WO2023232117A1 - 吡啶氮氧化合物的制备方法 - Google Patents

吡啶氮氧化合物的制备方法 Download PDF

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WO2023232117A1
WO2023232117A1 PCT/CN2023/097882 CN2023097882W WO2023232117A1 WO 2023232117 A1 WO2023232117 A1 WO 2023232117A1 CN 2023097882 W CN2023097882 W CN 2023097882W WO 2023232117 A1 WO2023232117 A1 WO 2023232117A1
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alkyl
optionally
compound represented
formula
compound
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PCT/CN2023/097882
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English (en)
French (fr)
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张勇
曹程
张飞
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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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a pyridine nitroxide compound and a method for preparing its crystal form.
  • the global analgesic drug market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023.
  • acute, moderate and severe cases mainly rely on opioids, accounting for about two-thirds of the analgesic market share, and will grow steadily at a compound annual growth rate of 2.5% in the future.
  • the number of chronic pain patients, mainly neuropathic pain and arthritis pain is increasing year by year.
  • the market is expected to show a compound annual growth rate of about 18%, which is the main driving force for the continued growth of the global pain market in the next ten years. .
  • NaV1.8 sodium channel subtype 1.8
  • afferent neurons including sensory neurons By controlling the entry and exit of sodium ions into cells, it maintains the excitability and action potential of nociceptive sensory neurons. It plays an important role in the release and persistence of pain and the regulation of pain sensitivity.
  • Patients with NaV1.8 activating mutations develop paroxysmal pain caused by small fiber neuropathy (damage to A ⁇ fibers and unmyelinated C-type fibers, which are mainly responsible for pain transmission). Diseases such as chronic inflammation and diabetes can cause an increase in the expression or properties of NaV1.8, thereby sensitizing nociceptive neurons and causing a variety of pain.
  • NaV1.8 gene knockout mice are insensitive to pain.
  • Patent application CN112479996A discloses a new type of NaV1.8 inhibitor, whose general formula is Also disclosed are compounds
  • the second step of this overall route has a low yield
  • the third step uses m-CPBA as an oxidant, which contains many impurities, which is not conducive to the quality control of the final compound as a raw material and is not suitable for industrial large-scale production.
  • the inventor developed a new synthesis method, which has a higher yield, lower cost and easier operation than methods in the prior art.
  • the operation is simpler, the product is purer, meets the quality standards of raw materials, and is suitable for industrial large-scale production.
  • the present invention provides a method for preparing the compound represented by formula (I) or its pharmaceutically acceptable salt or hydrate.
  • the method includes contacting a compound represented by formula (I-5) or a pharmaceutically acceptable salt thereof with a compound represented by formula (I-6) or a pharmaceutically acceptable salt thereof, to obtain The compound represented by formula (I) or its pharmaceutically acceptable salt or hydrate,
  • T 1 is selected from N or C(R 7 );
  • T 2 is selected from N or C(R 8 );
  • T 3 is selected from N or C(R 9 );
  • T 4 is selected from N or C(R 10 );
  • R 1 , R 2 , R 8 and R 9 are each independently selected from H, halogen, OH, NH 2 , CN, SF 5 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl Amino, vinyl-C 1-6 alkyl-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl-, 3-6 membered Heterocycloalkyl-C 1-6 alkyl-, 3-6 membered heterocycloalkyl-C 1-6 alkyl-O-, phenyl-C 1-3 alkyl-, C 3-6 cycloalkyl -C 1-3 alkyl-O-, 3-6 membered heterocycloalkyl-C 1-3 alkyl-O-, phenyl-C 1-3 alkyl-O-, phenyl-C 1-3 alkyl-O-, phenyl-C 1-3 alky
  • R 3 , R 4 , R 5 , R 6 , and R 10 are each independently selected from H, halogen, OH, NH 2 , SF 5 , CN, C 1-6 alkyl, C 1-6 alkylamino, C 1- 6 alkoxy, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl- and 3-6 Metaheterocycloalkyl-C 1-6 alkyl-, the C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 3-6 cycloalkyl, -OC 3- 6 -cycloalkyl, 3-6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl- or 3-6-membered heterocycloalkyl-C 1-6 alkyl- optionally substituted by 1 , 2 or 3 R substitutions;
  • R 7 is selected from H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, the C 1-6 alkyl, C 1-6 alkyl
  • the oxygen group or C 1-6 alkylamino group is optionally substituted by 1, 2 or 3 R;
  • L 2 is selected from O, S, NH and CH 2 , the CH 2 is optionally substituted by 1 or 2 R, and NH is optionally substituted by R;
  • R 13a and R 13b are independently selected from H, halogen and C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R;
  • R are independently selected from H, D, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and C 1-6 alkylamino, said C 1-6 alkyl, C 1-6 alkoxy , C 1- 6 alkylthio or C 1-6 alkylamino is optionally substituted by 1, 2 or 3 R';
  • R' is selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • the above-mentioned R is selected from H, D, F, Cl, Br, I, OH, NH 2 , Me, CF 3 , CHF 2 , CH 2 F,
  • the remaining variables are as defined in the present invention.
  • R 1 , R 2 , R 8 and R 9 are independently selected from H, halogen, OH, NH 2 , CN, SF 5 , C 1-3 alkyl, C 1-3 alkyl Oxygen, C 1-3 alkylamino, vinyl-C 1-3 alkyl-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 Alkyl-, 3-6 membered heterocycloalkyl-C 1-3 alkyl-, 3-6 membered heterocycloalkyl-C 1-3 alkyl-O-, phenyl-C 1-3 alkyl- , phenyl-C 1-3 alkyl-O-, phenyl-C 1-3 alkyl-NH-, pyridyl-C 1-3 alkyl-, pyrimidinyl-C 1-3 alkyl-, thiophene Base-C 1-3
  • R 1 , R 2 , R 8 , and R 9 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, SF 5 , Me, CF 3 , CHF 2.
  • the remaining variables are as defined in the present invention.
  • R 3 , R 4 , R 5 , R 6 , and R 10 are independently selected from H, halogen, OH, NH 2 , SF 5 , CN, C 1-3 alkyl, C 1 -3 alkylamino, C 1-3 alkoxy, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl -C 1- 3 alkyl- and 3 to 6-membered heterocycloalkyl-C 1-3 alkyl-, the C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy, C 3-6 Cycloalkyl, -OC 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl- or 3-6 membered heterocycloalkyl-C 1- 3Alkyl - optionally
  • R 3 , R 4 , R 5 , R 6 , and R 10 are independently selected from H, F, Cl, Br, I, OH, NH 2 , SF 5 , Me, CF 3 , CHF 2 , CH 2 F, CN, CH(F 2 )CH 3 , CD 3 , OCD 3 ,
  • the remaining variables are as defined in the present invention.
  • R 13a and R 13b are independently selected from H, F, Cl, Br, I and Me, and the remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I) or its optical isomer is selected from
  • the compound represented by the above formula (I) is selected from The remaining variables are as defined in the present invention.
  • the compound represented by the above-mentioned formula (I) is selected from The remaining variables are as defined in the present invention.
  • the compound represented by the above-mentioned formula (I) is selected from The remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-5) may be selected from The remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-5) is selected from The remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-6) is selected from The remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-6) is selected from The remaining variables are as defined in the present invention.
  • the above-mentioned contact is carried out under the conditions of a condensing agent, and the remaining variables are as defined in the present invention.
  • the above-mentioned condensation agent is selected from the group consisting of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole and N,N'-carbonyldiimidazole, the remaining variables are as defined in the present invention.
  • the inventor found that the condensation effect is good under the conditions of these condensation agents.
  • the above-mentioned condensation agent is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and the remaining variables are as described in the present invention. definition. The inventor found that the condensation effect is better under the conditions of these condensation agents.
  • the above-mentioned condensing agent is one of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate or N-methylimidazole, and the remaining variables are as defined in the present invention.
  • the above-mentioned condensing agent is a mixture of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole, and the remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-5) and the 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluoride The molar ratio of phosphate ester is 1: (1.0-2.0), and the remaining variables are as defined in the present invention. The inventors found that the condensation effect is good at these ratios.
  • the compound represented by the above formula (I-5) and the 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluoride The molar ratio of phosphate ester is 1: (1.2-1.5), and the remaining variables are as defined in the present invention. The inventors found that the condensation effect was better at these ratios.
  • the molar ratio of the compound represented by the above formula (I-5) to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1: (1.0-2.0 ), and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above formula (I-5) to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1: (1.1-1.2 ), and the remaining variables are as defined in the present invention.
  • the molar ratio of the above-mentioned N-methylimidazole to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1: (1.2-2.0), and the remaining variables As defined herein.
  • the molar ratio of the above-mentioned N-methylimidazole to the N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate is 1: (1.4-1.6), and the remaining variables As defined herein.
  • the above contact is carried out under alkaline conditions, and the remaining variables are as defined in the present invention.
  • the above-mentioned basic conditions are provided by N,N-diisopropylethylamine, and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above formula (I-5) to the N,N-diisopropylethylamine is 1: (1.0-5.0), and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above formula (I-5) to the N,N-diisopropylethylamine is 1: (2.5-3.0), and the remaining variables are as defined in the present invention.
  • the above contact is carried out under the condition that the solvent is N,N-dimethylformamide, acetonitrile or dichloromethane, and the remaining variables are as defined in the present invention.
  • the above-mentioned contact is carried out under the condition that the solvent is N,N-dimethylformamide, and the remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-5-A) is obtained by the substitution reaction of the compound represented by the formula (I-2) and the compound represented by the formula (I-3),
  • Rx is selected from C 1-6 alkyl, and the remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-2) or its optical isomer is selected from The remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-3) or its optical isomer is selected from The remaining variables are as defined in the present invention.
  • the above substitution reaction is carried out in the presence of a base, and the remaining variables are as defined in the present invention.
  • the above-mentioned base is selected from Cs 2 CO 3 , K 2 CO 3 and K 3 PO 4 , and the remaining variables are as defined in the present invention.
  • the above-mentioned base is Cs 2 CO 3 , and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above formula (I-2) to the Cs 2 CO 3 is 1: (1.3-1.5), and the remaining variables are as defined in the present invention.
