WO2020095452A1 - Procédé de fabrication de composé diméthoxybenzène - Google Patents

Procédé de fabrication de composé diméthoxybenzène Download PDF

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Publication number
WO2020095452A1
WO2020095452A1 PCT/JP2018/041744 JP2018041744W WO2020095452A1 WO 2020095452 A1 WO2020095452 A1 WO 2020095452A1 JP 2018041744 W JP2018041744 W JP 2018041744W WO 2020095452 A1 WO2020095452 A1 WO 2020095452A1
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WIPO (PCT)
Prior art keywords
salt
compound
pyrazolo
ethynyl
dimethoxyphenyl
Prior art date
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PCT/JP2018/041744
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English (en)
Japanese (ja)
Inventor
維志 近藤
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大鵬薬品工業株式会社
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Filing date
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Application filed by 大鵬薬品工業株式会社 filed Critical 大鵬薬品工業株式会社
Priority to PCT/JP2018/041744 priority Critical patent/WO2020095452A1/fr
Priority to AU2018448845A priority patent/AU2018448845B2/en
Priority to KR1020217017262A priority patent/KR20210088651A/ko
Priority to EP19881421.2A priority patent/EP3882248A4/fr
Priority to PCT/JP2019/043926 priority patent/WO2020096050A1/fr
Priority to US17/292,187 priority patent/US20210388002A1/en
Priority to MA054240A priority patent/MA54240A/fr
Priority to PCT/JP2019/043857 priority patent/WO2020096042A1/fr
Priority to CN201980087803.6A priority patent/CN113260618A/zh
Priority to JP2020555638A priority patent/JP7161546B2/ja
Priority to US17/292,289 priority patent/US20210387990A1/en
Publication of WO2020095452A1 publication Critical patent/WO2020095452A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method for producing a dimethoxybenzene compound or a pharmaceutically acceptable salt.
  • Acrylamide is a kind of amide composed of acrylic acid and amine.
  • Acrylamide is industrially produced by hydrating acrylonitrile, and is mainly used as a raw material for polyacrylamide.
  • As a general experimental method for producing acrylamide acryloyl chloride or acrylic anhydride is allowed to act on the amine of interest to produce it.
  • acrylamide derivatives are known as compounds having an antitumor effect, and it is disclosed that they can be induced into acrylamide derivatives by the above method. Further, a method for synthesizing a compound using 3-chloropropionyl chloride instead of acryloyl chloride or acrylic acid anhydride is also disclosed. (Patent Documents 1 to 3).
  • Compound A has excellent FGFR inhibitory action and antitumor activity. Therefore, the subject of the present invention is a compound A or a pharmaceutically acceptable salt thereof which is a production method capable of large-scale synthesis, has a simple and excellent operability, and satisfies the quality required as a pharmaceutical product. It is to provide a manufacturing method of.
  • the present invention includes the following [1] to [27].
  • L 1 and L 2 are the same or different and each represents a leaving group.
  • the amount of the [6] base used is (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-4.
  • [7] A step of producing a compound represented by the formula (A-1) or a salt thereof by the method described in [1], and removing L 2 from the obtained compound represented by the formula (A-1). Including the step of separating (S) -1- (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) A method for producing 2-propen-1-one or a pharmaceutically acceptable salt thereof.
  • the reaction is performed in the presence of at least one base selected from the group consisting of an organic amine base and an inorganic base. 7].
  • the amount of the [10] base used is (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-4.
  • the method according to [8], wherein the equivalent is neutralized with the acid addition salt of amine or a salt thereof, and is 0.5 to 10 equivalents.
  • L 1 and L 2 are the same or different and each represents a leaving group.
  • the amount of the [18] base used is (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-4.
  • the method according to [15], wherein the equivalent is neutralized with the acid addition salt of the amine or a salt thereof to be 0.5 to 10 equivalents.
  • Including the step of separating (S) -1- (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) A method for producing 2-propen-1-one or a pharmaceutically acceptable salt thereof.
  • a compound represented by the following formula (A-1) or a salt thereof [24] A compound represented by the following formula (A-1) or a salt thereof.
  • compound A is (S) -1- (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl. ) Pyrrolidin-1-yl) -2-propen-1-one, the structure of which is shown below.
  • the compound A or a pharmaceutically acceptable salt thereof may be a solvate (for example, a hydrate, etc.) or a non-solvate, and in the present invention, both are “compound A or It is included in the "pharmaceutically acceptable salt.”
