WO2023125397A1 - 作为免疫调节的芳环衍生物的制备方法 - Google Patents

作为免疫调节的芳环衍生物的制备方法 Download PDF

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WO2023125397A1
WO2023125397A1 PCT/CN2022/141877 CN2022141877W WO2023125397A1 WO 2023125397 A1 WO2023125397 A1 WO 2023125397A1 CN 2022141877 W CN2022141877 W CN 2022141877W WO 2023125397 A1 WO2023125397 A1 WO 2023125397A1
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formula
compound
compound represented
alkyl
compound shown
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PCT/CN2022/141877
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English (en)
French (fr)
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张勇
康樟平
叶龙兵
王明力
吴迎春
程宏明
彭建彪
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上海济煜医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, in particular, the invention relates to a preparation method of an aromatic ring derivative as an immune regulator.
  • Sphingosine-1-phosphate is an amphoteric biological signal molecule belonging to lysophospholipid (LP). S1P can regulate important physiological and biochemical functions by acting on five G protein-coupled receptor subtypes—sphingosine-1-phosphate receptor (S1PR 1-5 ) to activate complex downstream signals. The combination of S1P and different S1P receptors can regulate different physiological functions, and plays an important role in the maintenance of body health and the occurrence of diseases.
  • S1P1 receptor agonists interfere with lymphocyte trafficking, sequestering them in lymph nodes and other secondary lymphoid tissues. This results in a decrease in peripheral circulating lymphocytes, and the clinical value of lymphocyte sequestration is to exclude them from the field of inflammation and/or autoimmune responses in surrounding tissues.
  • This sequestration of lymphocytes (e.g. in lymph nodes) is thought to be the result of a simultaneous agonist-driven antagonism of the S1P1 receptor on T cells (thus reducing S1P mobilization of T cell efflux from the lymph node). ability) and sustained agonism of S1P1 receptors on lymph node endothelium (thereby improving barrier function against lymphocyte migration). Therefore, S1P 1 receptor agonists reduce the body's autoimmunity by preventing the transport of lymphocytes, and thus can be used as immunosuppressants for the treatment of various autoimmune diseases.
  • the S1P1 agonist Fingolimod has been approved by the FDA for the treatment of relapsing multiple sclerosis (Multiple Scleorosis, MS), which has opened up a new therapeutic field for the treatment of immune diseases.
  • FTY720 has clinical efficacy, it is a non-selective S1P receptor agonist, and the binding of FTY720 to S1P3 in vivo often leads to a series of important side effects, such as bradycardia, etc., which greatly limits its therapeutic immunity The range of application in the field of disease. Therefore, the discovery of the second-generation highly selective S1P1 agonist, making it a drug for the treatment of immune diseases with better curative effect, fewer side effects and wider application range, has become one of the hot spots of drug research.
  • Patent application CN113185446A discloses a S1P1 receptor agonist with novel structure, S1P1 receptor selectivity and short half-life. Its structure is shown in formula (I),
  • Example 16 of the patent application CN113185446A discloses the preparation method of the compound shown in the specific compound A6, which is as long as 12 steps, and the operation is cumbersome, as follows:
  • step reaction Among them, the introduction of methyl group in the first step reaction needs palladium catalysis, the cost is high, and it is a microwave reaction, which is not suitable for amplification; the second step is the ylide reaction, the Wittig reagent is relatively unstable, the post-processing is troublesome, and the formation of acid requires three steps.
  • the product generated after the third step reaction It is extremely unstable, which makes this step of separation and purification difficult, and the hydrolysis yield is low, which in turn makes the yield particularly low, making the production cost particularly high, which is not conducive to large-scale industrial production.
  • the present invention provides a completely different method for synthesizing the compound shown in formula (I) from the prior art, which can avoid the generation of this extremely unstable compound
  • the cost is saved, the yield is improved, the operation is simplified, and commercial mass production becomes possible.
  • the present invention proposes a preparation method of the compound represented by formula (I). According to an embodiment of the present invention, the method includes:
  • R 2 is selected from H, halogen, OH, NH 2 , CN and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 3 is selected from C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 2-6 alkenyl and 3-6 membered heterocycloalkyl, the C 3-7 cycloalkyl, C 3-7 Cycloalkenyl C 2-6 alkenyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;
  • R a is independently selected from H, halogen, OH, NH 2 , CN and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R b is selected from H, halogen, OH, NH 2 , CN and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and CF 3 ;
  • T1 is selected from N and CH;
  • T2 is selected from N and CH;
  • L is selected from single bonds, O and S;
  • the 3-6 membered heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S and N.
  • the inventor cleverly designed the reaction of the present invention, only one step reaction is required to realize the four-step reaction in the prior art, and the generation of unstable products is avoided, the yield is greatly improved compared with the prior art, and the operation is simple , cost saving, suitable for large-scale industrial production.
  • the above method may further include at least one of the following additional technical features:
  • the contacting is performed under the condition that the solvent is N,N-dimethylformamide.
  • the contacting is carried out in the presence of formic acid.
  • the contacting is carried out in the presence of triethylamine.
  • the molar ratio of the compound represented by the formula (I-A) to the compound represented by the formula (I-B) is 1:1-1:1.2.
  • the molar ratio of the compound represented by the formula (I-A) to formic acid is 1:5.0-1:13.3.
  • the molar ratio of the compound represented by the formula (I-A) to formic acid is 1:10.0. The inventors found that within this range, less impurities are produced and the treatment is more convenient.
  • the molar ratio of the compound represented by the formula (I-A) to triethylamine is 1:2.0-1:3.3.
  • the compound represented by the formula (I-A) is obtained by performing an oxidation reaction on the compound represented by the formula (I-C),
  • the present invention also proposes a preparation method of the compound represented by formula (I-A), which is obtained by performing an oxidation reaction on the compound represented by formula (I-C).
  • the oxidation reaction is carried out under the condition that the oxidizing agent is 2-iodobenzoic acid or manganese dioxide.
  • the oxidizing agent is 2-iodobenzoic acid or manganese dioxide.
  • the present invention when L 1 is selected from , the present invention also proposes a preparation method of the compound represented by formula (IC), which is obtained by performing a substitution reaction between the compound represented by formula (ID) and the compound represented by formula (IE).
  • the compound represented by the formula (I-E) is obtained by performing a nucleophilic substitution reaction on the compound represented by the formula (I-H),
  • Rh is selected from phenyl and heteroaryl.
  • the present invention also proposes a preparation method of the compound represented by the formula (I-E), which is obtained by performing a nucleophilic substitution reaction on the compound represented by the formula (I-H).
  • R f is selected from C 1-6 alkyl.
  • the present invention when L 1 is selected from , the present invention also proposes a preparation method of the compound represented by formula (IC), which is obtained by reducing the compound represented by formula (IF).
  • the compound represented by the formula (I-F) is obtained through a substitution reaction between the compound represented by the formula (I-D) and the compound represented by the formula (I-G),
  • the present invention also proposes a preparation method of the compound represented by formula (I-F), which is obtained through a substitution reaction between the compound represented by formula (I-D) and the compound represented by formula (I-G).
  • the compound represented by the formula (I-H) is obtained by reducing the compound represented by the formula (I-J),
  • R f is selected from C 1-6 alkyl.
  • the present invention also proposes a preparation method of the compound represented by formula (IH), which is obtained by reducing the compound represented by formula (IJ), wherein R f is selected from C 1- 6 alkyl.
  • the compound represented by formula (I-G) is obtained by reducing the compound represented by formula (I-J).
  • the present invention also proposes a preparation method of the compound represented by formula (I-G), which is obtained by reducing the compound represented by formula (I-J).
  • the compound represented by the formula (I-J) is obtained through the compound represented by the formula (I-K) and the compound represented by the formula (I-L) is obtained through the Fischer method of the Yap-Klingemann azo ester intermediate. The cyclization of indole was obtained,
  • the present invention also proposes a preparation method of the compound shown in the formula (I-J), which is through the compound shown in the formula (I-K) and the compound shown in the formula (I-L) through the Japp-Kling
  • the Fischer indole cyclization of the Gehmann azo ester intermediate was obtained.
  • the compound represented by the formula (I-J) is obtained by performing a Fischer indole synthesis reaction between the compound represented by the formula (I-W) and the compound represented by the formula (I-Z),
  • the present invention also proposes a preparation method of the compound shown in the formula (I-J), which is to carry out Fischer indole synthesis through the compound shown in the formula (I-W) and the compound shown in the formula (I-Z) The response is obtained.
  • the Fischer indole synthesis reaction is carried out in the presence of concentrated sulfuric acid.
  • the molar ratio of the concentrated sulfuric acid to the compound represented by the formula (I-W) is 0.5:1.
  • the present invention also proposes a compound represented by formula (II).
  • the compound represented by formula (II) is as follows,
  • R 2 is selected from H, halogen, OH, NH 2 , CN and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 3 is selected from C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 2-6 alkenyl and 3-6 membered heterocycloalkyl, the C 3-7 cycloalkyl, C 3-7 Cycloalkenyl C 2-6 alkenyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;
  • R a is independently selected from H, halogen, OH, NH 2 , CN and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R b is selected from H, halogen, OH, NH 2 , CN and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and CF 3 ;
  • T1 is selected from N and CH;
  • T2 is selected from N and CH;
  • T 3 is selected from N and C(R a );
  • L is selected from single bonds, O and S;
  • the 3-6 membered heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S and N.
  • the present invention also proposes a preparation method of the compound represented by formula (I).
  • the compound represented by the formula (I) is obtained by performing a lactam ring-opening reaction on the compound represented by the formula (II) according to claim 12 .
  • the above method may further include at least one of the following additional technical features:
  • R f is selected from C 1-6 alkyl.
  • the compound represented by the formula (II-A) is obtained by reducing the compound represented by the formula (II-B),
  • Rh is selected from phenyl and heteroaryl.
  • the compound represented by the formula (II-B) is obtained by performing a wittig reaction between the compound represented by the formula (II-C) and the compound represented by the formula (II-D),
  • the compound represented by the formula (II-C) is obtained by performing an oxidation reaction on the compound represented by the formula (I-H).
