WO2023098613A1 - Method for preparing dimethyl sulfinyl imine derivative - Google Patents

Method for preparing dimethyl sulfinyl imine derivative Download PDF

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WO2023098613A1
WO2023098613A1 PCT/CN2022/134644 CN2022134644W WO2023098613A1 WO 2023098613 A1 WO2023098613 A1 WO 2023098613A1 CN 2022134644 W CN2022134644 W CN 2022134644W WO 2023098613 A1 WO2023098613 A1 WO 2023098613A1
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compound
equivalent ratio
acid
reagent
preparation
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Chinese (zh)
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廖勇刚
奚正英
肖瑶
刘超男
韦昌青
钱文远
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202280080003.3A priority Critical patent/CN118302415A/en
Publication of WO2023098613A1 publication Critical patent/WO2023098613A1/en

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/36—Sulfur atoms
    • 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 invention relates to a preparation method of dimethylsulfinimide derivatives and intermediates thereof, in particular to a preparation method of the compound of formula (I) and intermediates thereof.
  • Inflammation is the basis for the occurrence and development of many diseases, and maintaining the balance of inflammatory responses is of great significance for the prevention and treatment of infection, autoimmune diseases and cancer.
  • the inflammasome plays an important role in the occurrence and development of inflammation-related diseases, and the nucleotide-binding oligomerization domain (NOD)-like receptor family contains pyrin domain protein 3 (NOD-like receptor family, pyrin domain-containing protein 3, NLRP3) inflammasome can be activated by a variety of pathogen-associated molecular patterns (pathogen-associated molecular patterns, PAMPs) and damage-associated molecular patterns (damage-associated molecular patterns, DAMPs), and then activate Caspase-1, which releases mature forms of the pro-inflammatory cytokines IL-1 ⁇ and IL-18, triggers an inflammatory response in the body, although this response can be used to defend against foreign pathogens , but aberrant or chronic activation of the NLRP3 inflammasome is known to cause downstream negative effects and
  • NLRP3 The activation of NLRP3 is closely related to the occurrence of many major human diseases. Mutations in NLRP3 itself can lead to a class of autoinflammatory diseases, including familial cold autoinflammatory syndrome (FCAS) and Moore-Weiss syndrome (MWS).
  • FCAS familial cold autoinflammatory syndrome
  • MFS Moore-Weiss syndrome
  • NLRP3 inflammasomes can be activated by various abnormal metabolites, including hyperglycemia, saturated fatty acids, cholesterol crystals, uric acid crystals, ⁇ -amyloid, etc. , neurodegenerative diseases, non-alcoholic fatty liver, inflammatory bowel disease and other diseases play an important role. Therefore, the NLRP3 inflammasome is an important potential target for various inflammation-related diseases.
  • NLRP3 antagonists have been reported in patents such as WO2018015445, WO2019025467, WO2020157069 and WO2021032591.
  • MCC950 a derivative of diarylsulfonylurea, can reduce the severity of mouse encephalomyelitis (experimental autoimmune encephalomyelitis, EAE) by inhibiting the activity of NLRP3 inflammasome.
  • Another small-molecule antagonist, CY-09 specifically blocks the assembly and activation of NLRP3 inflammasome, and is effective against cryopyrin-associated auto-inflammatory syndrome (CAPS) and type 2 diabetes in mice
  • CAS cryopyrin-associated auto-inflammatory syndrome
  • type 2 diabetes type 2 diabetes
  • Dapansutrile a very simple NLRP3 antagonist developed by Olatec, is currently in phase II clinical trials and is used for various inflammatory diseases such as gout and pain.
  • NLRP3 small molecule antagonists can provide potential therapeutic means for related inflammatory diseases, which has great significance and broad prospects.
  • the invention provides a preparation method of a compound of formula (I),
  • R 1 is selected from H and C 1-3 alkoxy, said C 1-3 alkoxy is optionally substituted by 1, 2 or 3 F;
  • R 2 is selected from OH, C 1-3 alkyl and -C 1-3 alkyl-OH, said C 1-3 alkyl and -C 1-3 alkyl-OH are independently optionally replaced by 1, 2 or 3 F replacements;
  • n is selected from 1, 2 and 3.
  • the synthesis of the compound 1-1-A comprises the following steps:
  • R is selected from H, OCH3 and NO2 ;
  • n, R 1 and R 2 are as defined in the present invention.
  • the preparation method of the compound of formula (I) comprises the following steps:
  • Base B-6 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen, LiHMDS, NaHMDS and KHMDS;
  • Reagent R-5 is selected from boron trichloride, boron tribromide, boron trifluoride, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, Pd/C, Raney Ni, PtO 2 , Pd(OH) 2 and CAN .
  • the base B-6 is selected from cesium carbonate
  • the reagent R-5 is selected from boron trichloride
  • the equivalent ratio of compound SM1 to compound SM2 is 1.0 to 1.5
  • the reagent R-5 and compound 1 The equivalent ratio of -1 is 2.0 to 4.0.
  • the equivalent ratio of the compound SM1 to the compound SM2 is 1.1, and the equivalent ratio of the reagent R-5 to the compound 1-1 is 3.0.
  • the present invention also provides a preparation method of compound SM2-A,
  • R 1 is selected from H and C 1-3 alkoxy, said C 1-3 alkoxy is optionally substituted by 1, 2 or 3 F;
  • R 2 is selected from OH, C 1-3 alkyl and -C 1-3 alkyl-OH, said C 1-3 alkyl and -C 1-3 alkyl-OH are independently optionally replaced by 1, 2 or 3 F replacements;
  • n is selected from 1, 2 and 3.
  • the synthesis of the SM2-A comprises the following steps:
  • n, R 1 and R 2 are as defined in the present invention.
  • the R 1 is selected from OCH 3
  • R 2 is selected from CH 3
  • n is selected from 1.
  • the compound SM2-7 is selected from
  • the SM2-A is selected from SM2.
  • the synthesis of the SM2 comprises the following steps:
  • R 4 is an amino protecting group, and the amino protecting group is selected from TBS, TMS, Boc, Trt and TBDPS;
  • Acid A-2 is selected from sulfuric acid, hydrochloric acid and trifluoroacetic acid;
  • Acid A-3 is selected from hydrochloric acid and tetrabutylammonium fluoride
  • Base B-3 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, potassium acetate, sodium acetate and sodium tert-butoxide;
  • Base B-4 is selected from sodium hydrogen, triethylamine, imidazole and diisopropylethylamine;
  • Base B-5 is selected from triethylamine and diisopropylethylamine
  • Catalyst C-1 is selected from Pd 2 (dba) 3 , Pd(OAc) 2 , Pd(dppf)Cl 2 and Pd(PPh 3 ) 4 ;
  • Ligand L-1 is selected from Xantphos, JohnPhos and dppf;
  • Reagent R-3 is selected from TBSOTf, TBSCl, TMSOTf, TMSCl, (Boc) 2O , TrtCl and TBDPSCl;
  • Reagent R-4 is selected from triphenylphosphine/hexachloroethane, triphenylphosphine/chlorine and dichlorotriphenylphosphine.