  • the above substitution reaction is carried out under the condition that the solvent is N,N-dimethylformamide or tetrahydrofuran, and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above formula (I-2) to the compound represented by the formula (I-3) is 1: (1.10-1.25), and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above formula (I-2) to the compound represented by the formula (I-3) is 1:1.15, and the remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-2) is obtained by esterification of the compound represented by the formula (I-1),
  • the remaining variables are as defined in the present invention.
  • the compound represented by the above formula (I-1) or its optical isomer is selected from The remaining variables are as defined in the present invention.
  • the above-mentioned esterification reaction is carried out in the presence of SOCl 2 , and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above formula (I-1) to the SOCl 2 is 1: (1.0-2.0), and the remaining variables As defined herein.
  • the molar ratio of the compound represented by the above formula (I-1) to the SOCl 2 is 1: (1.2-1.5), and the remaining variables are as defined in the present invention.
  • the above-mentioned esterification reaction is carried out under the condition that the solvent is ethanol, and the remaining variables are as defined in the present invention.
  • the ratio of the compound represented by the above formula (I-1) to the ethanol is (1:1672-2090). It should be noted that the ratio here refers to the molar volume ratio (moL:mL) , the remaining variables are as defined in the present invention.
  • the above-mentioned esterification reaction further includes post-treatment, and the remaining variables are as defined in the present invention.
  • the above-mentioned post-treatment is performed by adding sodium bicarbonate aqueous solution, and the remaining variables are as defined in the present invention.
  • the invention also provides an intermediate compound or a pharmaceutically acceptable salt thereof.
  • an intermediate compound or a pharmaceutically acceptable salt thereof According to embodiments of the present invention, the structure of the above-mentioned intermediate compound is as shown in compound 5,
  • the present invention also proposes the use of the compound represented by Compound 5 or its pharmaceutically acceptable salt in the preparation of the compound represented by Compound 7X or its optical isomer.
  • the invention also proposes The variables are as defined in the present invention.
  • the invention also proposes
  • the invention also proposes
  • the invention provides a method for preparing compound 1.
  • the method includes subjecting the compound represented by formula (X-1) to a chlorination reaction to obtain compound 1.
  • the chlorination reaction is carried out in a solvent of concentrated sulfuric acid, methanesulfonic acid, or trifluoroacetic acid. It is carried out under one or more conditions of , phosphoric acid or ethanesulfonic acid,
  • the invention provides a method for preparing compound 1.
  • the method includes subjecting the compound represented by formula (X-1) to a chlorination reaction to obtain compound 1, and the chlorination reaction is carried out under the condition that the solvent is concentrated sulfuric acid,
  • the present invention The method is easy to operate, does not use highly toxic reagents, and has a high yield.
  • the above-mentioned chlorination reaction is carried out under the conditions of chlorination reagents, and the remaining variables are as defined in the present invention.
  • the above-mentioned chlorinated reagent is selected from dichlorodimethylhydantoin and N-chlorosuccinimide, and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above-mentioned formula (X-1) to dichlorodimethylhydantoin is 1: (0.5-0.7), and the remaining variables are as defined in the present invention.
  • the molar ratio of the compound represented by the above-mentioned formula (X-1) to N-chlorosuccinimide is 1: (1.1-1.6), and the remaining variables are as defined in the present invention .
  • the above-mentioned chlorination reaction is carried out at a temperature of 55 to 60°C, and the remaining variables are as defined in the present invention. The inventor found that within this temperature range, the yield is higher.
  • the invention also provides a method for preparing compound 6.
  • the method includes subjecting the compound represented by formula (Y-2) to an oxidation reaction and a deprotection reaction to obtain compound 6,
  • the inventor found that the method for preparing compound 6 in the prior art is to use oxynicotinic acid as a starting material, use DPPA and tert-butyl alcohol to form a -Boc protected amino group, and remove -Boc protection to obtain the target product.
  • the cost used in this method is The DPPA is relatively high and the reaction process produces too many impurities, or the compound represented by formula (Y-2) is directly oxidized with MCPBA to directly oxidize pyridine. This method can easily produce a polymerization product of two molecules, and the yield is low.
  • the method proposed by the present invention is simple to operate, has cheap raw materials, and is convenient for post-processing, and is suitable for industrialization. Produce.
  • the compound represented by the above formula (Y-2) is obtained by acylating the compound represented by the formula (Y-1),
  • the remaining variables are as defined in the present invention.
  • the term "contacting" should be understood in a broad sense, and it can be any way that can cause a chemical reaction between at least two reactants, for example, it can be mixing two reactants under appropriate conditions. If necessary, the reactants that need to be contacted can be mixed under stirring. Therefore, 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 present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. 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 at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called proton transfer tautomers
  • proton transfer tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization.
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the 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 condition may but need not occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not occur.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.
  • 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.
  • room temperature or heating conditions means that the reaction is carried out at a certain temperature, and the certain temperature is room temperature or a specific temperature reached by heating.
  • the reaction of the present invention to prepare the compound of formula (III) from the compound of formula (IV) is carried out at room temperature or under heating conditions, which means that the reaction is carried out under certain temperature conditions, and the certain temperature is room temperature or by A specific temperature reached by heating; 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 described in the present invention react to a certain extent, such as the raw material consumption is approximately greater than 70%, greater than 80%, greater than 90%, greater than 95%, or after it is detected that the reaction raw materials have been consumed, post-processing is performed, such as cooling, collecting, Extraction, filtration, separation, purification or combinations 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 other methods.
  • Conventional methods can be used to post-process the reaction solution, for example, by evaporating the reaction solvent under reduced pressure or conventional distillation to collect the crude product and directly put it into the next step of the reaction; or directly filtering to obtain the crude product and directly put it into the next step of the reaction; or leave it alone. Afterwards, pour out the supernatant to obtain a crude product, which can be directly put into the next step of reaction; or an appropriate organic solvent or a combination thereof can be selected for extraction, distillation, crystallization, column chromatography, washing, beating and other purification steps.
  • reaction raw materials or other reagents can be added to the reaction system in a dropwise manner.
  • Each of the dropwise addition processes and each reaction step are performed under certain temperature conditions, and any temperature suitable for each dropwise addition process or each reaction process is included in the present invention.
  • many similar modifications, equivalent substitutions, or equivalents to the temperatures and temperature ranges described in the present invention are deemed to be within the scope of the present invention.
  • the present invention provides the preferred temperature or temperature range for each dripping process, as well as the preferred reaction temperature for each reaction.
  • the solvent used in each reaction step of the present invention is not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are deemed to be within the scope of the present invention.
  • the present invention provides preferred solvents used in each reaction step.
  • the products of each reaction step of the present invention can be purified by recrystallization under appropriate conditions.
  • the recrystallization solvent used is not particularly limited. 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 deemed to be within the scope of the present invention.
  • the solvent can be alcohols, ethers, alkanes, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, acetic acid, water, DMF or combinations thereof.
  • the moisture content in the solvent of the present invention is not particularly limited, that is, the moisture content of the solvent does not affect the occurrence of the reaction of the present invention.
  • Any solvent containing a certain amount of moisture that can be used in the present invention to a certain extent is regarded as a solvent according to 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 progress of the reaction; for example, in the step of using ethanol as the reaction solvent, using absolute ethanol is more conducive to the progress of 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, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention. However, 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.
  • a dash ("-") not between two letters or symbols indicates the attachment site of the substituent.
  • C 1-6 alkylcarbonyl - refers to the linkage of the molecule to the molecule through the carbonyl group The remaining part is connected to the C 1-6 alkyl group.
  • the "-" may be omitted.
  • the term “deuterium” refers to the group -D.
  • hydroxy refers to the group -OH.
  • halo or halogen as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • cyano refers to the group -CN.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , also include any range from n to n+m, for example, C1-12 includes C1-3 , 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 yuan to n The +m member indicates that the number of atoms in the ring is n to n+m.
  • 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-membered ring, and a 9-membered ring.
  • 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring , 5-7-membered ring, 6-7-membered ring, 6-8-membered ring and 6-10-membered ring, etc.
  • the number of atoms on a ring is usually defined as the number of ring members.
  • a "3-6 membered ring” refers to a “ring” with 3-6 atoms arranged around it.
  • C 1-6 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can Is it monovalent (such as CH 3 ), bivalent (-CH 2 -) or polyvalent (such as ).
  • Examples of C 1-6 alkyl groups include, but are not limited to, CH 3 , wait.
  • C 1-3 alkyl is used to mean 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 CH 3 ), divalent (-CH 2 -) or multivalent (such as subvalent ).
  • Examples of C 1-3 alkyl groups include , but are not limited to, CH 3 , wait.
  • C 1-6 alkoxy means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy oxygen group, s-butoxy group and t-butoxy group), pentyloxy group (including n-pentyloxy group, isopentyloxy group and neopentyloxy group), hexyloxy group, etc.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylamino means those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino group wait.
  • C 1-6 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , etc.
  • C 1-3 alkylamino means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups, etc.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 etc.
  • C 1-6 alkylthio means those containing 1 to 6 carbon atoms attached to the remainder of the molecule through a sulfur atom alkyl group.
  • the C 1-6 alkylthio group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkane Sulfur group etc.
  • Examples of C 1-6 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
  • C 1-3 alkylthio means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 and C 3 alkylthio groups, etc.
  • Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-6-membered heterocycloalkyl group includes 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc.
  • Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidin
  • 3-6 membered ring by itself or in combination with other terms means a saturated monocyclic group or an unsaturated monocyclic group consisting of 3 to 6 ring atoms, which can include pure carbocyclic rings, Rings containing heteroatoms may also be included. Where 3-6 refers to the number of atoms forming the ring. Examples of “3-6 membered rings” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, cyclopentanonyl, Cyclohexanone group, etc.
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” may be used interchangeably in the present invention
  • the term “5-6 membered heteroaryl” means 5 to 6 ring atoms. It consists of a monocyclic group with a conjugated ⁇ electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl).
  • azolyl group, etc. imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) 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.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyrid
  • heteroaryl ring refers to a heteroaryl ring as defined above.