  • the pharmaceutically acceptable salt of the compound A is not particularly limited, and examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid, addition salts with organic acids such as acetic acid, citric acid, tartaric acid and maleic acid, potassium and sodium. And the like, salts with alkaline metals such as calcium, salts with alkaline earth metals such as calcium and magnesium, ammonium salts, salts with organic bases such as ethylamine salts and arginine salts, and the like.
  • the description of “Compound A” may be intended to include pharmaceutically acceptable “salts” and “solvates” of Compound A.
  • compound B is (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-4.
  • -It is an amine.
  • the structure of Compound B is shown below.
  • the compound B or a salt thereof may be a solvate (for example, a hydrate or the like) or a non-solvate, and both are included in the “compound B or a salt thereof” in the present invention.
  • the salt of compound B is not particularly limited, but examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.
  • addition salts with alkyl sulfuric acid such as benzenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, etc., salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium.
  • alkali metals such as potassium and sodium
  • salts with alkaline earth metals such as calcium and magnesium.
  • Ammonium salts, ethylamine salts, salts with organic bases such as arginine salts, and the like.
  • the description with “compound B” may be intended to include “salt” and “solvate” of compound B.
  • the compound B used when deriving the compound A may be a free form or a salt, preferably an addition salt of an inorganic acid, an alkyl sulfuric acid or an organic acid, more preferably an addition salt of an alkyl sulfuric acid. And more preferably an addition salt of methanesulfonic acid.
  • compound B or a salt thereof can be obtained by deprotecting P 1 (P 1 represents a protecting group for an amino group) of the compound represented by formula (C).
  • P 1 represents a protecting group for an amino group
  • the compound represented by the general formula (C) can be obtained by the method described in International Publication WO2013 / 108809.
  • the free form of Compound B has the property of being easily dissolved in water, an organic solvent having high water solubility, and an organic solvent having high fat solubility.
  • the acid addition salt or base addition salt of Compound B has low solubility in an organic solvent and is easy to isolate and purify.
  • Examples of the amino group protecting group represented by P 1 include a protecting group that can be deprotected under acidic conditions, such as a tert-butoxycarbonyl group (Boc group). Those skilled in the art can appropriately select the method for deprotecting P 1 which is a protecting group.
  • P 1 is a protecting group that can be deprotected under acidic conditions such as a tert-butoxycarbonyl group
  • deprotection under acidic conditions is preferable, and acids such as hydrochloric acid, methanesulfonic acid, hydrogen iodide and trifluoroacetic acid can be used. You can choose.
  • Methanesulfonic acid is preferable from the viewpoints of reaction conditions, operability, and burden on manufacturing equipment.
  • the amount of the acid used is preferably 1 to 100 mol, based on 1 mol of the compound represented by the general formula (C).
  • compound B when P 1 is a protecting group that can be deprotected under acidic conditions such as a tert-butoxycarbonyl group, compound B can be obtained as an acid addition salt, which leads to compound A or a pharmaceutically acceptable salt thereof. be able to.
  • compound A or a salt thereof is produced from compound B or a salt thereof using an acryloylating reagent.
  • an acryloylating reagent of the present invention a compound represented by the following general formula (I-1-A) or the following general formula (I-2-A) can be used.
  • L 1 and L 2 are the same or different and each represents a leaving group.
  • the leaving group L 2 is bonded to the ⁇ -position of carbonyl.
  • the leaving group L 2 is bonded to the ⁇ -position of carbonyl. Both can be converted to acryloyl under basic conditions, and thus acrylamide in compound A can be constructed.
  • Examples of the leaving group L 1 include a halogen atom and the like, and preferably a chlorine atom.
  • a halogen atom As the leaving group L 2 , a halogen atom, —OSO 2 C n F n + 2 (n represents an integer of 1 to 4), a mesylate group (—OMs; Ms represents a mesyl group), a tosylate group (— OTs; Ts represents a p-tosyl group), a nosylate group (-ONs; Ns represents a p-nosyl group), an -OSO 2 Ph group (Ph represents a phenyl group), a phenoxy group (-OPh), etc.
  • a halogen atom is preferable, and a chlorine atom is more preferable.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Examples of the compound represented by the general formula (I-1-A) include 3-chloropropionyl chloride and 3-bromopropionyl chloride.