  • the R 4 is selected from TBS
  • the acid A-2 is selected from sulfuric acid
  • the acid A-3 is selected from hydrochloric acid
  • the base B-3 is selected from cesium carbonate
  • the base B-4 is selected from triethylamine
  • base B-5 is selected from triethylamine
  • catalyst C-1 is selected from Pd 2 (dba) 3
  • ligand L-1 is selected from Xantphos
  • reagent R-3 is selected from tert-butyldimethylsilyl trifluoromethane base sulfonate
  • reagent R-4 is selected from triphenylphosphine/hexachloroethane
  • the equivalent ratio of said triphenylphosphine to compound SM2-6 is 1.0 ⁇ 2.0
  • said hexachloroethane and compound SM2- The equivalent ratio of 6 is 1.0 to 2.0
  • the equivalent ratio of compound SM2-5 to compound SM2-4 is 1.0 to 2.0
  • the equivalent ratio of the compound SM2-5 to the compound SM2-4 is 1.3
  • the equivalent ratio of the reagent R-3 to the compound SM2-6 is 1.1
  • the ratio of triphenylphosphine to the compound SM2-6 is The equivalent ratio is 1.35
  • the equivalent ratio of hexachloroethane to compound SM2-6 is 1.5
  • the equivalent ratio of compound SM2-7 to compound SM2-6 is 1.1.
  • R 4 is TBS
  • the synthesis of the SM2-4 comprises the following steps:
  • the synthesis of the SM2-3 comprises the following steps:
  • the synthesis of the SM2-4 comprises the following steps:
  • Reagent R-1 is selected from NBS and liquid bromine
  • Reagent R-2 is selected from sodium hypochlorite, chlorine and dichlorohydantoin;
  • Acid A-1 is selected from hydrochloric acid and acetic acid
  • Base B-1 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, diisopropylethylamine, sodium hydrogen and sodium methoxide;
  • Base B-2 is selected from triethylamine and diisopropylethylamine.
  • the reagent R-1 is selected from NBS
  • the reagent R-2 is selected from 8% sodium hypochlorite aqueous solution
  • the acid A-1 is selected from hydrochloric acid
  • the base B-1 is selected from potassium carbonate
  • the base B-2 Be selected from triethylamine
  • the equivalent ratio of acid A-1 and compound SM2-3 is 1.0 ⁇ 6.0
  • the equivalent ratio of NaClO and compound SM2-3 is 1.0 ⁇ 6.0
  • the molar weight of NaClO is less than acid A-1
  • NH( The equivalent ratio of Bn) 2 to compound SM2-3 is 1.0-2.0.
  • the equivalent ratio of the acid A-1 to the compound SM2-3 is 5.0
  • the equivalent ratio of NaClO to the compound SM2-3 is 4.0
  • the equivalent ratio of NH(Bn) to the compound SM2-3 is 1.0.
  • the base B-1 is selected from potassium carbonate
  • the equivalent ratio of compound SM2-2 to compound SM2-1 is 1.0 to 1.5
  • reagent R-1 is selected from NBS, NBS and compound SM2-1
  • the equivalent ratio is 1.0 to 2.0.
  • the equivalent ratio of the compound SM2-2 to the compound SM2-1 is 1.1, and the equivalent ratio of the NBS to the compound SM2-1 is 1.2.
  • the raw material SM2-3 used in the present invention is 4-tert-butylbenzyl mercaptan, which is almost odorless in the raw material and follow-up reaction, which is beneficial to the enlarged production of the process, and avoids the unfriendly environment such as conventional mercaptan compound stench, unsuitable for industrialization, etc. shortcoming;
  • the raw materials are all common reagents, which are easy to obtain in the market, low in price, easy to control the reaction, and simple in post-treatment;
  • a chiral protecting group is introduced into compound SM2, and further, when compound 1-1 is synthesized, compound 1-1 of a single configuration is obtained by resolution of beating and recrystallization methods, which avoids chiral SFC separation operation, Moreover, column chromatography purification is not required, which greatly reduces process difficulty and process cost.
  • the compound of formula (I) of the present invention exhibits good NLRP3 inhibitory activity, and pk results show that it has good oral bioavailability, high exposure, good pharmacodynamic properties in vivo, and little effect on MSU-induced C57BL/6
  • the murine Air Pouch gout model has a good therapeutic effect and has the potential to treat gout and other diseases related to inflammatory cytokines.
  • the present invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediate.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
  • C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxyl protecting group” or “mercapto protecting group”.
  • amino-protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Trt), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS) and tert-butyldimethylsilyl (TBS) etc.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxy group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • DMF stands for N,N-dimethylformamide
  • DCM stands for dichloromethane
  • MeOH stands for methanol
  • DMSO dimethyl sulfoxide
  • NBS stands for N-bromosuccinimide
  • NaClO sodium hypochlorite
  • Xantphos stands for 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • JohnPhos stands for 2-(di-tert-butylphosphine)biphenyl
  • dppf stands for 1,1-bis(di phenylphosphino)ferrocene
  • Pd2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium
  • Pd(dppf) Cl2 represents 1,1-bis(diphenylphosphino)ferrocene chloride Palladium
  • Pd(OAc) 2 for palladium acetate
  • Pd(PPh 3 ) 4 for
  • each solvent used in the present invention can be obtained commercially, and the commercially available compounds adopt the catalog names of suppliers.
  • each solvent can be mixed first, and then added to the reaction liquid; or each single solvent can be sequentially added to the reaction liquid, and mixed in the reaction system.
  • Figure 1 The results of the inhibition experiment of the inflammatory cytokine IL-6 in APLV.
  • Figure 2 The results of the inhibition experiment of the inflammatory cytokine IL-1 ⁇ in APLV.
  • Embodiment 1 the synthesis of compound SM1
  • Embodiment 2 the synthesis of compound SM2
  • Embodiment 3 the synthesis of formula (I) compound
  • the filter cake and acetonitrile (17 L) were successively added into the reactor, the temperature of the reactor was adjusted to 55-65° C., and stirred for 1 hour. Suction filtration under reduced pressure, and the filter cake was washed with acetonitrile (0.5 L). The filter cake and acetonitrile (14 L) were successively added into the reactor, the temperature of the reactor was adjusted to 55-65° C., and stirred for 1 hour. Suction filtration under reduced pressure, and the filter cake was washed with acetonitrile (0.5 L). The filter cake and acetonitrile (11 L) were successively added into the reaction kettle, the temperature of the reaction kettle was adjusted to 55-65° C., and stirred for 1 hour.
