WO2020056553A1 - Procédé de préparation d'un composé hétérocyclique et de ses sels - Google Patents

Procédé de préparation d'un composé hétérocyclique et de ses sels Download PDF

Info

Publication number
WO2020056553A1
WO2020056553A1 PCT/CN2018/105997 CN2018105997W WO2020056553A1 WO 2020056553 A1 WO2020056553 A1 WO 2020056553A1 CN 2018105997 W CN2018105997 W CN 2018105997W WO 2020056553 A1 WO2020056553 A1 WO 2020056553A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
reaction
acid
solvent
heterocyclic
Prior art date
Application number
PCT/CN2018/105997
Other languages
English (en)
Chinese (zh)
Inventor
蔡岩
杨少强
吴加朋
李怀鑫
周广
徐本全
Original Assignee
海门华祥医药科技有限公司
南开大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 海门华祥医药科技有限公司, 南开大学 filed Critical 海门华祥医药科技有限公司
Priority to PCT/CN2018/105997 priority Critical patent/WO2020056553A1/fr
Publication of WO2020056553A1 publication Critical patent/WO2020056553A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the invention belongs to the field of organic chemical synthesis, and particularly relates to a method for preparing a heterocyclic compound and a salt thereof.
  • the heterocyclic compound shown by the following formula I has important applications in pharmaceutical compounds and pesticide chemistry, and is an important type of advantageous building block. But at present, its synthesis method usually uses the corresponding heterocyclic ketone as the raw material, after condensing with disubstituted amine, and then reacting with potassium cyanide to prepare the corresponding intermediate, and finally hydrogenating to obtain the target product, the specific process is shown in the following formula. At present, this method requires a large amount of highly toxic potassium cyanide. The feeding process requires strict protection. After the reaction, the content of cyanide ions in the waste liquid also needs to be detected and controlled. The overall process has a greater impact on environmental protection.
  • the existing technology has a complicated preparation route, and the raw material compound needs to undergo steps such as protecting groups, alkylation, reduction, and deprotection groups to obtain the target product, which is not conducive to industrial production.
  • the present invention first provides a heterocyclic compound represented by the following formula I,
  • Het represents a 3-20 membered heterocyclic group which is unsubstituted or optionally substituted with one or more R S1 ;
  • R 1 and R 2 are the same or different and are independently selected from hydrogen, unsubstituted or C 1-40 alkyl or C 3-20 cycloalkyl optionally substituted with one or more R S2 ;
  • R S1 and R S2 are the same or different, and are independently selected from C 1-40 alkyl, C 1-40 alkoxy, or C 3-20 membered cycloalkyl.
  • Het may be selected from the group consisting of oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, pyrazolidine, tetrahydropyran, or piperidine ;
  • R 1 , R 2 are the same or different and are independently selected from hydrogen, C 1-8 alkyl or C 3-10 cycloalkyl.
  • the compound of formula I is selected from compounds including, but not limited to, the following:
  • the invention also provides a salt of a compound of formula I, said salt being an acid addition salt formed at any salt-forming site in a compound of formula I.
  • the acid addition salt is selected from an inorganic acid addition salt or an organic acid addition salt.
  • the present invention also provides a method for preparing the compound of formula I, including:
  • step (1b) reacting compound III obtained in step (1a) with R 1 X 1 and R 2 X 2 to obtain compound VI;
  • R 1 and R 2 have the definitions described above;
  • R 3 is selected from C 1-40 alkyl or benzyl;
  • X, X 1, X 2, X 3 are the same or different, are independently selected from Cl, Br or I with one another;
  • step (1a) According to the preparation method of the present invention, in step (1a),
  • the reaction temperature may be -40 to 80 ° C, for example, -20 to 60 ° C;
  • the reaction time may be 1-3 hours, such as 2 hours;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent. Multiple; for example, one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably methanol;
  • the reaction may be performed under acidic or reducing conditions, preferably under acidic conditions;
  • step (1b) the preparation method of the present invention.
  • the reaction temperature may be -40 to 80 ° C, for example, -20 to 60 ° C;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent.
  • the solvent may be one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably N, N -dimethylformamide;
  • the reaction can be performed under basic conditions
  • step (1c) According to the preparation method of the present invention, in step (1c),
  • the reaction may include a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • the reaction may optionally include a co-catalyst, and when a co-catalyst is added, the co-catalyst may be a Lewis acid, such as cobalt chloride;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent. Multiple; for example, one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably tetrahydrofuran, methanol ;
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 0 ° C, 25 ° C, 60 ° C;
  • the reaction time may be 1-4 hours, such as 1 hour, 2 hours, and 3 hours;
  • step (2a) the preparation method of the present invention.
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 0 ° C, 25 ° C, 60 ° C;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent.
  • the solvent may be one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably N, N -dimethylformamide;
  • the reaction can be performed under basic conditions
  • step (2b) the preparation method of the present invention.
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 0 ° C, 25 ° C, 60 ° C;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent. Multiple; for example, one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably tetrahydrofuran;
