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WO2017202365A1 - 一种三氟甲基取代的吡喃衍生物制备方法 - Google Patents

一种三氟甲基取代的吡喃衍生物制备方法 Download PDF

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WO2017202365A1
WO2017202365A1 PCT/CN2017/085925 CN2017085925W WO2017202365A1 WO 2017202365 A1 WO2017202365 A1 WO 2017202365A1 CN 2017085925 W CN2017085925 W CN 2017085925W WO 2017202365 A1 WO2017202365 A1 WO 2017202365A1
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compound
formula
solvent
reaction
acid
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PCT/CN2017/085925
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English (en)
French (fr)
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张校伟
赵富强
刘兆军
隆元强
刘珍
张晨
王建民
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四川海思科制药有限公司
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Priority to CN201780011295.4A priority Critical patent/CN108699068B/zh
Publication of WO2017202365A1 publication Critical patent/WO2017202365A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for the preparation of a trifluoromethyl substituted pyran derivative.
  • Glucagon-like peptide 1 can participate in the regulation of blood glucose homeostasis, improve islet function, delay or even reverse the progression of type 2 diabetes through multiple pathways.
  • endogenous GLP-1 is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) after secretion into the blood and loses its activity.
  • DPP-4 inhibitor can selectively inhibit the enzymatic activity of DPP-4, prevent the inactivation of GLP-1 cleavage, increase the plasma level of active GLP-1, enhance its physiological effects, and reduce HbA1, fasting blood glucose and meals in patients with type 2 diabetes. After blood sugar levels.
  • WO2015192701 discloses a novel dipeptidyl peptidase IV (DPP-4) inhibitor represented by formula (I), which has a good inhibitory effect on the enzymatic activity of DPP-4 and has the potential to prevent and treat type II diabetes. .
  • the compound of the formula (I) has good stability and high bio-use degree, and is convenient for the development of the preparation and has clinical value.
  • the invention relates to a preparation method of a trifluoromethyl-substituted pyran derivative, which is a preparation method of the compound represented by the formula (I).
  • the method has mild reaction conditions, simple operation, high reaction yield and high product purity. It is easy to handle and suitable for industrial production.
  • the present invention is compared with the preparation method of the compound represented by the formula (I) disclosed in WO2015192701A1: 1)
  • the method for preparing the formula (III) from the formula (V) is optimized, and the intermediates (VI-A) and (VI-B) are omitted.
  • the separation is simultaneously purified by recrystallization or/and beating, which avoids separation by column chromatography, is more suitable for industrial production, and greatly improves the yield of formula (III).
  • the invention relates to a process for the preparation of a compound of formula (I):
  • the compound of the formula (II) is reacted in the presence of p-toluenesulfonic acid with a dichloromethane system or a system of an acidic reagent having a pKa ⁇ 5 and water to obtain a compound of the formula (I);
  • an organic solvent may be further added to the reaction;
  • P is an amino protecting group, preferably a tert-butoxycarbonyl group.
  • p-toluenesulfonic acid can be p-toluenesulfonic acid containing water of crystallization, such as p-toluenesulfonic acid monohydrate or p-toluenesulfonic acid tetrahydrate.
  • p-toluenesulfonic acid or p-toluenesulfonic acid containing water of crystallization is an excess, preferably a compound of formula (II) and p-toluenesulfonic acid or p-toluenesulfonic acid containing water of crystallization.
  • the molar ratio is 1:2.5 to 1:3, preferably 1:2.8.
  • trifluoroacetic acid is an excess, preferably, the mass ratio (w/w) of the compound of formula (II) to trifluoroacetic acid is from 1:3 to 1:6.
  • the acidic agent is selected from one or a mixture of two or more of hydrochloric acid, trifluoroacetic acid, and methanesulfonic acid
  • the organic solvent is selected from the group consisting of methanol, isopropanol, or ethanol.
  • the temperature of the reaction is from -20 to 30 °C.
  • the post-treatment of the reaction of p-toluenesulfonic acid with a dichloromethane system comprises the steps of:
  • seed crystals are added to step (3).
  • the base used in the step (2) of the post-treatment of the reaction of p-toluenesulfonic acid with a dichloromethane system is aqueous ammonia, and the pH of the solution is adjusted to a pH of 8 to 11, preferably 9 ⁇ 10.
  • Post-treatment of the reaction of an acidic reagent having a pKa ⁇ 5 with an aqueous system in certain embodiments comprises
  • Adding an organic solvent to the reaction solution adding water and/or an alkaline solution, layering, extracting, collecting the organic phase, and concentrating under reduced pressure to obtain a crude product.
  • the number of extractions of the aqueous phase after stratification can be increased, the organic phase can be collected, the organic phase can be post-treated by conventional washing or/and drying methods in the art, and then the organic phase is concentrated to obtain a crude product; the alkaline solution is pH.
  • a solution of >7 including, but not limited to, an aqueous ammonia solution, an aqueous solution of sodium carbonate, an aqueous solution of methylamine, an aqueous solution of potassium carbonate, an aqueous solution of sodium hydrogencarbonate, an aqueous solution of potassium hydrogencarbonate, an aqueous solution of lithium hydroxide, an aqueous solution of sodium hydroxide, and an aqueous solution of potassium hydroxide.
  • the crude product obtained above may be recrystallized or/and beaten; recrystallization or/and beating may be carried out in any suitable solvent system including, but not limited to, water, ester solvents, alcohol solvents, a mixed solvent of one or more of a nitrile solvent, an ether solvent, an aromatic hydrocarbon solvent, an alkane solvent, and a halogenated alkane solvent; further preferably water, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile , methanol, ethanol, isopropanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, n-heptane, cyclohexane, hexane One or a mixture of two or more of an alkane and petroleum ether.
  • a seed crystal of the compound of the formula (I) may be further added.
  • the crude product obtained by post-treatment of p-toluenesulfonic acid with a dichloromethane system or a system of an acidic reagent having a pKa ⁇ 5 and water is recrystallized or/and beaten in a solvent, recrystallized or /
  • the temperature of the beating is preferably -10 ° C - system reflux.
  • the recrystallized or/and beaten solvent is selected from the group consisting of water, methanol, methyl acetate, ethyl acetate, isopropyl acetate, n-heptane, cyclohexane, n-hexane, and petroleum ether.
  • the temperature is preferably -10 ° C to reflux.
  • the present invention relates to a process for the preparation of a compound of formula (II), wherein
  • a compound of the formula (III) and a compound of the formula (IV) are reacted in the presence of an organic acid to give an intermediate compound of the formula (II-M); an organic acid and an organic boron reducing agent are added, -10 to 25 ° C The reaction is carried out to obtain a compound of the formula (II);
  • P is an amino protecting group, preferably a tert-butoxycarbonyl group.
  • the polar aprotic solvent is non-limiting selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane.
  • sulfones preferably dichloromethane, Acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl
  • the organic acid has a pKa > -1.9, in which the pKa refers to a dissociation constant in water at 25 ° C, including but not limited to formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonate Acid or p-toluenesulfonic acid.
  • the organoboron reducing agent is selected from the group consisting of sodium tris(acetoxy)borohydride, sodium borohydride, sodium cyanoborohydride or decane borane.
  • the molar ratio of the compound of formula (III) to the organoboron reducing agent is from 1:2 to 1:8, preferably from 1:3 to 1:6, further preferably from 1:3 to 1:5.
  • the molar ratio of the compound of formula (III) to the organic acid is from 1:2 to 1:8, preferably from 1:3 to 1:6, further preferably from 1:3 to 1:5.
  • the molar ratio of the compound of formula (III) to the compound of formula (IV) is from 1:1 to 1:2, preferably from 1.1 to 1.5.
  • the mass ratio of polar aprotic solvent to the compound of formula (III) is from 1:1 to 10:1, preferably from 5:1 to 10:1.
  • the compound of formula (III) and the compound of formula (IV) will give a different reaction temperature for the intermediate compound of formula (II-M), preferably from -30 ° C to solvent reflux. Temperature; when the solvent for the reaction is N,N-dimethylacetamide, the reaction temperature is preferably -10 to 80 ° C, more preferably -10 to 60 ° C, still more preferably -10 to 40 ° C.
  • the compound of formula (III) and the compound of formula (IV) are in the presence of a molecular sieve, a dehydrating agent or a water-removing vessel to give an intermediate (II-M) compound, preferably at a temperature of from -20 to 25 °C.
  • the compound of formula (III) and the compound of formula (IV) are in the presence of a molecular sieve to give an intermediate (II-M) compound, preferably the weight ratio of the compound of formula (III) to the molecular sieve is 1:1. 1:5, preferably 1:1 to 1:3.
  • the compound of formula (II) is obtained by conventional post-treatment after reduction of the intermediate (II-M) compound.
  • Post-processing includes but is not limited to the following two options:
  • the first option includes the following steps:
  • the alkaline aqueous solution is preferably an aqueous ammonia solution, an aqueous solution of methylamine, an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate, an aqueous solution of sodium hydrogencarbonate, or a potassium hydrogencarbonate.
  • One or a mixture of two or more of an aqueous solution, an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, and an aqueous potassium hydroxide solution is more preferably an aqueous lithium hydroxide solution.
  • the aqueous phase after extraction in step (1) is further extracted with an organic solvent, and the organic phase is combined and washed with water and/or an aqueous solution of sodium chloride to obtain a first organic phase;
  • the first organic phase in step (2) is filtered through silica gel, the filter cake is washed with an organic solvent, the filtrate is combined, and the filtrate is concentrated to give a crude product.
  • the second option includes the following steps:
  • the base in the step (1) of the second embodiment is selected from the group consisting of an aqueous ammonia solution, an aqueous solution of methylamine, an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate, an aqueous solution of sodium hydrogencarbonate, an aqueous solution of potassium hydrogencarbonate, an aqueous solution of lithium hydroxide,
  • One or a mixture of two or more of an aqueous sodium hydroxide solution and an aqueous potassium hydroxide solution is preferably an aqueous ammonia solution.
  • water is added in two portions with stirring, and the volume ratio of methanol, first water addition, and second water addition is preferably 4:1:4.
  • step (3) of the first and second modes can be carried out in any suitable solvent system, and suitable solvents are preferably water, ester solvents, alcohol solvents, nitriles solvents, ethers. a mixed solvent of one or more of a solvent, an aromatic hydrocarbon solvent, an alkane solvent, and a halogenated alkane solvent; more preferably water, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether
  • the above mixture is more preferably one or a mixture of two or more of dichloromethane, toluene, petroleum ether
  • the invention also relates to a process for the preparation of a compound of formula (III):
  • P is selected from an amino-protecting group, preferably a tert-butoxycarbonyl group.
  • the method of preparing a compound of formula (III) comprises the steps of:
  • P is selected from an amino-protecting group, preferably a tert-butoxycarbonyl group.