  • the organic phase was washed with water (40L*2), washed with anhydrous sodium sulfate ( 2kg) to dry, pad silica gel (300g, 100-200 mesh) to aid in filtration, vacuum filtration under reduced pressure, and the filtrate was concentrated under reduced pressure at an external temperature of 40°C to about 1.5L suspension.
  • the filter cake was vacuum-dried at 40° C. for 12 hours to obtain the compound of formula (I) (500 g). MS ESI calcd.
  • Experimental example 1 IC 50 experiment of detecting NLRP3 antagonists using THP-1 cells
  • the human monocyte cell line THP1 was used to study the inhibitory activity (IC 50 ) of NLRP3 antagonists on the secretion of IL-1 ⁇ .
  • PMA crotyl alcohol-12-myristate-13-acetate
  • LPS lipopolysaccharide
  • Toll-like receptor TLR4 an antagonist of NLRP3 was added, followed by ATP to further mature and activate NLRP3 and activate downstream caspase-1.
  • Activated caspase-1 can enzymatically process pro-IL-1 ⁇ into mature IL-1 ⁇ that can be secreted.
  • NLRP3 antagonists can effectively inhibit the ATP-induced maturation and activation of NLRP3, as well as the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1 ⁇ .
  • the cells were stimulated with LPS, the final concentration of LPS was 100ng/mL, 200 ⁇ L/well was added to a 96-well plate, and cultured at 37° C., 5% CO 2 for 3 hours.
  • test compounds into the wells are: 5 ⁇ M, 1 ⁇ M, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM. Incubate for 1 h at 37°C in a 5% CO 2 incubator.
  • mice the clear solution obtained after dissolving the test compound was administered to female C57BL/6J mice via tail vein injection and intragastric administration (vehicle: 10% DMSO/10% solutol/80% water) (overnight fasting, 6- 8 weeks old).
  • vehicle 10% DMSO/10% solutol/80% water
  • IV intravenous injection group
  • blood was collected from the mandibular vein and centrifuged to obtain plasma.
  • the blood drug concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version6.3 pharmacokinetic software.
  • T 1/2 half-life
  • C max peak concentration
  • AUC 0-inf area under the plasma concentration-time curve from time 0 to extrapolation to infinity
  • AUC 0-last time from 0 to The area under the plasma concentration-time curve when the drug concentration can be finally detected
  • F bioavailability
  • Vd apparent volume of distribution
  • Cl clearance rate
  • T max peak time.
  • the compound of the present invention has good oral bioavailability, high exposure, and good pharmacodynamic properties in vivo.
  • the mouse air sac (Air Pouch) is a sac-like space similar to the human synovium, and injecting monosodium urate crystals (MSU) into the air sac can cause an acute inflammatory response similar to human gout.
  • MSU monosodium urate crystals
  • APLV air sac flushing fluid
  • mice C57BL/6 mice, male, 7-8 weeks old, Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • mice Healthy mice were used for numbering and grouping in the experiment, and sterile air was injected into the back of the mice on the day (Day1) and day 4 (Day4) to generate air sacs.
  • Day1 day 1
  • Day4 day 4
  • the drug was given first, the MSU crystalloid solution was infused into the air pouch 1 h later, and the air pouch flushing fluid (APLV) was collected 7 h later and analyzed.
  • the grouping and dosing regimen are shown in Table 4.
  • mice Healthy C57BL/6 mice were used for numbering and grouping in the experiment.
  • Day1 On the day of grouping (Day1) and the fourth day (Day4), 5 mL of sterile air was subcutaneously injected into the back of the mice to generate an air pouch.
  • Day7 On the seventh day (Day7), the mice in each group were given the vehicle or the test substance, and 1 hour later, the suspension of MSU crystals (saline, 3 mg/mL) was injected into the air bag. After 6 hours, air pouch flushing fluid (APLV) will be collected, and the levels of IL-6 and IL-1 ⁇ in APLV will be tested using ELISA kits. Results are expressed as mean ⁇ SEM. Statistical analysis was performed using a method of analysis of variance (ANOVA) followed by Dunnett's test and differences were considered significant when p ⁇ 0.05.
  • ANOVA analysis of variance
  • the reducing effect of the compound of formula (I) on IL-1 ⁇ is remarkable, and the reducing effect on IL-1 ⁇ under the dosage of 15mg/kg and 50mg/kg is all significantly better than MCC950 (50mg/kg dose), and the level of IL-1 ⁇ is extremely Low, reaching the same effect as dexamethasone (10mg/kg).
  • the results of the inhibition test of the inflammatory cytokine IL-6 in APLV are shown in Figure 1, and the results of the inhibition test of the inflammatory cytokine IL-1 ⁇ in APLV are shown in Figure 2, p means significant difference, *: p ⁇ 0.05; **: p ⁇ 0.01; ***p ⁇ 0.001.
  • the compound of the present invention has a good therapeutic effect on the MSU-induced C57BL/6 mouse Air Pouch gout model, and has the potential to treat gout and other diseases related to inflammatory cytokines.

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Abstract

Disclosed in the present invention is a method for preparing a dimethyl sulfinyl imine derivative and an intermediate thereof, and specifically disclosed is a method for preparing a compound of formula (I) and an intermediate thereof.

Description

二甲基亚磺酰亚胺衍生物的制备方法The preparation method of dimethylsulfinimide derivative
本发明主张如下优先权：The present invention claims the following priority:
CN202111467736.6，申请日2021年12月03日。CN202111467736.6, the application date is December 03, 2021.
技术领域technical field
本发明涉及一种二甲基亚磺酰亚胺衍生物及其中间体的制备方法，具体涉及式(I)化合物及其中间体的制备方法。The invention relates to a preparation method of dimethylsulfinimide derivatives and intermediates thereof, in particular to a preparation method of the compound of formula (I) and intermediates thereof.