  • the reaction may be performed under acidic or reducing conditions, preferably under acidic conditions;
  • step (2c) According to the preparation method of the present invention, in step (2c),
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 0 ° C, 25 ° C, 60 ° C;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent.
  • the solvent may be one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably N, N -dimethylformamide;
  • the reaction can be performed under basic conditions
  • step (2d) According to the preparation method of the present invention, in step (2d),
  • the reaction may include a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • the reaction may optionally include a co-catalyst, and when a co-catalyst is added, the co-catalyst may be a Lewis acid, such as cobalt chloride;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent. Multiple; for example, one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably tetrahydrofuran, methanol ;
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 0 ° C, 25 ° C, 60 ° C;
  • the reaction time may be 1-4 hours, such as 2 hours, 3 hours, and 4 hours.
  • step (3a) According to the preparation method of the present invention, in step (3a),
  • the reaction temperature may be -40 to 80 ° C, for example, -20 to 60 ° C;
  • the reaction time may be 1-3 hours, such as 2 hours;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent. Multiple; for example, one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably methanol;
  • the reaction may be performed under acidic or reducing conditions, preferably under acidic conditions;
  • step (3b) According to the preparation method of the present invention, in step (3b),
  • the reaction may include a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • a reducing agent selected from one, two or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • the reaction may optionally include a co-catalyst, and when a co-catalyst is added, the co-catalyst may be a Lewis acid, such as cobalt chloride;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent. Multiple; for example, one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably tetrahydrofuran, methanol ;
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 0 ° C, 25 ° C, 60 ° C;
  • the reaction time may be 1-4 hours, such as 2 hours, 3 hours, and 4 hours.
  • step (4a) the preparation method of the present invention.
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 0 ° C, 25 ° C, 60 ° C;
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent.
  • the solvent may be one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably N, N -dimethylformamide;
  • the reaction can be performed under basic conditions
  • step (4b) the preparation method of the present invention.
  • the reaction may include a reducing agent selected from one, two or more of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • a reducing agent selected from one, two or more of sodium borohydride, sodium cyanoborohydride, borane, lithium aluminum hydride, and lithium tri-tert-butoxy aluminum hydride.
  • the reaction can be performed under acidic conditions
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent.
  • the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent.
  • Multiple preferably ether solvents; for example, tetrahydrofuran;
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 0 ° C, 25 ° C, 60 ° C;
  • the reaction time may be 1-4 hours, such as 2 hours, 3 hours, and 4 hours.
  • the method described above further comprises the preparation of compound II, including:
  • step 2) Compound XIII obtained in step 1) is reacted with compound XIV to obtain compound II;
  • Het and R 3 have the definitions described above.
  • any site in the starting material or intermediate for preparing compound II may be protected, and then the protecting group may be removed;
  • step 1) In step 1),
  • the reaction may add a compound containing an azide group; the compound containing an azide group is selected from one of sodium azide, diphenyl azide phosphate (DPPA), and p-toluenesulfonyl azide. Species, two or more species, such as diphenyl azide phosphate (DPPA);
  • the reaction can be performed under basic conditions
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent.
  • the solvent may be one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably N, N -Dimethylformamide, toluene;
  • the reaction temperature may be -40 to 80 ° C, preferably -20 to 60 ° C, such as 20 ° C and 25 ° C;
  • the reaction time may be 1-4 hours, such as 2 hours and 3 hours;
  • step 2) the preparation method of the present invention.
  • the reaction temperature may be 20 to 180 ° C, preferably 50 to 150 ° C, such as 90 ° C and 110 ° C;
  • the reaction time may be 5-11 hours, such as 7 hours, 8 hours, 9 hours.
  • the present invention also provides a compound represented by the following formula II, or formula III, or formula VIII, or formula XIII:
  • Het, R 1 and R 3 have the definitions described above.
  • the present invention also provides a method for preparing a salt of the compound of the formula I, wherein the salt is an acid addition salt formed at any salt-forming site in the compound of the formula I, and includes: the compound of the formula I prepared by the above method By reacting with an acid or a system capable of generating an acid, a salt of a compound represented by the formula I is obtained.
  • the acid-generating system is selected from an alcohol solution of trimethylchlorosilane (TMSCl), such as an ethanol solution of trimethylchlorosilane;
  • TMSCl trimethylchlorosilane
  • the reaction may be performed in a solvent, and the solvent may be one, two or more of an ether solvent, an amide solvent, a sulfone solvent, an ester solvent, a nitrile solvent, an alcohol solvent, and an aromatic hydrocarbon solvent. Multiple; for example, one, two or more of tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, toluene; preferably methanol, for example Anhydrous methanol.