  • R is selected from H, F, Cl, Br, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and CF 3 , and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and the CH 3 or CH 2 CH 3 is optionally replaced by 1, 2 or 3 R substitutions, other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and CF 3 , and other variables are as defined in the present invention.
  • the above-mentioned R 3 is selected from C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 2-3 alkenyl and 3-6 membered heterocycloalkyl, and the C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, C 2-3 alkenyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 3 is selected from said Optionally substituted with 1, 2 or 3 R, other variables are as defined herein.
  • R a is selected from H, F, Cl, Br, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and the CH 3 or CH 2 CH 3 is optionally represented by 1, 2 or 3 R substitutions, other variables are as defined in the present invention.
  • R a is selected from H, F, Cl, Br, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and CF 3 , and other variables are as defined in the present invention.
  • R b is selected from H, F, Cl, Br, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and the CH 3 or CH 2 CH 3 is optionally replaced by 1, 2 or 3 R substitutions, other variables are as defined in the present invention.
  • R b is selected from H, F, Cl, Br, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and CF 3 , and other variables are as defined in the present invention.
  • the present invention when L is selected from , the present invention also proposes a preparation method of the compound shown in formula II), which is obtained by performing a substitution reaction between the compound shown in formula (ID) and the compound shown in formula (II-A),
  • R f is selected from C 1-6 alkyl.
  • the present invention also proposes a preparation method of the compound shown in formula (II-A), which is obtained by performing a reduction reaction on the compound shown in formula (II-B), wherein Rh is selected from from phenyl and heteroaryl.
  • the present invention also proposes a preparation method of the compound shown in the formula (II-B), which is carried out by the compound shown in the formula (II-C) and the compound shown in the formula (II-D) Wittig reaction obtained.
  • the present invention also proposes a preparation method of the compound represented by formula (II-C), which is obtained by performing an oxidation reaction on the compound represented by formula (I-H).
  • the compound represented by the formula (I) is selected from the following compounds or pharmaceutically acceptable salts thereof,
  • the compound represented by the formula (I) is selected from
  • the compound represented by the formula (I) is selected from
  • the compound represented by the formula (IA) is selected from
  • the compound represented by the formula (IA) is selected from
  • the compound represented by the formula (IC) is selected from
  • the compound represented by the formula (IC) is selected from
  • the compound represented by the formula (ID) is selected from
  • the compound represented by the formula (IE) is selected from
  • the compound represented by the formula (IH) is selected from
  • the compound represented by the formula (IF) is selected from
  • the compound represented by the formula (IF) is selected from
  • the compound represented by the formula (IJ) is selected from
  • the compound represented by the formula (IK) is selected from
  • the compound represented by the formula (IW) is selected from
  • the compound represented by the formula (IL) is selected from
  • the compound represented by the formula (IZ) is selected from
  • the compound represented by the formula (II) is selected from
  • the compound represented by the formula (II) is selected from
  • the compound represented by the formula (II-A) is selected from
  • the compound represented by the formula (II-B) is selected from
  • the compound represented by the formula (II-C) is selected from
  • the compound represented by the formula (II-D) is selected from
  • the term "contact” should be understood in a broad sense, and it can be any way that can cause at least two reactants to undergo a chemical reaction, for example, it can be mixing the two reactants under appropriate conditions.
  • the reactants that need to be contacted can be mixed under stirring, thus, the type of stirring is not particularly limited, for example, it can be mechanical stirring, that is, stirring under the action of mechanical force
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • "Optional" or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of.
  • substituent which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds. For example, can be selected from wait.
  • this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring.
  • the carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example, The linking group L is at this time
  • Both phenyl and cyclopentyl groups can be joined in the same direction as the reading order from left to right to form
  • the phenyl and cyclopentyl groups can also be joined in the opposite direction to the left-to-right reading order to form
  • Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "3-6 membered ring” means a "ring” with 3-6 atoms arranged around it.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
  • C2-6alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
  • the C 2-6 alkenyl includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl, etc.; it may be monovalent, divalent or multivalent.
  • Examples of C alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.
  • C2-3 alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
  • the C 2-3 alkenyl includes C 3 and C 2 alkenyl; the C 2-3 alkenyl can be monovalent, divalent or multivalent. Examples of C 2-3 alkenyl include, but are not limited to, ethenyl, propenyl, and the like.
  • C 3-7 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 7 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-7 cycloalkyl includes C 4-7 , C 5-7 , C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.
  • cycloalkenyl in the present invention refers to a cyclic alkenyl group.
  • C 3-7 cycloalkenyl includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkenyl.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is from n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-member
  • Room temperature in the present invention refers to a temperature from about 10°C to about 40°C. In some embodiments, “room temperature” refers to a temperature from about 20°C to about 30°C; in other embodiments, “room temperature” refers to 20°C, 22.5°C, 25°C, 27.5°C, and the like.
  • “at room temperature or under heating” means that the reaction is carried out at a certain temperature, and the certain temperature is room temperature or a specific temperature achieved by heating.
  • the reaction of preparing the compound of formula (III) from the compound of formula (IV) described in the present invention is carried out at room temperature or under heating conditions, which means that the reaction is carried out at a certain temperature, and the certain temperature is room temperature or by Heating to a specific temperature; for example, the reaction is carried out at room temperature (such as 20°C-30°C) or heated to 30°C-65°C, that is, the reaction is carried out at 20°C-65°C of.
  • reaction steps of the present invention are reacted to a certain extent such as raw material consumption is about greater than 70%, greater than 80%, greater than 90%, greater than 95%, or post-processing is carried out after the detection of reaction raw materials has been consumed, such as cooling, collection, Extraction, filtration, separation, purification or a combination thereof.
  • the degree of reaction can be detected by conventional methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC) and the like.
  • the reaction solution can be post-treated by conventional methods, for example, the crude product is collected after vacuum evaporation or conventional distillation of the reaction solvent, and is directly put into the next step of reaction; or directly filtered to obtain the crude product, which is directly put into the next step of reaction; Finally, pour out the supernatant to obtain the crude product, which is directly put into the next reaction; or choose an appropriate organic solvent or its combination to perform purification steps such as extraction, distillation, crystallization, column chromatography, rinsing, and beating.
  • the reaction raw materials or other reagents can be added to the reaction system by dropwise addition.
  • Each of the dropping processes and each step of the reaction are carried out under certain temperature conditions, and any temperature suitable for each dropping process or each reaction process is included in the present invention.
  • many similar modifications, equivalent replacements, or equivalents to the temperature and temperature range described in the present invention are considered to be within the scope of the present invention.
  • the present invention provides the preferred temperature or temperature range of each dropping process, and the preferred reaction temperature of each reaction.
  • the solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting material to a certain extent and does not inhibit the reaction is included in the present invention.
  • many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are considered to be within the scope of the present invention.
  • the present invention provides the preferred solvents used in each reaction step.
  • the product of each reaction step described in the present invention can be purified by recrystallization under appropriate conditions.
  • the recrystallization solvent used is not particularly limited, and any solvent that can dissolve the crude product to a certain extent and can precipitate crystals under certain conditions is included in the present invention.
  • many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are considered to be within the scope of the present invention.
  • the solvent may be alcohols, ethers, alkanes, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, acetic acid, water, DMF or combinations thereof.
  • the content of moisture in the solvent in the present invention is not particularly limited, that is, the content of moisture in the solvent does not affect the occurrence of the reaction in the present invention.
  • Any solvent containing a certain amount of water that can be used in the present invention to a certain extent is regarded as the solvent described in the present invention.
  • the moisture content in the solvent is approximately less than 0.05%, less than 0.1%, less than 0.2%, less than 0.5%, less than 5%, less than 10%, less than 25%, less than 30%, or 0%.
  • the moisture content of the solvent is within a certain range, which is more conducive to the reaction; for example, in the step of using ethanol as the reaction solvent, using absolute ethanol is more favorable to the reaction.
  • the moisture content of the solvent exceeds a certain range, which may affect the progress of the reaction (for example, affect the yield of the reaction), but does not affect the occurrence of the reaction.
  • the intermediate compounds involved in the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art Known equivalents, preferred embodiments include but are not limited to the examples of the present invention. But all should be considered to be included in the protection scope of the present invention.
  • the solvent used in the present invention is commercially available.
  • DMF stands for N,N-dimethylformamide
  • TEA stands for triethylamine
  • LiOH stands for lithium hydroxide
  • TEMPO stands for 2,2,6,6-tetramethylpiperidine oxide
  • BAIB stands for iodobenzenediacetic acid
  • IBX stands for 2-iodoxybenzoic acid
  • KF stands for potassium fluoride
  • NaOCl stands for sodium hypochlorite
  • NaBr stands for sodium bromide
  • NaHCO3 stands for sodium bicarbonate
  • MnO2 stands for manganese dioxide
  • Cs2CO3 stands for cesium carbonate
  • K2CO3 Represents potassium carbonate
  • TsOH represents p-toluenesulfonic acid
  • T3P represents propyl phosphoric anhydride
  • EA represents ethyl acetate
  • ZnCl2 represents zinc chloride
  • AcOH represents acetic acid
  • H3PO4 represents phosphoric acid
  • NMR spectral data were determined by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, using CDC1 3 , d 6 -DMSO, CD 3 OD, D 2 O or d 6 -acetone as solvent (with ppm as the unit), with TMS (0ppm) or chloroform (7.25ppm) as the reference standard.
  • the high performance liquid chromatograph is equipped with G1311B quaternary pump, G1329B automatic sampler, G1316A TCC (column temperature is kept at 30°C) and G1315D DAD detector.
  • the chromatographic column is Agilent Poroshell 120EC-C18 4 ⁇ m 4.6 ⁇ 150mm, 2.7 ⁇ m; the flow rate is 1.0mL/min; the detection wavelength is 226nm; the mobile phase and its gradient elution conditions are shown in Table 1 below.
