WO2023185791A1 - Procédé de préparation d'un dérivé de 2-aminopyridine - Google Patents

Procédé de préparation d'un dérivé de 2-aminopyridine Download PDF

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Publication number
WO2023185791A1
WO2023185791A1 PCT/CN2023/084260 CN2023084260W WO2023185791A1 WO 2023185791 A1 WO2023185791 A1 WO 2023185791A1 CN 2023084260 W CN2023084260 W CN 2023084260W WO 2023185791 A1 WO2023185791 A1 WO 2023185791A1
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compound
formula
preparation
add
reaction
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PCT/CN2023/084260
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Chinese (zh)
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范江
朱凤飞
陈一
刘畅
窦赢
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四川海思科制药有限公司
艾克赛特赫拉制药有限责任公司
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Publication of WO2023185791A1 publication Critical patent/WO2023185791A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the invention relates to a method for preparing 2-aminopyridine derivatives.
  • FXIa Factor XIa
  • FXIa Factor XIa
  • Selective inhibition of FXIa is expected to prevent pathological thrombosis while maintaining the physiological function of local hemostasis of tissue damage through the exogenous pathway. This may be due to the fact that while FXIa plays a key role in the classic intrinsic coagulation pathway (activating FIX and thereby activating FX), it also triggers a burst of thrombin after tissue factor (TF) activates the extrinsic coagulation pathway. Played a key mediating role in production.
  • TF tissue factor
  • FXIa Inhibition of FXIa prevents both coagulation activation due to contact with foreign surfaces (eg, extracorporeal circuits) and coagulation amplification induced by tissue factor (surgical "injury") exposure. Therefore, a local coagulation reaction (through tissue factor exposure) can still be triggered at the surgical incision or local trauma.
  • tissue factor tissue factor exposure
  • the FXIa inhibitor blocks the thrombin amplification mechanism, the thrombus expands from a small local vascular injury to a larger one. The occurrence of occlusive blood clots or emboli will be greatly reduced or eliminated. In this way, bleeding can be reduced while ensuring smooth operation of extracorporeal circulation.
  • FXIa FXIa
  • HIT heparin-induced thrombocytopenia
  • Other potential benefits of inhibiting FXIa over heparin may include preservation of coagulation cofactors during cardiopulmonary bypass, elimination of the risk of heparin-induced thrombocytopenia (HIT), easier use, and reduced risk of postoperative bleeding and subsequent complications. It could also be lower.
  • Compound VII is a novel, potent, selective small molecule factor XIa inhibitor (FXIa) designed to prevent thrombosis and limit the risk of bleeding.
  • FXIa factor XIa inhibitor
  • Compound VII is an anticoagulant product introduced by Hisco in 2019 from the American company eXIthera (a biotechnology company dedicated to discovering and developing effective anticoagulant drugs). It was originally code-named EP-7041 HCl. The intended indications for development of Compound VII are: anticoagulation in hemodialysis patients and systemic anticoagulation in intraoperative patients.
  • Patent WO2020092592A1 describes a method for preparing compounds of formula (VII), which requires column purification.
  • the present invention relates to a method for preparing a 2-aminopyridine derivative, that is, a method for preparing a compound represented by formula (VII).
  • the method has mild reaction conditions, simple operation, high reaction yield, high product purity, convenient post-processing, and is suitable for for industrial production.
  • the present invention optimizes the method of preparing formula (I) from formula (I) and formula (I-4).
  • the crude product is purified by beating to improve the purity of the intermediate of formula (I), which is suitable for industrial production.
  • the present invention optimizes the method of preparing formula (III) from formula (I) and formula (II), omitting the purification step of beating and crystallization, using organic solvents to back-extract impurities, adjusting the acid, and then using organic solvents to extract the product. , the operation is simpler, more suitable for industrial production, and also greatly improves the yield of formula (III).
  • the present invention optimizes the method of preparing formula (V) from formula (III) and formula (IV), adopts the beating method for purification, avoids separation by column chromatography, is more suitable for industrial production, and also greatly improves the efficiency of formula (V). Yield.