  • step (1) of preparing the compound of the formula (III) it is a significant advantage to directly add morpholine to the reaction solution in the prior art.
  • the reaction system In the prior art, in the process of adding morpholine, the reaction system is severely agglomerated and affected. The agitation of the reaction is not conducive to amplification.
  • agglomeration can be avoided, the yield of the reaction can be improved, and industrial production can be facilitated.
  • reaction of step (1) of preparing a compound of formula (III) is further carried out under molecular sieves, dehydrating agents or water-dispensing vessel conditions.
  • the polar aprotic solvent for the reaction of step (2) to prepare a compound of formula (III) is selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, One or a mixture of two or more of N,N-dimethylacetamide, N,N-dimethylformamide, and dimethyl sulfoxide.
  • the acidic reagent of step (3) for preparing a compound of formula (III) is selected from the group consisting of hydrochloric acid, formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.
  • the molar ratio of the compound of formula (V) to morpholine is from 1:1 to 1:3, preferably 1:1.5.
  • the compound of formula (VI-A) is S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate or S-(trifluoromethyl)dibenzothiophene trifluoromethyl
  • the molar ratio of tetrafluoroborate is 1:1 to 1:3, preferably 1:1 to 1:5, more preferably 1:1.2.
  • the molar ratio of the compound of formula (VI-A) to 4-dimethylaminopyridine is from 1:0.1 to 1:1.5, preferably from 1:1 to 1:5, more preferably 1:1.1.
  • step (1) of the preparation of the compound of formula (III) comprises the steps of:
  • the reaction solution is beaten; preferably the reaction solution is added to the stirred beating solvent; the beating solvent can be completed in any suitable solvent system, suitable solvents are preferably toluene, n-heptane, n-hexane, cyclohexane and petroleum One or two or more solvents in the ether;
  • step (1) of the preparation of the compound of formula (III) comprises the steps of:
  • the reaction solution is added to the stirred solvent;
  • the solvent can be completed in any suitable solvent system, suitable solvent is preferably one or two of toluene, n-heptane, n-hexane, cyclohexane and petroleum ether The above solvent;
  • step (2) of the preparation of the compound of formula (III) further comprises the following post-treatment step: adding an organic solvent and water, layering, extracting, obtaining an organic phase, and concentrating the organic phase.
  • step (3) of the method of preparing a compound of formula (III) further comprises the following post-processing steps:
  • the step (3) of the preparation of the compound of the formula (III) further comprises adding water and/or an organic solvent to the reaction liquid, layering, extracting, and collecting the organic phase; and the organic phase is optionally treated in the following manner: The organic phase is passed through silica gel and the resulting liquid is further concentrated to give a crude product; or the organic phase is further washed and/or dried and/or concentrated to give a crude product;
  • the crude product is recrystallized or/and beaten.
  • the method of preparing the compound of formula (III) step (3) may be carried out in any suitable solvent system, preferably a solvent, preferably water or ester. a solvent, an alcohol solvent, a nitrile solvent, an ether solvent, an aromatic hydrocarbon solvent, an alkane solvent, and a halogenated alkane solvent, or a mixed solvent of one or more; more preferably water, acetonitrile, tetrahydrofuran, 2-methyl One of tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dichloromethane, methyl acetate, ethyl acetate, isopropyl acetate, toluene, petroleum ether, n-hexane, cyclohexane and n-heptanekind or more than two solvents.
  • a solvent preferably water or ester.
  • the invention also relates to a process for the preparation of a compound of formula (IV):
  • P is an amino protecting group, preferably a tert-butoxycarbonyl group.
  • the hydrochloric acid-ethyl acetate solution is ready for use and is formed by dropwise addition of acetyl chloride to a mixture of ethyl acetate and ethanol, preferably at a concentration of 4 mol/L hydrochloric acid-ethyl acetate solution.
  • the mass to volume ratio of the compound of formula (VII) to the hydrochloric acid-ethyl acetate solution is from 1:3.5 to 1:8.
  • the method of preparing a compound of formula (IV) further comprises seeding crystals of a compound of formula (IV).
  • the present invention also relates to a compound of the formula (III-A), the formula (III-B), the formula (II-A), and the formula (II-B) shown below:
  • P is an amino protecting group, preferably a tert-butoxycarbonyl group.
  • the invention also relates to a process for the preparation of a compound of formula (III-A) and formula (III-B),
  • P is an amino protecting group, preferably a tert-butoxycarbonyl group.
  • the invention also relates to a process for the preparation of compounds of formula (II-A) and formula (II-B),
  • P is an amino protecting group, preferably a tert-butoxycarbonyl group.
  • the compounds of formula (II-A) and formula (II-B) are isolated by silica gel column chromatography.
  • the molar ratio of the compound of formula (III) to the compound of formula (IV) is from 1:1.1 to 1:2.
  • the compound P of the present invention is preferably a tert-butoxycarbonyl group.
  • the compound of the formula (III) according to the invention is a compound of the formula (III-1), a compound of the formula (III-2) or a mixture of the two:
  • P is an amino protecting group, preferably a tert-butoxycarbonyl group.
  • the method of extracting used in the post-treatment of the reaction in the present invention is a conventional method in the art, and the solvent to be extracted can be selected according to the solubility of the product and the solubility of the organic solvent in water, and common extraction solvents include, but are not limited to, dichloromethane, chloroform, Acetic acid One or a mixture of two or more of ethyl ester, methyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methanol and ethanol.
  • the number of extractions may be appropriately increased or decreased depending on the amount of product remaining in the aqueous phase.
  • the organic phase after extraction is optionally further subjected to washing or/and drying treatment conventional in the art.
  • the separation method used in the present invention is a conventional separation method conventionally used in the art, such as silica gel column chromatography, high performance liquid chromatography, and thin layer chromatography.
  • the reaction process of the present invention tracks the progress of the reaction by HPLC, 1 H NMR or thin layer chromatography to determine whether the reaction is over.
  • “Closed reactor” means a reaction vessel in which the reaction system is in a closed state, such as a reaction vessel, and a closed tube.
  • the “configuration transition end point” as used in the present invention means that the 1H NMR (solvent is DMSO-d6) shift ( ⁇ ) has a peak area ratio of H ( ⁇ 5.2) to H ( ⁇ 4.4) of >2:1.
  • the 1H NMR shift ( ⁇ ) allows for some movement due to the different control of the experimental conditions due to the different 1H NMR instruments.
  • Figure 1 is a 1 H NMR spectrum of Compound 2.
  • Figure 2 is a 1 H- 1 H NOESY map of Compound 2.
  • Figure 3 is a 1 H- 1 H COSY spectrum of Compound 2.
  • Figure 4 is a 1 H- 1 H NOESY map of compound 6-b.
  • Figure 5 is a 1 H- 1 H NOESY map of compound 7-a.
  • Figure 6 is a 1 H- 1 H COSY spectrum of compound 7-a.
  • Figure 7 is a 1 H- 1 H NOESY map of compound 7-b.
  • Figure 8 is a 1 H- 1 H COSY pattern of compound 7-b.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS), two-dimensional hydrogen homonuclear displacement correlation spectrum ( 1 H- 1 H COSY), two-dimensional nuclear Overhofer enhancement spectrum ( 1 analysis of stereoisomers H- 1 H NOESY) is used.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ The NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR NMR was measured using a (Bruker Avance III 400) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), deuterated Acetone, internal standard is tetramethylsilane (TMS), external standard is 85% phosphoric acid aqueous solution.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • TMS 85% phosphoric acid aqueous solution.
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is 20 ° C ⁇ 30 ° C.
  • Boc is a tert-butyloxycarbonyl group.
  • Method 1 Compound 1a (1.0 kg, 3.06 mol) was placed in a 5 L round bottom flask containing toluene (3 L), warmed to 80 ° C, and morpholine (400 g) was slowly added dropwise. After the dropwise addition was completed, the mixture was heated to reflux, and Dean-Stark was reacted in water for 3.5 hours. The reaction solution was pumped into a 20 L round bottom flask containing n-heptane (15 L), beaten for 1.5 hours, cooled to room temperature, filtered, and the filter cake was washed once with n-heptane (5 L) to collect solids and blast at 50 °C. Drying gave Compound 1 (1.13 kg, yield 93%, HPLC (265nm): 90.0%).
  • Method 2 6.51Kg of toluene and 2.50Kg of compound 1a are added to the reaction kettle; stirring, heating to 70-80 ° C, 1.00 Kg of morpholine is added dropwise; after the addition is completed, the temperature is further increased to reflux, and the reaction mixture is refluxed for 5 hours; It was added to 25.10 Kg of n-heptane; it was cooled to room temperature and stirred for 1 hour; the filter cake was collected by filtration and dried at 50 ° C to obtain 2.89 Kg of Compound 1; yield 95.38%, HPLC (265 nm): 92.2%.
  • Method 1 In a 100 L reactor, the compound 1 obtained in Example 1 (prepared in the method of Example 1) (1 kg, 2.53 mol) was added to N,N-dimethylacetamide (10 L) under a nitrogen atmosphere. In the mixture, 4-dimethylaminopyridine (296 g, 2.53 mmol) was added under stirring, and the temperature was lowered to -10 ° C, which was the liquid A. Add S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate (1.22 kg, 3.04 mol) and N,N-dimethylacetamide (2 L) to a 5 L flask and stir until clear.
  • Example 1 prepared in the first method of Example 1 (prepared in the first method of Example 1) (10 g) was added to N,N-dimethylacetamide (100 mL), and 4-dimethylamino group was added under stirring. Pyridine (3.3 g), cooled to -10 ° C, which is liquid A. S-(Trifluoromethyl)dibenzothiophene trifluoromethanesulfonate (12.2 g) in N,N-dimethylacetamide (20 mL) was added dropwise to solution A. After the addition, the reaction was kept at -10 ° C for 5 hours, and allowed to stand at room temperature for 16 hours.
  • Method 2 27.43 Kg of N,N-dimethylacetamide and 2.88 Kg of Compound 1 (prepared by Method 2 of Example 1) were added to the reaction vessel; stirred, cooled to -10 to 0 ° C; and added to 0.93 Kg 4- Methylaminopyridine; control temperature -10 ⁇ 0 ° C, add 3.52Kg S-(trifluoromethyl) dibenzothiophene trifluoromethanesulfonate; add the reaction for 5 hours; then heat to 5 ⁇ 15 ° C, The reaction was carried out for 15.5 hours; ethyl acetate and deionized water were added to the reaction mixture, and the organic layer was concentrated under reduced pressure to give a residue.
  • Compound 2 is a mixture of two stereoisomers and contains the following structure:
  • the deuterated acetone was used as the solvent.
  • the 1 HNMR of the compound 2 is shown in Fig. 1
  • the 1 H- 1 H NOESY spectrum is shown in Fig. 2
  • the 1 H- 1 H COSY spectrum is shown in Fig. 3.