  • the invention also provides the use of the compound of formula I, or a salt of a compound of formula I, or a compound of formula II, or a compound of formula III, or a compound of formula VIII, or a compound of formula XIII as an intermediate in the preparation of other compounds.
  • the present invention provides the use of a compound represented by the following formula or a salt thereof as an intermediate in the preparation of other compounds,
  • the invention discloses a method for preparing a heterocyclic compound and a salt thereof.
  • the present invention avoids the use of the highly toxic substance cyanide, and the problem of the absence of cyanide ion residues in the reaction products and reaction wastes greatly reduces the burden on environmental protection.
  • the reaction raw materials of the present invention have low price, simple preparation method and high yield, and are suitable for industrialized large-scale production.
  • the method of the present invention can avoid the use of cyanide on the one hand, and on the other hand, can maintain a yield equivalent to that of the preparation method of the prior art, although the reaction route is increased relative to the prior art.
  • the method of the present invention can also be used to synthesize heterocyclic compounds with large steric hindrance (R 1 and R 2 are large sterically hindered groups) and their salts, or heterocyclic compounds with different substituents in R 1 and R 2 .
  • R 1 and R 2 are large sterically hindered groups
  • the synthesis of heterocyclic compounds in which R 1 and R 2 are large hindering groups or different substituents is difficult to obtain by the existing method is improved.
  • C 1-40 alkyl is understood to preferably mean a straight or branched chain saturated monovalent hydrocarbon group having 1 to 40 carbon atoms, preferably a C 1-10 alkyl group.
  • C 1-10 alkyl is understood to preferably mean a straight or branched chain saturated monovalent hydrocarbon group 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 Methyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, and the like or their isomers.
  • 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, and more particularly, the group has 1, 2 or 3 carbon atoms ("C 1-3 alkyl”), such as methyl, ethyl, n-propyl 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 Or isopropyl.
  • C 3-20 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic A hydrocarbyl group such as a decalin ring.
  • C 1-40 alkoxy is understood to be C 1-40 alkyl-O, wherein C 1-40 alkyl has the definition described above.
  • 3-20 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 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 1-5, preferably 1-3 heteroatoms selected from N, O, and S.
  • the heterocyclyl can be attached to the rest of the molecule through any of the carbon atoms or nitrogen atoms, if present.
  • the heterocyclic group may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl, and a 5-membered ring such as tetrahydrofuranyl, dioxolyl, and pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithioalkyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or a 7-membered ring, such as diazacycloheptyl.
  • a 4-membered ring such as azetidinyl, oxetanyl, and a 5-membered ring such as tetrahydrofuranyl, dioxolyl, and pyrrole Alkyl, imidazolidin
  • the heterocyclyl may be benzo-fused.
  • 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) -based ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrole And [1,2-a] pyrazine-2 (1H) -based ring.
  • the nitrogen atom-containing ring 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] thiadi Azinyl, 4,5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • ether-based solvent includes, but is not limited to, diethyl ether, methyl ethyl ether, dipropyl ether, dibutyl ether, 1,4-dioxane, furan, methylfuran, and tetrahydrofuran.
  • amide-based solvent includes, but is not limited to, N, N-dimethylformamide, N, N-dimethylacetamide.
  • sulfone-based solvent includes, but is not limited to, dimethylsulfoxide, dimethylsulfone, sulfolane, and 2,4-dimethylsulfolane.
  • esters solvents includes, but is not limited to, methyl acetate, ethyl acetate, hexyl acetate, and phenyl acetate.
  • nitrile-based solvent includes, but is not limited to, acetonitrile.
  • alcoholic solvent includes, but is not limited to, methanol, ethanol, propanol, isopropanol, butanol, pentanol, decanol, n-dodecanol, cyclopentanol, cyclohexanol, benzyl alcohol, and phenylethanol.
  • aromatic solvent includes, but is not limited to, toluene and chlorobenzene.
  • the acid used in the acidic condition according to the present invention may be selected from Lewis acid or Bronsted acid, such as organic or inorganic acid, such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, SbF 5 , AsF 5 , TaF 5.
  • Lewis acid or Bronsted acid such as organic or inorganic acid, such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, SbF 5 , AsF 5 , TaF 5.
  • Lewis acid or Bronsted acid such as organic or inorganic acid, such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, SbF 5 , AsF 5 , TaF 5.
  • NbF 5 aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, and n
  • the acid according to the present invention may be selected from Lewis acids or Bronsted acids, such as organic or inorganic acids, such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, SbF 5 , AsF 5 , TaF 5 , NbF 5 , Aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, nitric acid, one, two or more.
  • Lewis acids or Bronsted acids such as organic or inorganic acids, such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, SbF 5 , AsF 5 , TaF 5 , NbF 5 , Aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, nitric acid, one, two or more.
  • the base used in the basic conditions of the present invention may be an organic base or an inorganic base, such as triethylamine, sodium hydride, potassium carbonate, n-butyllithium, LiHMDS (bis (trimethylsilyl) amino lithium), One, two or more of sodium hydroxide.