背景技术Background technique
炎症是多种疾病发生、发展的基础，维持炎症应答平衡对防治感染、自身免疫疾病和癌症等有重要意义。炎症小体(inflammasome)在炎症相关疾病的发生发展中发挥重要作用，核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain,NOD)样受体家族含pyrin结构域蛋白3(NOD-like receptor family，pyrin domain-containing protein 3，NLRP3)炎症小体能够被多种病原相关分子模式(pathogen-associated molecular patterns,PAMPs)和损伤相关分子模式(damage-associated molecular patterns,DAMPs)激活，进而活化半胱氨酸天冬氨酸蛋白酶-1(caspase-1)，释放成熟形式的促炎因子白细胞介素IL-1β和IL-18，引起机体的炎症反应，虽然这种反应可用于抵御外来病原体，但已知NLRP3炎性体的异常或慢性激活会引起下游的负面影响以及许多疾病的发作和进展。Inflammation is the basis for the occurrence and development of many diseases, and maintaining the balance of inflammatory responses is of great significance for the prevention and treatment of infection, autoimmune diseases and cancer. The inflammasome plays an important role in the occurrence and development of inflammation-related diseases, and the nucleotide-binding oligomerization domain (NOD)-like receptor family contains pyrin domain protein 3 (NOD-like receptor family, pyrin domain-containing protein 3, NLRP3) inflammasome can be activated by a variety of pathogen-associated molecular patterns (pathogen-associated molecular patterns, PAMPs) and damage-associated molecular patterns (damage-associated molecular patterns, DAMPs), and then activate Caspase-1, which releases mature forms of the pro-inflammatory cytokines IL-1β and IL-18, triggers an inflammatory response in the body, although this response can be used to defend against foreign pathogens , but aberrant or chronic activation of the NLRP3 inflammasome is known to cause downstream negative effects and the onset and progression of many diseases.
NLRP3活化与多种人类重大疾病的发生有着密切的关系。NLRP3自身的突变会导致一类自身炎症性疾病，包括括家族性寒冷型自身炎症性综合征(FCAS)、穆-韦二氏综合征(MWS)。另外NLRP3炎症小体能够被各种异常代谢产物，包括高血糖、饱和脂肪酸、胆固醇结晶、尿酸结晶、β-淀粉样蛋白等激活，所以NLRP3炎症小体在2型糖尿病、动脉粥样硬化、痛风、神经退行性疾病、非酒精性脂肪肝、炎症性肠病等等疾病的发生中起重要作用。因此NLRP3炎症小体是多种炎症相关疾病重要的潜在靶点。The activation of NLRP3 is closely related to the occurrence of many major human diseases. Mutations in NLRP3 itself can lead to a class of autoinflammatory diseases, including familial cold autoinflammatory syndrome (FCAS) and Moore-Weiss syndrome (MWS). In addition, NLRP3 inflammasomes can be activated by various abnormal metabolites, including hyperglycemia, saturated fatty acids, cholesterol crystals, uric acid crystals, β-amyloid, etc. , neurodegenerative diseases, non-alcoholic fatty liver, inflammatory bowel disease and other diseases play an important role. Therefore, the NLRP3 inflammasome is an important potential target for various inflammation-related diseases.
有多种NLRP3拮抗剂在WO2018015445、WO2019025467、WO2020157069和WO2021032591等专利中被报道。二芳基磺酰脲的衍生物MCC950通过抑制NLRP3炎症小体活性，可以减轻小鼠脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)的严重程度。另一种小分子拮抗剂CY-09，特异性地阻断NLRP3炎症小体的组装与活化，对于小鼠低温相关的自身炎症综合征(cryopyrin-associated auto-inflammatory syndrome,CAPS)和Ⅱ型糖尿病模型有显著的治疗效果。Olatec公司开发的结构非常简单的NLRP3拮抗剂Dapansutrile目前处于临床II期，用于痛风、疼痛等多种炎性疾病。A variety of NLRP3 antagonists have been reported in patents such as WO2018015445, WO2019025467, WO2020157069 and WO2021032591. MCC950, a derivative of diarylsulfonylurea, can reduce the severity of mouse encephalomyelitis (experimental autoimmune encephalomyelitis, EAE) by inhibiting the activity of NLRP3 inflammasome. Another small-molecule antagonist, CY-09, specifically blocks the assembly and activation of NLRP3 inflammasome, and is effective against cryopyrin-associated auto-inflammatory syndrome (CAPS) and type 2 diabetes in mice The model has a significant therapeutic effect. Dapansutrile, a very simple NLRP3 antagonist developed by Olatec, is currently in phase II clinical trials and is used for various inflammatory diseases such as gout and pain.
Figure PCTCN2022134644-appb-000001
Figure PCTCN2022134644-appb-000001
开发靶向的NLRP3小分子拮抗剂，能为与其相关的炎症性疾病提供潜在的治疗手段，有着重要意义和广阔的前景。目前，仍然存在开发新的NLRP3拮抗剂用于治疗炎症性疾病的需求。The development of targeted NLRP3 small molecule antagonists can provide potential therapeutic means for related inflammatory diseases, which has great significance and broad prospects. Currently, there remains a need to develop new NLRP3 antagonists for the treatment of inflammatory diseases.
发明内容Contents of the invention
本发明提供了一种式(Ⅰ)化合物的制备方法，The invention provides a preparation method of a compound of formula (I),
Figure PCTCN2022134644-appb-000002
Figure PCTCN2022134644-appb-000002
其包含如下步骤：It includes the following steps:
Figure PCTCN2022134644-appb-000003
Figure PCTCN2022134644-appb-000003
其中，in,
R 1选自H和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个F取代； R 1 is selected from H and C 1-3 alkoxy, said C 1-3 alkoxy is optionally substituted by 1, 2 or 3 F;
R 2选自OH、C 1-3烷基和-C 1-3烷基-OH，所述C 1-3烷基和-C 1-3烷基-OH分别独立地任选被1、2或3个F取代； R 2 is selected from OH, C 1-3 alkyl and -C 1-3 alkyl-OH, said C 1-3 alkyl and -C 1-3 alkyl-OH are independently optionally replaced by 1, 2 or 3 F replacements;
n选自1、2和3。n is selected from 1, 2 and 3.
在本发明的一些方案中，所述化合物1-1-A的合成包含如下步骤：In some schemes of the present invention, the synthesis of the compound 1-1-A comprises the following steps:
Figure PCTCN2022134644-appb-000004
Figure PCTCN2022134644-appb-000004
其中，in,
R 3选自-N＝C＝O和
Figure PCTCN2022134644-appb-000005
R 3 is selected from -N=C=O and
Figure PCTCN2022134644-appb-000005
R选自H、OCH 3和NO 2； R is selected from H, OCH3 and NO2 ;
n、R 1和R 2如本发明所定义。 n, R 1 and R 2 are as defined in the present invention.