  • aryl and aromatic follow Hückel's rule, where the number of ⁇ electrons is equal to 4n+2 and n is zero or any positive integer up to 6.
  • carbonyl refers to the group -C(O)-, which may also be expressed as -CO-.
  • amino refers to the group -NH2 .
  • optional means that the subsequently described event may or may not occur, and that the description includes circumstances in which the stated event occurs as well as circumstances in which the stated event does not occur.
  • optionally substituted alkyl refers to unsubstituted alkyl and substituted alkyl, where alkyl is as defined herein.
  • substituted or “substituted by” means that one or more hydrogen atoms on a given atom or group are replaced, e.g., by Replacement by one or more substituents selected from a given group of substituents, provided that the normal valency of that given atom is not exceeded.
  • two hydrogen atoms on a single atom are replaced by oxygen.
  • a chemically correct and stable compound means that the compound is sufficiently stable that it can be isolated from the reaction mixture and the chemical structure of the compound can be determined, and subsequently formulated into a preparation that has at least practical utility.
  • substituted or “substituted” as used herein means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, e.g.
  • substituents are independently selected from: deuterium (D), halogen, OH, mercapto, cyano, -CD 3 , alkyl (preferably C 1-6 alkyl) , alkoxy (preferably C 1-6 alkoxy), haloalkyl (preferably halo C 1 - 6 alkyl), haloalkoxy (preferably halo C 1 - 6 alkoxy), -C(O) NR a R b and -N(R a )C(O)R b and -C(O)OC 1-4 alkyl (where R a and R b are each independently selected from hydrogen, C 1-4 alkyl, Halogenated C 1-4 alkyl), carboxyl (COOH), cycloalkyl (preferably 3-8 membered cycloalkyl), heterocyclyl (preferably 3-8 membered heterocyclyl), aryl, heteroaryl, Aryl C 1 - 6 alkyl
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • SOCl 2 represents sulfoxide chloride
  • Cs 2 CO 3 represents cesium carbonate
  • NaHCO 3 represents sodium bicarbonate
  • K 2 CO 3 represents potassium carbonate
  • K 3 PO 4 represents potassium phosphate
  • DMF represents dimethylformamide
  • THF represents tetrahydrofuran.
  • T3P represents 1-propylphosphonic anhydride
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • EDCI represents 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HOBt represents 1-hydroxybenzotriazole
  • CDI represents N,N'-carbonyldiimidazole
  • DCM represents dichloromethane
  • DIPEA represents N,N-diisopropylethylamine
  • DCDMH stands for dichlorodimethylhydantoin
  • NCS stands for N-chlorosuccinimide
  • MTBE stands for methyl tert-butyl ether
  • TCFH stands for N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate
  • NMI stands for N-methylimidazole.
  • the volume nV used in the present invention generally refers to n times the volume, which is the weight ratio of the solvent volume to the compound used, and the unit is mL/g.
  • the ethanol volume 8V used in Table 3 means that the volume of ethanol is 8 times the volume. , that is, the volume of ethanol (mL/) is 8 times the weight of compound 1 (g).
  • the raw materials used in the present invention are all commercially available unless otherwise specified.
  • Centrifugation 2 Centrifuge the material in the reaction kettle through a centrifuge, and rinse the filter cake with process water (42.8kg, 7.2X) to obtain a wet product. If the wet product passes the test, proceed to the next step.
  • Mobile phase mobile phase A, 0.05% formic acid aqueous solution, mobile phase B, 0.05% formic acid acetonitrile solution
  • Reaction 1 Under the protection of slight nitrogen, add compound 2 (6.0kg, 1.00X) and tetrahydrofuran (44.0kg, 7.33X) into the reaction kettle, and start stirring. Add compound 3 (5.1kg, 0.85X) and cesium carbonate (10.7kg, 1.78X), cool to 55-65°C, stir and react for 16-24 hours, cool to 15-25°C, and take samples for central control testing. After the in-process control is qualified (purity ratio of compound 2/(compound 2 + compound 4 + compound 5) ⁇ 4.0%), proceed to the next step. If the in-process control is unqualified, the reaction time is extended until the in-process control is qualified.
  • Reaction 2 Under the protection of slight nitrogen, add the prepared lithium hydroxide aqueous solution (35.8kg, 6.0X) to the reaction kettle R1, control the temperature to 55-65°C, and stir for 8-16 hours. Cool the temperature to 15-25°C and take samples for central control testing. After the intermediate control is qualified (purity ratio of compound 4/(compound 4 + compound 5) ⁇ 1.0%), proceed to the next step. If the central control is unqualified, the reaction time will be extended until the central control is qualified.
  • Mobile phase mobile phase A, 0.05% formic acid aqueous solution, mobile phase B, 0.05% formic acid acetonitrile solution
  • Washing 3 Add process water (80.0kg, 9.8X) to the organic phase, add it to reactor R1, control the internal temperature to 15-25°C, stir for 0.5-2 hours, let stand for 0.5-2 hours, separate into layers, and separate. Remove the aqueous phase and retain the organic phase. Add process water (80.8kg, 9.9X) to reactor R1, control the internal temperature to 15-25°C, stir for 0.5-2 hours, let stand for 0.5-2 hours, separate the layers, separate the water phase, and retain the organic phase.
  • Mobile phase mobile phase A, 0.05% formic acid aqueous solution, mobile phase B, 0.05% formic acid acetonitrile solution
  • Step 1 Add absolute ethanol (464 mL, 8.0 v/w) and compound 1 (58.0 g, 278 mmol) into the reaction bottle at room temperature, and stir to dissolve. Cool the temperature to 30-40°C, and add SOCl 2 (39.6g, 333mmol) dropwise. After the dropwise addition is completed, heat to 55-60°C and react for 4-8 hours. Take samples and control until the reaction is qualified. Add 10% potassium phosphate solution dropwise to adjust the pH to 6-8, precipitate the product, filter, add water to wash the filter cake to obtain a wet product, and dry at 30-40°C to obtain compound 2.
  • Step 2 Add THF (130mL, 8.0v/w) to the three-necked flask at room temperature, start stirring, add compound 2 (56.2g, 237mmol), compound 3 (48.5g, 272mmol), Cs 2 CO 3 (100.4 g, 308mmol), heat to 55-60°C and react for 20-24 hours. Take samples for control. After passing the control, add water (280mL), and react with lithium hydroxide monohydrate (24.9g, 593mmol) at 55-60°C for 2- 4 hours of sampling and control.
  • step 4 Add DCM (200ml) to the three-necked flask at room temperature, start stirring compound 5 (40.0g, 109mml), add HATU (53.8g, 144mmol) and compound 6 (19.1g, 131mmol). Add DIPEA (42.2g, 327mmol) dropwise at 30-35°C. After the dropwise addition is completed, react at 30-35°C for 16 hours. After passing the sampling control, cool the system to 25-35°C, add DCM (100ml), add 5% potassium carbonate aqueous solution (240ml, 6V) for washing, let it stand for layering, and add 7% sodium bicarbonate to the organic phase.
  • Synthesis of compound Y-2 Add IPA (30.0ml, 3V), water (30.0ml, 3V), Y-1 (10.0g, 106mmol) to the reaction bottle at room temperature, stir and dissolve. Cool the temperature to 0 ⁇ 5°C, add BOC 2 O (27.8g, 127mmol)/IPA (3.0V) dropwise, after the addition is completed, return to room temperature and react for 2 ⁇ 3 hours. The sampling process is qualified. 40-50°C, concentrate the reaction solution to dryness under reduced pressure, add MTBE (100ml) to dissolve, add water (100.0ml, 10V), wash once, and layer. The organic phase was concentrated to dryness to obtain product Y-2.
  • Synthesis of compound Y-3 Add Y-2 (10g, 52mmol) and DCM (100ml, 10V) to the reaction bottle at room temperature and stir. Cool the temperature to 0 ⁇ 10°C, add solid m-CPBA in batches, return to room temperature 20 ⁇ 25°C and react overnight. If the sampling control is qualified, add 10% Na 2 SO 3 (20ml, 2V) to the reaction bottle and wash it once. , then add 10% Na 2 SO 3 (20ml, 2V) and wash once.
  • Synthesis of compound 6 Add Y-3 solution (52mmol) to the reaction bottle at room temperature, control the temperature to 10-20°C, add HCl/1,4-Dioxane solution (520mmol, 10.0eq.) dropwise, and return to the temperature after the dropwise addition. React at room temperature for 3 to 4 hours, and the sampling control reaction is qualified. During the reaction, solids precipitate, filter to obtain a filter cake, add the filter cake to the reaction bottle, add acetonitrile (50 ml, 5V), beat at room temperature for 1 to 2 hours, filter to obtain a wet product, and dry at 45 to 50°C to obtain compound 6.
  • acetonitrile 50 ml, 5V
  • Example 3 The reaction conditions in Example 3 were screened, and the results are shown in Table 14 below.
  • references to the terms “one embodiment,” “some embodiments,” “an example,” “specific examples,” or “some examples” or the like means that specific features are described in connection with the embodiment or example. , structures, materials or features are included in at least one embodiment or example of the invention. In this specification, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine different embodiments or examples and features of different embodiments or examples described in this specification unless they are inconsistent with each other.