  • reaction solution was cooled to -10.degree. C., filtered and evaporated.
  • the filter cake was added to dichloromethane (5 L), and a mixed solution of aqueous ammonia (1 L) and water (1 L) was added thereto with stirring, and the layers were allowed to stand.
  • the aqueous layer was extracted with methylene chloride (4 mL).
  • Method 1 Compound 3 (142.0 g, 0.7595 mol) and Compound 2 (200.0 g, 0.5063 mol) were sequentially added to a reaction flask containing chloroform (400 mL) under stirring, and the mixture was stirred under reflux with heating, and Dean-Starks was separated. Reaction for 5 hours. After the reaction was terminated, the heating was stopped. After the reaction solution was stopped from boiling, the reaction solution was transferred to a 5 L three-necked flask, and the reaction mixture was diluted with 1,2-dichloroethane (1.6 L).
  • the reaction system was stirred under a nitrogen atmosphere to a temperature of 5 to 15 ° C, and sodium triacetoxyborohydride (375.6 g, 1.771 mol) and acetic acid (46.33 mL, 0.8100 mol) were added in that order, and the temperature was raised to 20 to 35. °C, reaction for 5 hours.
  • water (1.2 L) was slowly added, stirred for 5 minutes, and the layers were allowed to stand.
  • the aqueous layer was extracted with dichloromethane (400 mL ⁇ 2), and the organic phase was combined.
  • the organic phase was washed with water (600 mL) and aqueous ammonia (100 mL).
  • the crude product was dissolved in dichloromethane (1.4 L) under heating conditions (not higher than 45 ° C), dissolved completely, cooled to 20-30 ° C, and petroleum ether (2.8 L) was added within 3-8 minutes under stirring.
  • Dichloromethane (720 mL) was added to the solid at 10 to 35 ° C, stirred for 1 hour, petroleum ether (1.8 L) was added, and stirring was continued at room temperature for 2 hours.
  • the invention further optimizes the conditions for the reaction of the compound 2 with the compound 3 to form an intermediate enamine.
  • the specific optimization is shown in Table 1.
  • Method 2 nitrogen protection, 13.27Kg N,N-dimethylacetamide, 1.75Kg compound 2, 1.25Kg compound 3 and 3.58Kg 4A molecular sieves were added to the reaction vessel, cooled to 0 to 5 ° C, and 0.67 Kg of acetic acid was added; After the addition is completed, the temperature is raised to 5 to 15 ° C for 29 hours; the temperature is cooled to 0 to 10 ° C, 0.53 Kg of acetic acid is added; 4.25 Kg of NaBH(OAc) 3 is added in portions; after the addition is completed, the reaction is carried out at 5 to 15 ° C for 16.5 hours; Methyl chloride, 5% aqueous lithium hydroxide solution and deionized water, stirred and layered; the aqueous layer was further extracted twice with dichloromethane, and the organic layer was combined, washed with deionized water and then with sodium chloride solution; Filtration on silica gel, the residue was washed with eth
  • Method 1 p-toluenesulfonic acid monohydrate (752.3 g, 3.958 mol) was added to dichloromethane (8 L) in a 50 L reactor, and compound 4 (800 g, 1.413 mol) was added under a nitrogen atmosphere. The reaction was stirred at 20 to 25 ° C for 4 to 5 hours. After completion of the reaction, water (8.5 L) and methanol (800 mL) were added in that order and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted three times with a mixed solvent of dichloromethane (8L) and methanol (800 mL).
  • the organic phase was combined, and water (8 L) and aqueous ammonia (1.5 L) were added for 10 minutes, and the layers were separated.
  • the organic phase was washed successively with saturated sodium carbonate solution (8-10 L) and saturated brine (8-10 L). Dry and concentrate under reduced pressure at 35 ° C to give a crude material.
  • the internal temperature was controlled at 30 to 35 ° C under a nitrogen atmosphere, and the crude product was dissolved in ethyl acetate (3.5 L).
  • Trifluoroacetic acid (442 mL) was added to water (177 mL) in a 5 L three-necked flask, and the temperature was lowered to 5 to 10 °C. Under a nitrogen atmosphere, Compound 4 (200 g, 0.353 mol) was added under stirring, maintaining the temperature at 5 to 15 ° C, and trifluoroacetic acid (100 mL) was added. The reaction was stirred at 15 to 25 ° C for 4 to 5 hours while maintaining the temperature. After completion of the reaction, dichloromethane (1.6 L) was added under stirring, and water (200 mL) and aqueous ammonia (730 mL) were added dropwise at a temperature not higher than 25 °C.
  • the crude product obtained in the second method can also be purified by the following method: nitrogen protection, 3.52 kg of crude product (consistent with the reaction conditions of the method 2) is dissolved in 27.80 kg of methanol, 35.20 kg of deionized water is added under stirring, and the crystallization is stirred for 1 to 2 hours. Filter, collect the filter cake; filter cake was dried at 45-55 ° C for 10 hours; 2.80 kg of compound 5 was obtained (yield 79.55%, HPLC: 99.4% (267 nm)).
  • Method 3 nitrogen protection, 4mol / L hydrochloric acid solution (200ml) and ethanol (40ml) were added to the reaction flask, the temperature was lowered to 0 ⁇ 10 ° C, compound 4 (20g) was added; 20 ° C reaction for 1-2 hours.