  • the present invention optimizes the method of preparing formula (VI) from formula (V) and greatly improves the purity of formula (VI).
  • the present invention optimizes the preparation method of the compound represented by formula (VII) and adopts a salt transfer reagent suitable for industrial production.
  • the invention optimizes the synthesis yield of intermediates in each step, increases the overall yield, and thereby reduces production costs.
  • the present invention avoids the use of silica gel column chromatography for separation and purification, and uses conventional simple operating steps, which is more suitable for industrial production.
  • the present invention provides a method for preparing compound (I), which is prepared through the following reaction:
  • the amount of catalyst Pd/C is 9 to 15% of the mass of the compound of formula (I-4).
  • the amount of catalyst Pd/C is 10 to 13% of the mass of the compound of formula (I-4).
  • the amount of Pd in the catalyst Pd/C is 1 to 1.3% of the mass of the compound of formula (I-4).
  • the post-treatment includes: passing the reaction solution through Filter and concentrate to obtain a crude product, which is then pulped.
  • the post-treatment includes beating the crude product.
  • the solvent used for beating is selected from aromatic hydrocarbon solvents, alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, and ether solvents. Or one or a mixture of two or more nitrile solvents.
  • the solvent used for beating is selected from one or more of n-hexane, cyclohexane, methyl tert-butyl ether, petroleum ether and n-heptane. Mix solvents.
  • the solvent used for beating is selected from a mixed solution of n-hexane and methyl tert-butyl ether.
  • the solvent used for beating is selected from a mixed solution of n-hexane and methyl tert-butyl ether, with a volume ratio of 5 to 15:1, preferably 10:1.
  • the aprotic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, One or more mixed solvents of 4-dioxane and methyl tert-butyl ether, preferably tetrahydrofuran.
  • the starting amount of the compound of formula (I-4) is greater than or equal to 500 grams, preferably greater than or equal to 1 kilogram.
  • the present invention provides a method for preparing compound (III), which is prepared through the following reaction:
  • step b is: adding the compound of formula (I) and an organic lithium reagent to an aprotic polar solvent at -45 to -35°C to maintain the temperature of the reaction solution -45 ⁇ -35°C, add the aprotic polar solvent of the compound of formula (II), stir for an appropriate time at -45 ⁇ -35°C, then raise the temperature to 0 ⁇ 25°C for reaction to obtain the compound of formula (III).
  • the aprotic polarity in step b is
  • the solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, and dimethyl sulfoxide, preferably from tetrahydrofuran;
  • the organic lithium reagent is selected from lithium diisopropylamide, n-butyllithium or tert-butyllithium, preferably from diisopropylamide lithium.
  • the aprotic polar solvent in step b is selected from tetrahydrofuran; the organolithium reagent is selected from lithium diisopropylamide.
  • the temperature of the reaction liquid is controlled at -70 to -30°C, preferably -45 to -35°C.
  • the reaction of the compound of formula (I) and the compound of formula (II) in step b is completed and further post-processing is performed to obtain the compound of formula (III).
  • the post-processing includes: adding water and raising the temperature. Stir, after a suitable time, cool down, concentrate, add water, extract with organic solvent (1), collect the aqueous phase, add organic solvent (2), cool down and stir, add acidic reagent to adjust acidity, separate the liquids, add organic solvent (2) for extraction, The organic phases were combined, dried and concentrated.
  • the organic solvents (1) and (2) used for post-treatment in step b are respectively selected from dichloromethane, 1,2-dichloroethane, and ethyl acetate. , diethyl ether, 2-methyltetrahydrofuran, or a mixture of two or more solvents.
  • the organic solvent (1) used for post-treatment in step b is selected from ethyl acetate, and the organic solvent (2) is selected from 2-methyltetrahydrofuran.
  • the acidic reagent used for post-treatment in step b is selected from hydrochloric acid and sulfuric acid, preferably from hydrochloric acid.
  • the acidity range adjusted in the post-treatment in step b is selected from pH to 2-4.
  • the acidity range adjusted in the post-treatment in step b is selected from pH to 3.1 to 3.3.
  • the process of preparing the compound of formula (III) from the compounds of formula (I) and formula (II) as raw materials does not include the step of beating and crystallization (purification).