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Abstract

本发明公开了吡啶氮氧化合物的制备方法，具体地，本发明公开了一种制备式(I)所示化合物或其药学上可接受的盐、水合物的方法，其特征在于，将式(I-5)所示化合物或其药学上可接受的盐与式(I-6)所示化合物或其药学上可接受的盐进行接触，获得式(I)所示化合物或其药学上可接受的盐、水合物，该方法操作简单，收率高，适合工业化大生产。

Description

吡啶氮氧化合物的制备方法
本申请主张如下优先权：
1)CN202210629774.5，2022.06.02；
2)CN202310570708.X，2023.05.19。
技术领域
本发明属于药物化学领域，具体地，本发明涉及吡啶氮氧化合物及其晶型制备方法。
背景技术
疼痛是临床上最常见的症状之一，是继呼吸、脉搏、血压和体温之后的第五生命体征，严重影响患者的生活质量。据统计，2018年全球镇痛药市场约为360亿美元，预计2023年将达到560亿美元。其中急性中重度主要依赖于阿片类药物，占镇痛药市场份额的三分之二左右，未来将以2.5％的年复合增长率稳定增长。而以神经病理性疼痛(neuropathic pain)和关节炎疼痛为主的慢性疼痛患者数量逐年增加，预计市场将呈现18％左右的年复合增长率，是驱动未来十年全球疼痛市场持续增长的主要推动力。
近年来的研究成果逐步揭示了钠离子通道亚型1.8(NaV1.8)在痛觉的发生和传递方面起重要作用。NaV1.8是一种电压门控钠离子通道，主要表达在包括感觉神经元在内的传入神经元上，通过控制钠离子进出细胞，在维持伤害性感觉神经元的兴奋性、动作电位的发放和持续以及痛觉敏感性的调节等方面，发挥着重要作用。NaV1.8激活性突变病人出现小纤维神经病变(主要负责痛觉传递的Aδ纤维和无髓纤维C型纤维受损)导致的阵发性疼痛。慢性炎症和糖尿病等疾病会引起NaV1.8表达增加或性质改变从而敏化伤害感受神经元，引起多种疼痛。而NaV1.8基因敲除小鼠对痛觉不敏感。
专利申请CN112479996A(公开日2021年03月12日)公开了一种新型NaV1.8抑制剂，其通式为同时还公开了化合物
申请号为PCT/CN2022/080430(申请日2022年03月11日)的专利申请文件，公开了化合物7X的晶型A和晶型B。
发明内容
发明人发现，专利申请CN112479996A中化合物7X的合成路线如下：
其中该整体路线中第二步收率低，且第三步使用m-CPBA作为氧化剂，杂质多，不利于最终化合物作为原料药的质量控制，不适合工业化大生产。
基于此，发明人开发了一种新的合成方法，该方法相对于现有技术中的方法收率更高，成本更低，操 作更简单，产品更纯，符合原料药的质量标准，适合工业化大生产。
在本发明的第一方面，本发明提出了一种制备式(I)所示化合物或其药学上可接受的盐、水合物的方法。根据本发明的实施例，所述方法包括将式(I-5)所示化合物或其药学上可接受的盐与式(I-6)所示化合物或药学上可接受的盐进行接触，获得式(I)所示化合物或其药学上可接受的盐、水合物，
T1选自N或C(R7)；
T2选自N或C(R8)；
T3选自N或C(R9)；
T4选自N或C(R10)；
R1、R2、R8、R9分别独立地选自H、卤素、OH、NH2、CN、SF5、C1-6烷基、C1-6烷氧基、C1-6烷氨基、乙烯基-C1-6烷基-、C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-6烷基-、3～6元杂环烷基-C1-6烷基-、3～6元杂环烷基-C1-6烷基-O-、苯基-C1-3烷基-、C3-6环烷基-C1-3烷基-O-、3～6元杂环烷基-C1-3烷基-O-、苯基-C1-3烷基-O-、苯基-C1-3烷基-NH-、5～6元杂芳基-C1-3烷基-、5～6元杂芳基-C1-3烷基-O-和5～6元杂芳基-C1- 3烷基-NH-，所述C1-6烷基、C1-6烷氧基、C1-6烷氨基、乙烯基-C1-6烷基-、C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-6烷基-、3～6元杂环烷基-C1-6烷基-、3～6元杂环烷基-C1-6烷基-O-、苯基-C1-3烷基-、C3-6环烷基-C1-3烷基-O-、3～6元杂环烷基-C1-3烷基-O-、苯基-C1-3烷基-O-、苯基-C1-3烷基-NH-、5～6元杂芳基-C1- 3烷基-、5～6元杂芳基-C1-3烷基-O-或5～6元杂芳基-C1-3烷基-NH-任选被1、2或3个R取代；
R3、R4、R5、R6、R10分别独立地选自H、卤素、OH、NH2、SF5、CN、C1-6烷基、C1-6烷氨基、C1-6烷氧基、C3-6环烷基、-O-C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-6烷基-和3～6元杂环烷基-C1-6烷基-，所述C1-6烷基、C1-6烷氨基、C1-6烷氧基、C3-6环烷基、-O-C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-6烷基-或3～6元杂环烷基-C1-6烷基-任选被1、2或3个R取代；
R7选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基和C1-6烷氨基，所述C1-6烷基、C1-6烷氧基或C1-6烷氨基任选被1、2或3个R取代；
L2选自O、S、NH和CH2，所述CH2任选被1或2个R取代，NH任选被R取代；
R13a、R13b分别独立地选自H、卤素和C1-6烷基，所述C1-6烷基任选被1、2或3个R取代；
R分别独立地选自H、D、卤素、OH、NH2、CN、C1-6烷基、C1-6烷氧基、C1-6烷硫基和C1- 6烷氨基，所述C1-6烷基、C1-6烷氧基、C1-6烷硫基或C1-6烷氨基任选被1、2或3个R’取代；
R’选自F、Cl、Br、I、OH、NH2和CH3；
上述3～6元杂环烷基或5～6元杂芳基包含1、2或3个独立选自-O-、-NH-、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O)2-和N的杂原子或杂原子团。
本发明的一些方案中，上述R选自H、D、F、Cl、Br、I、OH、NH2、Me、CF3、CHF2、CH2F、其余变量如本发明所定义。
本发明的一些方案中，上述R1、R2、R8、R9分别独立地选自H、卤素、OH、NH2、CN、SF5、C1-3烷基、C1-3烷氧基、C1-3烷氨基、乙烯基-C1-3烷基-、C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-3烷基-、3～6元杂环烷基-C1-3烷基-、3～6元杂环烷基-C1-3烷基-O-、苯基-C1-3烷基-、苯基-C1-3烷基-O-、苯基-C1-3烷基-NH-、吡啶基-C1-3烷基-、嘧啶基-C1-3烷基-、噻吩基-C1-3烷基-、噻唑基-C1-3烷基-、吡唑基-C1-3烷基-、咪唑基-C1-3烷基-、吡啶基-C1-3烷基-O-、嘧啶基-C1-3烷基-O-、噻吩基-C1-3烷基-O-、噻唑基-C1-3烷基-O-、吡唑基-C1-3烷基-O-、咪唑基-C1-3烷基-O-、吡啶基-C1-3烷基-NH-、嘧啶基-C1-3烷基-NH-、噻吩基-C1-3烷基-NH-、噻唑基-C1-3烷基-NH-、吡唑基-C1-3烷基-NH-和咪唑基-C1-3烷基-NH-，所述C1-3烷基、C1-3烷氧基、C1-3烷氨基、乙烯基-C1-3烷基-、C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-3烷基-、3～6元杂环烷基-C1- 3烷基-、3～6元杂环烷基-C1-3烷基-O-、苯基-C1-3烷基-、苯基-C1-3烷基-O-、苯基-C1-3烷基-NH-、吡啶基-C1- 3烷基-、嘧啶基-C1-3烷基-、噻吩基-C1-3烷基-、噻唑基-C1-3烷基-、吡唑基-C1-3烷基-、咪唑基-C1-3烷基-、吡啶基-C1-3烷基-O-、嘧啶基-C1-3烷基-O-、噻吩基-C1-3烷基-O-、噻唑基-C1-3烷基-O-、吡唑基-C1-3烷基-O-、咪唑基-C1-3烷基-O-、吡啶基-C1-3烷基-NH-、嘧啶基-C1-3烷基-NH-、噻吩基-C1-3烷基-NH-、噻唑基-C1-3烷基-NH-、吡唑基-C1-3烷基-NH-或咪唑基-C1-3烷基-NH-任选被1、2或3个R取代，其余变量如本发明所定义。
本发明的一些方案中，上述R1、R2、R8、R9分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、SF5、Me、CF3、CHF2、CH2F、CF3CF2、OCF3、HOCH2CH2O、CH3NHCH2CH2O、(CH3)2NCH2CH2O 其余变量如本发明所定义。
本发明的一些方案中，上述结构单元选自 其余变量如本发明所定义。
本发明的一些方案中，上述R3、R4、R5、R6、R10分别独立地选自H、卤素、OH、NH2、SF5、CN、C1-3烷基、C1-3烷氨基、C1-3烷氧基、C3-6环烷基、-O-C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-3烷基-和3～6元杂环烷基-C1-3烷基-，所述C1-3烷基、C1-3烷氨基、C1-3烷氧基、C3-6环烷基、-O-C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-3烷基-或3～6元杂环烷基-C1-3烷基-任选被1、2或3个R取代，其余变量如本发明所定义。
本发明的一些方案中，上述R3、R4、R5、R6、R10分别独立地选自H、F、Cl、Br、I、OH、NH2、SF5、Me、CF3、CHF2、CH2F、CN、CH(F2)CH3、CD3、OCD3、 其余变量如本发明所定义。
本发明的一些方案中，上述结构单元选自 其余变量如本发明所定义。
本发明的一些方案中，上述R13a、R13b分别独立地选自H、F、Cl、Br、I和Me，其余变量如本发明所定义。
本发明的一些方案中，上述式(I)所示化合物或其光学异构体选自
本发明的一些方案中，上述式(I)所示化合物选自其余变量如本发明所定义。
本发明的一些方案中，上述所述式(I)所示化合物选自其余变量如本发明所定义。
本发明的一些方案中，上述所述式(I)所示化合物选自其余变量如本发明所定义。
本发明的一些方案中，上述式(I-5)所示化合物或选自其余变量如本发明所定义。
本发明的一些方案中，上述式(I-5)所示化合物选自其余变量如本发明所定义。
本发明的一些方案中，上述式(I-6)所示化合物选自其余变量如本发明所定义。
本发明的一些方案中，上述式(I-6)所示化合物选自其余变量如本发明所定义。
本发明的一些方案中，上述接触是在缩合剂的条件下进行的，其余变量如本发明所定义。
本发明的一些方案中，上述缩合剂选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐/1-羟基苯并三唑和N,N'-羰基二咪唑，其余变量如本发明所定义。发明人发现，在这些缩合剂的条件下缩合效果好。
本发明的一些方案中，上述缩合剂为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，其余变量如本发明所定义。发明人发现，在这些缩合剂的条件下缩合效果更好。
本发明的一些方案中，上述缩合剂为N,N,N',N'-四甲基氯甲脒六氟磷酸盐或N-甲基咪唑中的一种，其余变量如本发明所定义。
本发明的一些方案中，上述缩合剂为N,N,N',N'-四甲基氯甲脒六氟磷酸盐和N-甲基咪唑的混合物，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-5)所示化合物与所述2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯的摩尔比为1：(1.0-2.0)，其余变量如本发明所定义。发明人发现，在这些比例下缩合效果好。
