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WO2020056553A1 - 杂环化合物及其盐的制备方法 - Google Patents

杂环化合物及其盐的制备方法 Download PDF

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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
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compound
reaction
acid
solvent
heterocyclic
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PCT/CN2018/105997
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English (en)
French (fr)
Inventor
蔡岩
杨少强
吴加朋
李怀鑫
周广
徐本全
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海门华祥医药科技有限公司
南开大学
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Priority to PCT/CN2018/105997 priority Critical patent/WO2020056553A1/zh
Publication of WO2020056553A1 publication Critical patent/WO2020056553A1/zh

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    • 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.

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Abstract

本发明属于有机化学领域，具体涉及式I所示杂环化合物及其盐的制备方法。与现有技术相比，本发明避免了剧毒物质氰化物的使用，反应后的产物以及反应废弃物中不存在氰根离子残余的问题，大大减轻了环保负担。而且，本发明反应原料的价格低，制备方法简单，产率高，适于工业化的大规模生产。另外，发明人意外地发现，采用方案4的方法，例如使用还原剂和在酸性条件下进行，可以使化合物VIII一步反应同时实现脱保护基、烷基化和氰基还原，得到目标产物。极大地改善了现有技术需要进行多步反应的缺陷。

Description

杂环化合物及其盐的制备方法 技术领域
本发明属于有机化学合成领域，具体涉及一种杂环化合物及其盐的制备方法。
背景技术
下式I所示的杂环化合物在药物化合物和农药化学中有着重要的应用，是一类重要的优势构建模块。但目前其合成方法通常为以相应的杂环酮为原料，与二取代胺缩合后，再与氰化钾反应，制备得到相应的中间体，最后氢化得到目标产物，具体过程如下式所示。目前这种方法需要大量使用剧毒的氰化钾，投料过程需要做到严格防护，反应后对废液中的氰根离子的含量也需要检测和控制，整体工艺对环保影响较大。
Figure PCTCN2018105997-appb-000001
此外，现有工艺制备路线繁琐，原料化合物需经历上保护基、烷基化、还原和脱保护基等步骤才能获得目标产物，不利于工业化生产。
发明内容
为改善上述问题，本发明首先提供一种下式I所示的杂环化合物，
Figure PCTCN2018105997-appb-000002
其中，Het代表无取代或任选被一个或多个R S1取代的3-20元杂环基；
R 1、R 2相同或不同，彼此独立地选自氢、无取代或任选被一个或多个R S2取代的C 1-40烷基或C 3-20环烷基；
R S1、R S2相同或不同，彼此独立地选自C 1-40烷基、C 1-40烷氧基或C 3-20元环烷基。
根据本发明的实施方案，Het可以选自氧杂环丁烷、硫杂环丁烷、氮杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、吡唑烷、四氢吡喃或哌啶；
根据本发明的实施方案，R 1、R 2相同或不同，彼此独立地选自氢、C 1-8烷基或C 3-10环烷基。