  • Dichloromethane (300ml) was added to the reaction solution, and 5% aqueous ammonia was added dropwise to adjust the pH to 8-9; the organic layer was separated, washed, and dried and filtered; n-heptane (750 ml) was added to the filtrate, and the precipitate was precipitated, filtered, and collected.
  • the filter cake was dried 10.5 g, yield 63.8%; HPLC: 99.2% (267 nm).
  • the reaction solution was cooled to about -10 ° C, filtered under reduced pressure, and the filter cake was washed once with ethyl acetate (2L).
  • the filter cake was added to dichloromethane (5 L), and a mixed solution of aqueous ammonia (1 L) and water (1 L) was added thereto, and the aqueous layer was extracted with dichloromethane (4L ⁇ 4). Filter under reduced pressure and concentrate to dryness under reduced pressure.
  • the concentrate was added to dichloromethane (1.2 L), petroleum ether (6 L) was added dropwise with stirring, and the solid was gradually precipitated. After stirring, the mixture was crystallized for about 2 hours, filtered under reduced pressure, and the filter cake was washed with petroleum ether (2 L).
  • the organic phase was washed successively with saturated sodium carbonate solution (8-10 L) and saturated brine (8-10 L). Dry and concentrate under reduced pressure at 35 ° C to give a crude material.
  • the internal temperature was controlled at 30 to 35 ° C under a nitrogen atmosphere, and the crude product was dissolved in ethyl acetate (3.5 L). The internal temperature was maintained at 25 to 35 ° C, and n-heptane (7 L) was added dropwise with stirring.

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Abstract

提供一种三氟甲基取代的吡喃衍生物及其中间体的制备方法，即式(I)所示化合物及其中间体的制备方法，该方法反应条件温和，操作简单，反应产率高，产品纯度高，后处理方便，适合于工业化生产。

Description

一种三氟甲基取代的吡喃衍生物制备方法 技术领域
本发明涉及一种三氟甲基取代的吡喃衍生物制备方法。
背景技术
胰升糖素样肽1(GLP-1)可通过多个途径参与机体血糖稳态调节、改善胰岛功能、延缓甚至逆转2型糖尿病病程的进展。但内源性GLP-1在分泌释放入血后快速被二肽基肽酶4(DPP-4)裂解而失去活性。DPP-4抑制剂可选择性抑制DPP-4的酶活性，阻止GLP-1裂解失活，提高活性GLP-1的血浆水平，增强其生理作用，降低2型糖尿病患者的HbA1、空腹血糖和餐后血糖水平。
WO2015192701公开了式(I)所示的一种新型的二肽基肽酶IV(DPP-4)抑制剂，对DPP-4的酶活性具有良好的抑制作用，具有预防、治疗II型糖尿病的潜力。
Figure PCTCN2017085925-appb-000001
式(I)化合物稳定性好，生物口服利用度高，便于制剂的开发，具有临床价值。
发明内容
本发明涉及一种三氟甲基取代的吡喃衍生物的制备方法，即式(I)所示化合物的制备方法，该方法反应条件温和，操作简单，反应产率高，产品纯度高，后处理方便，适合于工业化生产。
本发明较WO2015192701A1公开的式(I)所示的化合物制备方法而言：1)优化了由式(V)制备式(III)的方法，省去中间体(VI-A)与(VI-B)的分离，同时采用重结晶或/和打浆的方法纯化，避免了柱层析方法分离，更适合工业化生产，也大大提高了式(III)的产率。
2)优化了式(III)中间体与式(IV)中间体发生反应得到式(II)化合物的工艺，使用极性非质子性溶剂避免了现有技术中在甲苯条件下蒸干溶剂的非常规操作，反应条件更为温和，反应更彻底，整个反应收率提高。同时反应条件适合放大，符合工业化生产。同时，现有技术中采用蒸干溶剂甲苯的方法，反应温度高，浓度变化大，不容易控制产物，也不便于监控反应进程。而本发明优化后的反应可以更好的监控进程。提高了式(II)的产率。
3)优化了式(II)化合物生成式(I)化合物的工艺，现有技术中采用三氟乙酸与二氯甲烷反应体系，后处理不宜控制，浓缩三氟乙酸对产物稳定性有影响，副产物随着投料量增大而增大。本发明采用对甲基苯磺酸与二氯甲烷反应体系或者pKa≤5的酸性试剂与水的反应体系，明显减少降解 产物和其它杂质的含量。同时，三氟乙酸与水的反应体系，减少了三氟乙酸的使用量，减少有机溶剂的使用，简化了后处理操作，对环境更友好。
4)优化各反应步骤的后处理，避免使用硅胶柱层析分离纯化，使用常规简单的操作步骤，更适合工业化生产。
具体而言，本发明涉及一种式(I)所示化合物的制备方法：
Figure PCTCN2017085925-appb-000002
式(II)化合物在对甲基苯磺酸与二氯甲烷体系或者在pKa≤5的酸性试剂与水的体系存在下进行反应，得到式(I)化合物；
作为选择，反应中可进一步加入有机溶剂；
其中，P为氨基保护基，优选叔丁氧羰基。
在某些实施方案中，对甲基苯磺酸可以为含有结晶水的对甲苯磺酸，如对甲苯磺酸一水合物或对甲苯磺酸四水合物。
在某些实施方案中，对甲基苯磺酸或含有结晶水的对甲苯磺酸为过量物质，优选地，式(II)化合物与对甲基苯磺酸或含有结晶水的对甲苯磺酸的摩尔比1:2.5～1:3,优选1:2.8。
在某些实施方案中，三氟醋酸为过量物质，优选地，式(II)化合物与三氟醋酸的质量比(w/w)为1:3～1:6。
在某些实施方案中，酸性试剂选自盐酸、三氟乙酸和甲磺酸中的一种或两种以上的混合物，有机溶剂选自甲醇、异丙醇或乙醇。
在某些实施方案中，反应的温度为-20～30℃。
式(II)化合物反应结束通过常规的后处理可得到式(I)化合物。
在某些实施方案中，对甲基苯磺酸与二氯甲烷体系反应的后处理包含如下步骤：
(1)、反应液中加入水和有机溶剂，分层，萃取；
(2)、将(1)中所得的有机相用碱调节溶液至碱性，有机相浓缩得粗产品；
(3)、将(2)中粗产品重结晶或打浆；
作为选择，步骤(3)中加入晶种。
在某些实施方案中，对甲基苯磺酸与二氯甲烷体系反应的后处理的步骤(2)中所用的碱为氨水，调至碱性时溶液的pH值为8～11，优选9～10。
在某些实施方案中pKa≤5的酸性试剂与水体系的反应的后处理包含
反应液中加入有机溶剂，滴加水和/或碱性溶液，分层，萃取，收集有机相，减压浓缩得粗产 品；根据情况，可增加分层后水相的萃取次数，收集有机相，有机相可用本领域常规的洗涤或/和干燥方式进行后处理，然后浓缩有机相得到粗产品；碱性溶液是pH>7的溶液，包括，但不限于氨水溶液、碳酸钠水溶液、甲胺水溶液、碳酸钾水溶液、碳酸氢钠水溶液、碳酸氢钾水溶液、氢氧化锂水溶液、氢氧化钠水溶液和氢氧化钾水溶液中的一种或两种以上的混合溶液；
作为选择，将上述所得粗产品进行重结晶或/和打浆；重结晶或/和打浆可以在任何合适的溶剂体系中完成，合适的溶剂包括，但不限于水、酯类溶剂、醇类溶剂、腈类溶剂、醚类溶剂、芳烃类溶剂、烷烃类溶剂和卤代烷烃类溶剂中的一种或两种以上的混合溶剂；进一步优选水、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙腈、甲醇、乙醇、异丙醇、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲苯、正庚烷、环己烷、正己烷和石油醚中的一种或两种以上的混合溶剂。
作为选择，粗产品进行重结晶或/和打浆时，可以进一步加入式(I)化合物的晶种。
在某些实施方案中，对甲基苯磺酸与二氯甲烷体系或者在pKa≤5的酸性试剂与水的体系后处理中得到的粗产品在溶剂中重结晶或/和打浆，重结晶或/和打浆的温度优选-10℃～体系回流。在某些实施方案中，当重结晶或/和打浆的溶剂选自水、甲醇、乙酸甲酯、乙酸乙酯、乙酸异丙酯、正庚烷、环己烷、正己烷和石油醚中的一种或两种以上的混合溶剂时，温度优选-10℃～回流。
本发明涉及式(II)化合物的制备方法，其中，
Figure PCTCN2017085925-appb-000003
极性非质子溶剂中，式(III)化合物和式(IV)化合物在有机酸存在下反应，得到中间态式(II-M)化合物；加入有机酸和有机硼还原剂，-10～25℃下反应，得到式(II)化合物；
P为氨基保护基，优选叔丁氧羰基。
在某些实施方案中，极性非质子溶剂非限制性的选自二氯甲烷、氯仿、1,2-二氯乙烷、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲基叔丁基醚、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺和二甲基亚砜中的一种或两种以上的混合物，优选二氯甲烷、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲基叔丁基醚、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺和二甲基亚砜中的一种或两种以上的混合物。
在某些实施方案中，有机酸pKa≥-1.9，在该方案中，pKa是指在25℃，水中的解离常数，包括但不限于甲酸、三氟乙酸、乙酸、甲磺酸、苯磺酸或对甲苯磺酸。
在某些实施方案中，有机硼还原剂选自三(乙酰氧基)硼氢化钠、硼氢化钠、氰基硼氢化钠或癸硼烷。
在某些实施方案中，式(III)化合物与有机硼还原剂的摩尔比为1:2～1:8，优选1:3～1:6，进一步优选1:3～1:5。
在某些实施方案中，式(III)化合物与有机酸的摩尔比为1:2～1:8，优选1:3～1:6，进一步优选1:3～1:5。
在某些实施方案中，式(III)化合物与式(IV)化合物的摩尔比为1:1～1:2，优选1.1～1.5。
在某些实施方案中，极性非质子溶剂与式(III)化合物的质量比为1:1～10:1，优选5:1～10:1。
在某些实施方案中，根据反应溶剂的不同，式(III)化合物和式(IV)化合物得到中间态式(II-M)化合物的反应温度有所不同，优选为-30℃至溶剂回流的温度；当反应的溶剂为N，N-二甲基乙酰胺时，反应的温度优选-10～80℃，更优选-10～60℃，进一步优选-10～40℃。