  • Examples of general formula (I-2-A) include 2-chloropropionyl chloride and 2-bromopropionyl chloride.
  • the following general formula (I-1-B), the following general formula (I-1-C), the following general formula (I-2-B), or the following general formula (I-2-B) Compounds represented by I-2-C) can be used.
  • the compound represented by the following general formula (I-1-B), the following general formula (I-1-C), the following general formula (I-2-B), or the following general formula (I-2-C) is , An acid anhydride.
  • L 2 is the same or different and represents a leaving group.
  • L 2 examples include the above-mentioned leaving groups, preferably a halogen atom, and more preferably a chlorine atom.
  • Examples of the compound represented by the general formula (I-1-B) include 3-chloropropionic acid anhydride, 3-bromopropionic acid anhydride, 3-chloropropionic acid 3-bromopropionic acid anhydride, and the like. Preferred is 3-chloropropionic anhydride.
  • Examples of the compound represented by the general formula (I-1-C) include 3-chloropropionic anhydride acrylic acid, 3-bromopropionic anhydride acrylic acid, and the like. 3-chloropropionic acrylic acid is preferable. Anhydrous.
  • Examples of the compound represented by the general formula (I-2-B) include 2-chloropropionic acid anhydride, 2-bromopropionic acid anhydride, 2-chloropropionic acid 2-bromopropionic acid anhydride, and the like. Preferred is 2-chloropropionic anhydride.
  • Examples of the compound represented by the general formula (I-2-C) include acrylic acid 2-chloropropionic anhydride, acrylic acid 2-bromopropionic anhydride and the like, preferably acrylic acid 2-chloropropionic acid. Anhydrous.
  • the acryloylating reagent is preferably the compound represented by the general formula (I-1-A) or the general formula (I-2-A), more preferably the general formula (I-1-A). And more preferably 3-chloropropionyl chloride.
  • the above general formula (I-1-A), general formula (I-1-B), general formula (I-1-C), general formula (I-2-A), general formula (I- 2-B) or an acryloylating reagent which is a compound represented by the general formula (I-2-C) has an amount of 1.0 to 1.3 molar equivalents relative to 1 molar equivalent of compound B or a salt thereof. , More preferably 1.05 to 1.3 molar equivalents, and even more preferably 1.1 to 1.2 molar equivalents.
  • the acryloylating reagent can be used in an amount of 1.0 molar equivalent or more per 1 molar equivalent of compound B or a salt thereof. It is preferably 1.0 to 3.0 molar equivalents, more preferably 1.1 to 2.0 molar equivalents.
  • the acryloylating reagent as the acryloylating reagent, the above general formula (I-1-A), general formula (I-1-B), general formula (I-1-C), general formula (I-2-A), A compound represented by the general formula (I-2-B) or the general formula (I-2-C) can be used. Therefore, when the compound represented by the general formula (I-1-A) or the general formula (I-2-A) is used, the reaction proceeds in the following two steps to give the compound A or a pharmaceutically acceptable compound thereof. Salts can be produced.
  • the compound represented by the general formula (A-1) or the general formula (A-2) or the salt thereof is an intermediate compound. Obtained as a body.
  • compound A may be derived by eliminating L 2 from the intermediate without isolating these intermediates.
  • the compound represented by the general formula (A-1) becomes (S) -1- (3- (4-Amino-3-((3,5-dimethoxy) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) -3-chloropropan-1-one (hereinafter , "A-1-3CP compound").
  • the compound represented by the general formula (I-2-A) as an intermediate is 1-((S ) -3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) -2-chloropropane- 1-one (hereinafter, also referred to as “A-1-2CP compound”).
  • the compound B or a salt thereof and the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof can be used to determine whether or not the reaction has proceeded when the compound A is derived from the compound B. It can be used to confirm. Furthermore, since these compounds or salts thereof can be contained in the compound A as impurities, they can be used to confirm the presence of impurities.
  • the present inventor tried a method of suppressing the amount of acryloyl chloride used in order to remove or suppress the production of the diamide compound, and it was revealed that the compound B remained and the yield was reduced.
  • a method of adjusting the pH to decompose the diamide was tried, the number of steps was increased, the compound A could not be efficiently mass-produced, and the compound A was also decomposed and the yield was decreased. Became clear.