  • the present invention provides a method for preparing compound (V), which is prepared through the following reaction:
  • step b involves the preparation method of compound (III) which is the same as some embodiments of the aforementioned preparation method of compound (III).
  • the post-treatment in step c includes beating the crude product.
  • the solvent used for pulping in step c is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, n-hexane, cyclohexane, and methyl tert-butyl ether.
  • One or more mixed solvents of petroleum ether and n-heptane is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, n-hexane, cyclohexane, and methyl tert-butyl ether.
  • the solvent used for pulping in step c is selected from ethyl acetate, and the pulping temperature is 10-20°C.
  • the post-treatment in step c includes beating and crystallizing the crude product, the beating solvent is selected from ethyl acetate, and the crystallization solvent is selected from methyl tert-butyl ether.
  • the aprotic solvent in step c is selected from dichloromethane, chloroform or 1,2-dichloroethane, preferably from dichloromethane; the alkaline reagent is selected from 1 ,8-diazabicyclo(5.4.0)undec-7-ene.
  • the step of column chromatography is not included in the process of preparing the compound of formula (V) from the compounds of formula (III) and (IV) as raw materials.
  • the present invention provides a method for preparing compound (VI), which is prepared through the following reaction:
  • step b involves the preparation method of compound (III) which is the same as some embodiments of the aforementioned preparation method of compound (III).
  • step c involves the preparation method of compound (V) which is the same as some embodiments of the aforementioned preparation method of compound (V).
  • the organic acid in step d is selected from trifluoroacetic acid
  • the silane reagent is selected from triethylsilane.
  • the present invention provides a method for preparing compound (VII), which is prepared through the following reaction:
  • the compound of formula (V) is added to an organic acid, a silane reagent is added, and the compound of formula (VI) is obtained through post-treatment;
  • the compound of formula (VI) reacts with a transsalting reagent, and the compound of formula (VII) is obtained after post-treatment.
  • step b involves the preparation method of compound (III) which is the same as some embodiments of the aforementioned preparation method of compound (III).
  • step c involves the preparation method of compound (V) which is the same as some embodiments of the aforementioned preparation method of compound (V).
  • step d involves the preparation method of compound (VI) which is the same as some embodiments of the aforementioned preparation method of compound (VI).
  • the salt transfer reagent in step e is selected from the group consisting of hydrogen chloride in ethyl acetate, hydrogen chloride in isopropyl acetate, hydrogen perchloride methyl tert-butyl ether, or hydrogen chloride dimethyl ether.
  • Oxygen hexacyclic solution is preferably a solution of hydrogen chloride in ethyl acetate; the aprotic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxy
  • the aprotic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxy
  • the aprotic solvent in step e is selected from acetonitrile
  • the salt transfer reagent is selected from hydrogen chloride in ethyl acetate, hydrogen chloride in isopropyl acetate, hydrogen chloride in methyl tert. Butyl ether solution or hydrogen chloride dioxane solution.
  • the post-treatment in step e includes purifying the crude product of formula (VII).
  • the post-treatment in step e includes the following purification steps:
  • the present invention provides a method for preparing compound (VII), which is prepared through the following reaction:
  • the present invention relates to a method for preparing compound (VII), the method comprising the following steps:
  • the compound of formula (I-4) reacts in the presence of an aprotic solvent, catalyst Pd/C and hydrogen to form a compound of formula (I); the amount of the catalyst Pd/C is 9 times the mass of the compound of formula (I-4) ⁇ 15%, the aprotic solvent is selected from tetrahydrogen Furans;
  • the compound of formula (I) and the organolithium reagent to an aprotic polar solvent, Keep the temperature of the reaction solution at -45 ⁇ -35°C, add the aprotic polar solvent of the compound of formula (II), keep it at -45 ⁇ -35°C and stir for an appropriate time, then raise the temperature to 0 ⁇ 25°C for reaction to obtain the compound of formula (III) ;
  • the aprotic polar solvent is selected from tetrahydrofuran, and the organolithium reagent is selected from lithium diisopropylamide;
  • the compound of formula (VI) is reacted with a transsalting reagent in acetonitrile, and the compound of formula (VII) is obtained after post-treatment; the said transsalting reagent is selected from the ethyl acetate solution of hydrogen chloride.