在某些实施方案中，式(III)化合物和式(IV)化合物在分子筛、脱水剂或分水容器存在下，得到中间态式(II-M)化合物，优选的反应温度为-20～25℃。
在某些实施方案中，式(III)化合物和式(IV)化合物在分子筛存在下，得到中间态式(II-M)化合物，优选式(III)化合物与分子筛的重量比为1:1～1:5，优选1:1～1:3。
在某些实施方案中，中间态式(II-M)化合物经还原后，通过常规的后处理得到式(II)化合物。后处理包括但不限于如下两种方案：
第一种方案包括如下步骤：
(1)、加碱性水溶液和有机溶剂，分层，萃取，得到第一有机相；碱性水溶液优选氨水溶液、甲胺水溶液、碳酸钠水溶液、碳酸钾水溶液、碳酸氢钠水溶液、碳酸氢钾水溶液、氢氧化锂水溶液、氢氧化钠水溶液和氢氧化钾水溶液中的一种或两种以上的混合溶液，更优选氢氧化锂水溶液。
(2)、将(1)中第一有机相用硅胶过滤，得到滤液，滤液浓缩得到粗产品；
(3)、将(2)中粗产品重结晶得到式(II)化合物；
作为选择，步骤(1)中萃取后的水相继续用有机溶剂萃取，合并有机相后用水和/或氯化钠水溶液洗涤，得到第一有机相；
作为选择，步骤(2)中第一有机相用硅胶过滤，滤饼继续用有机溶剂洗涤，合并滤液，滤液浓缩得到粗产品。
第二种方案包括如下步骤：
(1)、加水，分层，萃取，有机相直接浓缩或任选进一步用水和/或碱溶液洗涤，干燥，过滤，浓缩得浓缩物；
(2)、将(1)中浓缩物溶于甲醇，室温搅拌下加入水，析出固体，过滤得过滤物；
(3)、将(2)中过滤物溶于有机溶剂中，分层，干燥有机层，硅胶柱层析法分离，层析液浓缩得到粗产品；
(4)、将(3)中所得粗产品重结晶或/和打浆。
某些实施方案中，第二种方案的步骤(1)中的碱选自氨水溶液、甲胺水溶液、碳酸钠水溶液、碳酸钾水溶液、碳酸氢钠水溶液、碳酸氢钾水溶液、氢氧化锂水溶液、氢氧化钠水溶液和氢氧化钾水溶液中的一种或两种以上的混合溶液，优选氨水溶液。某些实施方案中，第二种方案的步骤(2)中搅拌下分两次加水，甲醇、第一次加水、第二次加水三者体积比优选4:1:4。第一种和第二种方案的步骤(3)的重结晶或/和打浆可以在任何合适的溶剂体系中完成，合适的溶剂优选水、酯类溶剂、醇类溶剂、腈类溶剂、醚类溶剂、芳烃类溶剂、烷烃类溶剂和卤代烷烃类溶剂中的一种或两种以上的混合溶剂；更优选水、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙醚、异丙醚、甲基叔丁基醚、二氯甲烷、乙酸甲酯、乙酸乙酯、乙酸异丙酯、甲苯、石油醚、正己烷、环己烷和正庚烷中的一种或两种以上的混合物，进一步优选二氯甲烷、甲苯、石油醚、正己烷、环己烷和正庚烷中的一种或两种以上的混合物，进一步优选二氯甲烷和石油醚的混合溶剂，两者优选的混合重量比为0.8:1～1:5，更优选0.8:1～1:2。
本发明还涉及一种式(III)化合物的制备方法：
Figure PCTCN2017085925-appb-000004
包含如下步骤：
(1)、式(V)化合物溶于甲苯中，50～100℃下滴加吗啉，然后回流反应，经后处理得到式(VI-A)化合物；
(2)、-10～25℃，极性非质子溶剂中，在碱性试剂4-二甲氨基吡啶存在下，式(VI-A)化合物与S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐或S-(三氟甲基)二苯并噻吩三氟甲基四氟硼酸盐反应，经后处理后得到中间态(VI-A-M)；
(3)、中间态(VI-A-M)在水或有机溶剂和水的混合溶剂中，在酸性试剂存在下反应得到式(III)化合物；
其中，P选自氨基保护基，优选叔丁氧羰基。
某些实施方案中，式(III)化合物的制备方法：包含如下步骤：
(1)、式(V)化合物溶于甲苯中，50～100℃下滴加吗啉，然后回流反应，经后处理得到式(VI-A)化合物；
(2)、-10～25℃，极性非质子溶剂中，在碱性试剂4-二甲氨基吡啶存在下，式(VI-A)化合物与 S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐或S-(三氟甲基)二苯并噻吩三氟甲基四氟硼酸盐反应；
(3)、在水或有机溶剂和水的混合溶剂中，在酸性试剂存在下反应得到式(III)化合物；
其中，P选自氨基保护基，优选叔丁氧羰基。
在制备式(III)化合物的步骤(1)中，与现有技术中直接将吗啉加入反应液中是显著优点的，现有技术中存在加入吗啉过程中，反应体系严重结块，影响反应的搅拌情况，不利于放大。在本实施方案中，通过在加热条件下(50～100℃)滴加吗啉，可避免结块现象，提高反应的产率，有利于工业化的生产。
某些实施方案中，制备式(III)化合物的步骤(1)的反应进一步在分子筛、脱水剂或者分水容器条件下进行。
某些实施方案中，制备式(III)化合物的步骤(2)的反应的极性非质子溶剂选自二氯甲烷、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺和二甲基亚砜中的一种或两种以上的混合物。
某些实施方案中，制备式(III)化合物的步骤(3)的酸性试剂选自盐酸、甲酸、三氟乙酸、乙酸、甲磺酸、苯磺酸或对甲苯磺酸。
某些实施方案中，式(V)化合物与吗啉的摩尔比为1:1～1:3，优选1:1.5。
某些实施方案中，式(VI-A)化合物与S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐或S-(三氟甲基)二苯并噻吩三氟甲基四氟硼酸盐的摩尔比为1:1～1:3，优选1:1～1:5，更优选1:1.2。
某些实施方案中，式(VI-A)化合物与4-二甲氨基吡啶的摩尔比为1:0.1～1:1.5，优选1:1～1:5，更优选1:1.1。
某些实施方案中，式(III)化合物的制备方法步骤(1)中所述后处理包括如下步骤：
(1)、将反应液打浆；优选将反应液加入搅拌的打浆溶剂中；打浆溶剂可以在任何合适的溶剂体系中完成，合适的溶剂优选甲苯、正庚烷、正己烷、环己烷和石油醚中的一种或两种以上的溶剂；
(2)、过滤，滤饼干燥。
某些实施方案中，式(III)化合物的制备方法步骤(1)中所述后处理包括如下步骤：
(1)、将反应液加入搅拌的溶剂中；溶剂可以在任何合适的溶剂体系中完成，合适的溶剂优选甲苯、正庚烷、正己烷、环己烷和石油醚中的一种或两种以上的溶剂；
(2)、过滤，滤饼干燥。
某些实施方案中，式(III)化合物的制备方法步骤(2)进一步包括如下后处理步骤：加入有机溶剂和水，分层，萃取，得到有机相，有机相浓缩。
某些实施方案中，式(III)化合物的制备方法步骤(3)进一步包括如下后处理步骤：
(1)、反应液中加入水和/或有机溶剂，分层，萃取，收集有机相；有机相任选用以下方式处理： 有机相用硅胶过滤，得到滤液，滤液浓缩得到粗产品；或有机相进一步洗涤和/或干燥和/或浓缩得到粗产品；
(2)、将(1)中粗产品重结晶或/和打浆。
某些实施方案中，式(III)化合物的制备方法步骤(3)进一步包括向反应液中加入水和/或有机溶剂，分层，萃取，收集有机相；有机相任选用以下方式处理：有机相经过硅胶，得到的液体进一步浓缩得到粗产品；或有机相进一步洗涤和/或干燥和/或浓缩得到粗产品；
作为选择，将粗产品重结晶或/和打浆。
某些实施方案中，式(III)化合物的制备方法步骤(3)后处理步骤(2)中的重结晶或/和打浆溶剂可以在任何合适的溶剂体系中完成，合适的溶剂优选水、酯类溶剂、醇类溶剂、腈类溶剂、醚类溶剂、芳烃类溶剂、烷烃类溶剂和卤代烷烃类溶剂中的一种或两种以上的混合溶剂；更优选水、乙腈、四氢呋喃、2-甲基四氢呋喃、乙醚、异丙醚、甲基叔丁基醚、二氯甲烷、乙酸甲酯、乙酸乙酯、乙酸异丙酯、甲苯、石油醚、正己烷、环己烷和正庚烷中的一种或两种以上的溶剂。
本发明还涉及一种式(IV)化合物的制备方法：
Figure PCTCN2017085925-appb-000005
-10～10℃，式(VII)化合物与盐酸-乙酸乙酯溶液反应；
其中，P为氨基保护基，优选叔丁氧羰基。
某些实施方案中，盐酸-乙酸乙酯溶液为现配制现用，通过将乙酰氯滴入乙酸乙酯与乙醇的混合液中形成，优选浓度为4mol/L盐酸-乙酸乙酯溶液。
某些实施方案中，式(VII)化合物与盐酸-乙酸乙酯溶液的质量体积比为1:3.5～1:8。
某些实施方案中，式(IV)化合物的制备方法进一步包括加入式(IV)化合物晶种结晶。
本发明还涉及如下所示式(III-A)、式(III-B)、式(II-A)、式(II-B)化合物：
Figure PCTCN2017085925-appb-000006
其中，P为氨基保护基，优选叔丁氧羰基。
本发明还涉及一种制备式(III-A)和式(III-B)化合物的方法，
Figure PCTCN2017085925-appb-000007
-10℃至室温下，N,N-二甲基乙酰胺、4-二甲氨基吡啶、式(VI-A)化合物与S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐的N,N-二甲基乙酰胺溶液反应，经分离得到式(III-A)和式(III-B)化合物；
其中，P为氨基保护基，优选叔丁氧羰基。
本发明还涉及一种制备式(II-A)和式(II-B)化合物的方法，
Figure PCTCN2017085925-appb-000008
氯仿作溶剂，加热回流，式(III)化合物和式(IV)化合物通过Dean-Starks分水器进行反应，经分离得到式(II-A)和式(II-B)化合物；
其中，P为氨基保护基，优选叔丁氧羰基。
某些实施方案中，通过硅胶柱层析分离得到式(II-A)和式(II-B)化合物。
某些实施方案中，式(III)化合物和式(IV)化合物的摩尔比为1:1.1～1:2。
本发明所述的化合物P优选为叔丁氧羰基。
本发明所述的式(III)化合物为式(III-1)化合物、式(III-2)化合物或者两者的混合物：
Figure PCTCN2017085925-appb-000009
其中，P为氨基保护基，优选叔丁氧羰基。
本发明中反应的后处理中使用萃取的方法为本领域常规方法，萃取的溶剂可根据产物的溶解度以及有机溶剂在水中的溶解度进行选择，常见的萃取溶剂包括但不限于二氯甲烷、氯仿、乙酸 乙酯、乙酸甲酯、乙酸异丙酯、乙醚、异丙醚、甲基叔丁基醚、甲醇和乙醇中的一种或两种以上的混合溶剂。萃取的次数可根据产物残留在水相中的量适当的增减。萃取后的有机相任选进一步采用本领域常规的洗涤或/和干燥处理。
本发明所用的分离方法为化学本领域常规常用分离方法，比如硅胶柱层析法、高效液相色谱法、薄层色谱法。
"可选择性地"意味着随后所描述地事件或环境可以但不必发生，包括该事件或环境发生或不发生的场合。
本发明反应过程通过HPLC、1HNMR或薄层色谱法跟踪反应进程，判断反应是否结束。
“密闭反应器”是指反应体系处于封闭状态的反应容器，比如反应釜，封管。
本发明所述的“构型转换终点”是指1H NMR(溶剂为DMSO-d6)位移(δ)在H(δ5.2)与H(δ4.4)峰面积比>2:1。由于1HNMR仪器不同，实验条件的控制不同，1H NMR位移(δ)允许有一定的移动。
附图说明
图1是化合物2的1HNMR图谱。
图2是化合物2的1H-1H NOESY图谱。
图3是化合物2的1H-1H COSY图谱。
图4是化合物6-b的1H-1H NOESY图谱。
图5是化合物7-a的1H-1H NOESY图谱。
图6是化合物7-a的1H-1H COSY图谱。
图7是化合物7-b的1H-1H NOESY图谱。
图8是化合物7-b的1H-1H COSY图谱。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的，二维氢同核位移相关谱(1H-1H COSY)、二维核奥弗豪泽增强谱(1H-1H NOESY)用于立体异构体的分析。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，氘代丙酮，内标为四甲基硅烷(TMS)，外标为85％磷酸水溶液。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温。
室温为20℃～30℃。