在本发明的一些方案中，所述式(Ⅰ)化合物的制备方法，其包含如下步骤：In some schemes of the present invention, the preparation method of the compound of formula (I) comprises the following steps:
Figure PCTCN2022134644-appb-000006
Figure PCTCN2022134644-appb-000006
其中，in,
碱B-6选自碳酸钾、碳酸钠、碳酸铯、钠氢、LiHMDS、NaHMDS和KHMDS；Base B-6 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen, LiHMDS, NaHMDS and KHMDS;
试剂R-5选自三氯化硼、三溴化硼、三氟化硼、三氟乙酸、盐酸、氢溴酸、硫酸、Pd/C、Raney Ni、PtO 2、Pd(OH) 2和CAN。 Reagent R-5 is selected from boron trichloride, boron tribromide, boron trifluoride, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, Pd/C, Raney Ni, PtO 2 , Pd(OH) 2 and CAN .
在本发明的一些方案中，所述碱B-6选自碳酸铯，试剂R-5选自三氯化硼，化合物SM1与化合物SM2的当量比为1.0～1.5，试剂R-5与化合物1-1的当量比为2.0～4.0。In some schemes of the present invention, the base B-6 is selected from cesium carbonate, the reagent R-5 is selected from boron trichloride, the equivalent ratio of compound SM1 to compound SM2 is 1.0 to 1.5, and the reagent R-5 and compound 1 The equivalent ratio of -1 is 2.0 to 4.0.
在本发明的一些方案中，所述化合物SM1与化合物SM2的当量比为1.1，试剂R-5与化合物1-1的当量比为3.0。In some schemes of the present invention, the equivalent ratio of the compound SM1 to the compound SM2 is 1.1, and the equivalent ratio of the reagent R-5 to the compound 1-1 is 3.0.
本发明还提供了化合物SM2-A的制备方法，The present invention also provides a preparation method of compound SM2-A,
Figure PCTCN2022134644-appb-000007
Figure PCTCN2022134644-appb-000007
其包含如下步骤：It includes the following steps:
Figure PCTCN2022134644-appb-000008
Figure PCTCN2022134644-appb-000008
其中，in,
R 1选自H和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个F取代； R 1 is selected from H and C 1-3 alkoxy, said C 1-3 alkoxy is optionally substituted by 1, 2 or 3 F;
R 2选自OH、C 1-3烷基和-C 1-3烷基-OH，所述C 1-3烷基和-C 1-3烷基-OH分别独立地任选被1、2或3个F取代； R 2 is selected from OH, C 1-3 alkyl and -C 1-3 alkyl-OH, said C 1-3 alkyl and -C 1-3 alkyl-OH are independently optionally replaced by 1, 2 or 3 F replacements;
n选自1、2和3。n is selected from 1, 2 and 3.
在本发明的一些方案中，所述SM2-A的合成包含如下步骤：In some schemes of the present invention, the synthesis of the SM2-A comprises the following steps:
Figure PCTCN2022134644-appb-000009
Figure PCTCN2022134644-appb-000009
其中，n、R 1和R 2如本发明所定义。 Wherein, n, R 1 and R 2 are as defined in the present invention.
在本发明的一些方案中，所述R 1选自OCH 3，R 2选自CH 3，n选自1。 In some embodiments of the present invention, the R 1 is selected from OCH 3 , R 2 is selected from CH 3 , and n is selected from 1.
在本发明的一些方案中，所述化合物SM2-7选自
Figure PCTCN2022134644-appb-000010
In some schemes of the present invention, the compound SM2-7 is selected from
Figure PCTCN2022134644-appb-000010
在本发明的一些方案中，所述SM2-A选自SM2。In some aspects of the present invention, the SM2-A is selected from SM2.
在本发明的一些方案中，所述SM2的合成包含如下步骤：In some schemes of the present invention, the synthesis of the SM2 comprises the following steps:
Figure PCTCN2022134644-appb-000011
Figure PCTCN2022134644-appb-000011
其中，in,
R 4为氨基保护基，所述氨基保护基选自TBS、TMS、Boc、Trt和TBDPS； R 4 is an amino protecting group, and the amino protecting group is selected from TBS, TMS, Boc, Trt and TBDPS;
酸A-2选自硫酸、盐酸和三氟乙酸；Acid A-2 is selected from sulfuric acid, hydrochloric acid and trifluoroacetic acid;
酸A-3选自盐酸和四丁基氟化铵；Acid A-3 is selected from hydrochloric acid and tetrabutylammonium fluoride;
碱B-3选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、磷酸钾、醋酸钾、醋酸钠和叔丁醇钠；Base B-3 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, potassium acetate, sodium acetate and sodium tert-butoxide;
碱B-4选自钠氢、三乙胺、咪唑和二异丙基乙胺；Base B-4 is selected from sodium hydrogen, triethylamine, imidazole and diisopropylethylamine;
碱B-5选自三乙胺和二异丙基乙胺；Base B-5 is selected from triethylamine and diisopropylethylamine;
催化剂C-1选自Pd 2(dba) 3、Pd(OAc) 2、Pd(dppf)Cl 2和Pd(PPh 3) 4； Catalyst C-1 is selected from Pd 2 (dba) 3 , Pd(OAc) 2 , Pd(dppf)Cl 2 and Pd(PPh 3 ) 4 ;
配体L-1选自Xantphos、JohnPhos和dppf；Ligand L-1 is selected from Xantphos, JohnPhos and dppf;
试剂R-3选自TBSOTf、TBSCl、TMSOTf、TMSCl、(Boc) 2O、TrtCl和TBDPSCl； Reagent R-3 is selected from TBSOTf, TBSCl, TMSOTf, TMSCl, (Boc) 2O , TrtCl and TBDPSCl;
试剂R-4选自三苯基膦/六氯乙烷、三苯基膦/氯气和二氯三苯基膦。Reagent R-4 is selected from triphenylphosphine/hexachloroethane, triphenylphosphine/chlorine and dichlorotriphenylphosphine.