  • Mobile phase A is 0.05% formic acid aqueous solution
  • Mobile phase B is 0.05% formic acid acetonitrile solution
  • sodium nitrite aqueous solution purified water: 6.2Kg; sodium nitrite: 2.5Kg, 36.2mol
  • Step 2 add tetrahydrofuran (39.1Kg) and compound C (4.3Kg, 13.9mol) into reaction kettle 1, and replace with nitrogen. Cool to 0-5°C, slowly drop into red aluminum (70% toluene solution, 8.3Kg, 28.8mol) at 0-5°C, heat up to 5-10°C, keep stirring at 5-10°C for 1-5 hours, liquid The phase detection reaction is complete.
  • Step 3 Add compound D methanol solution (13.0Kg, reduced purity 3.7Kg, 13.8mol) and methanol (20.4Kg) into reaction kettle 1.
  • the catalyst preparation tank was replaced with nitrogen, and 10% wet palladium carbon (0.37Kg) and methanol (3.0Kg) were added.
  • Step 4 Add compound E (0.66Kg, 3.72mol), N,N-dimethylformamide (3.2Kg), compound F (1.00Kg, 3.81mol), cesium carbonate (2.47Kg, 7.58mol) to the reactor ). Raise the temperature to 45-55° C., heat and stir for 3-6 hours, and the liquid phase detection reaction is complete. Cool down to 20-30°C, filter with diatomaceous earth (0.67Kg), rinse the filter cake with 2-methyltetrahydrofuran (5.8kg), wash the filtrate with water (3.40Kg), and wash the water phase with 2-methyltetrahydrofuran (1.7 Kg) extraction. The combined organic phases were washed with 15% brine (3.3Kg).
  • Step 5 Add compound G in N,N-dimethylformamide solution (4.03kg, 2.16mol), tetrahydrofuran (6.2Kg), manganese dioxide (1.64Kg) into the reaction kettle, heat up to 64-73°C, After 16 hours of reaction, the liquid phase detection reaction was completed. Cool down to 20-30°C, filter with diatomaceous earth (1.74Kg), and wash the filter cake with 2-methyltetrahydrofuran (10.4kg). Cool down to 5-15°C, add 5% sodium bisulfite solution (8.7kg) dropwise, stir, let stand, separate liquids, and extract the aqueous phase with 2-methyltetrahydrofuran (7.4Kg).
  • Step 6 Add N,N-dimethylformamide (1.84kg) to the reaction kettle, lower it to 0-10°C, add formic acid (0.44kg, 9.56mol), and add triethylamine (0.32kg, 3.16mol) , stirred for 10-20 minutes, added compound H (0.38kg, 0.95mol), compound I-B (0.18kg, 1.25mol), raised the temperature to 75-85°C, reacted for 12 hours, and the reaction was completed by liquid phase detection. Decrease to 15-25°C, add 2-methyltetrahydrofuran (3.31kg), purified water (3.84Kg), dropwise add 2M hydrochloric acid solution (1.52kg) to adjust the pH value to 1-2, stir, stand still, and separate layers.
  • the organic phase was washed with 10% brine (3.80Kg). Concentrate the organic phase to 1.5-2.0V, adjust the internal temperature to 35-45°C, add n-heptane (4.17kg) dropwise, cool down to 5-15°C, beat for 4-6 hours, filter, and dry the filter cake to obtain 0.3585kg Compound A6, purity: 96.7%, yield 85.0%.
  • Step 1 Same as Step 1 of Example 1
  • Step 2 Add compound C (1.0eq.) and methanol (10.0v) into the reaction kettle.
  • the catalyst preparation tank was replaced with nitrogen, and 10% wet palladium carbon (10% W) was added. Nitrogen was replaced three times, hydrogen was replaced three times, hydrogen was introduced, the pressure of the reactor was controlled at 0.50-0.60MPA, the temperature was raised to 40-45°C, and the reaction was completed for 16-18 hours.
  • Step 3 Add compound J (1.0eq.), acetonitrile (10v), compound F (1.0eq.), cesium carbonate (2.0eq.) into the reaction flask. Raise the temperature to 45-55°C, heat and stir for 3-6 hours, and detect that the reaction is complete. Cool down to 20-30°C, filter with diatomaceous earth (0.67Kg), rinse the filter cake with 2-methyltetrahydrofuran, wash the filtrate with water, and extract the aqueous phase with 2-methyltetrahydrofuran. The combined organic phases were washed with 15% brine (3.3Kg).
  • Step 4 add tetrahydrofuran (10.0v) and compound K (1.0eq.) to the reaction kettle, and replace with nitrogen. Cool to 0-5°C, slowly drop red aluminum (70% toluene solution, 2.1eq.) at 0-5°C, heat up to 5-10°C, keep stirring at 5-10°C for 1-5 hours, and detect that the reaction is complete . Add 10% aqueous sodium hydroxide solution dropwise at 0-10°C, stir at 5-15°C for 30-40 minutes, let stand, separate layers, wash the organic phase with saline, and concentrate the organic phase to dryness under reduced pressure to obtain compound G. The yield 84%.
  • Step 5 Dissolve compound G (1.0eq.) in dichloromethane (10v) at room temperature, add TEMPO (0.1eq.), BAIB (1.1eq.) is added, and stir at 25°C until the reaction of the raw materials is complete. After filtration, the filtrate was washed with aqueous sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, and concentrated to remove the organic solvent to obtain compound H with a yield of 70%.
  • TEMPO 0.1eq.
  • BAIB 1.1eq.
  • Step 1 Same as Step 1 of Example 1
  • Step 2 same as embodiment 1 step 2
  • Step 3 Dissolve compound D (1.0eq.) in tetrahydrofuran (10.0v/w) at room temperature, add active manganese dioxide (10.0eq.), after the addition is complete, replace nitrogen and heat to 68°C (internal temperature) and stir React until the raw materials are completely reacted.
  • the reaction mixture was cooled to 25°C, filtered with diatomaceous earth to remove manganese dioxide, the filtrate was washed with 5% sodium bisulfite solution, concentrated under reduced pressure to 1-2v, slurried with n-heptane, filtered, and dried to obtain compound L. Rate 80%.
  • Step 4 add tetrahydrofuran (10.0v) to compound L (1.0eq.), add compound W (1.1eq.), and stir the reaction at room temperature until the reaction of the raw materials is complete. After washing with aqueous sodium bicarbonate solution, the organic phase was concentrated and slurried with n-heptane to finally obtain compound M with a yield of 80%.
  • Step 5 Add compound M (1.0eq.) and tetrahydrofuran (10.0v) into the reaction kettle.
  • the catalyst preparation tank was replaced with nitrogen, and 10% wet palladium carbon (10% W) was added. Nitrogen was replaced three times, hydrogen was replaced three times, hydrogen was introduced, the pressure of the reactor was controlled at 0.50-0.60MPA, the temperature was raised to 40-45°C, and the reaction was completed for 16-18 hours. The temperature was lowered to 20-30° C., the reaction liquid was pressure-filtered with nitrogen, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain Compound N with a yield of 95.0%.
  • Step 6 Under nitrogen, compound N (3.0g, 1.0eq.) and compound F (3.5g, 1.1eq.) and cesium carbonate (7.88g, 2.0eq.) were added to dry acetonitrile (39.3g, 13.0 v) The reaction was stirred at 50° C. for 2 hours, and IPC showed that the raw materials were completely reacted. After adding 2M lithium hydroxide aqueous solution, a large amount of solids were precipitated, cooled to room temperature, filtered, and the filter cake was dried to obtain 3.84 g of compound P with a purity of 99.6% and a yield of 74.1%.
  • Step 7 Add compound P (3.5g, 1.0eq.), ethanol (30.0mL), water (10.0mL), lithium hydroxide (1.0g, 3eq.) into the reaction flask, heat up to 60°C and stir the reaction to the raw material After the reaction was complete, dilute hydrochloric acid was used to adjust the pH to 4-5 to obtain 2.5 g of compound A6 with a yield of 68.5%.
  • Step 6 in Example 1 was screened for conditions, and the specific reaction conditions are shown in Table 2 below.
  • Step 5 in Example 1 was screened for conditions, and the specific reaction conditions are shown in Table 3 below.
  • the relative conversion rate is higher under the oxidation condition that the oxidizing agent is IBX and MnO 2 , and the reaction conversion rate of other conditions is low.
  • Step 4 in Example 1 was screened for conditions, and the specific reaction conditions are shown in Table 4 below.