  • the crystallization conditions were examined, but it was difficult to efficiently remove the diamide compound. Therefore, from the above viewpoint, it is considered difficult to mass-produce the compound A using acryloyl chloride while maintaining the quality as a drug.
  • the above general formula (I-1-A), general formula (I-1-B), general formula (I-1-C), general formula (I-2-A), general formula (I- 2-B) or the compound represented by the general formula (I-2-C) is used, and the compound B or a salt thereof is represented by the general formula (A-1) or the general formula (A-2).
  • the compound or its salt is derived, it is converted to a diamide compound via a compound represented by the general formula (A-1-diamide) or the general formula (A-2-diamide) as a by-product as follows. Can be induced.
  • the compound represented by diamide, general formula (A-1-diamide) or general formula (A-2-diamide) is compound A or a pharmaceutically acceptable salt, general formula (A-1) or a salt thereof. , Or the presence of impurities contained in the general formula (A-1) or a salt thereof.
  • L 1 and L 2 in the compound represented by the general formula (I-2-C) are chlorine atoms
  • the general formula (A-1-diamide) is represented by (S) -3-chloro-N- (1- (1- (3-chloropropanoyl) pyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) Pupanamide (hereinafter, also referred to as "3CP diamide").
  • L 1 and L 2 in the compound represented by the general formula (I-2-C) are chlorine atoms
  • the general formula (A-2-diamide) is represented by 2-chloro-N- (1- ( (3S) -1- (2-chloropropanoyl) pyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) Propanamide (hereinafter, also referred to as "2CP diamide").
  • a base for example, at least an equivalent amount to the compound B
  • Base when a compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof is derived from the compound B as an intermediate, a base (for example, at least an equivalent amount to the compound B) is used. Base). Furthermore, when the compound A is derived from these intermediates, it can be carried out in the presence of a base (for example, at least an equivalent amount of the base to the intermediate). When both steps are performed in the presence of a base, the bases in each step may be the same or different.
  • Examples of the base used when deriving from the compound B or a salt thereof into the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof include trimethylamine, triethylamine, diisopropylethylamine and N-methyl.
  • Organic amine bases such as morpholine, diazabicycloundecene (DBU), diazabicyclononene (DBN), pyridine, 4-dimethylaminopyridine (DMAP); lithium hydroxide, sodium hydroxide, magnesium hydroxide, potassium hydroxide , Calcium hydroxide, cesium hydroxide, lithium acetate, sodium acetate, magnesium acetate, potassium acetate, calcium acetate, cesium acetate, lithium carbonate, sodium carbonate, magnesium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, lithium hydrogen carbonate, carbonic acid Hydrogen Nato Inorganic bases such as sodium, potassium hydrogen carbonate, cesium hydrogen carbonate, lithium phosphate, sodium phosphate, magnesium phosphate, potassium phosphate, calcium phosphate, and cesium phosphate, and the like, preferably an organic amine base or an inorganic base.
  • DBU diazabicycloundecene
  • DBN diazabicyclononene
  • a base containing a hydroxide ion More preferably a base containing a hydroxide ion, further preferably a base containing an alkali metal ion (eg, sodium ion, potassium ion) and a hydroxide ion, and further preferably sodium hydroxide or potassium hydroxide.
  • the base may be used alone or in combination of two or more.
  • the same bases as mentioned above can be mentioned, preferably Is an inorganic base, more preferably a base containing a hydroxide ion, further preferably a base containing an alkali metal ion (for example, sodium ion, potassium ion) and a hydroxide ion, and further preferably hydroxylated.
  • Sodium or potassium hydroxide preferably sodium or potassium hydroxide.
  • the bases shown above are roughly classified into monovalent bases, divalent bases, or trivalent bases.
  • the monovalent base is a base capable of accepting one proton in one molecule, and examples thereof include triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide and sodium hydrogen carbonate.
  • the divalent base is a base capable of accepting two protons in one molecule, and examples thereof include sodium carbonate.
  • the trivalent base is a base capable of accepting three protons in one molecule, and examples thereof include potassium phosphate.
  • the amount of the base Is 0.5 to 10 equivalents, preferably 1 to 10 equivalents, of the free form of Compound B, after subtracting the equivalent of the compound B or its salt neutralized with the acid addition salt of Compound B. More preferred is 1 to 5 equivalents, more preferred is 1 to 3 equivalents, and even more preferred is 1 to 2 equivalents.