在本发明的一些方案中，所述R 4选自TBS，酸A-2选自硫酸，酸A-3选自盐酸，碱B-3选自碳酸铯，碱B-4选自三乙胺，碱B-5选自三乙胺，催化剂C-1选自Pd 2(dba) 3，配体L-1选自Xantphos，试剂R-3选自叔丁基二甲基硅基三氟甲基磺酸酯，试剂R-4选自三苯基膦/六氯乙烷，所述三苯基膦与化合物SM2-6的当量比为1.0～2.0，所述六氯乙烷与化合物SM2-6的当量比为1.0～2.0；化合物SM2-5与化合物SM2-4的当量比为1.0～2.0，催化剂C-1与化合物SM2-4的当量比为0.01～0.1，配体L-1与化合物SM2-4的当量比为0.02～0.2，酸A-2与化合物SM2-4的当量比为10～20，试剂R-3与化合物SM2-6的当量比为1.0～2.0，试剂R-4与化合物SM2-6的当量比为1.0～2.0，化合物SM2-7与化合物SM2-6的当量比为1.0～2.0。 In some schemes of the present invention, the R 4 is selected from TBS, the acid A-2 is selected from sulfuric acid, the acid A-3 is selected from hydrochloric acid, the base B-3 is selected from cesium carbonate, and the base B-4 is selected from triethylamine , base B-5 is selected from triethylamine, catalyst C-1 is selected from Pd 2 (dba) 3 , ligand L-1 is selected from Xantphos, reagent R-3 is selected from tert-butyldimethylsilyl trifluoromethane base sulfonate, reagent R-4 is selected from triphenylphosphine/hexachloroethane, the equivalent ratio of said triphenylphosphine to compound SM2-6 is 1.0～2.0, said hexachloroethane and compound SM2- The equivalent ratio of 6 is 1.0 to 2.0; the equivalent ratio of compound SM2-5 to compound SM2-4 is 1.0 to 2.0, the equivalent ratio of catalyst C-1 to compound SM2-4 is 0.01 to 0.1, and the ligand L-1 and compound The equivalent ratio of SM2-4 is 0.02～0.2, the equivalent ratio of acid A-2 and compound SM2-4 is 10～20, the equivalent ratio of reagent R-3 and compound SM2-6 is 1.0～2.0, reagent R-4 and The equivalent ratio of compound SM2-6 is 1.0-2.0, and the equivalent ratio of compound SM2-7 and compound SM2-6 is 1.0-2.0.
在本发明的一些方案中，所述化合物SM2-5与化合物SM2-4的当量比为1.3，试剂R-3与化合物SM2-6的当量比为1.1，三苯基膦与化合物SM2-6的当量比为1.35，六氯乙烷与化合物SM2-6的当量比为1.5，化合物SM2-7与化合物SM2-6的当量比为1.1。In some schemes of the present invention, the equivalent ratio of the compound SM2-5 to the compound SM2-4 is 1.3, the equivalent ratio of the reagent R-3 to the compound SM2-6 is 1.1, and the ratio of triphenylphosphine to the compound SM2-6 is The equivalent ratio is 1.35, the equivalent ratio of hexachloroethane to compound SM2-6 is 1.5, and the equivalent ratio of compound SM2-7 to compound SM2-6 is 1.1.
在本发明的一些方案中，所述化合物SM2-6-2的手性拆分方法，In some schemes of the present invention, the chiral resolution method of the compound SM2-6-2,
Figure PCTCN2022134644-appb-000012
Figure PCTCN2022134644-appb-000012
其中，R 4为TBS； Wherein, R 4 is TBS;
其包含如下步骤：It includes the following steps:
将化合物SM2-6-2的粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷:甲醇＝200:1～100:1)得到化合物SM2-6-2a和化合物SM2-6-2b。TLC检测(展开剂，石油醚:乙酸乙酯＝1:1)，化合物SM2-6-2a：R f＝0.37；化合物SM2-6-2b：R f＝0.42。 The crude compound SM2-6-2 was purified by silica gel column chromatography (eluent: dichloromethane:methanol=200:1-100:1) to obtain compound SM2-6-2a and compound SM2-6-2b. TLC detection (developing solvent, petroleum ether:ethyl acetate=1:1), compound SM2-6-2a: R f =0.37; compound SM2-6-2b: R f =0.42.
在本发明的一些方案中，所述SM2-4的合成包含如下步骤：In some schemes of the present invention, the synthesis of the SM2-4 comprises the following steps:
Figure PCTCN2022134644-appb-000013
Figure PCTCN2022134644-appb-000013
在本发明的一些方案中，所述SM2-3的合成包含如下步骤：In some schemes of the present invention, the synthesis of the SM2-3 comprises the following steps:
Figure PCTCN2022134644-appb-000014
Figure PCTCN2022134644-appb-000014
在本发明的一些方案中，所述SM2-4的合成包含如下步骤：In some schemes of the present invention, the synthesis of the SM2-4 comprises the following steps:
Figure PCTCN2022134644-appb-000015
Figure PCTCN2022134644-appb-000015
其中，in,
试剂R-1选自NBS和液溴；Reagent R-1 is selected from NBS and liquid bromine;
试剂R-2选自次氯酸钠、氯气和二氯海因；Reagent R-2 is selected from sodium hypochlorite, chlorine and dichlorohydantoin;
酸A-1选自盐酸和醋酸；Acid A-1 is selected from hydrochloric acid and acetic acid;
碱B-1选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、磷酸钾、二异丙基乙胺、钠氢和甲醇钠；Base B-1 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, diisopropylethylamine, sodium hydrogen and sodium methoxide;
碱B-2选自三乙胺和二异丙基乙胺。Base B-2 is selected from triethylamine and diisopropylethylamine.
在本发明的一些方案中，所述试剂R-1选自NBS，试剂R-2选自8％次氯酸钠水溶液，酸A-1选自盐酸，碱B-1选自碳酸钾，碱B-2选自三乙胺；酸A-1与化合物SM2-3的当量比为1.0～6.0，NaClO与化合物SM2-3的当量比为1.0～6.0，且NaClO的摩尔量小于酸A-1，NH(Bn) 2与化合物SM2-3的当量比为1.0～2.0。 In some schemes of the present invention, the reagent R-1 is selected from NBS, the reagent R-2 is selected from 8% sodium hypochlorite aqueous solution, the acid A-1 is selected from hydrochloric acid, the base B-1 is selected from potassium carbonate, and the base B-2 Be selected from triethylamine; The equivalent ratio of acid A-1 and compound SM2-3 is 1.0～6.0, the equivalent ratio of NaClO and compound SM2-3 is 1.0～6.0, and the molar weight of NaClO is less than acid A-1, NH( The equivalent ratio of Bn) 2 to compound SM2-3 is 1.0-2.0.
在本发明的一些方案中，所述酸A-1与化合物SM2-3的当量比为5.0，NaClO与化合物SM2-3的当量比为4.0，NH(Bn) 2与化合物SM2-3的当量比为1.0。 In some schemes of the present invention, the equivalent ratio of the acid A-1 to the compound SM2-3 is 5.0, the equivalent ratio of NaClO to the compound SM2-3 is 4.0 , and the equivalent ratio of NH(Bn) to the compound SM2-3 is 1.0.
在本发明的一些方案中，所述碱B-1选自碳酸钾，化合物SM2-2与化合物SM2-1的当量比为1.0～1.5，试剂R-1选自NBS，NBS与化合物SM2-1的当量比为1.0～2.0。In some schemes of the present invention, the base B-1 is selected from potassium carbonate, the equivalent ratio of compound SM2-2 to compound SM2-1 is 1.0 to 1.5, reagent R-1 is selected from NBS, NBS and compound SM2-1 The equivalent ratio is 1.0 to 2.0.