  • Steps one to five are the same as in Example 3,

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Abstract

提供了作为免疫调节的芳环衍生物的制备方法，具体地，提供式（I）所述化合物的制备方法，将式（I-A）所示化合物与式（I-B）所述化合物进行接触，获得式（I）所示化合物，该方法操作简单，收率高。

Description

作为免疫调节的芳环衍生物的制备方法
本申请要求申请日为2021年12月27日的中国专利申请CN202111619527.9的优先权和申请日为2022年12月21日的中国专利申请CN202211652573.3。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，具体地，本发明涉及作为免疫调节的芳环衍生物的制备方法。
背景技术
鞘氨醇-1-磷酸(Sphingosine-1-phosphate，S1P)是属于溶血磷脂(lysophospholipid，LP)的一种两性生物信号分子。S1P可通过作用于5种G蛋白偶联受体亚型——鞘氨醇-1-磷酸受体(S1PR 1-5)激活复杂的下游信号，从而调节重要的生理生化功能。S1P与不同的S1P受体结合可调节不同的生理功能，在维持机体健康以及疾病发生过程中起着重要的作用。
S1P1受体激动剂干扰淋巴细胞归巢(lymphocyte trafficking)，将它们隔离(sequestering)在淋巴结和其它二级淋巴组织中。这导致外周循环淋巴细胞减少，淋巴细胞隔离在临床上的价值是将它们从周围组织中的炎症和/或自身免疫反应视域中排除。这种对淋巴细胞的隔离(例如在淋巴结中)被认为是以下同时作用的结果：由激动剂驱动的对T细胞上S1P1受体的功能性拮抗作用(因此降低S1P动员T细胞从淋巴结中流出的能力)和对淋巴结内皮上S1P1受体的持续激动作用(从而提高对抗淋巴细胞迁移的屏障功能)。因此，S1P 1受体激动剂通过阻止淋巴细胞的运输来降低人体自身免疫能力，因而可以作为免疫抑制剂用于治疗各种身免疫性疾病。
其中S1P1激动剂芬戈莫德(Fingolimod，FTY720)被FDA批准用于复发性多发性硬化症(Multiple Scleorosis，MS)的治疗，为免疫性疾病的治疗开辟了新的治疗领域。尽管FTY720具有临床功效，但它是一个非选择性的S1P受体激动剂，FTY720在体内与S1P3的结合往往会导致一系列重要的副作用，如心动过缓等，从而大大限制了其治疗免疫性疾病领域的应用范围。因此，发现第二代高选择性S1P1激动剂，使之成为疗效更好、副作用更小以及应用范围更广的免疫性疾病治疗药物成为了药物研究的热点之一。
目前公开了一些S1P1受体激动剂的专利申请，其中包括：CN103221391A、CN113185446A等。
专利申请CN113185446A(公开日：2021月07月30日)公开了一种具有新型结构的具有S1P1受体选择性、半衰期较短的S1P1受体激动剂，其结构如式(I)所示，
Figure PCTCN2022141877-appb-000001
专利申请CN113185446A(公开日：2021月07月30日)的实施例16公开了具体化合物A6所示化合物的制备方法，长达12步，操作繁琐，具体如下所示：
Figure PCTCN2022141877-appb-000002
Figure PCTCN2022141877-appb-000003
目前式(I)所示化合物及其合成方法仅在专利申请CN113185446A中公开，因而需要开发更多的式(I)所示化合物合成方法。
发明内容
发明人发现，现有技术CN113185446A中，从式(I-A)所示化合物到式(I)所示化合物需要经过4
Figure PCTCN2022141877-appb-000004
步反应
Figure PCTCN2022141877-appb-000005
其中第一步反应中甲基引入需要钯催化，成本高，且为微波反应，不宜放大；第二步为叶立德反应，Wittig试剂相对较为不稳定，后处理麻烦，且生成酸需要三步反应，同时第三步反应后生成的产物
Figure PCTCN2022141877-appb-000006
极其不稳定，使得该步分离纯化难度大，水解收率低，进而使得收率特别低下，使得生产成本特别高，不利于工业化大生产。
基于上述问题的发现，本发明提供了与现有技术完全的不同的方法合成式(I)所示化合物，能避免这一极其不稳定的化合物的生成
Figure PCTCN2022141877-appb-000007
节约了成本，提高了收率，简化了操作，使得商业化大生产成为可能。
在本发明的一方面，本发明提出了一种式(I)所示化合物的制备方法。根据本发明的实施例，所述方法包括：
Figure PCTCN2022141877-appb-000008
将式(I-A)所示化合物与式(I-B)所示化合物进行接触，获得式(I)所示化合物，
其中，
R 2选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R 3选自C 3-7环烷基、C 3-7环烯基、C 2-6烯基和3～6元杂环烷基，所述C 3-7环烷基、C 3-7环烯基C 2-6烯基或3～6元杂环烷基任选被1、2或3个R取代；
R a分别独立地选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R b选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R分别独立地选自H、F、Cl、Br、OH、NH 2、CN、C 1-3烷基和CF 3；
T 1选自N和CH；
T 2选自N和CH；
L 1选自
Figure PCTCN2022141877-appb-000009
L 2选自单键、O和S；
所述3～6元杂环烷基包含1、2或3个独立选自O、NH、S和N的杂原子或杂原子团。发明人巧妙地设计了本发明的反应，仅需要1步反应就可以实现现有技术中的4步反应，且避免了不稳定的产物的生成，相对于现有技术收率大幅提升，操作简单，节约成本，适合工业化大生产。
根据本发明的实施例，上述方法还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述接触是在溶剂为N,N-二甲基甲酰胺的条件下进行的。
根据本发明的实施例，所述接触是在甲酸存在的条件下进行的。
根据本发明的实施例，所述接触是在为三乙胺存在的条件下进行的。
根据本发明的实施例，所述式(I-A)所示化合物与式(I-B)所示化合物的摩尔比为1:1-1:1.2。
根据本发明的实施例，所述式(I-A)所示化合物与甲酸的摩尔比为1:5.0-1:13.3。发明人发现，低于或者高于该摩尔比，可能会导致有相应的杂质生成。
根据本发明的实施例，所述式(I-A)所示化合物与甲酸的摩尔比为1:10.0。发明人发现，在该范围内，杂质生成较少，处理较方便。
根据本发明的实施例，所述式(I-A)所示化合物与三乙胺的摩尔比为1:2.0-1:3.3。
根据本发明的实施例，所述式(I-A)所示化合物是通过式(I-C)所示化合物进行氧化反应获得的，
Figure PCTCN2022141877-appb-000010
在本发明的一方面，本发明还提出了一种式(I-A)所示化合物的制备方法，其是通过式(I-C)所示化合物进行氧化反应获得的。
根据本发明的实施例，所述氧化反应是在氧化剂为2-碘酰基苯甲酸或二氧化锰条件下进行的。发明人发现，这两种氧化剂的条件下进行氧化反应的收率更高。
根据本发明的实施例，当L 1选自
Figure PCTCN2022141877-appb-000011
时，所述式(I-C)所示化合物是通过式(I-D)所示化合物与式(I-E)所示化合物进行取代反应获得的，
Figure PCTCN2022141877-appb-000012
在本发明的一方面，当L 1选自
Figure PCTCN2022141877-appb-000013
时，本发明还提出了一种式(I-C)所示化合物的制备方法，其是通过式(I-D)所示化合物与式(I-E)所示化合物进行取代反应获得。
根据本发明的实施例，所述式(I-E)所示化合物是通过式(I-H)所示化合物进行亲核取代反应获得的，
Figure PCTCN2022141877-appb-000014
其中，R h选自苯基和杂芳基。
在本发明的一方面，本发明还提出了一种式(I-E)所示化合物的制备方法，其是通过式(I-H)所示化合物进行亲核取代反应获得。
根据本发明的实施例，当L 1选自
Figure PCTCN2022141877-appb-000015
时，所述式(I-C)所示化合物是通过式(I-F)所示的化合物进行还原反应获得的，
Figure PCTCN2022141877-appb-000016
其中，R f选自C 1-6烷基。
在本发明的一方面，当L 1选自
Figure PCTCN2022141877-appb-000017
时，本发明还提出了一种式(I-C)所示化合物的制备方法，其是通过式(I-F)所示的化合物进行还原反应获得的。
根据本发明的实施例，所述式(I-F)所示化合物是通过式(I-D)所示化合物与式(I-G)所示化合物进行取代反应获得的，
Figure PCTCN2022141877-appb-000018
在本发明的一方面，本发明还提出了一种式(I-F)所示化合物的制备方法，其是通过式(I-D)所示化合物与式(I-G)所示化合物进行取代反应获得。
根据本发明的实施例，所述式(I-H)所示化合物是通过式(I-J)所示化合物进行还原反应获得的，
Figure PCTCN2022141877-appb-000019
其中，R f选自C 1-6烷基。
在本发明的一方面，本发明还提出了一种式(I-H)所示化合物的制备方法，其是通过式(I-J)所示化合物进行还原反应获得的，其中，R f选自C 1-6烷基。
根据本发明的实施例，所述式(I-G)所示化合物是通过式(I-J)所示化合物进行还原反应获得的。
在本发明的一方面，本发明还提出了一种式(I-G)所示化合物的制备方法，其是通过式(I-J)所示化合物进行还原反应获得的。
根据本发明的实施例，所述式(I-J)所示化合物是通过式(I-K)所示化合物与式(I-L)所示化合物是通过雅普－克林格曼偶氮酯中间体的费歇尔吲哚环化获得获得的，
Figure PCTCN2022141877-appb-000020
在本发明的一方面，本发明还提出了一种式(I-J)所示化合物的制备方法，其是通过式(I-K)所示化合物与式(I-L)所示化合物是通过雅普－克林格曼偶氮酯中间体的费歇尔吲哚环化获得获得。
根据本发明的实施例，所述式(I-J)所示化合物是通过式(I-W)所示化合物与式(I-Z)所示化合物进行费歇尔吲哚合成反应获得的，
Figure PCTCN2022141877-appb-000021
在本发明的一方面，本发明还提出了一种式(I-J)所示化合物的制备方法，其是过式(I-W)所示化合物与式(I-Z)所示化合物进行费歇尔吲哚合成反应获得。
根据本发明的实施例，所述费歇尔吲哚合成反应是在浓硫酸存在的条件下进行的。
根据本发明的实施例，所述浓硫酸与所述式(I-W)所示化合物的摩尔比为0.5:1。
在本发明的另一方面，本发明还提出了一种式(II)所示化合物。根据本发明的实施例，式(II)所示化合物如下所示，
Figure PCTCN2022141877-appb-000022
其中，R 2选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R 3选自C 3-7环烷基、C 3-7环烯基、C 2-6烯基和3～6元杂环烷基，所述C 3-7环烷基、C 3-7环烯基C 2-6烯基或3～6元杂环烷基任选被1、2或3个R取代；