  • organic base such as triethylamine, sodium hydride, potassium carbonate, n-butyllithium, LiHMDS (bis (trimethylsilyl) amino lithium), One, two or more of sodium hydroxide.
  • the target compound can be isolated according to a known method, for example, by extraction, filtration, or column chromatography.
  • An acid addition salt of a compound of formula I may be an acid addition salt formed at any salt-formable site of a compound of formula I with a sufficiently basic nitrogen atom in a chain or ring and an organic or inorganic acid, for example with an inorganic acid as follows Acid addition salts: for example, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate salts, or acid addition salts with organic acids such as formic acid, Acetic acid, acetoacetic acid, pyruvate, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzene Formic acid, camphoric acid, cinnamic acid, cyclopentaneprop
  • FIG. 1 is a nuclear magnetic hydrogen spectrum of Compound 2.
  • FIG. 2 is a nuclear magnetic hydrogen spectrum of Compound 8.
  • FIG. 3 is a mass spectrum of Compound 8.
  • 11g of compound 2 was dissolved in 200mL DMF, then the system was cooled in an ice bath, and then 4g of 60% sodium hydride solid was added in portions. After the addition was completed, the system continued to stir for 10min, and then 10g of methyl iodide was gradually added dropwise. After the addition was completed, the system continued to stir for 10 minutes in an ice bath, and then stirred at room temperature for reaction. TLC monitored the reaction until the conversion of the raw materials was complete. Then, 20 mL of saturated sodium sulfite solution was added to quench the reaction. The quenched system was filtered and the filtrate was collected.
  • the ethyl acetate phase was collected and dried over anhydrous sodium sulfate.
  • the dried ethyl acetate phase was collected and the solvent was removed.
  • the residue was purified on a silica gel column to obtain 0.8 g of light. Yellow solid powder, compound 5, yielded 67%.
  • the reaction was monitored by TLC until the conversion of the raw materials was complete. Then, 20 mL of saturated sodium sulfite solution was added to quench the reaction. The quenched system was filtered, and the filtrate was collected. The solvent was removed and the residue was dissolved in ethyl acetate. The insoluble matter was removed by filtration. The filtrate was collected and washed once with saturated sodium bicarbonate. The ethyl acetate phase was collected and dried over anhydrous sodium sulfate. The dried ethyl acetate phase was collected. The solvent was removed by spin, and the residue was subjected to silica gel column purification to obtain 0.25 g of a pale yellow solid powder, that is, compound 5, with a total yield of 38%.
  • the system continues to stir in the -5 °C low-temperature reaction kettle for 10min, and then the reaction is stirred at room temperature.
  • the system is brown.
  • the reaction was turbid, and the reaction was monitored by TLC until the conversion of the raw materials was completed.
  • the reaction was quenched by adding 2 mL of a saturated sodium sulfite solution. After quenching, the system was turbid brown, and the pH was 8-9.
  • the quenched system was filtered, and the filtrate was collected, and then the system solvent was removed by a mechanical pump.
  • the system is cooled again in a -20 ° C low-temperature reaction kettle, and the reaction is quenched by adding sodium bicarbonate solution. After that, the system was filtered, the filtrate was collected, the solvent was drained, and the residue was dissolved with ethyl acrylate (EA), and dried with anhydrous sodium sulfate. After the drying was completed, the system was concentrated to obtain about 2 g of a yellow liquid, which was directly purified without purification. For salt formation, dissolve it in 10mL of absolute ethanol, then heat the system to 40 ° C, and then gradually drop in 2.7gTMSCl. The system will produce a large amount of white solid precipitate. The precipitated solid was collected by filtration, washed once with a small amount of ethanol, and then dried to obtain 2.7 g of a white solid, that is, the target compound, with a yield of 69%.
  • EA ethyl acrylate
  • lithium butoxyaluminum hydride can also be prepared to obtain the target compound with a yield of 60 to 75%, which indicates that acidic conditions can be beneficial to the reaction.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte au domaine de la chimie organique, et concerne en particulier un procédé de préparation d'un composé hétérocyclique représenté par la formule I et des sels de celui-ci. Par comparaison avec l'état de la technique, l'invention permet d'éviter l'utilisation de cyanure, qui est une substance hautement toxique, et ne laisse aucun ion de groupe cyano résiduel dans des produits de réaction et des déchets de réaction, réduisant ainsi de manière considérable l'impact sur l'environnement. La présente invention utilise des matières premières de réaction à faible coût, a un procédé de préparation simple, un rendement élevé, et est appropriée pour une production à grande échelle. De plus, les inventeurs ont découvert de manière inattendue que par l'utilisation du procédé du schéma 4, par exemple à l'aide d'un agent réducteur et d'une réaction dans des conditions acides, le composé VIII peut être mis à réagir en une étape et permet d'obtenir de manière simultanée une déprotection, une alkylation et une réduction d'ions de groupe cyano afin d'obtenir un produit cible. La présente invention permet de réduire de manière considérable les inconvénients de l'état de la technique nécessitant des réactions en plusieurs étapes.
PCT/CN2018/105997 2018-09-17 2018-09-17 Procédé de préparation d'un composé hétérocyclique et de ses sels WO2020056553A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2018/105997 WO2020056553A1 (fr) 2018-09-17 2018-09-17 Procédé de préparation d'un composé hétérocyclique et de ses sels