作为实例，所述式I化合物选自包括但不限于如下化合物：
Figure PCTCN2018105997-appb-000003
本发明还提供式I化合物的盐，所述盐为式I化合物中任意可成盐位点形成的酸加成盐。
根据本发明，所述酸加成盐选自无机酸加成盐或有机酸加成盐。
本发明还提供上述式I化合物的制备方法，包括：
方案1：
Figure PCTCN2018105997-appb-000004
(1a)化合物II进行反应，得到化合物III；
(1b)步骤(1a)得到的化合物III与R 1X 1及R 2X 2进行反应，得到化合物VI；
(1c)步骤(1b)得到的化合物VI反应得到化合物I；或者
方案2：
Figure PCTCN2018105997-appb-000005
(2a)化合物II与化合物VII进行反应，得到化合物VIII；
(2b)步骤(2a)得到的化合物VIII进行反应，得到化合物IX；
(2c)步骤(2b)得到的化合物IX与化合物XI进行反应，得到化合物VI；
(2d)步骤(2c)得到的化合物VI进行反应，得到化合物I；或者
方案3：
Figure PCTCN2018105997-appb-000006
(3a)化合物II进行反应，得到化合物III；
(3b)步骤(3a)得到的化合物III反应得到化合物I；或者
方案4：
Figure PCTCN2018105997-appb-000007
(4a)化合物II与化合物VII进行反应，得到化合物VIII；
(4b)步骤(4a)得到的化合物VIII进行反应，得到化合物I；
其中，Het、R 1、R 2具有上文所述的定义；R 3选自C 1-40烷基或苄基；
X、X 1、X 2、X 3相同或不同，彼此独立地选自Cl、Br或I；
方案1或方案2中R 1、R 2均不为H。
如果需要，可将方案1-4中任何原料或中间体中的具有反应活性的位点进行保护，之后再进行脱保护。
根据本发明的制备方法，步骤(1a)中，
所述反应的温度可以为-40～80℃，例如-20～60℃；
所述反应的时间可以为1-3小时，例如2小时；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为甲醇；
所述反应可以在酸性或还原性条件下进行，优选在酸性条件下进行；
根据本发明的制备方法，步骤(1b)中，
所述反应的温度可以为-40～80℃，例如-20～60℃；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、 甲醇、甲苯中的一种、两种或更多种；优选为N,N-二甲基甲酰胺；
所述反应可以在碱性条件下进行；
根据本发明的制备方法，步骤(1c)中，
所述反应可以加入还原剂，所述还原剂选自硼氢化钠、氰基硼氢化钠、硼烷、氢化铝锂、三叔丁氧基氢化铝锂中的一种、两种或更多种，例如硼氢化钠、氢化铝锂；
所述反应可以任选加入或不加助催化剂，当加入助催化剂时，所述助催化剂可以为路易斯酸，例如氯化钴；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为四氢呋喃、甲醇；
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如0℃、25℃、60℃；
所述反应的时间可以为1-4小时，例如1小时、2小时、3小时；
根据本发明的制备方法，步骤(2a)中，
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如0℃、25℃、60℃；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为N,N-二甲基甲酰胺；
所述反应可以在碱性条件下进行；
根据本发明的制备方法，步骤(2b)中，
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如0℃、25℃、60℃；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、 甲醇、甲苯中的一种、两种或更多种；优选为四氢呋喃；
所述反应可以在酸性或还原性条件下进行，优选在酸性条件下进行；
根据本发明的制备方法，步骤(2c)中，
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如0℃、25℃、60℃；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为N,N-二甲基甲酰胺；