R a分别独立地选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R b选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R分别独立地选自H、F、Cl、Br、OH、NH 2、CN、C 1-3烷基和CF 3；
T 1选自N和CH；
T 2选自N和CH；
T 3选自N和C(R a)；
L 1选自
Figure PCTCN2022141877-appb-000023
L 2选自单键、O和S；
所述3～6元杂环烷基包含1、2或3个独立选自O、NH、S和N的杂原子或杂原子团。发明人，通过 引入该化合物来避免现有技术中
Figure PCTCN2022141877-appb-000024
这一极其不稳定的化合物的生成，大大提高了收率。
在本发明的再一方面，本发明还提出了一种式(I)所示化合物的制备方法。根据本发明的实施例，所述式(I)所示化合物是通过权利要求12所述的式(II)所示化合物进行内酰胺开环反应获得的。
根据本发明的实施例，上述方法还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，当L 1选自
Figure PCTCN2022141877-appb-000025
时，所述式(II)所示化合物是通过式(I-D)所示化合物与式(II-A)所示化合物进行取代反应获得的，
Figure PCTCN2022141877-appb-000026
其中，R f选自C 1-6烷基。
根据本发明的实施例，所述式(II-A)所示化合物是通过式(II-B)所示化合物进行还原反应获得的，
Figure PCTCN2022141877-appb-000027
其中，R h选自苯基和杂芳基。
根据本发明的实施例，所述式(II-B)所示化合物是通过式(II-C)所示化合物与式(II-D)所示化合物进行wittig反应获得的，
Figure PCTCN2022141877-appb-000028
根据本发明的实施例，所述式(II-C)所示化合物是通过式(I-H)所示化合物进行氧化反应获得的。
本发明的一些方案中，上述R选自H、F、Cl、Br、OH、NH 2、CN、CH 3、CH 2CH 3和CF 3，其它变量如本发明所定义。
本发明的一些方案中，上述R 2选自H、F、Cl、Br、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3或CH 2CH 3任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R 2选自H、F、Cl、Br、OH、NH 2、CN、CH 3、CH 2CH 3和CF 3，其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自C 3-6环烷基、C 3-6环烯基、C 2-3烯基和3～6元杂环烷基，所述C 3-6环烷基、C 3-6环烯基、C 2-3烯基或3～6元杂环烷基任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自
Figure PCTCN2022141877-appb-000029
所述
Figure PCTCN2022141877-appb-000030
任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自
Figure PCTCN2022141877-appb-000031
其它变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022141877-appb-000032
选自
Figure PCTCN2022141877-appb-000033
Figure PCTCN2022141877-appb-000034
其它变量如本发明所定义。
本发明的一些方案中，上述R a选自H、F、Cl、Br、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3或CH 2CH 3任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R a选自H、F、Cl、Br、OH、NH 2、CN、CH 3、CH 2CH 3和CF 3，其它变量如本发明所定义。
本发明的一些方案中，上述R b选自H、F、Cl、Br、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3或CH 2CH 3任选被1、2或3个R取代，其它变量如本发明所定义。
本发明的一些方案中，上述R b选自H、F、Cl、Br、OH、NH 2、CN、CH 3、CH 2CH 3和CF 3，其它变量如本发明所定义。
本发明的一些方案中，当L 1选自
Figure PCTCN2022141877-appb-000035
时，本发明还提出了一种式II)所示化合物的制备方法，其是通过式(I-D)所示化合物与式(II-A)所示化合物进行取代反应获得的，
Figure PCTCN2022141877-appb-000036
其中，R f选自C 1-6烷基。
本发明的一些方案中，本发明还提出了一种式(II-A)所示化合物的制备方法，其是通过式(II-B)所示化合物进行还原反应获得的，其中，R h选自苯基和杂芳基。
本发明的一些方案中，本发明还提出了一种式(II-B)所示化合物的制备方法，其是通过式(II-C)所示化合物与式(II-D)所示化合物进行wittig反应获得的。
本发明的一些方案中，本发明还提出了一种式(II-C)所示化合物的制备方法，其是通过式(I-H)所示化合物进行氧化反应获得的。
本发明的一些方案中，所述式(I)所示化合物选自下式化合物或其药学上可接受的盐，
Figure PCTCN2022141877-appb-000037
Figure PCTCN2022141877-appb-000038
本发明的一些方案中，所述式(I)所示化合物选自
Figure PCTCN2022141877-appb-000039
本发明的一些方案中，所述式(I)所示化合物选自
Figure PCTCN2022141877-appb-000040
本发明的一些方案中，所述式(I-A)所示化合物选自
Figure PCTCN2022141877-appb-000041
本发明的一些方案中，所述式(I-A)所示化合物选自
Figure PCTCN2022141877-appb-000042
本发明的一些方案中，所述式(I-C)所示化合物选自
Figure PCTCN2022141877-appb-000043
本发明的一些方案中，所述式(I-C)所示化合物选自
Figure PCTCN2022141877-appb-000044
本发明的一些方案中，所述式(I-D)所示化合物选自
Figure PCTCN2022141877-appb-000045
本发明的一些方案中，所述式(I-E)所示化合物选自
Figure PCTCN2022141877-appb-000046
本发明的一些方案中，所述式(I-H)所示化合物选自
Figure PCTCN2022141877-appb-000047
本发明的一些方案中，所述式(I-F)所示化合物选自
Figure PCTCN2022141877-appb-000048
本发明的一些方案中，所述式(I-F)所示化合物选自
Figure PCTCN2022141877-appb-000049
本发明的一些方案中，所述式(I-J)所示化合物选自
Figure PCTCN2022141877-appb-000050
本发明的一些方案中，所述式(I-K)所示化合物选自
Figure PCTCN2022141877-appb-000051
本发明的一些方案中，所述式(I-W)所示化合物选自
Figure PCTCN2022141877-appb-000052
本发明的一些方案中，所述式(I-L)所示化合物选自
Figure PCTCN2022141877-appb-000053
本发明的一些方案中，所述式(I-Z)所示化合物选自
Figure PCTCN2022141877-appb-000054
本发明的一些方案中，所述式(II)所示化合物选自
Figure PCTCN2022141877-appb-000055
本发明的一些方案中，所述式(II)所示化合物选自
Figure PCTCN2022141877-appb-000056
本发明的一些方案中，所述式(II-A)所示化合物选自
Figure PCTCN2022141877-appb-000057
本发明的一些方案中，所述式(II-B)所示化合物选自
Figure PCTCN2022141877-appb-000058
本发明的一些方案中，所述式(II-C)所示化合物选自
Figure PCTCN2022141877-appb-000059
本发明的一些方案中，所述式(II-D)所示化合物选自
Figure PCTCN2022141877-appb-000060
本发明的一些方案中，式(I)所示化合物的制备方法如下所示：
Figure PCTCN2022141877-appb-000061
，其中变量如本发明所定义。
本发明的一些方案中，式(I)所示化合物的制备方法如下所示：
Figure PCTCN2022141877-appb-000062
其中变量如本发明所定义。
本发明的一些方案中，式(I)所示化合物的制备方法如下所示：
Figure PCTCN2022141877-appb-000063
其中变量如本发明所定义。
本发明的一些方案中，A6所示化合物的制备方法如下所示：
Figure PCTCN2022141877-appb-000064
其中变量如本发明所定义。
本发明的一些方案中，A6所示化合物的制备方法如下所示：
Figure PCTCN2022141877-appb-000065
其中变量如本发明所定义。
本发明的一些方案中，A6所示化合物的制备方法如下所示：
Figure PCTCN2022141877-appb-000066
其中变量如本发明所定义。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“接触”应做广义理解，其可以是任何能够使得至少两种反应物发生化学反应的方式，例如可以是将两种反应物在适当的条件下进行混合。根据需要，可以在搅拌下，将需要进行接触的反应物进行混合，由此，搅拌的类型并不受特别限制，例如可以为机械搅拌，即在机械力的作用下进行搅拌
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体 (prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。术语“任选被…取代”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，
Figure PCTCN2022141877-appb-000067
可以选自
Figure PCTCN2022141877-appb-000068
Figure PCTCN2022141877-appb-000069
等。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如
Figure PCTCN2022141877-appb-000070
中L 2代表单键时表示该结构实际上是