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2018/105997 WO2020056553A1 (fr) 2018-09-17 2018-09-17 Procédé de préparation d'un composé hétérocyclique et de ses sels

Publications (1)

Publication Number Publication Date
WO2020056553A1 true WO2020056553A1 (fr) 2020-03-26

Family

ID=69886762

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/105997 WO2020056553A1 (fr) 2018-09-17 2018-09-17 Procédé de préparation d'un composé hétérocyclique et de ses sels

Country Status (1)

Country Link
WO (1) WO2020056553A1 (fr)

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3655692A (en) * 1967-09-11 1972-04-11 Merck & Co Inc 3-amino-tetrahydrothiophene-3-carboxylic acids
US5646167A (en) * 1993-01-06 1997-07-08 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamix acids
WO2011051282A1 (fr) * 2009-10-27 2011-05-05 N.V. Organon Dérivés de (1,1, 1,3, 3,3-hexafluoro- 2 -hydroxypropan- 2 -yl) phényle, compositions pharmaceutiques en comportant et leur utilisation pour le traitement de l'athérosclérose
CN102803235A (zh) * 2009-06-15 2012-11-28 贝林格尔.英格海姆国际有限公司 选择性调节cb2受体的化合物
WO2013052394A1 (fr) * 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 2-pyridyl carboxamide
CN103958477A (zh) * 2011-11-29 2014-07-30 (株)威沃尊 新苯甲酰胺衍生物及其用途
CN104245671A (zh) * 2012-04-17 2014-12-24 富士胶片株式会社 含氮杂环化合物或其盐
WO2015095258A1 (fr) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Composés hétérocycliques spirocycliques utiles en tant qu'inhibiteurs de l'intégrase du vih
CN105992765A (zh) * 2013-08-08 2016-10-05 拜耳制药股份公司 取代的吡唑并[1,5-a]吡啶-3-甲酰胺及其用途
WO2017115329A1 (fr) * 2015-12-30 2017-07-06 Hetero Research Foundation Nouveaux dérivés de triterpénone en c-3 en tant qu'inhibiteurs du vih
WO2018005678A1 (fr) * 2016-06-29 2018-01-04 The Regents Of The University Of California Composés et compositions pour le traitement du cancer