  • the elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present invention all include their isotope conditions, and the elements carbon, hydrogen, oxygen involved in the groups and compounds described in the present invention , sulfur or nitrogen are optionally further replaced by 1 to 5 of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen) ), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N , the isotope of fluorine is 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C, 13 C and 14
  • the extraction method used in the post-treatment of the reaction in the present invention is a conventional method in this field.
  • the extraction solvent can be selected according to the solubility of the product and the solubility of the organic solvent in water.
  • Common extraction solvents include but are not limited to dichloromethane, chloroform, One or a mixed solvent of two or more of ethyl acetate, methyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, methanol and ethanol.
  • the number of extractions can be appropriately increased or decreased according to the amount of product remaining in the aqueous phase.
  • the extracted organic phase is optionally further subjected to conventional washing and/or drying treatments in this field.
  • the separation method used in the present invention is a conventional separation method in the field of chemistry, such as silica gel column chromatography, high performance liquid chromatography, and thin layer chromatography.
  • Silane reagent refers to hydrogen silane compounds containing Si-H bonds, including but not limited to simple alkyl silanes, such as Et 3 SiH, Et 2 SiH 2 ; different phenyl silanes, such as Ph 2 SiH 2 , PhMe 2 SiH, Ph 2 MeSiH; alkane Silicones, such as polymethylhydrogensiloxane (PMHS), diethoxymethylsilane (DEMS); halogenated silanes, such as trichlorosilane.
  • simple alkyl silanes such as Et 3 SiH, Et 2 SiH 2
  • different phenyl silanes such as Ph 2 SiH 2 , PhMe 2 SiH, Ph 2 MeSiH
  • alkane Silicones such as polymethylhydrogensiloxane (PMHS), diethoxymethylsilane (DEMS); halogenated silanes, such as trichlorosilane.
  • PMHS polymethylhydrogensiloxane
  • DEMS die
  • Salting reagent refers to an acid reagent formed by dissolving an acid in an organic solvent.
  • the organic solvent is selected from the group consisting of methylene chloride, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, and dioxygen.
  • One or two or more mixed solvents of hexacyclic ring, methyl tert-butyl ether, methanol and ethanol, the acid is selected from hydrogen chloride, which includes but is not limited to hydrogen chloride in ethyl acetate solution, hydrogen chloride in isopropyl acetate solution, hydrogen chloride methyl tert-butyl ether solution or hydrogen chloride dioxane solution.
  • the reaction process of the present invention is tracked through HPLC, 1 HNMR or thin layer chromatography to determine whether the reaction is completed.
  • Solid reactor refers to a reaction vessel in which the reaction system is in a closed state, such as a reactor or sealed tube.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS), two-dimensional hydrogen homonuclear shift correlation spectroscopy ( 1 H- 1 H COSY), two-dimensional nuclear Overhauser enhanced spectroscopy ( 1 H- 1 H NOESY) was used for the analysis of stereoisomers.
  • NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR NMR was measured using a (Bruker Avance III 400) nuclear magnetic instrument, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), deuterated Acetone, the internal standard is tetramethylsilane (TMS), and the external standard is 85% phosphoric acid aqueous solution.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • the external standard is 85% phosphoric acid aqueous solution.
  • HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm).
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology. Waiting for the company.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature.
  • Room temperature is 20°C ⁇ 30°C.
  • OTs p-toluenesulfonyl
  • Bn benzyl
  • TBS tert-butyldimethylsilyl
  • TMS tetramethylsilyl
  • ACN acetonitrile
  • DBU 1,8-diazabicyclo (5.4. 0) Undec-7-ene
  • DCM dichloromethane
  • EA ethyl acetate
  • IPA isopropyl alcohol
  • LDA lithium diisopropylamide
  • MTBE methyl tert-butyl ether
  • PMB 4- Methoxybenzyl
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran.