Figure PCTCN2022141877-appb-000071
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022141877-appb-000072
中连接基团L为
Figure PCTCN2022141877-appb-000073
此时
Figure PCTCN2022141877-appb-000074
既可以按与从左往右的读取顺序相同的方向连接苯基和环戊基构成
Figure PCTCN2022141877-appb-000075
也可以按照与从左往右的读取顺序相反的方向连接苯基和环戊基构成
Figure PCTCN2022141877-appb-000076
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。除非另有规定，环上原子的数目通常被定义为环的元数，例如，“3-6元环”是指环绕排列3-6个原子的“环”。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，“C 2-6烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至6个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C 2-6烯基包括C 2-4、C 2-3、C 4、C 3和C 2烯基等；其可以是一价、二价或者多价。C 2-6烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基、己间二烯基等。
除非另有规定，“C 2-3烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至3个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C 2-3烯基包括C 3和C 2烯基；所述C 2-3烯基可以是一价、二价或者多价。C 2-3烯基的实例包括但不限于乙烯基、丙烯基等。
除非另有规定，“C 3-7环烷基”表示由3至7个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-7环烷基包括C 4-7、C 5-7、C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，本发明术语“环烯基”是指环状烯基。“C 3-7环烯基”包括C 3、C 4、C 5、C 6和C 7环烯基。环烯基的实例包括但不限于环丁烯基、环戊烯基和环己烯基。除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
本发明中“室温”指的是温度由大约10℃到大约40℃。在一些实施方案中，“室温”指的是温度由大约20℃到大约30℃；在外一些实施方案中，“室温”指的是20℃，22.5℃，25℃，27.5℃等等。
本发明中“室温或加热条件下”是指所述反应是在一定温度下进行的，所述的一定温度为室温或通过加热达到的某一具体温度。例如，本发明所述的由式(IV)化合物制备式(III)化合物的反应在室温或加热条件下进行，表示该反应是在一定温度条件下进行的，所述的一定温度为室温或通过加热达到的某一具体温度；例如，该反应是在室温(如20℃-30℃)或加热至30℃-65℃的条件下进行的，即，该反应是在20℃-65℃下进行的。
在本发明的上下文中，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现1％、2％、5％、7％、8％或10％等差异。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。每当公开一个数值范围中的一个下限，DL，和一个上限，DU，时，任何处于该公开了的范围之内的数值会被明确地公开。
本发明所述的所有反应步骤反应到一定程度如原料消耗大约大于70％，大于80％，大于90％，大于95％，或经检测反应原料已经消耗完毕后进行后处理，如冷却，收集，提取，过滤，分离，净化处理或其组合。可以通过常规的方法如薄层层析法(TLC)、高效液相色谱法(HPLC)、气相色谱法(GC)等方法检测反应程度。可以采用常规的方法对反应溶液进行后处理，例如，通过减压蒸发或常规蒸馏反应溶剂后收集粗产物，直接投入下一步反应；或直接过滤得到粗产物，直接投入下一步反应；或静置后，倾倒 出上层清液得到粗产物，直接投入下一步反应；或选择适当的有机溶剂或其组合进行萃取，蒸馏，结晶，柱层析，润洗，打浆等纯化步骤。
本发明中的术语“大约”是用于修饰一个上下相差10％的数值。在一些实施方案中，“大约”用于修饰一个上下相差5％的数值。在一些实施方案中，“大约”用于修饰一个上下相差3％或2％或1％的数值。可以理解的是，“大约”修饰的数值误差范围是取决于其所修饰的数值的实际或合理的误差范围。
本发明所述各步反应过程中，反应原料或其他试剂可以通过滴加的方式加入到反应体系中。所述各滴加过程以及所述的各步反应均在一定温度条件下进行，任何适合使用于各滴加过程或各反应过程的温度均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的温度及温度范围，均视为本发明的包含范围。本发明给出了各滴加过程较佳的温度或温度范围，以及各反应较佳的反应温度。
本发明所述的各反应步骤所使用的溶剂没有特别限制，任何在一定程度上能溶解起始原料并且不抑制反应的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。本发明给出了各反应步骤所使用的较佳的溶剂。
本发明所述的各反应步骤的产物，在合适的条件下，可以通过重结晶的方式进行纯化。所使用的重结晶溶剂没有特别限制，任何在一定程度上能溶解粗产物并且在一定条件下能析出结晶的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。其中，所述的溶剂可以是醇类，醚类，烷烃类，卤代烃类，酯类，酮类，芳烃类，乙腈，乙酸，水，DMF或它们的组合。例如水，乙酸，甲醇，乙醇，正丙醇，异丙醇，正丁醇，异丁醇，叔丁醇，石油醚，正戊烷，正己烷，正庚烷，环己烷，DMF，四氢呋喃，乙醚，异丙醚，二氧六环，甲基叔丁基醚，二甲氧乙烷，二乙二醇二甲醚，三甘醇二甲醚，二氯甲烷，1,2-二氯乙烷，氯仿，四氯化碳，乙酸乙酯，乙酸异丙酯，丙酮，丁酮，苯，甲苯，二甲苯或它们的组合。
本发明所述的溶剂中水分的含量，没有特别的限制，即，溶剂中水分的含量不影响本发明所述反应的发生。任何在一定程度上能在本发明中使用的含有一定量的水分的溶剂，均视为本发明所述的溶剂。如溶剂中水分的含量大约小于0.05％，小于0.1％，小于0.2％，小于0.5％，小于5％，小于10％，小于25％，小于30％，或为0％。在一些实施方案中，所述溶剂的水分含量在一定范围内，更有利于反应的进行；例如，在以乙醇作为反应溶剂的步骤，使用无水乙醇，更有利反应的进行。在一些实施方案中，所述溶剂的水分含量超出一定范围，可能会影响反应的进行(例如，影响反应的收率)，但并不影响反应的发生。
本发明的涉及的中间化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。但均应认为包含在本发明的保护范围内。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：
DMF代表N,N-二甲基甲酰胺，TEA代表三乙胺，LiOH代表氢氧化锂，TEMPO代表2,2,6,6-四甲基哌啶氧化物，BAIB代表碘苯二乙酸，IBX代表2-碘酰基苯甲酸，KF代表氟化钾，NaOCl代表次氯酸钠，NaBr代表溴化钠，NaHCO 3代表碳酸氢钠，MnO 2代表二氧化锰，Cs 2CO 3代表碳酸铯，K 2CO 3代表碳酸钾，TsOH代表对甲苯磺酸，T3P代表丙基磷酸酐，EA代表乙酸乙酯，ZnCl 2代表氯化锌，AcOH代表醋酸，H 3PO 4代表磷酸，EtOH代表乙醇，DCM代表二氯甲烷，hr代表小时，eq.代表当量，Rt.代表室温，V代表体积。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022141877-appb-000077
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
本发明所使用的原料如无特殊说明，均来自市售。
核磁共振光谱数据通过Bruker Avance 400核磁共振谱仪或Bruker Avance III HD 600核磁共振谱仪来测定，以CDC1 3,d 6-DMSO,CD 3OD,D 2O或d 6-丙酮为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰),d(doublet，双峰),t(triplet，三重峰),m(multiplet，多重峰),br(broadened，宽峰),dd(doublet of doublets，双二重峰),dt(doublet of triplets，双三重峰),td(triplet of doublets，三双重峰),ddd(doublet of doublet of doublets，双双二重峰),ddt(doublet of doublet of triplets，双双三重峰),dddd(doublet of doublet of doublet of doublets，双双双二重峰)。偶合常数，用赫兹(Hz)表示。
化合物纯度是通过Agilent 1260高效液相色谱(HPLC)来评价的。其中，高效液相色谱仪配备G1311B四元泵、G1329B自动采样器、G1316A TCC(柱温保持在30℃)和G1315D DAD检测器。色谱柱为Agilent Poroshell 120EC-C18 4μm 4.6×150mm，2.7μm；流速为1.0mL/min；检测波长226nm；流动相及其梯度洗脱条件如下表1所示。
流动相A为0.05％甲酸水溶液；流动相B为0.05％甲酸乙腈溶液；
表1
时间(min) 流动相A(％) 流动相B(％)
0.0 90 10
15.0 30 70
35.0 10 90
50.0 10 90
50.1 90 10
55.0 90 10
实施例1
Figure PCTCN2022141877-appb-000078
步骤一：向反应釜1中加入浓盐酸(8.7Kg)，化合物A(HCl)(6.9Kg,29.3mol)。反应体系冷却至0～5℃，滴加亚硝酸钠水溶液(纯化水：6.2Kg；亚硝酸钠：2.5Kg，36.2mol)，0～5℃搅拌至少半小时，液相检测反应1完成，0～5℃加入三水乙酸钠(4.5Kg)调pH＝3～4。向另一反应釜2中加入乙醇(20.0 Kg)，化合物B(5.3Kg,33.5mol)，纯化水(30.3Kg)，冷却至-5～5℃。在-5～5℃滴加29％氢氧化钾水溶液(6.3Kg,32.1mol)，-5～0℃搅拌0-10分钟，控制反应釜2内温在-5～5℃，将反应釜1中物料缓慢滴入反应釜2中。0～5℃加入三水乙酸钠(2.3Kg)调pH＝6～7，0～5℃保温4小时，升温至10～20℃，再搅拌至少12小时，液相检测反应2完成。40℃减压浓缩至无明显馏分，降温至20～30℃，用二氯甲烷(18.0Kg)萃取三次，有机相10％食盐水(17.3Kg)洗涤，有机相浓缩至大约2.5V～3.0V，加入乙醇(24.3Kg)进行浓缩置换溶剂，浓缩剩余体积2.5V～3.0V，降温至20～30℃。向反应釜1中加入33％盐酸乙醇溶液(6.0Kg)，无水乙醇(12.9Kg)，升温至60-65℃，将反应釜2中物料滴加至反应釜1，升温至76～82℃，保温搅拌4小时，液相检测反应3完成。降温至10～20℃，搅拌2小时，过滤，滤饼用纯化水(23.9Kg)洗至pH＝6～7。向反应釜2加入滤饼，正庚烷(19.4Kg)，10～20℃打浆2～3小时，过滤，滤饼干燥得到化合物C，黄棕色固体4.33Kg，纯度98.84％，收率47.8％。