  • L 2 is eliminated from the compound represented by formula (A-1) or formula (A-2) or a salt thereof to give compound A or a pharmaceutically acceptable salt thereof.
  • the amount of the base used to derive the salt is preferably 1 to 10 equivalents, more preferably 1 to 5.0 equivalents of the free form of compound B with respect to 1 equivalent of compound B or a salt thereof.
  • the optimum amount according to the above can be calculated in consideration of the valence.
  • L 2 is eliminated from the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof to give a compound A or a pharmaceutically acceptable salt thereof.
  • the amount of the base is the amount of the compound represented by the general formula (A-1) or the general formula (A-2) or the salt represented by the general formula (A -1) or the compound represented by the general formula (A-2) by subtracting the acid addition salt of the compound represented by the general formula (A-2) and the neutralized equivalent. It can be 1 to 5 equivalents of the free form.
  • the compound represented by the general formula (A-1) or the general formula (A-2) can be 1 to 10 equivalents of the theoretical yield of the free form (ie, the amount of the free form of compound B).
  • the optimum amount according to the above can be calculated in consideration of the valence.
  • the solvent employed when deriving from the compound B or a salt thereof into the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof is a compound B and an acryloyl group.
  • acetonitrile, water, N-methyl-2-pyrrolidone, tetrahydrofuran, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 1 , 4-dioxane or a mixed solvent thereof is preferable, and acetonitrile, water or a mixed solvent thereof is preferable.
  • the capacity of the solvent is not particularly limited, and is preferably 1 to 50 times by volume (v / w), more preferably 2 to 30 times by volume (v / w) with respect to 1 weight of the compound B or a salt thereof. And more preferably 10 to 20 times the capacity (v / w).
  • the ratio of each solvent when using the mixed solvent is not particularly limited. For example, when a mixed solvent of acetonitrile and water is used, the ratio of each solvent is not particularly limited, and is preferably 0.1 to 2 times volume (v / v) of water with respect to 1 volume of acetonitrile, and more preferably The volume is 0.1 to 1 times the volume (v / v), and more preferably 0.5 to 1 volume (v / v).
  • the temperature of the solvent used when deriving from the compound B or a salt thereof into the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof is the melting point of the solvent.
  • the compound B can stably exist, but it is preferably 0 to 50 ° C., more preferably 25 to 35 ° C.
  • a condensing agent can be used.
  • the condensing agent include DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), EDC (WSCI, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), BOP (benzotriazol-1-yloxy-tris-).
  • the compound B or its salt is derived to the compound of the general formula (A-1) or the general formula (A-2) or its salt, and the compound of the general formula (A-1) or the general formula (A -2) A method for confirming the reaction employed when derivatizing compound A or a pharmaceutically acceptable salt thereof by desorbing L 2 from the compound or a salt thereof represented by high performance liquid chromatography (Hereinafter, also referred to as HPLC), each chromatography such as thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • the step of inducing the salt thereof has been completed. Further, when the peak area of the compound represented by the general formula (A-1) or the general formula (A-2) is 1% or less of the total peak area, the general formula (A-1) or the general formula (A It can be judged that the induction to compound A was completed by removing L 2 from the compound represented by -2) or a salt thereof.
  • HPLC measurement conditions are not particularly limited as long as Compound A, Compound B and the compound represented by Formula (A-1) or Formula (A-2) can be detected.
  • the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof when the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof is isolated, these compounds may be purified by a method such as recrystallization. You may use it in the next process, without performing. Further, L 2 is eliminated from the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof to complete the induction to the compound A or a pharmaceutically acceptable salt thereof. After being treated, Compound A or a pharmaceutically acceptable salt thereof can be purified.
  • the purification method from the viewpoint of the present invention being used for mass production, it is preferable to employ a method by crystallization without performing purification by column chromatography.
  • a method of adding a solvent having a low solubility of Compound A or a pharmaceutically acceptable salt thereof can be mentioned. Be done.
  • the solvent to be added include water.
  • the amount of the solvent to be added is not particularly limited as long as the compound A or a pharmaceutically acceptable salt thereof is precipitated, and is preferably 0.5 to 5 times the volume (v / v) of the reaction solvent. Yes, more preferably 1 to 3 times the capacity (v / v), and even more preferably 1.5 to 2 times the capacity (v / v).
