is understood to preferably denote a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 a carbon atom, especially 2 or 3 carbon atoms ("C 2-3 alkenyl”), it being understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or yoke.
  • the alkenyl group is, for example, a vinyl group, an allyl group, (E)-2-methylvinyl group, (Z)-2-methylvinyl group, (E)-but-2-alkenyl group, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene , hex-5-alkenyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl,
  • alkynyl is understood to mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2 to 40 carbon atoms, preferably "C 2 -C 10 alkynyl".
  • C 2 -C 10 alkynyl is understood to preferably denote a straight-chain or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 Or 10 carbon atoms, especially 2 or 3 carbon atoms ("C 2 -C 3 -alkynyl").
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, Hex-5-alkynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl 4-ynyl, 2-methylpent-3-yny
  • cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having from 3 to 20 carbon atoms, preferably “C 3-10 cycloalkyl”.
  • C 3-10 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group or a cyclodecyl group, or a bicyclic ring.
  • a hydrocarbon group such as a decalin ring.
  • heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing from 1 to 5 heteroatoms independently selected from N, O and S, preferably “3-10 membered heterocyclyl".
  • 3-10 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing from 1 to 5, preferably from 1 to 3, heteroatoms selected from N, O and S.
  • the heterocyclic group can be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclic group may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or a trithiaalkyl group; or a 7-membered ring such as a diazepanyl group.
  • a 4-membered ring such as azetidinyl, oxetanyl
  • a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidin
  • the heterocyclic group can be benzofused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5,5 membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring such as hexahydropyrrole.
  • [1,2-a]pyrazine-2(1H)-yl ring [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing a nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiene.
  • the heterocyclic group is non-aromatic.
  • aryl is understood to mean preferably a monovalent, aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 aryl".
  • C 6-14 aryl is understood to mean preferably a monovalent, bicyclic or monovalent aromatic or partially aromatic having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
  • C 6-14 aryl a tricyclic hydrocarbon ring
  • C 6 aryl a ring having 6 carbon atoms
  • C 9 aryl a ring having 9 carbon atoms a ring
  • C 9 aryl such as an indanyl or fluorenyl group
  • C 10 aryl a ring having 10 carbon atoms
  • C13 aryl a ring having 13 carbon atoms
  • fluorenyl group or a ring having 14 carbon atoms (“ C14 aryl”
  • C14 aryl a tricyclic hydrocarbon ring
  • heteroaryl is understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having from 5 to 20 ring atoms and containing from 1 to 5 heteroatoms independently selected from N, O and S.
  • An atom such as "5-14 membered heteroaryl”.
  • the term “5-14 membered heteroaryl” is understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and which contain 1-5, preferably 1-3, each independently selected from N, O and S heteroatoms and, in each case The benzo can be fused.
  • the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia Diazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzene And a triazolyl group, a carbazolyl group, a fluorenyl group, an isodecyl group, etc.; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, etc., and a benzo derivative thereof
  • a heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridyl or pyridinyl includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl And pyridin-4-yl;
  • thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl.
  • alkyl such as “C 1-40 alkyl”
  • alkyloxy such as “alkyloxy”
  • alkoxy such as the terms "alkoxy” and the like.
  • alkenyl such as “alkynyl”, “cycloalkyl”, “heterocyclyl”, “aryl” and “heteroaryl”
  • alkenyl such as "alkynyl”, “cycloalkyl”, “heterocyclyl”, “aryl” and “heteroaryl”
  • the nitrogen atom may be optionally further oxidized to form an oxynitride.
  • a buffer solution of ammonium hexafluorophosphate or ammonium hexafluorophosphate and phosphoric acid can significantly improve the separation of the compound of formula I from impurities.
  • ammonium hexafluorophosphate can form an ion pair with impurities in the compound to be separated, thereby increasing the retention time of the impurities, thereby improving the separation effect.
  • the preparation method of the compound of the formula II of the invention has the advantages of convenient operation, short cycle and low cost, avoiding the use of a large amount of silica gel, quartz sand and organic solvent, and the three wastes are less in emissions and more environmentally friendly.
  • the Applicant has surprisingly found that the compound of the formula II obtained by the preparation method of the present invention has high purity and the content of the rearranged product can be less than 0.5%, which significantly improves the existing column chromatography.
  • the technical problems of batch purification and long product purification cycle cannot be amplified during the application process.
  • the production method of the present invention it is not necessary to first obtain a crude product by column chromatography as in the method disclosed in the prior art, and then recrystallize to obtain a purified product having a lower overall yield.
  • the preparation method and the analysis method of the invention better satisfy the long-term needs in the field, such as convenient preparation, one-step, low cost, high comprehensive yield, good purity, low rearrangement impurity content, and the like. Industrial scale production and purity analysis of II compounds.
  • Figure 1 shows the results of HPLC detection of the product of step 2 of Example 2 of the present invention.
  • Mobile phase A a mixed solution of 20 mM ammonium hexafluorophosphate and 0.25% phosphoric acid (v/v). Weigh about 3.26 g of ammonium hexafluorophosphate, add 1 L of water to dissolve, add 2.5 mL of phosphoric acid, shake well, sonicate for 10 min, and filter.
  • Diluent Mix acetonitrile and methanol in a ratio of 7/3 (v/v), mix with water in a ratio of 7/3 (v/v), add 0.1% phosphoric acid (v/v), and shake well.
  • Step 1 The crude oil of the compound of formula 5 is crystallized as a solid
  • step 1 After recrystallization from step 1, 8.4 kg of the compound of formula 5 was added to 18.5 L of tert-butyl ketone, and the mixture was beaten at room temperature for 2 h, filtered, and dried under reduced pressure to obtain a product of 8.64 kg, purity 99.2%, yield 90.9%, wherein the rearranged impurity content was 0.42%.
  • the compound of the formula 5 obtained in the step 2 (200 g) was dissolved in tetrahydrofuran (800 ml), stirred at 10 ° C to form a solution, and potassium maleimide (39.8 g) was added to the solution, the reaction was kept for 4 h, filtered, and the solution was concentrated to dry.
  • the mixture was vacuum dried at ° C for 24 h, and the degree of vacuum was ⁇ 500 Pa.
  • 165 g of the potassium salt of the finished product of the formula 5 was obtained, the purity was 99.4%, the yield was 78.1%, and the content of the rearranged impurities was 0.05%.
  • Step 1 The crude oil of the compound of formula 5 is crystallized as a solid
  • the compound of the formula 5 obtained in the step 2 (200 g) was dissolved in dichloromethane (600 ml), stirred at 20 ° C to form a solution, and potassium phthalimide (54.6 g) was added to the solution, the reaction was kept for 4 h, and filtered.
  • the solution was concentrated to dryness, then added with ethyl acetate (2 L), stirred and evaporated, and then, the mixture was stirred and stirred at room temperature for 3h, filtered, and the filter cake was beaten twice with ethyl acetate (1 L each time), and the cake was pulverized and sieved (0.4 mm).
  • Step 1 The crude oil of the compound of formula 5 is crystallized as a solid
  • the compound of the above formula 5 (200 g) was dissolved in chloroform (600 ml), stirred at 15 ° C to form a solution, potassium phthalimide (54.6 g) was added to the solution, the reaction was kept for 2 h, filtered, and the solution was concentrated to dry.
  • the genotoxic impurities (GTI-001, GTI-002, of the potassium salt of the finished compound of Example 2 (batch 1), and the potassium salt of the finished compound of the formula 5 (batch 2 and 3) obtained in this example were repeated.
  • GTI-003) content detection the test results are shown in Table 1. It can be seen from the results of Table 1 that the product prepared according to the present invention has a genotoxic impurity content within the toxicological threshold range, and meets the requirements for genotoxic impurities in ICH-M7, and the safety of the finished product is further improved.
  • the detection limit of GTI-002 and GTI-003 is 0.1ppm.
  • the structure of GTI-001 is The molecular weight is 152.09;
  • GTI-002 The structure of GTI-002 is The molecular weight is 168.20;
  • GTI-003 The structure of GTI-003 is The molecular weight is 258.70;