步骤二：反应釜1中加入四氢呋喃(39.1Kg)，化合物C(4.3Kg，13.9mol)，氮气置换。冷却至0～5℃，0～5℃缓慢滴入红铝(70％甲苯溶液,8.3Kg，28.8mol)，升温至5～10℃，在5～10℃下保温搅拌1～5小时，液相检测反应完成。在0～10℃滴入10％氢氧化钠水溶液(21.7Kg)，5～15℃搅拌30～40分钟，静置，分层，有机相用26.7％食盐水(17.2Kg)洗涤，有机相减压浓缩至2.5V～3.5V，加入甲醇(52.5Kg)进行浓缩置换溶剂，浓缩剩余体积2.5V～3.0V，降温至10～20℃。溶液称重13.1Kg，化合物D纯度92.7％，含量30.1％，含量收率106％。
步骤三：反应釜1中加入化合物D甲醇溶液(13.0Kg，折纯3.7Kg，13.8mol)，甲醇(20.4Kg)。催化剂配制罐氮气置换，加入10％湿钯碳(0.37Kg)，甲醇(3.0Kg)。将配制罐内的10％湿钯碳甲醇混合液加入反应釜1中，反应釜1氮气置换3次，20-25℃氢气置换三次，通入氢气，控制反应釜1压力为0.50～0.60MPA，升温至40～45℃，反应16-18小时，液相检测反应完成。降温至20～30℃，反应液氮气压滤，滤饼用甲醇(11.7Kg)洗涤两次，滤液减压浓缩至约1.5～2.0V，加入异丙醇(29.0Kg)进行浓缩置换溶剂，浓缩剩余体积1.5V～2.0V，控制内温10～20℃滴加正庚烷(7.6Kg)，打浆12小时，离心，滤饼用正庚烷洗涤，滤饼干燥得到1.84Kg化合物E，纯度99.2％，收率75.0％。
步骤四：向反应釜中加入化合物E(0.66Kg，3.72mol)，N,N-二甲基甲酰胺(3.2Kg)，化合物F(1.00Kg，3.81mol)，碳酸铯(2.47Kg，7.58mol)。升温至45-55℃，保温搅拌3-6小时，液相检测反应完成。降温至20-30℃，垫硅藻土(0.67Kg)过滤，滤饼用2-甲基四氢呋喃(5.8kg)淋洗，滤液用水(3.40Kg)洗涤，水相用2-甲基四氢呋喃(1.7Kg)萃取。合并有机相用15％食盐水(3.3Kg)洗涤。浓缩剩余体积2.5V～3.5V，加入N,N-二甲基甲酰胺(2.6Kg)进行浓缩置换溶剂，浓缩剩余体积5.5V～6.5V，温降至20～30℃。得到化合物G的N,N-二甲基甲酰胺溶液4.16kg，纯度:78.7％，含量：21.6％，收率：61.3％。
步骤五：向反应釜中加入化合物G的N,N-二甲基甲酰胺溶液(4.03kg，2.16mol)，四氢呋喃(6.2Kg)，二氧化锰(1.64Kg)，升温至64～73℃，反应16小时，液相检测反应完成。降温至20～30℃，垫硅藻土(1.74Kg)过滤，滤饼用2-甲基四氢呋喃(10.4kg)洗涤。降温至5～15℃，滴加5％亚硫酸氢钠溶液(8.7kg)，搅拌，静置，分液，水相用2-甲基四氢呋喃(7.4Kg)萃取。有机相合并，控制内温5～15℃滴加5％亚硫酸氢钠溶液(2.61kg)，搅拌，静置，分液。有机相用10％食盐水(4.34Kg)洗涤，有机相浓缩至1.0～2.0V，加入甲基叔丁基醚(3.8Kg)进行浓缩置换溶剂，浓缩至1.8～2.2V，控制内温20～30℃加入甲基叔丁基醚(0.6Kg)和正庚烷(1.1Kg)，搅拌6～7小时，过滤，滤饼干燥。干燥后滤饼50～60℃加2-甲基四氢呋喃(4.14Kg)溶解，控制内温30～40℃滴加正庚烷(4.90Kg)，降温至0～5℃搅拌4～5h，过滤，滤饼干燥得到0.3984Kg化合物H，黄色粉末，纯度99.41％，含量：96.7％，收率：46.0％。
步骤六：向反应釜中加入N,N-二甲基甲酰胺(1.84kg)，降至0～10℃，加入甲酸(0.44kg，9.56mol)，加入三乙胺(0.32kg，3.16mol)，搅拌10～20分钟，加入化合物H(0.38kg，0.95mol)，化合物I-B(0.18kg，1.25mol)，升温至75～85℃，反应12小时，液相检测反应完成。降至15～25℃，加入2-甲基四氢呋喃 (3.31kg)，纯化水(3.84Kg)，滴加2M盐酸溶液(1.52kg)调节PH值至1～2，搅拌，静置，分层。有机相用10％食盐水(3.80Kg)洗涤。有机相浓缩至1.5～2.0V，调节内温至35～45℃，滴加入正庚烷(4.17kg)，降温至5～15℃，打浆4～6小时，过滤，滤饼干燥，得到0.3585kg化合物A6，纯度：96.7％，收率85.0％。
实施例2
Figure PCTCN2022141877-appb-000079
步骤一：同实施例1步骤一
步骤二：反应釜中加入化合物C(1.0eq.)，甲醇(10.0v)。催化剂配制罐氮气置换，加入10％湿钯碳(10％W)。氮气置换3次，氢气置换三次，通入氢气，控制反应釜压力为0.50～0.60MPA，升温至40～45℃，反应16-18小时，检测反应完成。降温至20～30℃，反应液氮气压滤，滤饼用甲醇洗涤，滤液减压浓缩至约1.5～2.0V，控制内温10～20℃滴加正庚烷，打浆12小时，过滤，滤饼用洗涤，滤饼干燥得到化合物J，收率95.0％。
步骤三：向反应瓶中加入化合物J(1.0eq.)，乙腈(10v)，化合物F(1.0eq.)，碳酸铯(2.0eq.)。升温至45-55℃，保温搅拌3-6小时，检测反应完成。降温至20-30℃，垫硅藻土(0.67Kg)过滤，滤饼用2-甲基四氢呋喃淋洗，滤液用水洗涤，水相用2-甲基四氢呋喃萃取。合并有机相用15％食盐水(3.3Kg)洗涤。浓缩剩余体积2.5V～3.5V，控制内温10～20℃滴加正庚烷，打浆12小时，过滤，滤饼用洗涤，滤饼干燥得到化合物K，收率88％。
步骤四：反应釜中加入四氢呋喃(10.0v)，化合物K(1.0eq.)，氮气置换。冷却至0～5℃，0～5℃缓慢滴入红铝(70％甲苯溶液,2.1eq.)，升温至5～10℃，在5～10℃下保温搅拌1～5小时，检测反应完成。在0～10℃滴入10％氢氧化钠水溶液，5～15℃搅拌30～40分钟，静置，分层，有机相用食盐水洗涤，有机相减压浓缩至干得到化合物G，收率84％。
步骤五：室温下，将化合物G(1.0eq.)溶于二氯甲烷(10v)，加入TEMPO(0.1eq.)，BAIB(1.1eq.)加料完毕，25℃搅拌反应至原料反应完全。过滤，滤液用碳酸氢钠水溶液洗涤，有机相无水硫酸钠干燥，浓缩除去有机溶剂得到化合物H，收率70％。
步骤六：氮气保护下，DMF(7mL)冷却至0-5℃，缓慢加入甲酸(688mg，6.0eq.)和三乙胺(837mg，2.6eq.)，0-5℃搅拌10分钟，加入化合物H(1.0g，1.0eq.)和化合物I-B(359mg，1.0eq.)，80℃搅拌至中控原料小于2％，冷却至室温，加入LiOH水溶液(3mL，7.0eq.)和EtOH(5mL)，45℃搅拌至中控环化中间体小于1％，冷却至室温，加入EtOAc(20mL)，3N HCl aq.调节PH＝1-2，分层，水洗有机相，无水硫酸钠干燥，浓缩得到0.96g化合物A6，纯度85.5％，收率86％。
实施例3
Figure PCTCN2022141877-appb-000080
步骤一：同实施例1步骤一
步骤二：同实施例1步骤二
步骤三：室温下，将化合物D(1.0eq.)溶于四氢呋喃(10.0v/w)，加入活性二氧化锰(10.0eq.)，加料完毕，置换氮气保护加热至68℃(内温)搅拌反应至原料反应完全。将反应混合物冷却至25℃，用硅藻土过滤除去二氧化锰，滤液5％亚硫酸氢钠溶液洗涤，减压浓缩至1-2v，加正庚烷打浆，过滤，干燥得到化合物L，收率80％。
步骤四：化合物L(1.0eq.)中加入四氢呋喃(10.0v)，加入化合物W(1.1eq.)，室温下搅拌反应至原料反应完全。用碳酸氢钠水溶液洗涤，有机相浓缩，正庚烷打浆最终得到化合物M，收率80％。
步骤五：反应釜中加入化合物M(1.0eq.)，四氢呋喃(10.0v)。催化剂配制罐氮气置换，加入10％湿钯碳(10％W)。氮气置换3次，氢气置换三次，通入氢气，控制反应釜压力为0.50～0.60MPA，升温至40～45℃，反应16-18小时，检测反应完成。降温至20～30℃，反应液氮气压滤，滤饼用四氢呋喃洗涤，滤液减压浓缩得到化合物N，收率95.0％。
步骤六：在氮气下，将化合物N(3.0g，1.0eq.)和化合物F(3.5g,1.1eq.)和碳酸铯(7.88g,2.0eq.)加入至干燥的乙腈(39.3g,13.0v)，在50℃下搅拌反应2小时，IPC显示原料反应完全。加2M氢氧化锂水溶液，析出大量固体，降温至室温，过滤，滤饼干燥后得3.84克化合物P，纯度99.6％，收率74.1％。
步骤七：化合物P(3.5g，1.0eq.)，乙醇(30.0mL)，水(10.0mL)，氢氧化锂(1.0g,3eq.)加入到反应瓶中，升温至60℃搅拌反应至原料反应完全，稀盐酸调节调节PH＝4-5，得到2.5g化合物A6，收率68.5％。
实施例4
对实施例1中的步骤6进行条件筛选，具体反应条件如下表2所示。
Figure PCTCN2022141877-appb-000081
表2
Figure PCTCN2022141877-appb-000082
Figure PCTCN2022141877-appb-000083
由上表2可知，使用甲酸(6.0eq.)有内酰胺中间体生成，需要氢氧化锂水解，且杂质不易控制；增加甲酸当量至13.3eq.，杂质水平降低至0.3％，但是转化不彻底，反应16小时仍有不少杂质。即使延长反应时间至48小时，仍有杂质；甲酸(10.0当量)，使用1.2当量麦氏酸，平行投两批反应，杂质较少，合批进行后处理，经甲苯重结晶后得到99.38％纯度游离酸，几乎没有杂质，符合游离酸质量标准。
实施例5
对实施例1中的步骤5进行条件筛选，具体反应条件如下表3所示。
Figure PCTCN2022141877-appb-000084
表3
Figure PCTCN2022141877-appb-000085
Figure PCTCN2022141877-appb-000086
由上表3可知，在氧化剂为IBX和MnO 2的氧化条件下，相对转化率较高，其它条件反应转化率低。
实施例6
对实施例1中的步骤4进行条件筛选，具体反应条件如下表4所示。
Figure PCTCN2022141877-appb-000087
表4
Figure PCTCN2022141877-appb-000088
Figure PCTCN2022141877-appb-000089
由上表4可知，该步反应Cs 2CO 3:(2.0eq.)/DMF(5.0V)/50℃/3h和Cs 2CO 3:(2.0eq.)/DMF(5.0V)/35℃/4h以上两种条件下，反应更优。
实施例7
对如下步骤进行条件筛选，具体反应条件如下表5所示。
Figure PCTCN2022141877-appb-000090
表5
Figure PCTCN2022141877-appb-000091
由上表5可知，采用浓硫酸的条件下，反应更优。
实施例8
Figure PCTCN2022141877-appb-000092
步骤一～五同实施例3，
步骤六：
在室温下，将化合物N(30.0g，121mmol)溶于乙腈(500mL)，而后将化合物F(35.0g，133mmol)和碳酸铯(78.8g,242mmol)加入反应体系。加料完毕后，反应混合物在氩气氛围下50℃反应2小时。反应液冷却至室温，抽滤除去滤饼，滤液旋干得到56g化合物Y(收率：97.5％)，该化合物无需进一步处理可以直接用于下一步反应。(因不稳定未进行纯化)。