  • a compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof can be derived from the compound B or a salt thereof to a compound A or a pharmaceutically acceptable salt thereof without isolation.
  • the amount of the solvent to be added is 5 to 50 times by volume (v / w), preferably 10 to 40 times by volume (v / w), more preferably the weight of the compound B or a salt thereof. Is 15 to 30 times capacity (v / w).
  • the temperature at which crystallization is carried out is not particularly limited as long as Compound A or a pharmaceutically acceptable salt thereof is precipitated after the addition of the above solvent, and preferably 0 to 40 ° C. Yes, more preferably 20 to 30 ° C.
  • the time required for crystallization is, for example, 1 hour or more, and preferably 2 to 72 hours.
  • compound A or a pharmaceutically acceptable salt thereof can be isolated as a solid by crystallization and filtration. Since compound A or a pharmaceutically acceptable salt thereof is used as a drug, it is preferable that the time required for filtration is short in order to efficiently produce it in a large amount. Whether the filterability is good or bad cannot be determined by the absolute values such as the filtration time and the filtration rate, and therefore is relatively determined by comparing the process conditions. Therefore, the filtration area, the filter paper used for filtration, and the pressure during suction are aligned for comparison. The fact that the deposited particles are large and the filter paper is not clogged and the amount of the solvent to be filtered is small is a factor that makes it possible to judge that the filterability is excellent.
  • compound A or a pharmaceutically acceptable salt thereof is converted from compound B or a salt thereof without isolating the compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof.
  • the use of the general formula (I-1-A) or the general formula (I-2-A) is more preferable than the acryloyl chloride in the filtration of Compound A or a pharmaceutically acceptable salt thereof. Good sex. This was unexpected when producing Compound A or its salt.
  • the compound represented by the general formula (I-1-A) or the general formula (I-2-A) which can be used from the viewpoint of filterability, has a filterability higher than that when acryloyl chloride is used. Is not particularly limited as long as it is improved, but it is preferably a compound represented by the general formula (I-1-A), and more preferably 3-chloropropionyl chloride.
  • the thus-obtained compound represented by the general formula (A-1) or the general formula (A-2) or a salt thereof, and the compound A or a pharmaceutically acceptable salt thereof are subjected to various quantitative analysis, It can be analyzed by qualitative analysis.
  • the step of reacting 1 equivalent of the compound B or a salt thereof with 1.0 to 1.3 equivalents of the compound represented by the general formula (I-1-A) is generally used.
  • the method for producing the compound represented by formula (A-1) or a salt thereof can be adopted.
  • 1 equivalent of the compound B or a salt thereof is used, wherein L 1 and L 2 are the same or different and the compound represented by the formula (I-1-A) 1.0 to A method for producing a compound represented by the general formula (A-1) or a salt thereof, comprising the step of reacting with 1.3 equivalents.
  • one equivalent of Compound B or a salt thereof is subtracted from the equivalent of the compound B or a salt thereof to be neutralized with an acid addition salt, and 1.0 to 10 equivalents of an organic amine base and a base containing a hydroxide ion are included.
  • one equivalent of Compound B or a salt thereof is subtracted from the equivalent of Compound B or a salt thereof to be neutralized with an acid addition salt, and 0.5 to 10 equivalents of an organic amine base, an alkali metal ion and a hydroxide are used.
  • a step of reacting compound B or a salt thereof with a compound represented by the general formula (I-1-A) in the presence of a base containing a hydroxide ion in another embodiment of the present invention, a step of reacting compound B or a salt thereof with a compound represented by the general formula (I-1-A) in the presence of a base containing a hydroxide ion.
  • the method of producing a compound represented by the general formula (A-1) or a salt thereof can be employed.
  • the compound B or a salt thereof is represented by the general formula (I-1-A), wherein L 1 and L 2 are the same or different and are halogen atoms in the presence of a base containing a hydroxide ion.
  • the compound represented by general formula (A-1) or a salt thereof which comprises a step of reacting compound B or a salt thereof with 3-chloropropionyl chloride in the presence of a base containing a hydroxide ion. Is a manufacturing method.
  • the compound B or a salt thereof is contained in an amount of 0.5 to 10 equivalents of an alkali metal ion and a hydroxide ion after subtracting the equivalent of the compound B or a salt thereof neutralized with an acid addition salt.
  • a method for producing a compound represented by the general formula (A-1) or a salt thereof which comprises the step of reacting with 3-chloropropionyl chloride in the presence of a base.