所述反应可以在碱性条件下进行；
根据本发明的制备方法，步骤(2d)中，
所述反应可以加入还原剂，所述还原剂选自硼氢化钠、氰基硼氢化钠、硼烷、氢化铝锂、三叔丁氧基氢化铝锂中的一种、两种或更多种，例如硼氢化钠、氢化铝锂；
所述反应可以任选加入或不加助催化剂，当加入助催化剂时，所述助催化剂可以为路易斯酸，例如氯化钴；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为四氢呋喃、甲醇；
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如0℃、25℃、60℃；
所述反应的时间可以为1-4小时，例如2小时、3小时、4小时。
根据本发明的制备方法，步骤(3a)中，
所述反应的温度可以为-40～80℃，例如-20～60℃；
所述反应的时间可以为1-3小时，例如2小时；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多 种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为甲醇；
所述反应可以在酸性或还原性条件下进行，优选在酸性条件下进行；
根据本发明的制备方法，步骤(3b)中，
所述反应可以加入还原剂，所述还原剂选自硼氢化钠、氰基硼氢化钠、硼烷、氢化铝锂、三叔丁氧基氢化铝锂中的一种、两种或更多种，例如硼氢化钠、氢化铝锂；
所述反应可以任选加入或不加助催化剂，当加入助催化剂时，所述助催化剂可以为路易斯酸，例如氯化钴；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为四氢呋喃、甲醇；
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如0℃、25℃、60℃；
所述反应的时间可以为1-4小时，例如2小时、3小时、4小时。
根据本发明的制备方法，步骤(4a)中，
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如0℃、25℃、60℃；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为N,N-二甲基甲酰胺；
所述反应可以在碱性条件下进行；
根据本发明的制备方法，步骤(4b)中，
所述反应可以加入还原剂，所述还原剂选自硼氢化钠、氰基硼氢化钠、硼烷、氢化铝锂、三叔丁氧基氢化铝锂中的一种、两种或更多种，例如氢化铝锂；
所述反应可以在酸性条件下进行；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；优选为醚类溶剂；例如四氢呋喃；
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如0℃、25℃、60℃；
所述反应的时间可以为1-4小时，例如2小时、3小时、4小时。
根据本发明，如上所述方法还包括化合物II的制备，包括：
Figure PCTCN2018105997-appb-000008
1)化合物XII进行反应，得到化合物XIII；
2)步骤1)得到的化合物XIII与化合物XIV进行反应，得到化合物II；
其中，Het、R 3具有上文所述的定义。
根据本发明，如果需要，可将制备化合物II的原料或中间体中的任何位点进行保护，之后再脱保护基；
根据本发明的制备方法，步骤1)中，
所述反应可以加入含有叠氮基团的化合物；所述含有叠氮基团的化合物选自叠氮化钠、叠氮磷酸二苯酯(DPPA)、对甲基苯磺酰基叠氮中的一种、两种或更多种，例如叠氮磷酸二苯酯(DPPA)；
所述反应可以在碱性条件下进行；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为N,N-二甲基甲酰胺、甲苯；
所述反应的温度可以为-40～80℃，优选为-20～60℃，例如20℃、25℃；
所述反应的时间可以为1-4小时，例如2小时、3小时；
根据本发明的制备方法，步骤2)中，
所述反应的温度可以为20～180℃，优选为50～150℃，例如90℃、110℃；
所述反应的时间可以为5-11小时，例如7小时、8小时、9小时。
本发明还提供下式II，或式III，或式VIII，或式XIII所示的化合物：
Figure PCTCN2018105997-appb-000009