步骤七：
将化合物Y(56.0g，118mmol)溶于四氢呋喃/乙醇(200mL/50mL)中，然后将氢氧化锂一水合物(9.90g，236mmol)的水溶液(50mL)于室温下滴加至反应体系中。室温下搅拌反应1h后，反应混合物用稀盐酸(1M)调pH至1～2，旋干大部分溶剂得到油状物。将得到的油状物用水稀释(200mL)，并用乙酸乙酯萃取(100mL*3)。有机相用饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤，滤液旋干得到粗产品。粗产品用甲苯和正己烷重结晶(toluene/n-hexane＝400mL：800mL，氩气保护下，粗产品加入400mL甲苯，加热至50℃，完全溶清后，加入正己烷800mL。加完后冷却至室温并搅拌约1小时，抽滤出固体，固体再用正己烷400mL打浆，抽滤得到白色固体。将所得到固体干燥得到21.0g A6，收率39.9％。
实施例9
Figure PCTCN2022141877-appb-000093
向反应瓶中加入乙醇(158.0g，10.0V)，浓硫酸(3.92g，0.5eq.)，搅拌10分钟。加化合物W(20.0g，1.0eq.)和2-丁酮酸乙酯(10.38g，1.0eq.)，升温到70～85℃(回流)，70～85℃搅拌3～4小时。液相检测反应结束，降温至5～15℃，滴加碳酸钠溶液(碳酸钠：8.45g，1.0eq.；水：44.0g，2.2V)，5～15℃保温3～5小时。过滤，滤饼用乙醇/水＝1/1体积比混合溶液淋洗(2V*2)。滤饼转移至反应瓶中，加入水(80.0g，4.0V)20～30℃打浆2～4小时，过滤，滤饼用水淋洗(30g，1.5V)。滤饼转移至反应瓶中，加入正庚烷(54.72g，4.0V)，20～30℃搅拌1～3小时，过滤，滤饼用正庚烷(2V*2)淋洗。滤饼40～50℃真空干燥至少12小时，得18.8g浅绿色固体，收率：76.2％，纯度：99.8％。
实施例10
Figure PCTCN2022141877-appb-000094
向反应釜中加入化合物E(4.84Kg，折纯4.35Kg，24.55mol)，N,N-二甲基甲酰胺(20.62Kg)，化合物F(6.50Kg，24.74mol)，碳酸铯(16.02Kg，49.17mol)。升温至35-45℃，保温搅拌3-12小时，液相检测反应完成。降温至20-30℃，垫硅藻土(2.50Kg)过滤，滤饼用2-甲基四氢呋喃(37.54kg)淋洗，滤液用水(21.74Kg)洗涤，水相用2-甲基四氢呋喃(11.30Kg)萃取。合并有机相用15％食盐水(21.75Kg)洗涤，取样测水分合格，加入2-甲基四氢呋喃(21.94kg)稀释至15.0-18.0V，搅拌20-40分钟，得到化合物G的2-甲基四氢呋喃溶液62.76kg，纯度:87.52％，含量：11.95％，收率：75.8％。
实施例11
Figure PCTCN2022141877-appb-000095
向反应釜中加入化合物G的2-甲基四氢呋喃溶液(31.28kg，折纯3.74Kg，9.27mol)，N,N-二甲基甲酰胺(5.32Kg)，降温至0～10℃，加入IBX(3.52Kg)，升温至15～25℃，反应16-48小时，液相检测反应完成。降温至20～30℃，垫硅藻土(1.00Kg)过滤，滤饼用2-甲基四氢呋喃(16.18kg)洗涤。降温至0～10℃，滴加10％硫代硫酸钠溶液(18.70kg)，搅拌，静置，分液，水相用2-甲基四氢呋喃(16.10Kg)萃取。有机相合并，控制内温5～15℃滴加5％碳酸钠水溶液(37.36kg)，搅拌，静置，分液。有机相加入10％食盐水(18.66Kg)，加入2N盐酸溶液(0.450Kg)调节PH：5～7，静置，分液。有机相浓缩至1.0～2.0V，加入甲基叔丁基醚(16.62Kg)进行浓缩置换溶剂，浓缩至1.5～2.5V，控制内温20～30℃加入甲基叔丁基醚(2.77Kg)和正庚烷(5.05Kg)，搅拌8～16小时，过滤，滤饼干燥。干燥得到3.29Kg化合物H，黄色粉末，纯度97.77％，含量：96.2％，收率：72.7％。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (18)

  1. 一种式(I)所示化合物的制备方法，其特征在于，
    Figure PCTCN2022141877-appb-100001
    将式(I-A)所示化合物与式(I-B)所示化合物进行接触，获得式(I)所示化合物，
    其中，
    R 2选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    R 3选自C 3-7环烷基、C 3-7环烯基、C 2-6烯基和3～6元杂环烷基，所述C 3-7环烷基、C 3-7环烯基C 2-6烯基或3～6元杂环烷基任选被1、2或3个R取代；
    R a分别独立地选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    R b选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    R分别独立地选自H、F、Cl、Br、OH、NH 2、CN、C 1-3烷基和CF 3；
    T 1选自N和CH；
    T 2选自N和CH；
    T 3选自N和C(R a)；
    L 1选自
    Figure PCTCN2022141877-appb-100002
    L 2选自单键、O和S；
    所述3～6元杂环烷基包含1、2或3个独立选自O、NH、S和N的杂原子或杂原子团。
  2. 根据权利要求1所述的方法，其特征在于，所述接触是在溶剂为N,N-二甲基甲酰胺的条件下进行的；
    任选地，所述接触是在甲酸存在的条件下进行的；
    任选地，所述接触是在为三乙胺存在的条件下进行的；
    任选地，所述式(I-A)所示化合物与式(I-B)所示化合物的摩尔比为1:1-1:1.2；
    任选地，所述式(I-A)所示化合物与甲酸的摩尔比为1:5.0-1:13.3；
    任选地，所述式(I-A)所示化合物与三乙胺的摩尔比为1:2.0-1:3.3。
  3. 根据权利要求1所述的方法，其特征在于，所述式(I-A)所示化合物是通过式(I-C)所示化合物进行氧化反应获得的，
    Figure PCTCN2022141877-appb-100003
  4. 根据权利要求3所述的方法，其特征在于，所述氧化反应是在氧化剂为2-碘酰基苯甲酸或二氧化锰条件下进行的。
  5. 根据权利要求3所述的方法，其特征在于，当L 1选自
    Figure PCTCN2022141877-appb-100004
    时，所述式(I-C)所示化合物是通过式(I-D)所示化合物与式(I-E)所示化合物进行取代反应获得的，
    Figure PCTCN2022141877-appb-100005
  6. 根据权利要求5所述的方法，其特征在于，所述式(I-E)所示化合物是通过式(I-H)所示化合物进行亲核取代反应获得的，
    Figure PCTCN2022141877-appb-100006
    其中，R h选自苯基和杂芳基。
  7. 根据权利要求3所述的方法，其特征在于，当L 1选自
    Figure PCTCN2022141877-appb-100007
    时，所述式(I-C)所示化合物是通过式(I-F)所示的化合物进行还原反应获得的，
    Figure PCTCN2022141877-appb-100008
    其中，R f选自C 1-6烷基。
  8. 根据权利要求7所述的方法，其特征在于，所述式(I-F)所示化合物是通过式(I-D)所示化合物与式(I-G)所示化合物进行取代反应获得的，
    Figure PCTCN2022141877-appb-100009
  9. 根据权利要求6所述的方法，其特征在于，所述式(I-H)所示化合物是通过式(I-J)所示化合物进行还原反应获得的，
    Figure PCTCN2022141877-appb-100010
    其中，R f选自C 1-6烷基。
  10. 根据权利要求8所述的方法，其特征在于，所述式(I-G)所示化合物是通过式(I-J)所示化合物进行还原反应获得的。
  11. 根据权利要求9或10所述的方法，其特征在于，所述式(I-J)所示化合物是通过式(I-K)所示化合物与式(I-L)所示化合物是通过雅普－克林格曼偶氮酯中间体的费歇尔吲哚环化获得的，
    Figure PCTCN2022141877-appb-100011
  12. 根据权利要求9或10所述的方法，其特征在于，所述式(I-J)所示化合物是通过式(I-W)所示化合物与式(I-Z)所示化合物进行费歇尔吲哚合成反应获得的，
    Figure PCTCN2022141877-appb-100012
  13. 一种式(II)所示化合物，其特征在于，
    Figure PCTCN2022141877-appb-100013
    其中，R 2选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    R 3选自C 3-7环烷基、C 3-7环烯基、C 2-6烯基和3～6元杂环烷基，所述C 3-7环烷基、C 3-7环烯基C 2-6烯基或3～6元杂环烷基任选被1、2或3个R取代；
    R a分别独立地选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    R b选自H、卤素、OH、NH 2、CN和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    R分别独立地选自H、F、Cl、Br、OH、NH 2、CN、C 1-3烷基和CF 3；
    T 1选自N和CH；
    T 2选自N和CH；
    L 1选自
    Figure PCTCN2022141877-appb-100014
    L 2选自单键、O和S；
    所述3～6元杂环烷基包含1、2或3个独立选自O、NH、S和N的杂原子或杂原子团。
  14. 一种式(I)所示化合物的制备方法，其特征在于，所述式(I)所示化合物是通过权利要求12所述的式(II)所示化合物进行内酰胺开环反应获得的。
  15. 根据权利要求13所述的化合物，其特征在于，当L 1选自
    Figure PCTCN2022141877-appb-100015
    时，所述式(II)所示化合物是通过式(I-D)所示化合物与式(II-A)所示化合物进行取代反应获得的，
    Figure PCTCN2022141877-appb-100016
    其中，R f选自C 1-6烷基。
  16. 根据权利要求15所述的化合物，其特征在于，所述式(II-A)所示化合物是通过式(II-B)所示化合物进行还原反应获得的，
    Figure PCTCN2022141877-appb-100017
    其中，R h选自苯基和杂芳基。
  17. 根据权利要求16所述的化合物，其特征在于，所述式(II-B)所示化合物是通过式(II-C)所示化合物与式(II-D)所示化合物进行wittig反应获得的，
    Figure PCTCN2022141877-appb-100018
  18. 根据权利要求17所述的化合物，其特征在于，所述式(II-C)所示化合物是通过式(I-H)所示化合物进行氧化反应获得的。
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