  • one equivalent of Compound B or a salt thereof is subtracted from the equivalent of Compound B or a salt thereof to be neutralized with an acid addition salt, and 0.5 to 10 equivalents are selected from the group consisting of sodium hydroxide and potassium hydroxide.
  • a method for producing a compound represented by general formula (A-1) or a salt thereof which comprises a step of reacting with 3-chloropropionyl chloride in the presence of at least one base selected from the group.
  • HPLC conditions in each process are as follows.
  • the internal temperature was cooled to 50 ° C., ethyl acetate (2255 g), SCAVENGER SH SILCA (250 g), and purified Shirasagi activated carbon (50 g) were added to the mixture, and the mixture was stirred for 21 hours.
  • Scavenger SH SILCA and purified Shirasagi activated carbon were removed from the mixture by suction filtration with a Nutsche. The residue was washed with 4 L of ethyl acetate and mixed with the filtrate. The solvent of the obtained filtrate was distilled off under reduced pressure, and when 6 L was distilled off, 2.5 L of acetonitrile was added.
  • reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the solvent of the organic layer was evaporated. The residue was purified by column chromatography (Biotage SNAP Ultra HP-Sphere; chloroform / methanol) to give the title compound (49 mg).
  • N-diisopropylethylamine (2.26 g) was added, and the internal temperature was adjusted to 30 ° C.
  • a solution prepared by diluting 3-chloropropionyl chloride (0.753 g) with acetonitrile (6 mL) was added thereto over 10 minutes, and after dropping, the mixture was stirred at 30 ° C. for 30 minutes.
  • a part of the reaction solution was taken and measured by HPLC (condition 3), and it was confirmed that the peak area of the compound B was less than 1.0% of the total peak area. At this time, the diamide compound and the 3CP diamide compound were not detected by HPLC.
  • Example 5 This suggests that the method of Example 5 is excellent in terms of product quality and suitable for mass production of pharmaceuticals.
  • Example 6 This suggests that the method of Example 6 is excellent in terms of product quality and suitable for mass production of pharmaceuticals.
  • the internal temperature was 10 ° C or lower.
  • Acryloyl chloride (1.219 g) was added thereto, and the mixture was stirred for 3 hours. A part of the reaction solution was taken and measured by HPLC (condition 2). It was confirmed that the peak area of the compound B was less than 1.0% of the total peak area and the peak area of the diamide compound was 2% or more. did.
  • reaction solution pH was adjusted to 7 to 8 using a 20% aqueous potassium hydroxide solution.
  • ethanol 40 mL was added thereto, and the mixture was heated to an internal temperature of 50 to 60 and dissolved.
  • Crystal II of compound A (25.2 mg; Patent Document 8) was added at an internal temperature of 50 ° C., and the mixture was stirred for 3 hours.
  • water 17.6.3 mL was added dropwise over 3 hours. The internal temperature was cooled from 50 ° C. to 25 ° C. over 15 hours and cooled.
  • the total solution containing the solution and the insoluble matter was 375 mL, of which the insoluble matter was collected by filtration, washed with water (30 mL), and the collected product was dried under reduced pressure at 60 ° C. to give the title compound ( 2.936 g, yield 78.2%) was obtained.
  • Comparative Example 1 takes a long time to collect the compound A by filtration, and thus the conditions may be insufficient as a method for mass production.
  • Comparative Example 2 may be insufficient as a method for manufacturing a pharmaceutical product in terms of product quality.
  • Comparative Example 7 may be insufficient as a method for manufacturing a pharmaceutical product in terms of product quality.
  • Comparative Example 8 may be insufficient as a method for manufacturing a pharmaceutical product in terms of product quality.
  • Comparative Example 10 may be insufficient as a method for producing a drug in terms of product quality.
  • the base equivalent (after subtraction of acid addition salt) is that the number of equivalents of the base required for the neutralization of the acid-added methanesulfonic acid of the dimethanesulfonate of compound B is subtracted. It is a value.