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3655692A (en) * 1967-09-11 1972-04-11 Merck & Co Inc 3-amino-tetrahydrothiophene-3-carboxylic acids
US5646167A (en) * 1993-01-06 1997-07-08 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamix acids
CN102803235A (zh) * 2009-06-15 2012-11-28 贝林格尔.英格海姆国际有限公司 选择性调节cb2受体的化合物
WO2011051282A1 (fr) * 2009-10-27 2011-05-05 N.V. Organon Dérivés de (1,1, 1,3, 3,3-hexafluoro- 2 -hydroxypropan- 2 -yl) phényle, compositions pharmaceutiques en comportant et leur utilisation pour le traitement de l'athérosclérose
WO2013052394A1 (fr) * 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 2-pyridyl carboxamide
CN103958477A (zh) * 2011-11-29 2014-07-30 (株)威沃尊 新苯甲酰胺衍生物及其用途
CN104245671A (zh) * 2012-04-17 2014-12-24 富士胶片株式会社 含氮杂环化合物或其盐
CN105992765A (zh) * 2013-08-08 2016-10-05 拜耳制药股份公司 取代的吡唑并[1,5-a]吡啶-3-甲酰胺及其用途
WO2015095258A1 (fr) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Composés hétérocycliques spirocycliques utiles en tant qu'inhibiteurs de l'intégrase du vih
WO2017115329A1 (fr) * 2015-12-30 2017-07-06 Hetero Research Foundation Nouveaux dérivés de triterpénone en c-3 en tant qu'inhibiteurs du vih
WO2018005678A1 (fr) * 2016-06-29 2018-01-04 The Regents Of The University Of California Composés et compositions pour le traitement du cancer

Non-Patent Citations (39)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 1 February 2016 (2016-02-01), Database accession no. 1856606-72-8 *
DATABASE Registry 1 July 2010 (2010-07-01), Database accession no. 1228950-00-2 *
DATABASE Registry 10 November 2016 (2016-11-10), Database accession no. 2028431-19-6 *
DATABASE Registry 11 February 2010 (2010-02-11), Database accession no. 1205749-01-4 *
DATABASE Registry 11 February 2010 (2010-02-11), Database accession no. 1205749-05-8 *
DATABASE Registry 11 February 2010 (2010-02-11), Database accession no. 1205749-53-6 *
DATABASE Registry 11 February 2010 (2010-02-11), Database accession no. 1205751-20-7 *
DATABASE Registry 11 February 2016 (2016-02-11), Database accession no. 1864215-72-4 *
DATABASE Registry 11 February 2016 (2016-02-11), Database accession no. 1864445-50-0 *
DATABASE Registry 11 November 2016 (2016-11-11), Database accession no. 2029755-73-3 *
DATABASE Registry 15 June 2015 (2015-06-15), Database accession no. 1780498-07-8 *
DATABASE Registry 16 November 1984 (1984-11-16), Database accession no. 50289-05-9 *
DATABASE Registry 16 October 2016 (2016-10-16), Database accession no. 2012738-80-4 *
DATABASE Registry 17 January 2014 (2014-01-17), Database accession no. 1523606-33-8 *
DATABASE Registry 17 June 2009 (2009-06-17), Database accession no. 1158792-81-4 *
DATABASE Registry 18 June 2015 (2015-06-18), Database accession no. 1783662-71-4 *
DATABASE Registry 2 November 2016 (2016-11-02), Database accession no. 2023269-53-4 *
DATABASE Registry 2 November 2016 (2016-11-02), Database accession no. 2023809-00-7 *
DATABASE Registry 20 June 2016 (2016-06-20), Database accession no. 1935017-85-8 *
DATABASE Registry 20 September 2016 (2016-09-20), Database accession no. 1996201-33-2 *
DATABASE Registry 21 January 2016 (2016-01-21), Database accession no. 1850376-56-5 *
DATABASE Registry 21 June 2016 (2016-06-21), Database accession no. 1935950-89-2 *
DATABASE Registry 26 February 2016 (2016-02-26), Database accession no. 1874677-59-4 *
DATABASE Registry 26 March 2018 (2018-03-26), Database accession no. 2199214-48-5 *
DATABASE Registry 26 September 2016 (2016-09-26), Database accession no. 1999576-05-4 *
DATABASE Registry 27 January 2014 (2014-01-27), Database accession no. 1531313-58-2 *
DATABASE Registry 28 June 2007 (2007-06-28), Database accession no. 939776-24-6 *
DATABASE Registry 3 June 2015 (2015-06-03), Database accession no. 1782565-06-3 *
DATABASE Registry 3 October 2016 (2016-10-03), Database accession no. 2004393-93-3 *
DATABASE Registry 3 October 2016 (2016-10-03), Database accession no. 2004666-75-3 *
DATABASE Registry 30 April 2007 (2007-04-30), Database accession no. 933700-87-9 *
DATABASE Registry 30 April 2007 (2007-04-30), Database accession no. 933700-99-3 *
DATABASE Registry 31 December 2013 (2013-12-31), Database accession no. 1507743-86-3 *
DATABASE Registry 31 October 2016 (2016-10-31), Database accession no. 2021682-44-8 *
DATABASE Registry 31 October 2016 (2016-10-31), Database accession no. 2021752-76-9 *
DATABASE Registry 31 October 2016 (2016-10-31), Database accession no. 2021991-38-6 *
DATABASE Registry 8 June 2009 (2009-06-08), Database accession no. 1153971-30-2 *
SUMMA, V. ET AL.: "Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV- Integrase Inhibitor for the Treatment of HIV-AIDS Infection", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 18, 9 March 2008 (2008-03-09), pages 5843 - 5855, XP002615638 *
YANG, D. ET AL.: "Serotoninergic properties of new conformationaily restricted benzamides", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 31, no. 3, 31 December 1996 (1996-12-31), pages 231 - 239, XP004040111, DOI: 10.1016/0223-5234(96)89139-2 *