本发明的一些方案中，上述式(I-5)所示化合物与所述2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯的摩尔比为1：(1.2-1.5)，其余变量如本发明所定义。发明人发现，在这些比例下缩合效果更好。
本发明的一些方案中，上述式(I-5)所示化合物与所述N,N,N',N'-四甲基氯甲脒六氟磷酸盐的摩尔比为1：(1.0-2.0)，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-5)所示化合物与所述N,N,N',N'-四甲基氯甲脒六氟磷酸盐的摩尔比为1：(1.1-1.2)，其余变量如本发明所定义。
本发明的一些方案中，上述N-甲基咪唑与所述N,N,N',N'-四甲基氯甲脒六氟磷酸盐的摩尔比为1：(1.2-2.0)，其余变量如本发明所定义。
本发明的一些方案中，上述N-甲基咪唑与所述N,N,N',N'-四甲基氯甲脒六氟磷酸盐的摩尔比为1：(1.4-1.6)，其余变量如本发明所定义。
本发明的一些方案中，上述接触是在碱性条件下进行的，其余变量如本发明所定义。
本发明的一些方案中，上述碱性条件是由N,N-二异丙基乙胺提供的，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-5)所示化合物与所述N,N-二异丙基乙胺的摩尔比为1：(1.0-5.0)，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-5)所示化合物与所述N,N-二异丙基乙胺的摩尔比为1：(2.5-3.0)，其余变量如本发明所定义。
本发明的一些方案中，上述接触是在溶剂为N,N-二甲基甲酰胺、乙腈或二氯甲烷的条件下进行的，其余变量如本发明所定义。
本发明的一些方案中，上述接触是在溶剂为N,N-二甲基甲酰胺的条件下进行的，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-5-A)所示化合物是通过式(I-2)所示化合物与式(I-3)所示化合物进行取代反应获得的，
其中，Rx选自C1-6烷基，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-2)所示化合物或其光学异构体选自其余变量如本发明所定义。
本发明的一些方案中，上述式(I-3)所示化合物或其光学异构体选自其余变量如本发明所定义。
本发明的一些方案中，上述取代反应是在碱的存在的条件下进行的，其余变量如本发明所定义。
本发明的一些方案中，上述碱选自Cs2CO3、K2CO3和K3PO4，其余变量如本发明所定义。发明人发现，上述采用上述碱收率高。
本发明的一些方案中，上述碱为Cs2CO3，其余变量如本发明所定义。发明人发现，上述采用Cs2CO3收率更高。
本发明的一些方案中，上述式(I-2)所示化合物与所述Cs2CO3的摩尔比为1：(1.3-1.5)，其余变量如本发明所定义。
本发明的一些方案中，上述取代反应是在溶剂为N,N-二甲基甲酰胺或四氢呋喃的条件下进行的，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-2)所示化合物与所述式(I-3)所示化合物的摩尔比为1：(1.10-1.25)，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-2)所示化合物与所述式(I-3)所示化合物的摩尔比为1:1.15，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-2)所示化合物是通过式(I-1)所示化合物进行酯化反应获得的，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-1)所示化合物或其光学异构体选自其余变量如本发明所定义。
本发明的一些方案中，上述酯化反应是在SOCl2存在的条件下进行的，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-1)所示化合物与所述SOCl2的摩尔比为1：(1.0-2.0)，其余变量 如本发明所定义。
本发明的一些方案中，上述式(I-1)所示化合物与所述SOCl2的摩尔比为1：(1.2-1.5)，其余变量如本发明所定义。
本发明的一些方案中，上述酯化反应是在溶剂为乙醇的条件下进行的，其余变量如本发明所定义。
本发明的一些方案中，上述式(I-1)所示化合物与所述乙醇的比例为(1：1672-2090)，需要说明的是，这里的比例是指摩尔体积比(moL:mL)，其余变量如本发明所定义。
本发明的一些方案中，上述酯化反应进一步包括后处理，其余变量如本发明所定义。
本发明的一些方案中，上述后处理是通过加入碳酸氢钠水溶液进行的，其余变量如本发明所定义。
在本发明的另一方面，本发明还提出了一种中间体化合物或其药学上可接受的盐。根据本发明的实施例，上述中间体化合物结构如化合物5所示，
在本发明的另一方面，本发明还提出了化合物5所示化合物或其药学上可接受的盐在制备化合物7X所示化合物或其光学异构体中的用途。
在本发明的另一方面，本发明还提出了其中变量如本发明所定义。
在本发明的另一方面，本发明还提出了
在本发明的另一方面，本发明还提出了
在本发明的另一方面，本发明提出了一种制备化合物1的方法。根据本发明的实施例，所述方法包括将式(X-1)所示的化合物进行氯代反应，获得化合物1，所述氯代反应是在溶剂为浓硫酸、甲磺酸、三氟乙酸、磷酸或乙磺酸中的一种或几种的条件下进行的，
在本发明的另一方面，本发明提出了一种制备化合物1的方法。根据本发明的实施例，所述方法包括将式(X-1)所示的化合物进行氯代反应，获得化合物1，所述氯代反应是在溶剂为浓硫酸的条件下进行的，
发明人发现，现有技术中制备化合物1的方法为使用付克烷基化反应，反应中使用到剧毒的四氯化碳，并且反应和后处理过程比较复杂，收率低，而本发明的方法操作方便，没有用到剧毒试剂，收率高，且发明人发明本发明的氯代反应需要在浓硫酸条件下进行，其他溶剂条件下不反应或反应收率低。
在本发明的一些方案中，上述氯代反应是在氯代试剂的条件下进行的，其余变量如本发明所定义。
在本发明的一些方案中，上述氯代试剂选自二氯二甲基海因和N-氯代丁二酰亚胺，其余变量如本发明所定义。
在本发明的一些方案中，上述所述式(X-1)所示的化合物与二氯二甲基海因的摩尔比为1：(0.5-0.7)，其余变量如本发明所定义。发明人发现，在上述比例下，该氯代反应的收率较高。
在本发明的一些方案中，上述所述式(X-1)所示的化合物与N-氯代丁二酰亚胺的摩尔比为1：(1.1-1.6)，其余变量如本发明所定义。发明人发现，在上述比例下，该氯代反应的收率更高。
在本发明的一些方案中，上述氯代反应是在温度为55～60℃的条件下进行的，其余变量如本发明所定义。发明人发现，该温度范围内，收率更高。
在本发明的另一方面，本发明还提出了一种制备化合物6的方法。根据本发明的实施例，所述方法包括将式(Y-2)所示化合物进行氧化反应和脱保护反应，获得化合物6，发明人发现，现有技术中制备化合物6的方法为使用氧烟酸作为起始原料，通过DPPA和叔丁醇做成-Boc保护的氨基，脱-Boc保护得到目标产物，该方法中使用成本较高的DPPA并且反应过程产生的杂质过多，或者直接将式(Y-2)所示化合物使用MCPBA直接氧化吡啶，该方法极易产生两分子产物的聚合产物，收率低。而本发明提出的方法，操作简单，原料便宜，后处理方便，适合工业化大生 产。
在本发明的一些方案中，上述式(Y-2)所示化合物是通过将式(Y-1)所示化合物进行酰化反应获得的，其余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。
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，可以选自等。
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。
本发明的数值无论是否修饰术语“大约”，均应理解为该数值是用了“大约”进行修饰，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。
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，C1-6烷基羰基-指通过羰基与分子 的其余部分连接的C1-6烷基。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如，卤素取代基，“-”可以被省略。
当基团价键上带有虚线时，例如在中，波浪线表示该基团与分子其它部分的连接点。
本文所用的术语“氢”指基团-H。
本文所用的术语“氘”指基团-D。
本文所述的术语“羟基”指基团-OH。
本文所用的术语“卤代”或“卤素”指氟(F)、氯(Cl)、溴(Br)和碘(I)。
本文所用的术语“氰基”指基团-CN。
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1- 3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12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。
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“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C6和C5烷基等；其可以是一价(如CH3)、二价(-CH2-)或者多价(如次)。C1-6烷基的实例包括但不限于CH3、 等。
除非另有规定，术语“C1-3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C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如CH3)、二价(-CH2-)或者多价(如次)。C1- 3烷基的实例包括但不限于CH3、等。
除非另有规定，术语“C1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷氧基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4和C3烷氧基等。C1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C1-6烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷氨基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4、C3和C2烷氨基等。C1-6烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-N(CH2CH3)(CH2CH3)、-NHCH2CH2CH3、-NHCH2(CH3)2、-NHCH2CH2CH2CH3等。
除非另有规定，术语“C1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氨基包括C1-2、C3和C2烷氨基等。C1-3烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-NHCH2CH2CH3、-NHCH2(CH3)2等。
除非另有规定，术语“C1-6烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至6个碳原子 的烷基基团。所述C1-6烷硫基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4、C3和C2烷硫基等。C1-6烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2等等。