在本发明的一些方案中，所述化合物SM2-2与化合物SM2-1的当量比为1.1，NBS与化合物SM2-1的当量比为1.2。In some schemes of the present invention, the equivalent ratio of the compound SM2-2 to the compound SM2-1 is 1.1, and the equivalent ratio of the NBS to the compound SM2-1 is 1.2.
技术效果technical effect
本发明给出的合成式(I)化合物及其中间体的工艺中，原料价格便宜易得，反应条件温和，易于控制，后处理简单，无一采用柱层析纯化，中间体和终产物都是通过简单重结晶或打浆纯化得到，容易放大生产，终产品手性纯度高，克服了分离纯化困难以及不易工业化等缺点。具体地：In the process for the synthesis of compounds of formula (I) and their intermediates provided by the present invention, the raw materials are cheap and easy to obtain, the reaction conditions are mild, easy to control, and the post-treatment is simple. None of them adopts column chromatography for purification, and the intermediates and final products are both It is obtained through simple recrystallization or beating and purification, easy to scale up production, and the final product has high chiral purity, which overcomes the shortcomings of separation and purification difficulties and difficult industrialization. specifically:
1)本发明所用原料SM2-3为4-叔丁基苄硫醇，原料和后续反应中几乎无臭，利于工艺放大生产，避免了常规的硫醇化合物恶臭、不适合工业化等环境不友好的缺点；1) The raw material SM2-3 used in the present invention is 4-tert-butylbenzyl mercaptan, which is almost odorless in the raw material and follow-up reaction, which is beneficial to the enlarged production of the process, and avoids the unfriendly environment such as conventional mercaptan compound stench, unsuitable for industrialization, etc. shortcoming;
2)本发明中制备化合物SM2-4时，原料均为常见试剂，在市场上容易获得，价格低廉，且反应容易控制，后处理简单；2) When preparing compound SM2-4 in the present invention, the raw materials are all common reagents, which are easy to obtain in the market, low in price, easy to control the reaction, and simple in post-treatment;
3)本发明中在化合物SM2中引入手性保护基，进一步在合成化合物1-1时，通过打浆和重结晶方法 拆分得到单一构型的化合物1-1，避免了手性SFC分离操作，且不需要柱层析纯化，大大降低了工艺难度和工艺成本。3) In the present invention, a chiral protecting group is introduced into compound SM2, and further, when compound 1-1 is synthesized, compound 1-1 of a single configuration is obtained by resolution of beating and recrystallization methods, which avoids chiral SFC separation operation, Moreover, column chromatography purification is not required, which greatly reduces process difficulty and process cost.
4)本发明式(I)化合物展示了良好的NLRP3抑制活性，且pk结果显示其具有良好的口服生物利用度，较高的暴露量，体内药效性质良好，对MSU诱导的C57BL/6小鼠Air Pouch痛风模型有较好的治疗效果，具有治疗痛风等其他与炎性细胞因子相关疾病的潜力。4) The compound of formula (I) of the present invention exhibits good NLRP3 inhibitory activity, and pk results show that it has good oral bioavailability, high exposure, good pharmacodynamic properties in vivo, and little effect on MSU-induced C57BL/6 The murine Air Pouch gout model has a good therapeutic effect and has the potential to treat gout and other diseases related to inflammatory cytokines.
因此，本发明在制备式(I)化合物及其中间体方面，具有很高的工业应用价值和经济价值。Therefore, the present invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediate.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotation, "(-)" means levorotation, and "(±)" means racemization.
除非另有说明，用楔形实线键
Figure PCTCN2022134644-appb-000016
和楔形虚线键
Figure PCTCN2022134644-appb-000017
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022134644-appb-000018
和直形虚线键
Figure PCTCN2022134644-appb-000019
表示立体中心的相对构型。 Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2022134644-appb-000016
and dotted wedge keys
Figure PCTCN2022134644-appb-000017
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure PCTCN2022134644-appb-000018
and straight dashed keys
Figure PCTCN2022134644-appb-000019
Indicates the relative configuration of the stereocenter.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term "C 1-3 alkoxy" denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合 用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Trt)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)、叔丁基二苯基硅烷基(TBDPS)和叔丁基二甲基甲硅烷基(TBS)等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxyl protecting group" or "mercapto protecting group". The term "amino-protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Trt), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS) and tert-butyldimethylsilyl (TBS) etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.
本发明采用下述缩略词：DMF代表N,N-二甲基甲酰胺；DCM代表二氯甲烷；MeOH代表甲醇；DMSO代表二甲亚砜；NBS代表N-溴代丁二酰亚胺；NaClO代表次氯酸钠；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；JohnPhos代表2-(二叔丁基膦)联苯；dppf代表1,1-双(二苯基膦基)二茂铁；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Pd(dppf)Cl 2代表1,1-双(二苯基膦)二茂铁氯化钯；Pd(OAc) 2代表醋酸钯；Pd(PPh 3) 4代表四(三苯基膦)钯；H 2SO 4代表硫酸；TBSOTf代表叔丁基二甲基硅基三氟甲基磺酸酯；TBSCl代表叔丁基二甲基氯硅烷；TMSOTf代表三甲硅基三氟甲磺酸酯；TMSCl代表三甲基氯硅烷；(Boc) 2O代表二碳酸二叔丁酯；TrtCl代表三苯基氯甲烷；TBDPSCl代表叔丁基二苯基氯硅烷；NH(Bn) 2代表二苄胺；LiHMDS代表二(三甲基硅基)氨基锂；NaHMDS代表二(三甲基硅基)氨基钠；KHMDS代表二(三甲基硅基)氨基钾；Pd/C代表钯/碳；Raney Ni代表雷尼镍；PtO 2代表二氧化铂；Pd(OH) 2代表氢氧化钯；CAN代表硝酸铈铵；室温代表15-30℃；eq代表当量。 The present invention adopts the following abbreviations: DMF stands for N,N-dimethylformamide; DCM stands for dichloromethane; MeOH stands for methanol; DMSO stands for dimethyl sulfoxide; NBS stands for N-bromosuccinimide; NaClO stands for sodium hypochlorite; Xantphos stands for 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; JohnPhos stands for 2-(di-tert-butylphosphine)biphenyl; dppf stands for 1,1-bis(di phenylphosphino)ferrocene; Pd2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium; Pd(dppf) Cl2 represents 1,1-bis(diphenylphosphino)ferrocene chloride Palladium; Pd(OAc) 2 for palladium acetate; Pd(PPh 3 ) 4 for tetrakis(triphenylphosphine)palladium; H 2 SO 4 for sulfuric acid; TBSOTf for tert-butyldimethylsilyltrifluoromethanesulfonic acid TBSCl represents tert-butyldimethylsilyl chloride; TMSOTf represents trimethylsilyl trifluoromethanesulfonate; TMSCl represents trimethylchlorosilane; (Boc) 2 O represents di-tert-butyl dicarbonate; TrtCl represents triphenyl TBDPSCl represents tert-butyldiphenylchlorosilane; NH(Bn) 2 represents dibenzylamine; LiHMDS represents lithium bis(trimethylsilyl)amide; NaHMDS represents sodium bis(trimethylsilyl)amide ; KHMDS stands for potassium bis(trimethylsilyl)amide; Pd/C stands for palladium/carbon ; Raney Ni stands for Raney nickel; PtO2 stands for platinum dioxide; Pd(OH)2 stands for palladium hydroxide; CAN stands for cerium nitrate Ammonium; room temperature means 15-30°C; eq means equivalent.