Boc为叔丁基氧基羰基。
实施例1：
N-[(2R,3S)-2-(2,5-二氟苯基)-5-吗啉基-3,4-二氢-2H-吡喃-3-基]氨基甲酸叔丁基酯(化合物1)
tert-butyl N-[(2R,3S)-2-(2,5-difluorophenyl)-5-morpholino-3,4-dihydro-2H-pyran-3-yl]carbamateand tert-butyl
Figure PCTCN2017085925-appb-000010
方法一：将化合物1a(1.0kg,3.06mol)加入含有甲苯(3L)的5L圆底烧瓶中，升温至80℃，缓慢滴加吗啉(400g)。滴加完毕，加热至回流，Dean-Stark分水反应3.5小时。趁热将反应液抽入含有正庚烷(15L)的20L圆底烧瓶中，打浆1.5小时，降至室温，过滤，滤饼用正庚烷(5L)洗涤一次，收集固体，50℃鼓风干燥，得化合物1(1.13kg,产率93％，HPLC(265nm)：90.0％)。
方法二：将6.51Kg甲苯和2.50Kg化合物1a加入反应釜；搅拌，升温至70～80℃，滴加1.00Kg吗啉；加料完毕，继续升温至回流，回流分水反应5小时；将反应液加入至25.10Kg正庚烷中；冷却降温至室温搅拌1小时；过滤并收集滤饼，50℃鼓风干燥，得2.89Kg化合物1；收率95.38％，HPLC(265nm)：92.2％。
实施例2
N-[(2R,3S)-2-(2,5-二氟苯基)-5-羰基-6-(三氟甲基)四氢吡喃-3-基]氨基甲酸叔丁基酯(化合物2)
tert-butyl N-[(2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate
Figure PCTCN2017085925-appb-000011
方法一：在100L反应釜中，氮气保护下，将实施例1中所得的化合物1(实施例1方法一制 备得到)(1kg,2.53mol)加入到N,N-二甲基乙酰胺(10L)中，搅拌状态下加入4-二甲氨基吡啶(296g,2.53mmol)，降温至-10℃，即为A液。将S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐(1.22kg,3.04mol)和N,N-二甲基乙酰胺(2L)加入5L烧瓶中，搅拌至澄清，在无水无氧氮气保护条件下，保持内温略低于-10℃，滴加至A液中，约30分钟滴加完毕。保持在-10℃下反应5小时，升至10～20℃静置16小时。降温至0℃，向上述反应液中加入冰水(36L)，控制加入速度保持温度低于20℃。用乙酸乙酯(20L与10L各一次)萃取，合并有机相，降温至0℃，加入冷至0℃的盐酸(10L,1mol/L)，加入过程中控制温度低于10℃。加毕，升至10-20℃搅拌反应1小时。反应液依次用水(10L×2)、饱和氯化钠溶液(10L)洗涤，无水硫酸钠(500g)干燥，45℃下减压浓缩至干得粗品。二氯甲烷(10L)溶解粗品，澄清后加入硅胶(2kg)，用20L单口瓶在旋转蒸发装置下减压浓缩至干粉状，继续置于旋转蒸发装置下减压旋转干燥5小时(水浴温度为50℃)至构型转换终点。将干燥后的固体在二氯甲烷(10L)中搅拌30分钟，砂芯漏斗过滤，二氯甲烷(15L)减压淋洗硅胶。滤液在40℃下减压浓缩至干。将正己烷(20L)加入残余物，加热回流打浆30分钟，降温至50℃以下停止搅拌，自然降至10-25℃，静置16小时，过滤，正己烷(10L)减压淋洗，40℃下减压干燥，得白色固体N-[(2R,3S)-2-(2,5-二氟苯基)-5-羰基-6-(三氟甲基)四氢吡喃-3-基]氨基甲酸叔丁基酯(化合物2)(609g,产率61％,HPLC(异构体合并总纯度):95.7％,dr(diastereo ratio,非对映异构体的比例)：82:18(2-2:2-1,通过HPLC(210nm)检测))。
小试-用盐酸溶液水解后粗品不用硅胶与其混合后处理：
氮气保护下，将实施例1中所得的化合物1(实施例1方法一制备得到)(10g)加入到N,N-二甲基乙酰胺(100mL)中，搅拌状态下加入4-二甲氨基吡啶(3.3g)，降温至-10℃，即为A液。将S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐(12.2g)的N,N-二甲基乙酰胺(20mL)滴加至A液中。加毕，保持在-10℃下反应5小时，升至室温静置16小时。向上述反应液中加入乙酸乙酯(100mL)和盐酸溶液(100mL,1mol/L)，加入过程中控制温度低于10℃。加毕，搅拌反应1小时。反应液依次用水、饱和氯化钠溶液洗涤、无水硫酸钠干燥，减压浓缩至干得淡黄色粗品(19g,产率＞100％,dr：6:5(2-2:2-1,通过HPLC(210nm)检测)。将正己烷(200mL)和粗品加热回流打浆30分钟，降温静置16小时，过滤烘干，得淡黄色固体化合物2(4.3g,产率43％,HPLC:75.6％，dr：54:32(2-2:2-1,通过HPLC(210nm)检测)。
方法二：将27.43Kg N，N-二甲基乙酰胺和2.88Kg化合物1(实施例1方法二制备得到)加入反应釜；搅拌，冷却降温至-10～0℃；加入0.93Kg 4-二甲基氨基吡啶；控制温度-10～0℃，加入3.52Kg S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐；加毕反应5小时；再升温至5～15℃，反应15.5小时；反应液中加入乙酸乙酯和去离子水，有机层减压浓缩，得残余物；氮气保护，将浓缩得到的残余物和38.50Kg二氯甲烷加入反应釜，搅拌下加入5.45Kg乙酸和1.45Kg去离子水；升温至回流反应5小时；反应液降温后，加入去离子水搅拌洗涤5次；干燥过滤，收集滤液；滤液用 硅胶过滤，滤渣用二氯甲烷洗涤；滤液减压浓缩至干，得到化合物2粗品；氮气保护，将化合物2粗品和正己烷加入反应釜中；60℃搅拌打浆；冷却降温后过滤打浆料液，收集滤饼，40℃真空干燥；得1.76Kg化合物2；收率61.32％，HPLC(210nm)：96.3％，dr：85:11(2-2:2-1,通过HPLC(210nm)检测)。
根据需要，为了获得更高非对映异构体纯度的化合物2-2，将化合物2(2.5g)进一步用二氯甲烷(15mL)溶解，然后加入抗溶剂正己烷(30mL)，室温搅拌，过滤得到化合物2-2(1.0g),HPLC(210nm)；dr：99:0.8 2-2:2-1,通过HPLC(210nm)检测)。
化合物2为两种立体异构体的混合物，包含的结构为如下：
Figure PCTCN2017085925-appb-000012
以氘代丙酮为溶剂，化合物2的1HNMR见图1，1H-1H NOESY图谱见图2，1H-1H COSY图谱见图3。
实施例3
2-甲磺酰基-5,6-二氢-4H-吡咯并[3,4-c]吡唑(化合物3)
2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole
Figure PCTCN2017085925-appb-000013
将乙酸乙酯(3100mL)和乙醇(985g,21.42mol)加入10L圆底烧瓶中，冷却至-5℃左右，搅拌下滴入乙酰氯(1.6kg,20.8mol)且温度控制在-10至0℃之间，加毕，升温至10～20℃反应30分钟。将反应体系冷却至-10℃，搅拌下加入2-(甲基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5(2H)-甲酸叔丁酯(3a)(1kg,3.48mol)，过程中有淡黄色固体生成，加毕，自然升温反应，1.5小时反应体系温度升至5～10℃，TLC监控显示反应完全。将反应液冷却至-10℃，减压过滤，滤饼用乙酸乙酯(2L)洗涤。将滤饼加入二氯甲烷(5L)中，搅拌下加入氨水(1L)和水(1L)的混合溶液，静置分层。水层用二氯甲烷(4L×4)萃取，合并有机层，无水硫酸钠干燥，旋转蒸发仪减压浓缩干，得到黄色油状粗品。将二氯甲烷(1.2L)加入粗品，搅拌下加入石油醚(600mL)，加入2-甲磺酰基-5,6-二氢-4H-吡咯并[3,4-c]吡唑晶种(3g)，待析出大量固体，加入石油醚(5.4L)，搅拌析晶2小时左右，减压过滤，滤饼石油醚(2L)洗涤，30℃真空干燥3～4小时，得类黄白色固体2-甲磺酰基-5,6-二氢-4H-吡咯并[3,4-c]吡唑(化合物3)(592g,产率90.9％)。
MS m/z(ESI):188.2[M+1]；
1H NMR(400MHz,CD3OD)δ7.85(s,1H),4.01-3.94(m,4H),3.36(s,3H)；
HPLC:99.09％(230nm)。
实施例4
N-[(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-甲基磺酰基-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-基]氨基甲酸叔丁基酯(化合物4)
tert-butyl N-[(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate
Figure PCTCN2017085925-appb-000014
方法一：在搅拌状态下，依次将化合物3(142.0g,0.7595mol)和化合物2(200.0g,0.5063mol)加入装有氯仿(400mL)的反应瓶中，加热搅拌回流，Dean-Starks分水反应5小时。反应结束停止加热，待反应液停止沸腾后，将反应液转入5L三口瓶中，加入1,2-二氯乙烷(1.6L)稀释反应液。在氮气氛围下，将反应体系搅拌降温至5～15℃，依次加入三乙酰氧基硼氢化钠(375.6g,1.7721mol)和乙酸(46.33mL,0.8100mol)，加毕，升温至20～35℃，反应5小时。反应结束，缓慢加入水(1.2L)，搅拌5分钟，静置分层，水层用二氯甲烷(400mLx2)萃取，合并有机相，用水(600mL)和氨水(100mL)的混合溶液洗涤有机相，无水硫酸钠干燥，减压浓缩。在5L三口瓶中，将浓缩所得的残留物加热(不高于50℃)溶于甲醇(1.6L)中，搅拌状态下降至室温，滴加水(400mL)，加毕继续搅拌30分钟。搅拌状态下再次滴加水(1.6L)，滴加完毕继续搅拌30分钟，过滤，得到淡黄色固体。将固体溶于二氯甲烷(2～3L)中，分层，有机相用无水硫酸钠干燥，将有机相直接倒入有干硅胶的硅胶柱中快速柱层析(600g硅胶，石油醚/乙酸乙酯(v/v)＝3:2)，将层析液浓缩得到粗品。将粗品在加热条件(不高于45℃)下溶解于二氯甲烷(1.4L)中，溶解完全，降温至20～30℃，搅拌状态下3～8分钟内加入石油醚(2.8L)，过程中有白色固体析出，加毕，立即过滤得到固体。10～35℃条件下，将二氯甲烷(720mL)加入其固体中，搅拌1小时，加入石油醚(1.8L)，室温下继续搅拌2小时。过滤，得到白色固体N-[(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-甲基磺酰基-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-基]氨基甲酸叔丁基酯(化合物4)(201g,收率70％,dr>99.95:0.05)。
1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.26–7.15(m,4H),4.84-4.75(m,1H),4.68(d,J＝10.5Hz,1H),3.94(t,2H),3.87–3.83(m,1H),3.80–3.72(m,2H),3.54-3.42(m,4H),2.25-2.22(m,1H),2.12-2.03(m,1H),1.20-1.12(m,9H)；
MS m/z(ESI):567.1[M+1]；
HPLC:98.9％(265nm)。
根据反应机理推测，化合物2与化合物3反应先生成中间体烯胺，烯胺经过还原胺化得到化合物4。
本发明进一步优化了化合物2与化合物3反应先生成中间体烯胺的条件，具体优化见表1所示。
表1：化合物2与化合物3反应先生成中间体烯胺的条件筛选