其中，Het、R 1、R 3具有上文所述的定义。
本发明还提供上述式I所示化合物的盐的制备方法，其中，所述盐为式I化合物中任意可成盐位点形成的酸加成盐，包括：将上述方法制备得到的式I化合物与酸反应或与可生成酸的体系反应，得到式I所示化合物的盐。
例如，所述可以生成酸的体系选自三甲基氯硅烷(TMSCl)的醇溶液，如三甲基氯硅烷的乙醇溶液；
所述反应可以在溶剂中进行，所述溶剂可以为醚类溶剂、酰胺类溶剂、砜类溶剂、酯类溶剂、腈类溶剂、醇类溶剂、芳烃类溶剂中的一种、两种或更多种；例如四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙腈、乙醇、甲醇、甲苯中的一种、两种或更多种；优选为甲醇，例如无水甲醇。
本发明还提供上述式I化合物、或式I化合物的盐、或式II化合物、或式III化合物、或式VIII化合物、或式XIII化合物作为中间体在制备其他化合物中的用途。
作为实例，本发明提供下式所示的化合物或其盐作为中间体在制备其他化合物中的用途，
Figure PCTCN2018105997-appb-000010
有益效果
本发明公开了杂环化合物及其盐的制备方法。与现有技术相比，本发明避免了剧毒物质氰化物的使用，反应后的产物以及反应废弃物中不存在氰根离子残余的问题，大大减轻了环保负担。而且，本发明反应原料的价格低，制备方法简单，产率高，适于工业化的大规模生产。并且，本发明的方法一方面可以避免氰化物的使用，另一方面，尽管反应路线相对于现有技术有所增加，但是仍能保持与现有技术制备方法相当的收率。
此外，本发明方法还可用于大位阻的杂环化合物(R 1、R 2为大位阻基团)及其盐，或R 1、R 2为不同取代基的杂环化合物的合成。改善了现有方法难以得到R 1、R 2为大位阻基团或不同取代基的杂环化合物的合成。
另外，发明人意外地发现，采用方案4的方法，特别是在还原剂和酸性条件下进行，可以使化合物VIII一步反应同时实现脱保护基、烷基化和氰基还原，得到目标产物，极大地改善了现有技术需要进行多步反应的缺陷。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
术语“C 1-40烷基”应理解为优选表示具有1～40个碳原子的直链或支链饱和一价烃基，优选为C 1-10烷基。“C 1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、 2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2、3、4、5、6个碳原子(“C 1-6烷基”)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基，更特别地，所述基团具有1、2或3个碳原子(“C 1-3烷基”)，例如甲基、乙基、正丙基或异丙基。
术语“C 3-20环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～20个碳原子，优选“C 3-10环烷基”。术语“C 3-10环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3、4、5、6、7、8、9或10个碳原子。所述C 3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。
术语“C 1-40烷氧基”应理解为C 1-40烷基-O，其中C 1-40烷基具有上文所述的定义。
术语“3-20元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个独立选自N、O和S的杂原子，优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二 氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。
术语“醚类溶剂”包括但不限于乙醚、甲基乙基醚、二丙醚、二丁醚、1,4-二氧六环、呋喃、甲基呋喃、四氢呋喃。
术语“酰胺类溶剂”包括但不限于N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
术语“砜类溶剂”包括但不限于二甲基亚砜、二甲基砜、环丁砜、2,4-二甲基环丁砜。
术语“酯类溶剂”包括但不限于乙酸甲酯、乙酸乙酯、乙酸己酯、乙酸苯酯。
术语“腈类溶剂”包括但不限于乙腈。