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Abstract

La présente invention concerne un procédé de préparation d'un dérivé de benzimidazole à faible teneur en impuretés. Le procédé selon la présente invention consiste à dissoudre un produit initial d'un composé de formule I ci-dessous avec un solvant organique S1, agiter et cristalliser la solution, et sécher le cristal pour obtenir un composé purifié de formule I, le solvant organique S1 pouvant être choisi parmi un, deux ou plus d'un solvant d'ester, un solvant d'alcane, un solvant d'éther, un solvant de nitrile, un solvant d'alcool, un solvant d'hydrocarbure halogéné et un solvant de cétone. Le procédé de préparation selon la présente invention permet de simplifier sensiblement le traitement, d'obtenir un produit de haute pureté avec un rendement élevé, et est capable de réduire de manière significative la quantité d'impuretés dans le produit.
PCT/CN2018/113598 2017-11-03 2018-11-02 Procédé de préparation d'un dérivé de benzimidazole à faible teneur en impuretés WO2019085983A1 (fr)

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CN1079966A (zh) * 1991-06-27 1993-12-29 武田药品工业株式会社 杂环化合物，其制备及应用
CN104774196A (zh) * 2014-01-09 2015-07-15 武汉朗来科技发展有限公司 一种苯并咪唑衍生物的制备方法
WO2016145622A1 (fr) * 2015-03-18 2016-09-22 武汉朗来科技发展有限公司 Dérivés de benzimidazole, leur procédé de préparation et leur utilisation médicinale
WO2017198205A1 (fr) * 2016-05-20 2017-11-23 武汉朗来科技发展有限公司 Composé et procédé pour sa préparation, composition et application correspondantes
WO2018064945A1 (fr) * 2016-10-08 2018-04-12 武汉朗来科技发展有限公司 Composition pharmaceutique

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CN102731407A (zh) * 2012-07-04 2012-10-17 宁波九胜创新医药科技有限公司 一种制备替米沙坦的方法
CN105237527B (zh) * 2012-09-28 2018-03-06 武汉朗来科技发展有限公司 苯并咪唑衍生物及其制备方法和医药用途
CN103265532A (zh) * 2013-06-17 2013-08-28 峨眉山天梁星制药有限公司 一种坎地沙坦酯c型晶的制备方法
CN104788429B (zh) * 2015-03-06 2018-07-06 浙江美诺华药物化学有限公司 一种通过脱除三苯甲基保护基制备沙坦类药物的方法
CN109305965B (zh) * 2017-07-28 2021-03-16 武汉朗来科技发展有限公司 苯并咪唑衍生物制备及分析方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1079966A (zh) * 1991-06-27 1993-12-29 武田药品工业株式会社 杂环化合物，其制备及应用
CN104774196A (zh) * 2014-01-09 2015-07-15 武汉朗来科技发展有限公司 一种苯并咪唑衍生物的制备方法
WO2016145622A1 (fr) * 2015-03-18 2016-09-22 武汉朗来科技发展有限公司 Dérivés de benzimidazole, leur procédé de préparation et leur utilisation médicinale
WO2017198205A1 (fr) * 2016-05-20 2017-11-23 武汉朗来科技发展有限公司 Composé et procédé pour sa préparation, composition et application correspondantes
WO2018064945A1 (fr) * 2016-10-08 2018-04-12 武汉朗来科技发展有限公司 Composition pharmaceutique

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