除非另有规定，术语“C1-3烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷硫基包括C1-3、C1-2和C3烷硫基等。C1-3烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2等。
除非另有规定，“C3-6环烷基”表示由3至6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C3-6环烷基包括C3-5、C4-5和C5-6环烷基等；其可以是一价、二价或者多价。C3-6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，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，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)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。
除非另有规定，术语“3-6元环”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和单环基团或不饱和单环基团，即可包含纯碳环，也可包含有杂原子的环。其中3-6是指形成环的原子的个数。3-6元环”的实例包括但不限于环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、环戊酮基、环己酮基等。
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)。
相应地，本文所用的术语“杂芳环”指如上定义的杂芳基的环。
如本文所用，“芳基”、“芳族”遵循休克尔规则(Hückel's rule)，其中π电子数等于4n+2，n为零或任何最多为6的正整数。
本文所用的术语“羰基”指基团–C(O)–，也可表示为-CO-。
本文所用的术语“氨基”指基团–NH2。
本文所用的术语“任选”指随后描述的事件可以发生或可以不发生，并且该描述包括所述事件发生的情形以及所述事件不发生的情形。例如，“任选被取代的烷基”指未取代的烷基和被取代的烷基，其中烷基如本文所定义。本领域技术人员应当理解，对于含有一个或多个取代基的任意基团而言，所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。
本文所用的术语“被取代的”或“被……取代”指给定原子或基团上的一个或多个氢原子被替换、例如被 一个或多个选自给定取代基组的取代基替换，条件是不超过该给定原子的正常化合价。当取代基是氧代(即＝O)时，则单个原子上的两个氢原子被氧替换。只有当取代基和/或变量的组合导致化学上正确且稳定的化合物时，这类组合才是允许的。化学上正确且稳定的化合物意味着化合物足够稳定，以至于能从反应混合物中被分离出来并能确定化合物的化学结构，并且随后能被配制成至少具有实际效用的制剂。例如，在没有明确列出取代基的情况下，本文所用的术语“被取代”或“取代”意指给定原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代，所述取代基独立地选自：氘(D)、卤素、OH、巯基、氰基、-CD3、烷基(优选C1-6烷基)、烷氧基(优选C1-6烷氧基)、卤代烷基(优选卤代C1-6烷基)、卤代烷氧基(优选卤代C1-6烷氧基)、-C(O)NRaRb和-N(Ra)C(O)Rb和-C(O)OC1-4烷基(其中Ra和Rb各自独立地选自氢、C1-4烷基、卤代C1-4烷基)、羧基(COOH)、环烷基(优选3-8元环烷基)、杂环基(优选3-8元杂环基)、芳基、杂芳基、芳基C1-6烷基、杂芳基C1-6烷基、OC1-6烷基苯基、-C1-6烷基OH(优选-C1-4烷基OH)、-C1-6烷基SH、-C1-6烷基O-C1-2、C1-6烷基NH2(优选C1-3烷基NH2)、N(C1-6烷基)2(优选N(C1-3烷基)2)、NH(C1-6烷基)(优选NH(C1-3烷基))、N(C1-6烷基)(C1-6烷基苯基)、NH(C1-6烷基苯基)、硝基、C(O)OC1-6烷基(优选C(O)OC1-3烷基)、NHC(O)(C1-6烷基)、NHC(O)(苯基)、N(C1-6烷基)C(O)(C1-6烷基)、N(C1-6烷基)C(O)(苯基)、C(O)C1-6烷基、C(O)杂芳基(优选C(O)-5-7元杂芳基)、C(O)C1-6烷基苯基、C(O)C1-6卤代烷基、OC(O)C1-6烷基(优选OC(O)C1-3烷基)、烷基磺酰基(例如-S(O)2-C1-6烷基)、烷基亚磺酰基(-S(O)-C1-6烷基)、-S(O)2-苯基、-S(O)2-C1-6卤代烷基、-S(O)2NH2、S(O)2NH(C1-6烷基)、S(O)2NH(苯基)、-NHS(O)2(C1-6烷基)、-NHS(O)2(苯基)和NHS(O)2(C1-6卤代烷基)，其中所述的烷基、环烷基、苯基、芳基、杂环基和杂芳基各自任选被一个或多个选自以下的取代基进一步取代：卤素、-OH、-NH2、环烷基、3-8元杂环基、C1-4烷基、C1-4卤代烷基-、-OC1-4烷基、-C1-4烷基OH、-C1-4烷基O-C1-4烷基、OC1-4卤代烷基、氰基、硝基、-C(O)-OH、C(O)OC1-6烷基、CON(C1-6烷基)2、CONH(C1-6烷基)、CONH2、NHC(O)(C1-6烷基)、NH(C1-6烷基)C(O)(C1-6烷基)、-SO2(C1-6烷基)、-SO2(苯基)、-SO2(C1-6卤代烷基)、-SO2NH2、SO2NH(C1-6烷基)、SO2NH(苯基)、-NHSO2(C1-6烷基)、-NHSO2(苯基)和NHSO2(C1-6卤代烷基)。当一个原子或基团被多个取代基取代时，所述取代基可以相同或不同。
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。
本发明采用下述缩略词：
SOCl2代表二氯亚砜，Cs2CO3代表碳酸铯，NaHCO3代表碳酸氢钠，K2CO3代表碳酸钾，K3PO4代表磷酸钾，DMF代表二甲基甲酰胺，THF代表四氢呋喃，T3P代表1-丙基磷酸酐，HATU代表2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，HOBt代表1-羟基苯并三唑，CDI代表N,N'-羰基二咪唑，DCM代表二氯甲烷，DIPEA代表N,N-二异丙基乙胺，DCDMH代表二氯二甲基海因，NCS代表N-氯代丁二酰亚胺，MTBE代表甲基叔丁基醚，TCFH代表N,N,N',N'-四甲基氯甲脒六氟磷酸盐，NMI代表N-甲基咪唑。
本发明中采用的体积nV一般是指n倍体积，为溶剂体积与所用化合物的重量比，单位为mL/g，例如表3中用到的乙醇体积8V，是指乙醇的体积为8倍体积，即乙醇的体积(mL/)是化合物1的重量(g)的8倍。
化合物依据本领域常规命名原则或者使用软件命名，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。
实施例1
步骤1
1)反应：微氮气保护下，将无水乙醇(38.4kg，6.45X)和化合物1(5.95kg,1.0X)加入至反应釜R1中，开启搅拌。将反应釜R1温度调整到0-10℃，微氮气保护下，控制反应釜温度0～20℃，将氯化亚砜(3.6kg，0.61X)缓慢滴加到反应釜中，滴加完毕升温至65～75℃搅拌8～16小时。降温至40～50℃，取样中控检测。中控合格(化合物1/(化合物1+化合物2)的纯度比)≤1.0％)后进行下一步操作。若检测不合格，继续搅拌反应，直至中控合格。
2)结晶：将反应釜内温降至15～25℃，滴加入预先配制好的10％磷酸钾(60.0kg，10.1X)水溶液，调节PH至6～8，搅拌3～6小时。
3)离心1：将反应釜中物料通过离心机离心，用工艺水(46.5kg，7.8X)淋洗滤饼。
4)打浆：将湿品(7.0kg，1.2X)和工艺水(61.2kg，10.3X)加入至反应釜R1中，15～25℃搅拌3～6小时。
5)离心2：将反应釜中物料通过离心机离心，滤饼用工艺水(42.8kg，7.2X)淋洗滤饼，得到湿品，湿品检测合格后进行下一步操作。
6)干燥：将湿品转移至真空烘箱，控制烘箱内温在30～40℃，减压干燥24～30小时。取样检测水分至合格(KF≤0.3％)。若不合格，则延长干燥时间直至水分合格。本批得到白色固体6.1kg，收率90.4％。1H NMR(400MHz,DMSO-d6)δ8.08–8.01(m,1H),7.89(d,J＝10.2Hz,1H),4.32(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).
HPLC条件
仪器：高效液相色谱仪(紫外检测器)Agilent 1260
柱子：Waters Xbridge C18/4.6×150mm,3.5μm
流动相：流动相A,0.05％甲酸水溶液，流动相B，0.05％甲酸乙腈溶液
流速：1.0ml/min
测定时间：28min
分析温度：35℃
检测波长：222nm/248nm
保留时间：化合物1：10.013min，化合物2：16.029min
表1
步骤2，3
1)反应1:微氮气保护下，将化合物2(6.0kg，1.00X)和四氢呋喃(44.0kg，7.33X)加至反应釜中，开启搅拌。加入化合物3(5.1kg，0.85X)、碳酸铯(10.7kg，1.78X)，降温至55-65℃搅拌反应16～24小时，降温至15～25℃，取样中控检测。中控合格(化合物2/(化合物2+化合物4+化合物5)的纯度比≤4.0％)后进入下一步操作，如中控不合格，则延长反应时间直至中控合格。
2)反应2:微氮气保护下，将配制好的氢氧化锂水溶液(35.8kg，6.0X)加至反应釜R1中，控制温度55～65℃，搅拌反应8～16小时。降温至15～25℃，取样中控检测。中控合格(化合物4/(化合物4+化合物5)的纯度比≤1.0％)后进入下一步操作。若中控不合格，则延长反应时间直至中控合格。
3)酸化：氮气保护下，控制温度在0-25℃，缓慢滴加35％盐酸(12kg，2.0X)至反应釜R1中。
4)萃取：向反应釜中加入甲基叔丁基醚(21.5kg，3.6X)。调整反应釜温度至15～25℃，搅拌0.5～2小时，静置0.5～2小时，分层，水相转移至钢塑复合桶。
5)洗涤:将配制好的10％氯化钠水溶液(35.35kg，5.9X)加至反应釜中，调整反应釜温度至15～25℃，搅拌0.5～2小时，静置0.5～2小时，分层，水相转移至钢塑复合桶。
6)浓缩:控制内温≤40℃，将反应釜中溶液减压浓缩至12-18L(2～3X)，加入无水乙醇(25.0kg，4.2X)。控制内温≤40℃，将反应釜中溶液减压浓缩至12～18L(2～3X)，加入无水乙醇(104.0kg，17.3X)。控制内温≤40℃，将反应釜中溶液减压浓缩至12-18L(2～3X)，加入无水乙醇(31.5kg，5.3X)至反应釜R1中。
7)结晶:反应釜温度控制在50～60℃，滴加入工艺水(78.0kg，13.0X)，并保温搅拌1～3小时。反应降温至15～25℃，降温时间控制在不少于2小时，15～25℃搅拌1～3小时。
8)离心:将反应釜中物料转移至离心机离心，加配制好的乙醇/工艺水＝1:1(v/v)溶液(26.1kg，4.3X)淋洗滤饼，得到湿品8.60Kg，湿品检测合格后进入下一步操作。
9)干燥：将湿品转移至真空烘箱，控制内温40～50℃减压干燥18小时以上至合格(KF:0.3％≤0.3％,EtOH:0.1％≤0.2％)，如不合格则延长干燥时间直至中控合格。得到白色固体化合物7(8.18kg)，收率85.4％。
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.50(s,1H),7.42–7.32(m,2H),7.12–7.02(m,2H).