术语“醇类溶剂”包括但不限于甲醇、乙醇、丙醇、异丙醇、丁醇、戊醇、癸醇、正十二醇、环戊醇、环己醇、苯甲醇、苯乙醇。
术语“芳烃类溶剂”包括但不限于甲苯、氯苯。
本发明所述的酸性条件使用的酸可以选自路易斯酸或布朗斯特酸，例如有机酸或无机酸，如甲酸、乙酸、三氟乙酸、盐酸、硝酸、硫酸、SbF 5、AsF 5、TaF 5、NbF 5、氯化铝、氯化铁、三氟化硼、五氯化铌、硝酸中的一种、两种或更多种。
本发明所述的酸可以选自路易斯酸或布朗斯特酸，例如有机酸或无机酸，如甲酸、乙酸、三氟乙酸、盐酸、硝酸、硫酸、SbF 5、AsF 5、TaF 5、NbF 5、氯化铝、氯化铁、三氟化硼、五氯化铌、硝酸中的一种、两种或更多种。
本发明所述的碱性条件使用的碱可以为有机碱或无机碱，如三乙胺、氢化钠、碳酸钾、正丁基锂、LiHMDS(双(三甲基硅基)胺基锂)、氢氧化钠中的一种、两种或更多种。
可以根据已知的方法，例如通过萃取、过滤或柱层析来分离目标化合物。
式I化合物的酸加成盐可以是式I化合物任意可成盐位点例如链或环中具有足够碱性的氮原子与有机酸或无机酸形成的酸加成盐，例如与如下无机酸形成 的酸加成盐：例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸，或硫酸氢盐、或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
附图说明
图1为化合物2的核磁氢谱图。
图2为化合物8的核磁氢谱图。
图3为化合物8的质谱谱图。
具体实施方式
下文将结合具体实施例对本发明做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1
Figure PCTCN2018105997-appb-000011
称取10g四氢吡喃-4-氰基-4-甲酸1置于50mL N,N-二甲基甲酰胺(DMF)中搅拌溶解，之后逐渐加入15mL三乙胺，继续搅拌约5min后，逐渐滴入40g叠氮磷酸二苯酯(DPPA)，滴加结束后室温搅拌反应，反应约3h后，TLC监测反应显示反应转化完全，制备得到的酰基叠氮化合物不经分离直接用于后续投料，之后向体系中加入200mL叔丁醇，之后将体系逐渐升温至110℃反应，反应过程中体系会产生气体，反应约8h后停止反应，将体系置于旋转蒸发仪上将体系溶剂旋去，剩余得到棕色油状液体，用乙酸乙酯将其溶解，用饱和碳酸氢钠溶液洗涤一次，之后收集有机相，无水硫酸钠干燥，干燥结束后，旋去溶剂得到11g浅黄色固体粉末，即化合物2，无需进一步纯化即可用于后续反应投料，收率75％。
实施例2
Figure PCTCN2018105997-appb-000012
称取5g化合物2将其溶于100mL甲醇中，之后体系置于冰浴下冷却，逐渐滴入50mL 6M的盐酸溶液，滴加结束后继续搅拌反应2h，反应结束后，将体系置于旋转蒸发仪上将体系溶剂旋去，得到暗白色固体粉末，将其进行硅胶柱纯化，得到黄色油状物1.7g，即化合物3，收率61％。
实施例3
Figure PCTCN2018105997-appb-000013
将11g化合物2置于200mL DMF中搅拌溶解，之后将体系置于冰浴下冷却，之后分批加入4g 60％的氢化钠固体，加入结束后，体系继续搅拌10min，之后 逐渐滴入10g碘甲烷，加入结束后，体系继续于冰浴下搅拌10min，之后置于室温搅拌反应，TLC监测反应至原料转化完全为止，之后加入20mL饱和亚硫酸钠溶液淬灭反应，将淬灭后的体系过滤，收集滤液，之后将体系溶剂除去，剩余物用乙酸乙酯溶解，将不溶物过滤除去，收集滤液，并用饱和碳酸氢钠洗涤一次，收集乙酸乙酯相，并用无水硫酸钠干燥，将干燥后的乙酸乙酯相收集并旋去溶剂，得到棕色油状物，对其进行硅胶柱纯化，得到9.4g亮黄色固体，即化合物4，收率80％。
实施例4
Figure PCTCN2018105997-appb-000014
称取1g化合物3溶于20mL DMF中，体系置于冰浴下冷却，之后加入0.7g60％的氢化钠固体，加入完毕后搅拌10min，之后加入2.5g碘甲烷，加入完毕后继续搅拌2h反应，TLC监测反应至原料转化完全为止，之后加入20mL饱和亚硫酸钠溶液淬灭反应，将淬灭后的体系过滤，收集滤液，之后将体系溶剂除去，剩余物用乙酸乙酯溶解，将不溶物过滤除去，收集滤液，并用饱和碳酸氢钠洗涤一次，收集乙酸乙酯相，并用无水硫酸钠干燥，将干燥后的乙酸乙酯相收集并旋去溶剂，对剩余物进行硅胶柱纯化，得到0.8g浅黄色固体粉末，即化合物5，收率67％。