Figure PCTCN2017085925-appb-000015
表1中：DMA＝N，N-二甲基乙酰胺，MTBE＝甲基叔丁基醚，eq1为4A分子筛与化合物2的重量比，eq2为乙酸与化合物2的摩尔比，化合物2的剩余通过HPLC其峰面积。
将表1中较好的条件5稍微改变，进行了工艺放大。
方法二：氮气保护，将13.27Kg N，N-二甲基乙酰胺、1.75Kg化合物2、1.25Kg化合物3和3.58Kg 4A分子筛加入反应釜，冷却降温至0～5℃，加入0.67Kg乙酸；加料完毕，升温至5～15℃反应29小时；冷却降温至0～10℃，加入0.53Kg乙酸；分批加入4.25Kg NaBH(OAc)3；加料完毕，5～15℃反应16.5小时；加入二氯甲烷、5％氢氧化锂水溶液和去离子水，搅拌分层；水层继续用二氯甲烷萃取两次，合并有机层后，依次用去离子水洗涤、氯化钠溶液洗涤；有机层用硅胶过滤，滤渣用乙酸乙酯-石油醚混合溶液(质量比W石油醚：W乙酸乙酯＝1.1:1.0)淋洗将滤液减压浓缩至干，得到化合物4粗品；将化合物4粗品用16.57Kg二氯甲烷和石油醚在15～25℃析晶打浆得到化合物4(HPLC(265nm)：97.9％，chiral HPLC(210nm):100％),根据需要，为了获得更高纯度的化合物4，将化合物4进一步用18.20Kg石油醚和9.63Kg二氯甲烷在15～25℃析晶；得2.09Kg化合物4；收率82.94％，HPLC(265nm)：99.2％，chiral HPLC(210nm)100％。
实施例5
(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-胺(化合物5)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine
Figure PCTCN2017085925-appb-000016
方法一:在50L反应釜中，将对甲基苯磺酸一水合物(752.3g,3.958mol)加入到二氯甲烷中(8L)中，氮气氛下，加入化合物4(800g,1.413mol)，20～25℃下搅拌反应4～5小时。反应结束，依次加入水(8.5L)、甲醇(800mL)，搅拌10分钟。分层，水层用二氯甲烷(8L)和甲醇(800mL)的混合溶剂萃取三次。合并有机相，加入水(8L)和氨水(1.5L)搅拌10分钟，分层，有机相依次用饱和碳酸钠溶液(8～10L)和饱和食盐水(8～10L)洗涤，无水硫酸钠干燥，于35℃减压浓缩得到粗品。氮气氛围下，内温控制在30～35℃，将粗品溶解于乙酸乙酯(3.5L)中。保持内温在25～35℃，搅拌下滴加正庚烷(2.5L)，加入(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-胺晶种(8g)，继续滴加正庚烷(4.5L)，加毕，室温下继续搅拌2小时，过滤，得到白色固体(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-胺(化合物5)(508g,产率:77.1％)。
1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.35–7.04(m,3H),4.86–4.63(qd,1H),4.50(d,1H),3.95(dd,2H),3.78(dd,2H),3.49(s,3H),3.45(m,1H),3.00(ddd,1H),2.33(m,1H),1.82(m,1H),1.48(br.,2H)；
MS m/z(ESI):467.1[M+1]；
HPLC：99.1％(267nm)。
方法二:在5L三口瓶中，将三氟乙酸(442mL)加入到水(177mL)中，降温至5～10℃。氮气氛围下，搅拌状态下加入化合物4(200g,0.353mol)，保持温度在5～15℃，补加三氟乙酸(100mL)。保持温度在15～25℃搅拌反应4～5小时。反应结束，搅拌状态下加入二氯甲烷(1.6L)，不高于25℃温度下，依次滴加入水(200mL)、氨水(730mL)。停止搅拌并分层，水层用二氯甲烷(300mLx2)萃取。合并有机相，依次用饱和碳酸钠溶液(800～1000mL)和饱和食盐水(800～1000mL)洗涤，无水硫酸钠干燥，于35℃减压浓缩得到粗品。氮气氛围下，内温控制在30～35℃，将粗品溶解于乙酸乙酯(900mL)中。保持内温在25～35℃，搅拌下滴加正庚烷(650mL)，加入(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-胺(化合物5晶种)(2g)，继续滴加正庚烷(1150mL)，加毕，室温下继续搅拌2小时，过滤，得到白色固体(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-胺(化合物5)(140g,产率:85.0％)。
HPLC：99.56％(267nm)。
方法二得到的粗品也可通过如下方式进行精制：氮气保护，3.52kg粗品(与方法二反应条件一致得到)用27.80kg甲醇溶解，搅拌下加入35.20kg去离子水，搅拌析晶1～2小时，过滤，收集滤饼；滤饼在45～55℃干燥10小时；得2.80kg化合物5(产率79.55％，HPLC：99.4％(267nm))。
方法三:氮气保护，将4mol/L盐酸溶液(200ml)和乙醇(40ml)加入反应瓶中，降温至0～10℃，加化合物4(20g)；20℃反应1～2小时。反应液中加入二氯甲烷(300ml)，滴加5％氨水，调节pH＝8～9；分出有机层，洗涤，干燥过滤；滤液中加入正庚烷(750ml)，析出沉淀，过滤，收集滤饼，干燥10.5g，收率63.8％；HPLC：99.2％(267nm)。
实施例6
N-[(2R,3S,6S)-2-(2,5-二氟苯基)-5-吗啉基6-(三氟甲基)-3,6-二氢-2H-吡喃-3-基)氨基甲酸叔丁酯(化合物6-a)和N-[(2R,3S,6R)-2-(2,5-二氟苯基)-5-吗啉基6-(三氟甲基)-3,6-二氢-2H-吡喃-3-基)氨基甲酸叔丁酯(化合物6-b)
tert-butyl N-[(2R,3S,6S)-2-(2,5-difluorophenyl)-5-morpholino-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate(6-a)和tert-butyl N-[(2R,3S,6R)-2-(2,5-difluorophenyl)-5-morpholino-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate(6-b)
Figure PCTCN2017085925-appb-000017
在250mL反应瓶中，氮气保护下，将实施例1中方法一所得的化合物1(5.0g,12.63mmol)加入到N,N-二甲基乙酰胺(25mL)中，搅拌状态下加入4-二甲氨基吡啶(1.85g,15.15mmol)，降温至-10℃，即为A液。将S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐(6.10g,15.15mmol)和N,N-二甲基乙酰胺(15mL)加入25mL烧瓶中，搅拌至澄清，在无水无氧氮气保护条件下，保持内温略低于-10℃，滴加至A液中，约30分钟滴加完毕。保持在-10℃下反应5小时，升至10～20℃静置16小时。降温至0℃，向上述反应液中加入冰水(50mL)，控制加入速度，保持温度低于20℃。用乙酸乙酯(100mL与50mL各一次)萃取，合并有机相，饱和氯化钠水溶液(300mL)洗涤一次，无水硫酸钠干燥，浓缩。残余物用柱层析分离纯化(硅胶100g,洗脱剂：石油醚/乙酸乙酯 (v/v)＝7:1-3:1)，得白色固体N-[(2R,3S,6S)-2-(2,5-二氟苯基)-5-吗啉基6-(三氟甲基)-3,6-二氢-2H-吡喃-3-基)氨基甲酸叔丁酯(化合物6-a)(2.1g,产率38％)和N-[(2R,3S,6R)-2-(2,5-二氟苯基)-5-吗啉基6-(三氟甲基)-3,6-二氢-2H-吡喃-3-基)氨基甲酸叔丁酯(化合物6-b)(1.0g,产率18％)。
化合物6-a:
1H NMR(400MHz,DMSO-d6)δ7.27-7.12(m,4H),5.37-5.33(m,1H),4.95(s,1H),4.72(d,J＝9.5Hz,1H),4.44-4.40(m,1H),3.63–3.57(m,4H),3.04–3.01(m,2H),2.62–2.59(m,2H),1.23–1.13(m,9H).
化合物6-b:
1H NMR(400MHz,DMSO-d6)δ7.24–7.07(m,4H),5.43-5.42(m,1H),5.04(s,1H),4.51(d,J＝9.3Hz,1H),4.41-4.39(m,1H),3.62-3.58(m,4H),2.96-2.92(m,2H),2.60–2.57(m,2H),1.23–1.20(m,9H).
以DMSO-d6为溶剂，化合物6-b的1H-1H NOESY图谱见图4。
实施例7
N-[(2R,3S,6S)-2-(2,5-二氟苯基)-5-(2-甲磺酰基-4,6-二氢吡咯[3,4-c]吡唑-5-基)-6-(三氟甲基)-3,6-二氢-2H-吡喃-3-基)氨基甲酸叔丁酯(化合物7-a)和N-[(2R,3S,6R)-2-(2,5-二氟苯基)-5-(2-甲磺酰基-4,6-二氢吡咯[3,4-c]吡唑-5-基)-6-(三氟甲基)-3,6-二氢-2H-吡喃-3-基)氨基甲酸叔丁酯(化合物7-b)
tert-butyl N-[(2R,3S,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate(7-a)和tert-butyl N-[(2R,3S,6R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate(7-b)
Figure PCTCN2017085925-appb-000018
在搅拌状态下，依次将化合物2(5.0g,12.66mmol)和化合物3(3.55g,18.99mmol)加入装有氯仿(10mL)的反应瓶中，加热搅拌回流，Dean-Starks分水反应5小时。反应结束，停止加热，浓缩。残余物柱层析分离纯化(硅胶80g,洗脱剂：石油醚/乙酸乙酯(v/v)＝4:1-3:1)，分别得到白色固体N-[(2R,3S,6S)-2-(2,5-二氟苯基)-5-(2-甲磺酰基-4,6-二氢吡咯[3,4-c]吡唑-5-基)-6-(三氟甲基)-3,6-二氢-2H-吡喃-3-基)氨基甲酸叔丁酯(化合物7-a)(6.0g,产率85％)和白色固体N-[(2R,3S,6R)-2-(2,5-二氟苯基)-5-(2-甲磺酰基-4,6-二氢吡咯[3,4-c]吡唑-5-基)-6-(三氟甲基)-3,6-二氢-2H-吡喃-3-基)氨基甲酸叔丁酯(化合物7-b)(0.4g,产率5.6％)。
化合物7-a:
1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.28-7.06(m,4H),5.43–5.38(m,1H),4.93(s,1H),4.86(d,J＝9.7Hz,1H),4.56-4.51(m,1H),4.39-4.32(m,2H),4.08–4.04(m,2H),3.52(s,3H),1.25-1.23(m,9H).
MS m/z(ESI):565.1[M+1].
以DMSO-d6为溶剂，化合物7-a的1H-1H NOESY图谱见图5。
以DMSO-d6为溶剂，化合物7-a的1H-1H COSY图谱见图6。
化合物7-b:
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.25–7.08(m,4H),5.49–5.46(m,1H),4.90(s,1H),4.47(d,J＝9.2Hz,1H),4.42-4.37(m,1H),4.31–4.21(m,4H),3.52(s,3H),1.23–1.18(m,9H).
MS m/z(ESI):565.1[M+1].