  • “ND” indicates that it is below the detection limit, and “NA” indicates that it is not measured.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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Abstract

L'invention concerne un procédé de fabrication d'un composé représenté par la formule (A-1) ou d'un sel de celui-ci, lequel procédé de fabrication inclut une étape au cours de laquelle une （Ｓ）－３－（（３，５－diméthoxyphényl）ethynyl）－１－（pyrrolidin－３－yl）－１Ｈ－pyrazolo［３，４－ｄ］pyrimidin－４－amine ou un sel de celle-ci est mis en réaction avec un composé représenté par la formule （Ｉ－１－Ａ）. (La formule （Ｉ－１－Ａ） et la formule （Ａ－１） sont telles que définies dans la description.)
PCT/JP2018/041744 2018-11-09 2018-11-09 Procédé de fabrication de composé diméthoxybenzène WO2020095452A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
PCT/JP2018/041744 WO2020095452A1 (fr) 2018-11-09 2018-11-09 Procédé de fabrication de composé diméthoxybenzène
AU2018448845A AU2018448845B2 (en) 2018-11-09 2018-11-09 Method for producing dimethoxybenzene compound
KR1020217017262A KR20210088651A (ko) 2018-11-09 2018-11-09 디메톡시벤젠 화합물의 제조 방법
EP19881421.2A EP3882248A4 (fr) 2018-11-09 2019-11-08 Analogues de composés de diméthoxybenzène, procédés d'analyse desdits composés et produits standard desdits composés
PCT/JP2019/043926 WO2020096050A1 (fr) 2018-11-09 2019-11-08 Analogues de composés de diméthoxybenzène, procédés d'analyse desdits composés et produits standard desdits composés
US17/292,187 US20210388002A1 (en) 2018-11-09 2019-11-08 Dimethoxybenzene compound analogs, methods for analyzing said compounds and standard products of said compounds
MA054240A MA54240A (fr) 2018-11-09 2019-11-08 Analogues de composés de diméthoxybenzène, procédés d'analyse desdits composés et produits standard desdits composés
PCT/JP2019/043857 WO2020096042A1 (fr) 2018-11-09 2019-11-08 Procédé de fabrication de composé diméthoxybenzène
CN201980087803.6A CN113260618A (zh) 2018-11-09 2019-11-08 二甲氧基苯化合物类似物、分析所述化合物的方法和所述化合物的标准品
JP2020555638A JP7161546B2 (ja) 2018-11-09 2019-11-08 ジメトキシベンゼン化合物の類縁物質、該化合物の分析方法及び標準品
US17/292,289 US20210387990A1 (en) 2018-11-09 2019-11-08 Method for producing dimethoxybenzene compound

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US11883404B2 (en) 2016-03-04 2024-01-30 Taiho Pharmaceuticals Co., Ltd. Preparation and composition for treatment of malignant tumors
US11975002B2 (en) 2016-03-04 2024-05-07 Taiho Pharmaceutical Co., Ltd. Preparation and composition for treatment of malignant tumors

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US10124003B2 (en) 2013-07-18 2018-11-13 Taiho Pharmaceutical Co., Ltd. Therapeutic agent for FGFR inhibitor-resistant cancer
MA41350A (fr) 2015-01-14 2017-11-21 Janssen Pharmaceutica Nv Synthèse d'un inhibiteur de la tyrosine kinase de bruton
SG11201707384YA (en) 2015-03-31 2017-10-30 Taiho Pharmaceutical Co Ltd Crystal of 3,5-disubstituted benzene alkynyl compound
KR20240014585A (ko) 2016-03-04 2024-02-01 다이호야쿠힌고교 가부시키가이샤 악성 종양 치료용 제제 및 조성물
JP2018002662A (ja) 2016-07-01 2018-01-11 大鵬薬品工業株式会社 キノリルピロロピリミジル縮合環化合物を合成するために有用な中間体

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WO2013108809A1 (fr) * 2012-01-19 2013-07-25 大鵬薬品工業株式会社 Composé d'alkynylbenzène 3,5-disubstitué et un sel de celui-ci
CN105859721A (zh) * 2015-01-22 2016-08-17 浙江京新药业股份有限公司 一种伊布鲁替尼的制备方法

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Publication number Priority date Publication date Assignee Title
US11883404B2 (en) 2016-03-04 2024-01-30 Taiho Pharmaceuticals Co., Ltd. Preparation and composition for treatment of malignant tumors
US11975002B2 (en) 2016-03-04 2024-05-07 Taiho Pharmaceutical Co., Ltd. Preparation and composition for treatment of malignant tumors
US11833151B2 (en) 2018-03-19 2023-12-05 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition including sodium alkyl sulfate

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