实施例5
Figure PCTCN2018105997-appb-000015
称取1g化合物4溶于10mL四氢呋喃中，将体系置于冰浴下冷却，之后逐 渐滴入10mL 6M的盐酸溶液，继续搅拌反应1h，之后TLC监测反应显示原料转化完全，将体系旋干，得到浅黄色固体，即化合物6的粗品，不经纯化直接用于后续反应，将其溶于10mL DMF中，体系置于冰浴下冷却，之后加入0.6g 60％的氢化钠固体，加入完毕后搅拌10min，之后加入2.3g碘甲烷，加入完毕后继续搅拌2h反应，TLC监测反应至原料转化完全为止，之后加入20mL饱和亚硫酸钠溶液淬灭反应，将淬灭后的体系过滤，收集滤液，之后将体系溶剂除去，剩余物用乙酸乙酯溶解，将不溶物过滤除去，收集滤液，并用饱和碳酸氢钠洗涤一次，收集乙酸乙酯相，并用无水硫酸钠干燥，将干燥后的乙酸乙酯相收集并旋去溶剂，对剩余物进行硅胶柱纯化，得到0.25g浅黄色固体粉末，即化合物5，总收率38％。
实施例6
Figure PCTCN2018105997-appb-000016
称取1g化合物5溶于20mL四氢呋喃中，将体系置于冰浴下冷却并氮气保护，之后称取1.5g氢化铝锂配制成四氢呋喃悬浊液，将其逐渐滴入到反应体系中，滴加结束后，继续搅拌反应3h，之后加入20mL 6M的氢氧化钠溶液淬灭反应，淬灭完毕后继续搅拌30min，之后将体系过滤，收集滤液，旋去溶剂后，剩余物用乙酸乙酯溶解，用饱和氯化钠溶液洗涤一次，收集乙酸乙酯相，并用无水硫酸钠干燥，将干燥后的乙酸乙酯相收集并旋去溶剂，对剩余物进行硅胶柱纯化，得到米黄色液体0.56g，即化合物7，收率56％。
实施例7
Figure PCTCN2018105997-appb-000017
称取1g化合物5溶于20mL无水甲醇中，加入0.5g无水氯化钴，将体系置于冰浴下冷却，之后分批加入1.7g硼氢化钠，继续搅拌反应1h，之后加热至60℃反应2h，之后加入20mL饱和氯化铵溶液淬灭反应，淬灭完毕后继续搅拌30min，之后将体系过滤，收集滤液，旋去溶剂后，剩余物用乙酸乙酯溶解，用饱和氯化钠溶液洗涤一次，收集乙酸乙酯相，并用无水硫酸钠干燥，将干燥后的乙酸乙酯相收集并旋去溶剂，对剩余物进行硅胶柱纯化，得到米黄色液体0.62g，即化合物7，收率62％。
实施例8
Figure PCTCN2018105997-appb-000018
称取1g化合物7溶于20mL无水甲醇中，体系置于冰浴下冷却，之后加入210μL 6M的盐酸溶液，继续搅拌1h，之后将溶剂旋干，得到白色固体1.3g，即化合物7的盐酸盐，收率89％。
实施例9
Figure PCTCN2018105997-appb-000019
称取10g原料置于50mL干燥的甲苯中搅拌，体系呈浑浊状态，原料不溶，之后逐渐加入6.9mL三乙胺(1.05eq)，体系很快变为浅棕色透明，加入过程 中体系有轻微放热现象，搅拌约5min后，用恒压滴液逐渐滴入18.6g DPPA(1.05eq)，体系逐渐变为橙黄色透明，过程中无明显放热现象，滴加结束后室温搅拌反应，反应约3h后，TLC监测反应显示反应转化完全，之后向体系中加入50mL叔丁醇，并对体系进行氮气保护，之后逐渐升温至90℃反应，反应过程中体系会产生气体，注意放气，不要让体系内压过大，反应约8h后停止反应，将体系置于旋转蒸发仪上将体系溶剂旋去，剩余得到棕色油状液体，用甲基叔丁基醚(MTBE)多次对其进行萃取，萃取至油状物中无明显产物为止，之后合并萃取相，用饱和碳酸氢钠溶液洗涤一次，之后收集有机相，无水硫酸钠干燥，干燥结束后，旋去溶剂得到11g浅黄色固体粉末，即化合物2，无需进一步纯化即可用于下一步反应投料，收率75％。
实施例10
Figure PCTCN2018105997-appb-000020
将上述得到的11g化合物2置于100mL干燥的DMF中搅拌溶解，之后将体系置于-5℃低温反应釜中冷却，之后分批加入2.1g 60％的NaH(1.1eq)，加料过程中控制体系内温不超过5℃，加入NaH的过程中体系会产生许多气泡，并变为棕黄色浑浊，加入结束后，体系继续搅拌10min，之后逐渐滴入7.6g碘甲烷(1.1eq)，加料过程中控制体系内温不超过5℃，随着滴加进行体系粘稠度会增大，加入结束后，体系继续于-5℃低温反应釜中搅拌10min，之后置于室温搅拌反应，体系呈咖啡色浑浊，TLC监测反应至原料转化完全为止，之后加入2mL饱和亚硫酸钠溶液淬灭反应，淬灭后体系呈棕褐色浑浊，pH＝8-9。将淬灭后的体系过滤，收集滤液，之后用机械泵将体系溶剂除去，剩余物用MTBE溶解，将不溶物过滤除去，收集滤液，并用饱和碳酸氢钠洗涤一次，收集MTBE 相，并用无水硫酸钠干燥，将干燥后的MTBE相收集并旋去溶剂，得到12.6g棕色油状物，之后用石油醚对得到的油状物进行重结晶，会得到大量亮黄色固体，过滤收集并用少量冷的石油醚洗涤一次，之后收集，自然晾干，得到9.4g亮黄色固体，即产物中间体4，可直接用于下一步反应。