Similar Documents

Publication Publication Date Title
CN106046022B (zh) 具有hiv整合酶抑制活性的化合物的制造方法
RU2135498C1 (ru) Пиразоло- и пирролопиридины
JP4236926B2 (ja) メタンスルホンアミド−ベンゾフラン、その製造方法および合成中間体としての使用。
BR112021005593A2 (pt) fabricação de compostos e composições para a inibição da atividade de shp2
CN114437031B (zh) 一种6-甲基尼古丁的合成方法
Tormos et al. The indophenine reaction revisited. Properties of a soluble dialkyl derivative
PL173659B1 (pl) Sposób wytwarzania nowych pochodnych piperydyny
WO2022012630A1 (fr) Procédé de synthèse d'un composé c-nucléosidique
CN114315823B (zh) 盐酸小檗碱及其类似物的中间体及其制备方法
JP3044055B2 (ja) １，２―エタンジオール誘導体およびその塩
EP1362854B1 (fr) Dérivé benzo[b]thiophène et procédé de production correspondant
CN107501301B (zh) 二硒吩并[2,3-b:3′,2′-d]硒吩及其制备方法
WO2020056553A1 (fr) Procédé de préparation d'un composé hétérocyclique et de ses sels
HU223578B1 (hu) Eljárás fibrinogénreceptor-antagonista hatású 0-[4-(4-heterociklusos)-alkil]-tirozin-származékok előállítására
CN109836400B (zh) 杂环化合物及其盐的制备方法
JP2022515070A (ja) アミド誘導体の不純物及びその使用
CN108976198B (zh) 一种3-(4-吡啶)吲哚类化合物的合成方法
AU5878001A (en) Novel benzothiophene derivatives
JP7094942B2 (ja) ベンズイミダゾール誘導体の製造方法
Baudry et al. Synthetic studies in the 5-thio-D-xylopyranose series part 1: A ready access to C-hetaryl 5-thio-D-xylopyranosides by electrophilic substitution
JP7344983B2 (ja) ケノデオキシコール酸誘導体の調製方法
CN113582953B (zh) 一种盐酸胺碘酮关键中间体的制备方法
JP5711669B2 (ja) スピロケタール誘導体の製造方法
CN111087358B (zh) 普赛莫德的制备方法
EP3303329B1 (fr) Procédés pour fabriquer des dérivés d'indazole

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18934016

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18934016

Country of ref document: EP

Kind code of ref document: A1