  • Reaction In a 50L reaction kettle, add 9.6L toluene and 14.4L cyclohexane, start stirring, then add 3.001kg I-1, 14.624kg benzyl alcohol and 5.359kg p-toluenesulfonic acid monohydrate in sequence, and raise the temperature to 80-90°C The reflux reaction took about 12 hours, and LCMS monitored that the reaction was complete.
  • Post-processing The reaction solution was cooled to 10 ⁇ 5°C, stirred for 2 hours, filtered, and the filter cake was beaten with 30L methyl tert-butyl ether for 0.5h, filtered, and p-toluenesulfonate white solid was obtained.
  • the wet product was 14.321kg.
  • Post-processing Control the temperature at 0-10°C, add 30L 20% ammonium chloride solution to the reaction solution, then adjust the pH to ⁇ 6 with 1M hydrochloric acid solution, extract the water phase twice with 20L ethyl acetate, combine the organic phases, and use 20L 10 % sodium chloride solution, and the organic phase was concentrated under reduced pressure at 45°C until no obvious fraction flows out to obtain the crude product. Add 10L methyl tert-butyl ether and beat for 2 hours, filter, and rinse the filter cake with 1L methyl tert-butyl ether. , dried under vacuum at 50°C for about 16 hours, and obtained 1598.0g of light yellow solid, with a yield of 48.8%.
  • Step 3 (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid benzyl ester (I-4)
  • Post-treatment The organic phase was washed with 5L 20% ammonium chloride aqueous solution, 5L 3% citric acid aqueous solution and 5L 20% brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45°C until no obvious fractions flowed out. 2901g of brown liquid was obtained, and the yield was calculated as 100%, which was directly used in the next reaction.
  • Post-processing filter, concentrate under reduced pressure at 50°C until no obvious fraction flows out to obtain crude product, add a mixed solution of 15L n-hexane and 1.5L methyl tert-butyl ether, stir and beat for 1 hour, filter, and rinse the filter cake with 2L n-hexane. Wash twice.
  • Reaction In a 100L reaction kettle, add 36.0kg tetrahydrofuran and 2.0kg I in sequence, replace with nitrogen three times, cool to -40 ⁇ 5°C under nitrogen protection, control the temperature to -40 ⁇ 5°C, and drop 9.0L diisopropylamino Lithium (2M), add it completely, keep it at -40 ⁇ 5°C and stir for 1 hour, control the temperature at -40 ⁇ 5°C, add dropwise the tetrahydrofuran solution of II (3.54kg II dissolved in 16.0kg tetrahydrofuran), finish adding it, keep it at -40°C Stir at ⁇ 5°C for 2 hours, raise the temperature to 15 ⁇ 5°C and react for about 12 hours. Sampling was monitored by HPLC. The target II content was ⁇ 20.0% and the reaction was stopped.
  • Post-processing Add 20kg of water to the reaction solution, raise the temperature to 60 ⁇ 5°C and stir for about 1 hour, lower the temperature to 30 ⁇ 5°C, and concentrate the tetrahydrofuran until no obvious fraction flows out. Add 10kg of water. The water phase is extracted with 15kg of ethyl acetate each time. Extract three times. Add 25kg of 2-methyltetrahydrofuran to the water phase. Cool the temperature to 10 ⁇ 5°C.
  • Step 6 (2S,3R)-3-((2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)methyl)-1-(((R)-1-cyclo Hexylethyl)carbamoyl)-4-oxoazetidine-2-carboxylic acid (V)
  • Reaction In a 100L reaction kettle, add 20.22kg methylene chloride and 3.80kg III in sequence, replace with nitrogen twice, cool to 5 ⁇ 5°C under nitrogen protection, control the temperature to 10 ⁇ 5°C, add 4.3951kg DBU dropwise, and complete the addition. , control the temperature to 10 ⁇ 5°C, add 2.5281kg IV dropwise, after the addition is completed, raise the temperature to 20 ⁇ 5°C and react for about 16 hours. Sampling and HPLC monitoring showed that the target III content was ⁇ 2.0% and the reaction was stopped.