ESI+,[M+H]+:366.9746,[M+H]+:368.9719
HPLC条件
仪器：高效液相色谱仪(紫外检测器)Agilent 1260
柱子：Waters Xbridge C18/4.6×150mm,3.5μm
流动相：流动相A,0.05％甲酸水溶液，流动相B，0.05％甲酸乙腈溶液
流速：1.0ml/min
测定时间：28min
分析温度：35℃
检测波长：222nm/248nm
保留时间：化合物2：16.029min，化合物3：10.712min，化合物4：18.792min，化合物5：16.232min。
步骤4
1)反应:氮气保护下，向干燥反应釜中加入DCM(56.5kg，6.93X)、中间体化合物5(8.15kg,1.0X)，开启搅拌。加入起始原料化合物6(3.95kg，0.48X)和HATU(10.2kg,1.25X)。控制20～30℃，向反应釜内滴加DIPEA(8.5kg,1.05X)。滴完升温至25～35℃搅拌8～16小时。取样中控检测，中控合格(化合物5/(化合物5+化合物7)的纯度比≤1.0％)后进入下一步操作，若不合格则延长反应时间，直至中控合格。
2)洗涤1:降温至15～25℃，加入DCM(27.0kg，3.3X)、配置好的5％K2CO3水溶液(49.0kg，6.0X)，控制内温15-25℃搅拌0.5～2小时，静置0.5～2小时，分层，分出水相，保留有机相。
3)洗涤2:加入配置好的7％NaHCO3水溶液(81.0kg，9.9X)，控制内温15～25℃搅拌0.5～2小时，静置0.5～2小时，分层，分出水相，保留有机相。加入配置好的7％NaHCO3水溶液(83.0kg，10.2X)，控制内温15～25℃搅拌0.5～2小时，静置0.5～2小时，分层，分出水相，保留有机相。
4)洗涤3:向有机相中加工艺水(80.0kg，9.8X)加到反应釜R1中控制内温15～25℃搅拌搅拌0.5～2小时，静置0.5～2小时，分层，分出水相，保留有机相。加工艺水(80.8kg，9.9X)加到反应釜R1中控制内温15～25℃搅拌0.5～2小时，静置0.5～2小时，分层，分出水相，保留有机相。
5)浓缩：将有机相转移至反应釜中，控制内温≤35℃，减压浓缩至16～24L(2.0～3.0X)，加乙腈(97.0kg，11.9X)至反应釜R1中，控制内温≤40℃，继续减压浓缩溶剂。浓缩至减压浓缩至73～81L(9.0～10.0X)，加乙腈(32.8kg，4.0X)至反应釜R1中，控制内温≤40℃，继续减压浓缩溶剂减压浓缩至73～81L(9.0～10.0X)。停止浓缩。
6)结晶：反应升温至50～60℃，将工艺水(135.2kg，16.6X)滴加至反应釜中。缓慢降温至40～50℃，40～50℃搅拌2～4小时，将内温降至0～10℃，搅拌6～8小时。
7)离心:将反应釜物料转移至离心机离心，加工艺水(17.5kg，2.1X)漂洗滤饼，取样检测合格(IM-A≤0.15％)后进入下一步操作，若不合格则重复结晶操作。
8)干燥：将滤饼转移至真空烘箱，35～45℃减压干燥18～24小时至水分(KF≤5.0％)合格。得到化合物7(9.68kg)，收率91.4％，化合物7的水分测试显示化合物与水摩尔比1：1，TGA显示50～150度失重3.5％，通过水分子量折算成摩尔比接近1：1。
ESI+,[M+H]+:459.0019,[M+H]+:461.0090
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.61(s,1H),8.03(s,1H),8.00(ddd,J＝6.3,1.8,1.0Hz,1H),7.48–7.43(m,2H),7.41–7.34(m,3H),7.20–7.15(m,2H).
HPLC条件
仪器：高效液相色谱仪(紫外检测器)Agilent 1260
柱子：Waters Xbridge C18/4.6×150mm,3.5μm
流动相：流动相A,0.05％甲酸水溶液，流动相B，0.05％甲酸乙腈溶液
流速：1.0ml/min
测定时间：28min
分析温度：35℃
检测波长：222nm/248nm
保留时间：化合物5：16.232min，化合物6：1.729min，化合物7：13.976min。
实施例2
步骤1：室温下向反应瓶中加入无水乙醇(464mL，8.0v/w)，化合物1(58.0g,278mmol)，搅拌溶清。降温至30～40℃，滴加SOCl2(39.6g,333mmol)。滴加完毕，加热至55-60℃反应4-8小时，取样中控至反应合格。滴加入10％磷酸钾溶液调节PH至6～8，析出产品，过滤，滤饼加水洗涤后得到湿品，30～40℃烘干得到化合物2。
步骤2，3：室温下向三口瓶中加入THF(130mL，8.0v/w),开始搅拌，加入化合物2(56.2g,237mmol)，化合物3(48.5g,272mmol)，Cs2CO3(100.4g,308mmol)，加热至55-60℃反应20-24小时取样中控，中控合格后，加入水(280mL)，一水合氢氧化锂(24.9g，593mmol)在55-60℃反应2-4小时取样中控，中控合格后降温至20-30℃，滴加浓盐酸(101ml，1.8vol)，滴完加入MTBE(130mL)搅拌10-15分钟，分层，有机相加入10％氯化钠溶液(280mL，5vol)洗涤。将有机相减压浓缩至2-3体积，加入无水乙醇(280mL，5V)继续浓缩至2-3体积，加入无水乙醇至约10体积。控制至20-30℃滴加水(504mL，9V)析出固体，过滤得到湿品在40-50℃烘干，得到化合物5。
步骤4的合成：室温下向三口瓶中加入DCM(200ml),化合物5(40.0g,109mml)开始搅拌，加入HATU(53.8g,144mmol)，化合物6(19.1g,131mmol)。30～35℃滴加DIPEA(42.2g,327mmol)，滴加完毕，30～35℃反应16小时。取样中控合格后，将体系降温至25～35℃，并补加DCM(100ml)，加入5％碳酸钾水溶液(240ml,6V)洗涤，静置分层，有机相加入7％的碳酸氢钠水溶液(400ml，10V)洗涤2次，再加入水(400ml，10V)洗涤2次。将有机相减压浓缩至剩余3.0～3.5V，补加乙腈(480ml，12V)继续浓缩置换溶剂2次，浓缩至剩余10V，体系升温至50～60℃溶清，滴加水(560ml，14V)，滴毕，于50～60℃保温1h。降温至0～10℃并搅拌2h。过滤得到湿品，在45～50℃下减压烘干得到化合物7。
实施例3
向反应瓶中加入浓硫酸(5ml,5V).，在20～25℃，加入化合物X-1(1g,1.0eq)，分批加入DCDMH(0.55eq)，升温至50～55℃反应过夜，中控合格后，反应液降温至20～25℃。将反应液滴加入20V冰水浴中，滴加完毕恢复到20～25℃搅拌2小时。过滤，滤饼加水洗涤，得到湿品，经过纯化。50～60℃干燥得到化合物1，收率50-60％。
实施例4
化合物Y-2的合成：室温下向反应瓶中加入IPA(30.0ml,3V).，水(30.0ml,3V)，Y-1(10.0g,106mmol)，搅拌溶清。降温至0～5℃，滴加BOC2O(27.8g,127mmol)/IPA(3.0V)，滴加完毕，恢复至室温反应2～3小时，取样中控合格。40～50℃，减压浓缩干反应液，加入MTBE(100ml)溶解，加水(100.0ml,10V)洗涤一次，分层。将有机相浓缩干得到产品Y-2。
化合物Y-3的合成：室温下向反应瓶中加入Y-2(10g,52mmol),DCM(100ml,10V)，搅拌。降温至0～10℃，分批加入固体m-CPBA，加完恢复至室温20～25℃反应过夜，取样中控合格，向反应瓶中加入10％Na2SO3(20ml,2V)洗涤一次，再加入10％Na2SO3(20ml,2V)洗涤一次。分层，水相加入乙酸乙酯(50ml,5V)萃取，有机相浓缩干，加入乙酸乙酯(100ml,10V)，两次乙酸乙酯相合并，过硅胶垫，得到滤液。将滤液浓缩干，加入1.4-二氧六环(50ml,5V)溶解，得到Y-3溶液。
化合物6的合成：室温下向反应瓶中加入Y-3溶液(52mmol)，控制温度10～20℃，滴加HCl/1,4-Dioxane溶液(520mmol,10.0eq.)，滴加完毕恢复至室温反应3～4小时，取样中控反应合格。反应过程析出固体，过滤得到滤饼，将滤饼加入反应瓶，加入乙腈(50ml,5V)，室温打浆1～2小时，过滤得到湿品，45～50℃干燥得到化合物6。
实施例5
氮气保护下，向干燥反应釜R1中加入CH3CN(62.2kg)、化合物5(13.5kg)，开启搅拌。加入化合物6(6.5kg)和TCFH(15.5kg)。控制0～10℃，向反应釜内滴加NMI(10.5kg)。滴完升温至25～35℃搅拌2～4小时。取样中控检测，中控合格后进入下一步操作。控制25～35℃，滴加配置好的3％K3PO4水溶液(138kg)，控制内温25～35℃搅拌2～4小时。将反应釜物料转移至离心机离心，加工艺水(37.1kg)漂洗滤饼。将上述湿品和工艺水(140kg)加入至反应釜R1中，35～45℃搅拌2～4小时。将反应釜物料转移至离心机离心，加工艺水(211.7kg)漂洗滤饼。将上述湿品和工艺水(140kg)加入至反应釜R1中，35～45℃搅拌2～4小时。将反应釜物料转移至离心机离心，加工艺水(185.4kg)漂洗滤饼。将滤饼转移至真空烘箱，35～45℃减压干燥18～24小时至水分(KF≤5.0％)合格。得到化合物7(15.7kg)，收率85％。
对比例1
保持其他条件与实施例2步骤1中的条件一致，仅改变步骤1中SOCl2的用量，其结果如下表2所示。
表2
对比例2
保持其他条件与实施例2步骤1中的条件一致，仅改变步骤1中乙醇体积的用量，其结果如下表3所示。
表3
对比例3
保持其他条件与实施例2步骤1中的条件一致，仅改变步骤1中后处理操作，其结果如下表4所示。
表4
对比例4
保持其他条件与实施例2步骤2中的条件一致，仅改变步骤2中碱的选择，其结果如下表5所示。
表5
对比例5