实施例11
Figure PCTCN2018105997-appb-000021
将3.9g氢化铝锂分批加入到40mL干燥的THF中，之后体系置于-20℃低温反应釜中冷却，体系氮气保护，之后缓慢滴入5g氯化铝，滴加过程体系剧烈放热，控制体系内温不超过0℃，滴加结束后，体系继续于-20℃下搅拌10min，之后将4.1g化合物4溶于40mL干燥的THF中，并逐渐滴入到上述还原体系中，滴加过程控制体系内温不超过0℃，滴加结束后，使体系逐渐升至室温反应3h，反应结束后再次将体系置于-20℃低温反应釜中冷却，加入碳酸氢钠溶液淬灭反应，之后将体系过滤，收集滤液，将溶剂抽干，剩余物用丙烯酸乙酯(EA)溶解，并加入无水硫酸钠干燥，干燥结束后，将体系浓缩可得到约2g黄色液体，不经纯化直接用于成盐，将其溶于10mL无水乙醇中，之后体系加热至40℃，之后逐渐滴入2.7g TMSCl，体系产生大量白色固体沉淀，体系继续于40℃搅拌1h，之后逐渐降至室温，将析出的固体过滤收集，用少量乙醇洗涤一次，之后干燥得到2.7g白色固体，即目标化合物，收率69％。
实施例12
采用实施例11相同的方法，将氯化铝替换为氯化铁、三氟化硼、五氯化铌、盐酸、硝酸，或者将氢化铝锂替换为氰基硼氢化钠、硼烷、三叔丁氧基氢化铝锂也可以制备得到目标化合物，收率在60～75％之间，表明酸性条件即可有利于 反应进行。
实施例13制备3-甲胺基-3-氨基氮杂环丁烷
Figure PCTCN2018105997-appb-000022
参考实施例1-7的方法，不同之处在于将原料替换为
Figure PCTCN2018105997-appb-000023
最后脱去氨基上的苄基保护，得到目标化合物。质谱数据：102.5[M+H] +。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种杂环化合物，其特征在于，所述杂环化合物的结构如下式I所示：
    Figure PCTCN2018105997-appb-100001
    其中，Het代表无取代或任选被一个或多个R S1取代的3-20元杂环基；
    R 1、R 2相同或不同，彼此独立地选自氢、无取代或任选被一个或多个R S2取代的C 1-40烷基或C 3-20环烷基；
    R S1、R S2相同或不同，彼此独立地选自C 1-40烷基、C 1-40烷氧基或C 3-20元环烷基。
  2. 根据权利要求1所述的杂环化合物，其特征在于，Het选自氧杂环丁烷、硫杂环丁烷、氮杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、吡唑烷、四氢吡喃或哌啶；
    R 1、R 2相同或不同，彼此独立地选自氢、C 1-8烷基或C 3-10环烷基；
    优选地，所述式I化合物选自如下化合物：
    Figure PCTCN2018105997-appb-100002
  3. 根据权利要求1或2所述杂环化合物的盐，其特征在于，所述盐为杂环化合物中任意可成盐位点形成的酸加成盐；
    优选地，所述酸加成盐选自无机酸加成盐或有机酸加成盐。
  4. 根据权利要求1或2所述杂环化合物的制备方法，其特征在于，所述制备方法包括：
    方案1：
    Figure PCTCN2018105997-appb-100003
    (1a)化合物II进行反应，得到化合物III；
    (1b)步骤(1a)得到的化合物III与R 1X 1及R 2X 2进行反应，得到化合物VI；
    (1c)步骤(1b)得到的化合物VI反应得到化合物I；或者
    方案2：
    Figure PCTCN2018105997-appb-100004
    (2a)化合物II与化合物VII进行反应，得到化合物VIII；
    (2b)步骤(2a)得到的化合物VIII进行反应，得到化合物IX；
    (2c)步骤(2b)得到的化合物IX与化合物XI进行反应，得到化合物VI；
    (2d)步骤(2c)得到的化合物VI进行反应，得到化合物I；或者
