WO2017202365A1 - Procédé de préparation d'un dérivé de pyranne substitué par un trifluorométhyle - Google Patents

Procédé de préparation d'un dérivé de pyranne substitué par un trifluorométhyle 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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Chinese (zh)
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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/fr

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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

L'invention concerne un procédé de préparation d'un dérivé de pyranne à substitution trifluorométhyle et un intermédiaire de celui-ci, en d'autres termes un procédé de préparation d'un composé tel que représenté dans la formule (I) et un intermédiaire de celui-ci. Le procédé est caractérisé par des conditions de réaction douces, des opérations simples, un rendement de réaction élevé, une pureté de produit élevée et un post-traitement commode, rendant le procédé approprié pour une production industrielle.
PCT/CN2017/085925 2016-05-25 2017-05-25 Procédé de préparation d'un dérivé de pyranne substitué par un trifluorométhyle WO2017202365A1 (fr)

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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

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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
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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
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
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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