  • Post-processing After the reaction, add 68.86kg methyl tert-butyl ether to beat and crystallize. After the addition is completed, stir at a temperature of 15 ⁇ 5°C for about 5 hours; filter. The filter cake is washed with 4.68kg methyl tert-butyl ether and filtered. Transfer the cake into the reaction kettle again, add 60.82kg ethyl acetate, stir at a temperature of 15 ⁇ 5°C for about 2 hours, filter, and wash the filter cake with 5.8kg ethyl acetate; beat the filter cake again with 60.80kg ethyl acetate.
  • Step 7 (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxo Azetidine-2-carboxylic acid trifluoroacetate (VI)
  • Reaction In a 100L reaction kettle, add 3.96kg V and 30.56kg trifluoroacetic acid in sequence, protect with nitrogen, cool to 5 ⁇ 5°C, stir and dissolve. Control the temperature at 10 ⁇ 5°C, add 3.00kg triethylsilane dropwise, complete the addition, and control the temperature at 25 ⁇ 5°C for about 12 hours. Take samples for HPLC monitoring. The target value of V content is ⁇ 1.0%, and the reaction is stopped.
  • Post-processing After the reaction, concentrate the reaction solution under reduced pressure at 45 ⁇ 5°C until no obvious fraction flows out. Add 31.28kg of acetonitrile, stir for about 20 minutes, filter, and extract the filtrate four times with 17.13kg of n-hexane, separate the liquids, and combine. Acetonitrile phase.
  • Step 8 (2S,3R)-3-((2-aminopyridin-4-yl)methyl)-1-(((R)-1-cyclohexylethyl)carbamoyl)-4-oxo Azetidine-2-carboxylic acid hydrochloride (VII)
  • Post-processing After the reaction, cool the reaction solution to 15 ⁇ 5°C, stir for about 2 hours, filter, wash the filter cake with 5.94kg ethyl acetate, collect the filter cake, and store the filter cake at 45 ⁇ 5°C, vacuum ⁇ -0.07MPa After drying for about 6 hours, the crude product VII was obtained. The weight was recorded as 1.69kg. The yield was calculated as V, and the yield was 64.1%. HPLC: 99.028%.
  • Refining In a 100L reaction kettle, add 1.69kg crude VII and 17.28kg isopropyl alcohol in sequence, raise the temperature to 45 ⁇ 5°C, stir to dissolve, and filter while hot. Transfer the filtrate into a 100L reaction kettle, add 32.52kg methyl tert-butyl ether dropwise, complete the dropwise addition in about 1 hour, control the temperature to 15 ⁇ 5°C and stir for about 2 hours, filter, and use 3.39kg methyl tert-butyl ether for the filter cake. Wash to obtain refined product 1, and repeat refining once to obtain refined product 2.
  • Drying Dry the wet product 2 at 45 ⁇ 5°C, vacuum ⁇ -0.07MPa, for about 25 hours, and collect the material to obtain VII.
  • the yield is 60.0%, HPLC: 99.90%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne un procédé pour préparer un dérivé de 2-aminopyridine et un intermédiaire de celui-ci, c'est-à-dire un procédé pour préparer un composé représenté par la formule (VII) et un intermédiaire de celui-ci. Le procédé est doux en termes de conditions de réaction, est simple à utiliser, a un rendement de réaction élevé, une pureté de produit élevée, est pratique pour le post-traitement, et approprié pour une production industrielle.
PCT/CN2023/084260 2022-03-28 2023-03-28 Procédé de préparation d'un dérivé de 2-aminopyridine WO2023185791A1 (fr)

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CN202210303813 2022-03-28

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019185046A1 (fr) * 2018-03-30 2019-10-03 上海美悦生物科技发展有限公司 Composé de lactame quaternaire et son utilisation pharmaceutique
CN112996495A (zh) * 2018-10-30 2021-06-18 艾克赛特赫拉制药有限责任公司 治疗化合物和组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019185046A1 (fr) * 2018-03-30 2019-10-03 上海美悦生物科技发展有限公司 Composé de lactame quaternaire et son utilisation pharmaceutique
CN112996495A (zh) * 2018-10-30 2021-06-18 艾克赛特赫拉制药有限责任公司 治疗化合物和组合物

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