    方案3：
    Figure PCTCN2018105997-appb-100005
    (3a)化合物II进行反应，得到化合物III；
    (3b)步骤(3a)得到的化合物III反应得到化合物I；或者
    方案4：
    Figure PCTCN2018105997-appb-100006
    (4a)化合物II与化合物VII进行反应，得到化合物VIII；
    (4b)步骤(4a)得到的化合物VIII进行反应，得到化合物I；
    上述化合物中，Het、R 1、R 2具有权利要求1或2所述定义；R 3选自C 1-40烷基或苄基；X、X 1、X 2、X 3相同或不同，彼此独立地选自Cl、Br或I；
    方案1或方案2中R 1、R 2均不为H。
  5. 根据权利要求4所述杂环化合物的制备方法，其特征在于，步骤(1a) 中，
    所述反应可以在酸性或还原性条件下进行；
    优选地，步骤(1b)中，
    所述反应可以在碱性条件下进行；
    优选地，步骤(1c)中，
    所述反应可以加入还原剂，所述还原剂选自硼氢化钠、氰基硼氢化钠、硼烷、氢化铝锂、三叔丁氧基氢化铝锂中的一种、两种或更多种；
    所述反应可以任选加入或不加助催化剂，当加入助催化剂时，所述助催化剂可以为路易斯酸；
    优选地，步骤(2a)中，
    所述反应可以在碱性条件下进行；
    优选地，步骤(2b)中，
    所述反应可以在酸性或还原性条件下进行；
    优选地，步骤(2c)中，
    所述反应可以在碱性条件下进行；
    优选地，步骤(2d)中，
    所述反应可以加入还原剂，所述还原剂选自硼氢化钠、氰基硼氢化钠、硼烷、氢化铝锂、三叔丁氧基氢化铝锂中的一种、两种或更多种；
    所述反应可以任选加入或不加助催化剂，当加入助催化剂时，所述助催化剂可以为路易斯酸；
    优选地，步骤(3a)中，
    所述反应可以在酸性或还原性条件下进行；
    优选地，步骤(3b)中，
    所述反应可以加入还原剂，所述还原剂选自硼氢化钠、氰基硼氢化钠、硼烷、氢化铝锂、三叔丁氧基氢化铝锂中的一种、两种或更多种；
    所述反应可以任选加入或不加助催化剂，当加入助催化剂时，所述助催化 剂可以为路易斯酸；
    优选地，步骤(4a)中，
    所述反应可以在碱性条件下进行；
    优选地，步骤(4b)中，
    所述反应可以加入还原剂，所述还原剂选自硼氢化钠、氰基硼氢化钠、硼烷、氢化铝锂、三叔丁氧基氢化铝锂中的一种、两种或更多种；
    所述反应可以在酸性条件下进行。
  6. 根据权利要求4或5所述杂环化合物的制备方法，其特征在于，所述制备方法包括化合物II的制备：
    Figure PCTCN2018105997-appb-100007
    1)化合物XII进行反应，得到化合物XIII；
    2)步骤1)得到的化合物XIII与化合物XIV进行反应，得到化合物II；
    其中，Het具有权利要求1或2所述的定义；R 3选自C 1-40烷基或苄基。
  7. 根据权利要求6所述杂环化合物的制备方法，其特征在于，步骤1)中，所述反应可以加入含有叠氮基团的化合物；所述含有叠氮基团的化合物选自叠氮化钠、叠氮磷酸二苯酯(DPPA)、对甲基苯磺酰基叠氮中的一种、两种或更多种；
    所述反应可以在碱性条件下进行。
  8. 下式II，或式III，或式VIII，或式XIII所示的化合物，
    Figure PCTCN2018105997-appb-100008
    其中，化合物中的Het、R 1具有权利要求1或2所述的定义；R 3选自C 1-40烷基或苄基。
  9. 如权利要求3所述杂环化合物的盐的制备方法，其特征在于，所述制备方法包括：将权利要求1或2所述的杂环化合物与酸反应或与可生成酸的体系反应得到杂环化合物的盐。
  10. 权利要求1或2所述的杂环化合物、或权利要求3所述的杂环化合物的盐、或权利要求8所述的式II化合物、或式III化合物、或式VIII化合物、或式XIII化合物作为中间体在制备其他化合物中的用途；
    优选下式所示的化合物或其盐作为中间体在制备其他化合物中的用途，
    Figure PCTCN2018105997-appb-100009
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