以DMSO-d6为溶剂，化合物7-b的1H-1H NOESY图谱见图7。
以DMSO-d6为溶剂，化合物7-b的1H-1H COSY图谱见图8。
实施例8
2-甲磺酰基-5,6-二氢-4H-吡咯并[3,4-c]吡唑(化合物3晶种)
2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole
Figure PCTCN2017085925-appb-000019
将乙酸乙酯(3100mL)和乙醇(985g,21.42mol)加入反应瓶中，冷却至-5℃左右，滴入乙酰氯(1.6kg,20.8mol)，保持温度-10至0℃，加完移去冷却，升温至10-20℃反应30分钟。将反应液冷却至-10℃左右，加入化合物3a(1kg,3.48mol)，过程中有淡黄色固体生成，加完移去冷却装置，自然升温反应，90分钟后反应体系温度5-10℃，TLC监控反应完全。将反应液冷却至-10℃左右，减压过滤，滤饼用乙酸乙酯(2L)洗涤一次。将滤饼加入二氯甲烷(5L)中，搅拌下加入氨水(1L)和水(1L)的混合溶液，水层用二氯甲烷(4L×4)提取，有机层合并，无水硫酸钠干燥，减压过滤，减压浓缩至干。将浓缩物加入二氯甲烷(1.2L)，搅拌下滴加石油醚(6L)，逐渐析出固体，加完搅拌析晶2小时左右，减压过滤，滤饼用石油醚(2L)洗涤，30℃真空干燥3-4小时，得类黄白色固体2-甲磺酰基-5,6-二氢-4H-吡咯并[3,4-c]吡唑(化合物3晶种)(592g,产率90.9％)。
MS m/z(ESI):188.2[M+1]；
1H NMR(400MHz,CD3OD)δ7.85(s,1H),4.01-3.94(m,4H),3.36(s,3H)；
HPLC:99.09％(230nm)。
实施例9
(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-胺(化合物5晶种)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine
Figure PCTCN2017085925-appb-000020
在50L反应釜中，将对甲基苯磺酸一水合物(752.3g,3.958mol)加入到二氯甲烷中(8L)中，氮气氛围下，加入化合物4(800g,1.413mol)，20～25℃下搅拌反应4～5小时。反应结束，依次加入水(8.5L)、甲醇(800mL)，搅拌10分钟。分层，水层用二氯甲烷(8L)和甲醇(800mL)的混合溶剂萃取三次。合并有机相，加入水(8L)和氨水(1.5L)搅拌10分钟，分层，有机相依次用饱和碳酸钠溶液(8～10L)和饱和食盐水(8～10L)洗涤，无水硫酸钠干燥，于35℃减压浓缩得到粗品。氮气氛围下，内温控制在30～35℃，将粗品溶解于乙酸乙酯(3.5L)中。保持内温在25～35℃，搅拌下滴加正庚烷(7L)，加毕，室温下继续搅拌2小时，过滤，得到白色固体(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-胺(化合物5晶种)(504g,产率:76.5％)。
HPLC：99.14％(267nm)。

Claims (20)

  1. 一种式(I)化合物的制备方法，
    Figure PCTCN2017085925-appb-100001
    其特征在于，式(II)化合物在对甲基苯磺酸与二氯甲烷体系或者在pKa≤5的酸性试剂与水的体系存在下进行反应，得到式(I)化合物；
    作为选择，反应中可进一步加入有机溶剂；
    其中，P为氨基保护基。
  2. 据权利要求1所述的制备方法，所述的酸性试剂选自盐酸、三氟乙酸和甲磺酸中的一种或两种以上的混合物，所述的有机溶剂选自甲醇、乙醇或异丙醇。
  3. 据权利要求1所述的制备方法，其中，反应的温度为-20～30℃。
  4. 据权利要求1～3任一所述的制备方法，式(II)化合物在pKa≤5的酸性试剂与水的体系反应结束进一步后处理得到式(I)化合物，所述后处理包含
    向反应液中加入有机溶剂，加入水和/或碱性溶液，分层，萃取，收集有机相，减压浓缩得粗产品；
    作为选择，将粗产品进行重结晶或/和打浆；
    作为选择，重结晶或/和打浆时可以加入式(I)化合物的晶种。
  5. 据权利要求4所述的制备方法，所述的碱性溶液选自氨水溶液、碳酸钠水溶液、甲胺水溶液、碳酸钾水溶液、碳酸氢钠水溶液、碳酸氢钾水溶液、氢氧化锂水溶液、氢氧化钠水溶液和氢氧化钾水溶液中的一种或两种以上的混合溶液；
    所述重结晶或/和打浆所用的溶剂选自水、酯类溶剂、醇类溶剂、腈类溶剂、醚类溶剂、芳烃类溶剂、烷烃类溶剂和卤代烷烃类溶剂中的一种或两种以上的混合溶剂。
  6. 一种式(II)化合物的制备方法，其特征在于，
    Figure PCTCN2017085925-appb-100002
    极性非质子溶剂中，式(III)化合物和式(IV)化合物在有机酸存在下反应，得到中间态式(II-M) 化合物；加入有机酸和有机硼还原剂，-10～25℃下反应，得到式(II)化合物；
    P为氨基保护基。
  7. 根据权利要求6所述的方法，其中：
    所述的极性非质子溶剂选自二氯甲烷、氯仿、1,2-二氯乙烷、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲基叔丁基醚、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺和二甲基亚砜中的一种或两种以上的混合物；
    有机酸选自甲酸、三氟乙酸、乙酸、甲磺酸、苯磺酸或对甲苯磺酸；
    有机硼还原剂选自三(乙酰氧基)硼氢化钠、硼氢化钠氰基硼氢化钠或癸硼烷。
  8. 根据权利要求6～7任一所述的方法，其中反应是在分子筛、脱水剂或分水容器存在下进行。
  9. 一种式(III)化合物的制备方法：
    Figure PCTCN2017085925-appb-100003
    包含如下步骤：
    (1)、式(V)化合物溶于甲苯中，50～100℃下滴加吗啉，然后回流反应，经后处理得到式(VI-A)化合物；
    (2)、-10～25℃，极性非质子溶剂中，在碱性试剂4-二甲氨基吡啶存在下，式(VI-A)化合物与S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐或S-(三氟甲基)二苯并噻吩三氟甲基四氟硼酸盐反应，经后处理后得到中间态(VI-A-M)；
    (3)、中间态(VI-A-M)在水或者有机溶剂和水的混合溶剂，在酸性试剂存在下反应得到式(III)化合物；
    其中，P选自氨基保护基；
    作为选择，步骤(2)和(3)之间中间态(VI-A-M)的后处理可以省略。
  10. 根据权利要求9所述的制备方法，其中步骤(1)中的反应进一步在分子筛、脱水剂或者分水容器条件下进行。
  11. 根据权利要求9所述的制备方法，其中步骤(2)中所述的极性非质子溶剂选自二氯甲烷、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺和二甲基亚砜中的一种或两种以上的混合物。
  12. 根据权利要求9所述的制备方法，其中步骤(3)中所述的酸性试剂选自盐酸、三氟乙酸和甲酸、乙酸、甲磺酸、苯磺酸或对甲苯磺酸，有机溶剂选自二氯甲烷。
  13. 根据权利要求9～12任一所述的制备方法，其中步骤(1)中所述后处理包括如下步骤：
    (1)、向反应液中加入正庚烷、正己烷、环己烷和石油醚中的一种或两种以上的溶剂；
    (2)、过滤，滤饼干燥。
  14. 根据权利要求9～12任一所述的制备方法，其中步骤(2)中所述后处理为：加入有机溶剂和水，分层，萃取，得到有机相，有机相浓缩。
  15. 根据权利要求9～12任一所述的制备方法，其中步骤(3)中所述后处理包含反应液中加入水和/或有机溶剂，分层，萃取，收集有机相，有机相任选用以下方式处理：有机相经过硅胶，得到的液体进一步浓缩得到粗产品；或者有机相进一步洗涤和/或干燥和/或浓缩得到粗产品；
    作为选择，将粗产品重结晶或/和打浆。
  16. 根据权利要求15所述的制备方法，其中，粗产品重结晶或/和打浆所用的溶剂选自水、乙腈、四氢呋喃、2-甲基四氢呋喃、乙醚、异丙醚、甲基叔丁基醚、二氯甲烷、乙酸甲酯、乙酸乙酯、乙酸异丙酯、甲苯、正己烷、环己烷、石油醚和正庚烷中的一种或两种以上的混合溶剂。
  17. 如下所示式(III-A)、式(III-B)、式(II-A)、式(II-B)化合物：
    Figure PCTCN2017085925-appb-100004
    其中，P为氨基保护基。
  18. 一种制备式(III-A)和式(III-B)化合物的方法，
    Figure PCTCN2017085925-appb-100005
    -10℃至室温下，N,N-二甲基乙酰胺、4-二甲氨基吡啶、式(VI-A)化合物与S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐的N,N-二甲基乙酰胺溶液反应，经分离得到式(III-A)和式(III-B)化合物；
    其中，P为氨基保护基。
  19. 一种制备式(II-A)和式(II-B)化合物的方法，
    Figure PCTCN2017085925-appb-100006
    氯仿作溶剂，加热回流，式(III)化合物和式(IV)化合物通过Dean-Starks分水反应，经分离得到式(II-A)和式(II-B)化合物；
    其中，P为氨基保护基。
  20. 根据权利要求1-16或18-19任一项所述的方法，其中P为叔丁氧羰基。
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110894198A (zh) * 2018-09-13 2020-03-20 齐鲁制药有限公司 一种黄嘌呤类化合物及其制备方法和用途
CN111253348A (zh) * 2020-03-06 2020-06-09 天津全和诚科技有限责任公司 一种2,3,5-三苄氧基-d-核糖酸-1,4-内酯的制备方法
CN111683659A (zh) * 2018-02-06 2020-09-18 四川海思科制药有限公司 一种氨基吡喃衍生物的组合物
CN111689919A (zh) * 2020-07-22 2020-09-22 天津市中升挑战生物科技有限公司 一种异噁唑啉类驱虫药的合成方法
CN113651861A (zh) * 2020-05-12 2021-11-16 鲁南制药集团股份有限公司 一种托吡酯杂质
CN113929612A (zh) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 一种依托度酸中间体的制备方法
CN114364668A (zh) * 2019-06-21 2022-04-15 甘李药业股份有限公司 Cdk4/6抑制剂、及其盐和中间体的制备方法
CN115124578A (zh) * 2021-03-29 2022-09-30 上海医药工业研究院 一种络塞维中间体、其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007126745A2 (en) * 2006-03-28 2007-11-08 Merck & Co., Inc. Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2014018350A1 (en) * 2012-07-23 2014-01-30 Merck Sharp & Dohme Corp. Treating diabetes with dipeptidyl peptidase-iv inhibitors
WO2015192701A1 (zh) * 2014-06-17 2015-12-23 四川海思科制药有限公司 氨基吡喃环衍生物及其组合物和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101410400B (zh) * 2006-03-28 2012-09-05 默沙东公司 作为用于糖尿病治疗或者预防的二肽基肽酶-ⅳ抑制剂的氨基四氢吡喃
JO2870B1 (en) * 2008-11-13 2015-03-15 ميرك شارب اند دوهم كورب Amino Tetra Hydro Pirans as Inhibitors of Peptide Dipeptide IV for the Treatment or Prevention of Diabetes
CN109071551B (zh) * 2016-05-25 2020-12-08 四川海思科制药有限公司 一种三氟甲基取代的吡喃衍生物的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007126745A2 (en) * 2006-03-28 2007-11-08 Merck & Co., Inc. Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2014018350A1 (en) * 2012-07-23 2014-01-30 Merck Sharp & Dohme Corp. Treating diabetes with dipeptidyl peptidase-iv inhibitors
WO2015192701A1 (zh) * 2014-06-17 2015-12-23 四川海思科制药有限公司 氨基吡喃环衍生物及其组合物和应用

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111683659A (zh) * 2018-02-06 2020-09-18 四川海思科制药有限公司 一种氨基吡喃衍生物的组合物
CN111683659B (zh) * 2018-02-06 2023-08-29 四川海思科制药有限公司 一种氨基吡喃衍生物的组合物
US11974985B2 (en) 2018-02-06 2024-05-07 Haisco Pharmaceutical Group Co., Ltd. Composition of aminopyran derivative
CN110894198A (zh) * 2018-09-13 2020-03-20 齐鲁制药有限公司 一种黄嘌呤类化合物及其制备方法和用途
CN114364668A (zh) * 2019-06-21 2022-04-15 甘李药业股份有限公司 Cdk4/6抑制剂、及其盐和中间体的制备方法
CN111253348A (zh) * 2020-03-06 2020-06-09 天津全和诚科技有限责任公司 一种2,3,5-三苄氧基-d-核糖酸-1,4-内酯的制备方法
CN113651861A (zh) * 2020-05-12 2021-11-16 鲁南制药集团股份有限公司 一种托吡酯杂质
CN113929612A (zh) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 一种依托度酸中间体的制备方法
CN113929612B (zh) * 2020-06-29 2024-05-14 鲁南制药集团股份有限公司 一种依托度酸中间体的制备方法
CN111689919A (zh) * 2020-07-22 2020-09-22 天津市中升挑战生物科技有限公司 一种异噁唑啉类驱虫药的合成方法
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CN115124578B (zh) * 2021-03-29 2024-05-10 上海医药工业研究院 一种络塞维中间体、其制备方法和用途

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