保持其他条件与实施例2步骤2中的条件一致，仅改变步骤2中溶剂的选择，其结果如下表6所示。
表6
对比例6
保持其他条件与实施例2步骤2中的条件一致，仅改变步骤2中碳酸铯的选择，其结果如下表7所示。
表7
对比例7
保持其他条件与实施例2步骤2中的条件一致，仅改变步骤2中化合物3的用量，其结果如下表7所示。
表8
对比例8
保持其他条件与实施例2步骤4中的条件一致，仅改变步骤4中缩合剂的种类，其结果如下表9所示。
表9
对比例9
保持其他条件与实施例2步骤4中的条件一致，仅改变步骤4中溶剂的种类，其结果如下表10所示。
表10
对比例10
保持其他条件与实施例2步骤4中的条件一致，仅改变步骤4中HATU的用量，其结果如下表11所示。
表11

对比例11
保持其他条件与实施例2步骤4中的条件一致，仅改变步骤4中DIPEA的用量，其结果如下表12所示。
表12
对比例12
保持其他条件与实施例2步骤4中的条件一致，仅改变步骤4中后处理条件，其结果如下表13所示。
表13
对比例13
对实施例3中的反应条件进行筛选，其结果如下表14所示。
表14

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。
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。

Claims (11)

  1. 一种制备式(I)所示化合物或其药学上可接受的盐、水合物的方法，其特征在于，包括将式(I-5)所示化合物或其药学上可接受的盐与式(I-6)所示化合物或药学上可接受的盐进行接触，获得式(I)所示化合物或其药学上可接受的盐、水合物，
    T1选自N或C(R7)；
    T2选自N或C(R8)；
    T3选自N或C(R9)；
    T4选自N或C(R10)；
    R1、R2、R8、R9分别独立地选自H、卤素、OH、NH2、CN、SF5、C1-6烷基、C1-6烷氧基、C1-6烷氨基、乙烯基-C1-6烷基-、C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-6烷基-、3～6元杂环烷基-C1-6烷基-、3～6元杂环烷基-C1-6烷基-O-、苯基-C1-3烷基-、C3-6环烷基-C1-3烷基-O-、3～6元杂环烷基-C1-3烷基-O-、苯基-C1- 3烷基-O-、苯基-C1-3烷基-NH-、5～6元杂芳基-C1-3烷基-、5～6元杂芳基-C1-3烷基-O-和5～6元杂芳基-C1-3烷基-NH-，所述C1-6烷基、C1-6烷氧基、C1-6烷氨基、乙烯基-C1-6烷基-、C3-6环烷基、3～6元杂环烷基、C3- 6环烷基-C1-6烷基-、3～6元杂环烷基-C1-6烷基-、3～6元杂环烷基-C1-6烷基-O-、苯基-C1-3烷基-、C3-6环烷基-C1-3烷基-O-、3～6元杂环烷基-C1-3烷基-O-、苯基-C1-3烷基-O-、苯基-C1-3烷基-NH-、5～6元杂芳基-C1-3烷基-、5～6元杂芳基-C1-3烷基-O-或5～6元杂芳基-C1-3烷基-NH-任选被1、2或3个R取代；
    R3、R4、R5、R6、R10分别独立地选自H、卤素、OH、NH2、SF5、CN、C1-6烷基、C1-6烷氨基、C1-6烷氧基、C3-6环烷基、-O-C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-6烷基-和3～6元杂环烷基-C1-6烷基-，所述C1-6烷基、C1-6烷氨基、C1-6烷氧基、C3-6环烷基、-O-C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-6烷基-或3～6元杂环烷基-C1-6烷基-任选被1、2或3个R取代；
    R7选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基和C1-6烷氨基，所述C1-6烷基、C1-6烷氧基或C1-6烷氨基任选被1、2或3个R取代；
    L2选自O、S、NH和CH2，所述CH2任选被1或2个R取代，NH任选被R取代；
    R13a、R13b分别独立地选自H、卤素和C1-6烷基，所述C1-6烷基任选被1、2或3个R取代；
    R分别独立地选自H、D、卤素、OH、NH2、CN、C1-6烷基、C1-6烷氧基、C1-6烷硫基和C1-6烷氨基，所述C1-6烷基、C1-6烷氧基、C1-6烷硫基或C1-6烷氨基任选被1、2或3个R’取代；
    R’选自F、Cl、Br、I、OH、NH2和CH3；
    上述3～6元杂环烷基或5～6元杂芳基包含1、2或3个独立选自-O-、-NH-、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O)2-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，所述式(I)所示化合物选自
    任选地，所述式(I)所示化合物选自
    任选地，所述式(I)所示化合物选自
    任选地，所述式(I-5)所示化合物选自
    任选地，所述式(I-5)所示化合物选自
    任选地，所述式(I-6)所示化合物选自
    任选地，所述式(I-6)所示化合物选自
  3. 根据权利要求1所述的方法，其特征在于，所述接触是在缩合剂的条件下进行的；
    任选地，所述缩合剂选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐/1-羟基苯并三唑和N,N'-羰基二咪唑、N,N,N',N'-四甲基氯甲脒六氟磷酸盐或N-甲基咪唑；
    任选地，所述缩合剂为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
    任选地，所述缩合剂为N,N,N',N'-四甲基氯甲脒六氟磷酸盐和N-甲基咪唑；
    任选地，所述式(I-5)所示化合物与所述2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯的摩尔比为1：(1.0-2.0)，任选为1：(1.2-1.5)；
    任选地，所述式(I-5)所示化合物与所述N,N,N',N'-四甲基氯甲脒六氟磷酸盐的摩尔比为1：(1.0-2.0)，任选为1：(1.1-1.2)；
    任选地，所述N-甲基咪唑与所述N,N,N',N'-四甲基氯甲脒六氟磷酸盐的摩尔比为1：(1.2-2.0)，任选为1：(1.4-1.6)；
    任选地，所述接触是在碱性条件下进行的；
    任选地，所述碱性条件是由N,N-二异丙基乙胺提供的；
    任选地，所述式(I-5)所示化合物与所述N,N-二异丙基乙胺的摩尔比为1:(1.0-5.0)，任选为1：(2.5-3.0)；
    任选地，所述接触是在溶剂为N,N-二甲基甲酰胺、乙腈或二氯甲烷的条件下进行的；
    任选地，所述接触是在溶剂为N,N-二甲基甲酰胺的条件下进行的。
  4. 根据权利要求2所述的方法，其特征在于，所述式(I-5-A)所示化合物是通过式(I-2)所示化合物与式(I-3)所示化合物进行取代反应获得的，
    其中，Rx选自C1-6烷基；
    任选地，所述式(I-2)所示化合物或其光学异构体选自
    任选地，所述式(I-3)所示化合物或其光学异构体选自
    任选地，所述取代反应是在碱的存在的条件下进行的；
    任选地，所述碱选自Cs2CO3、K2CO3和K3PO4；
    任选地，所述碱为Cs2CO3；
    任选地，所述式(I-2)所示化合物与所述Cs2CO3的摩尔比为1：(1.3-1.5)；
    任选地，所述取代反应是在溶剂为N,N-二甲基甲酰胺或四氢呋喃的条件下进行的；
    任选地，所述式(I-2)所示化合物与所述式(I-3)所示化合物的摩尔比为1：(1.10-1.25)，任选为1:1.15。
  5. 根据权利要求4所述的方法，其特征在于，所述式(I-2)所示化合物是通过式(I-1)所示化合物进行酯化反应获得的，
    任选地，所述式(I-1)所示化合物或其光学异构体选自
    任选地，所述酯化反应是在SOCl2存在的条件下进行的；
    任选地，所述式(I-1)所示化合物与所述SOCl2的摩尔比为1：(1.0-2.0)，任选为1：(1.2-1.5)；
    任选地，所述酯化反应是在溶剂为乙醇的条件下进行的；
    任选地，所述式(I-1)所示化合物与所述乙醇的比例为1：(1672-2090)；
    任选地，所述酯化反应进一步包括后处理；
    任选地，所述后处理是通过加入碳酸氢钠水溶液进行的。
  6. 一种中间体化合物或其药学上可接受的盐，其特征在于，结构如化合物5所示，
  7. 化合物5所示化合物或其药学上可接受的盐在制备化合物7X所示化合物或其光学异构体中的用途。
  8. 一种制备化合物1的方法，其特征在于，包括将式(X-1)所示的化合物进行氯代反应，获得化合物1，所述氯代反应是在溶剂为浓硫酸、甲磺酸、三氟乙酸、磷酸或乙磺酸中的一种或几种的条件下进行的，
  9. 根据权利要求8所述的方法，其特征在于，所述氯代反应是在氯代试剂的条件下进行的；
    任选地，所述氯代试剂选自二氯二甲基海因和N-氯代丁二酰亚胺；
    任选地，所述式(X-1)所示的化合物与二氯二甲基海因的摩尔比为1：(0.5-0.7)；
    任选地，所述式(X-1)所示的化合物与N-氯代丁二酰亚胺的摩尔比为1：(1.1-1.6)；
    任选地，所述氯代反应是在温度为55～60℃的条件下进行的。
  10. 一种制备化合物6的方法，其特征在于，包括将式(Y-2)所示化合物进行氧化反应和脱保护反应，获得化合物6，
  11. 根据权利要求10所述的方法，其特征在于，所述式(Y-2)所示化合物是通过将式(Y-1)所示化合物进行酰化反应获得的，
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