本发明所使用的溶剂可经市售获得，市售化合物采用供应商目录名称。将混合溶剂加入到反应液中时，可以先将各个溶剂混合，然后加入到反应液中；或依次向反应液中加入各个单一溶剂，在反应体系中混合。The solvents used in the present invention can be obtained commercially, and the commercially available compounds adopt the catalog names of suppliers. When adding the mixed solvent to the reaction liquid, each solvent can be mixed first, and then added to the reaction liquid; or each single solvent can be sequentially added to the reaction liquid, and mixed in the reaction system.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022134644-appb-000020
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to the conventional naming principles in this field or using
Figure PCTCN2022134644-appb-000020
The software is named, and the commercially available compounds adopt the supplier catalog name.
附图说明Description of drawings
图1：APLV中的炎性细胞因子IL-6的抑制实验结果。Figure 1: The results of the inhibition experiment of the inflammatory cytokine IL-6 in APLV.
图2：APLV中的炎性细胞因子IL-1β的抑制实验结果。Figure 2: The results of the inhibition experiment of the inflammatory cytokine IL-1β in APLV.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
实施例1：化合物SM1的合成Embodiment 1: the synthesis of compound SM1
Figure PCTCN2022134644-appb-000021
Figure PCTCN2022134644-appb-000021
将乙腈(12L)、水(8L)、化合物SM1-1(2kg，11.54mol，1.0eq)和碳酸氢钠(1.16kg，13.85mol，1.2eq)依次加入反应釜，调节反应釜温度至0～5℃，向反应釜中缓慢滴加化合物SM1-2(1.9kg，12.12mol，1.05eq)，调节反应釜温度至20～30℃，搅拌3小时。向反应釜中加入水(20L)，搅拌0.5小时。减压抽滤，滤饼用水(2L)洗涤，再用叔丁基甲基醚(5L)洗涤。滤饼真空干燥得到白色固体中间体SM1(2.5kg)。MS ESI计算值C 19H 19NO 2[M+H] +294，实测值294； 1H NMR(400MHz,CDCl 3)δppm 7.47-7.36(m,2H),7.28-7.18(m,3H),7.06(s,1H),6.53(br s,1H),2.93(br t,J＝7.0Hz,8H),2.13(quin,J＝7.40Hz,4H)。 Add acetonitrile (12L), water (8L), compound SM1-1 (2kg, 11.54mol, 1.0eq) and sodium bicarbonate (1.16kg, 13.85mol, 1.2eq) into the reactor in sequence, and adjust the temperature of the reactor to 0～ At 5°C, compound SM1-2 (1.9kg, 12.12mol, 1.05eq) was slowly added dropwise into the reactor, the temperature of the reactor was adjusted to 20-30°C, and stirred for 3 hours. Water (20 L) was added to the reaction kettle and stirred for 0.5 hours. Suction filtration under reduced pressure, the filter cake was washed with water (2 L) and then with tert-butyl methyl ether (5 L). The filter cake was dried under vacuum to give intermediate SM1 (2.5 kg) as a white solid. MS ESI calculated value C 19 H 19 NO 2 [M+H] + 294, found value 294; 1 H NMR (400MHz, CDCl 3 ) δppm 7.47-7.36(m,2H), 7.28-7.18(m,3H), 7.06 (s, 1H), 6.53 (br s, 1H), 2.93 (br t, J=7.0Hz, 8H), 2.13 (quin, J=7.40Hz, 4H).
实施例2：化合物SM2的合成Embodiment 2: the synthesis of compound SM2
Figure PCTCN2022134644-appb-000022
Figure PCTCN2022134644-appb-000022
步骤1：化合物SM2-3的合成Step 1: Synthesis of compound SM2-3
在室温下，将DMF(100L)，化合物SM2-1(50kg，304.83mol，27.47L，1.0eq)，化合物SM2-2(60.46kg，335.32mol，1.1eq)和碳酸钾(84.26kg，609.67mol，2.0eq)加入500L反应釜，在室温下搅拌8小时，搅拌过程中自然升温，继续保持外温90℃搅拌10小时。停止搅拌静置，分离出上清液，下层浑浊相加250L水溶解，水相用二氯甲烷(60L，30L)萃取两次，合并有机相后减压浓缩。剩余物与上清液合并后加入500L反应釜，降温至5℃，分批加入NBS(65.11kg，365.80mol，1.2eq)，维持内温不超过40℃，保持内温30℃搅拌2小时。降温至5℃，缓慢滴加碳酸氢钠水溶液(15kg碳酸氢钠+200L水)，维持内温不超过25℃，加完后内温维持0～5℃搅拌8小时。减压过滤，滤饼用水冲洗2次。收集滤饼，即 得到化合物SM2-3，湿品直接用于下一步。MS ESI计算值C 14H 16BrNS 2[M+H；M+2+H] +342；344，实测值342；344。 At room temperature, DMF (100L), compound SM2-1 (50kg, 304.83mol, 27.47L, 1.0eq), compound SM2-2 (60.46kg, 335.32mol, 1.1eq) and potassium carbonate (84.26kg, 609.67mol , 2.0eq) was added into a 500L reactor, stirred at room temperature for 8 hours, the temperature rose naturally during the stirring process, and continued to keep the external temperature at 90°C for 10 hours. Stop stirring and let it stand, separate the supernatant, add 250L water to dissolve the turbid lower layer, extract the aqueous phase with dichloromethane (60L, 30L) twice, combine the organic phases and concentrate under reduced pressure. The residue and the supernatant were combined and added to a 500L reactor, cooled to 5°C, and NBS (65.11kg, 365.80mol, 1.2eq) was added in batches, keeping the internal temperature not exceeding 40°C and stirring for 2 hours at an internal temperature of 30°C. Cool down to 5°C, slowly add aqueous sodium bicarbonate solution (15kg sodium bicarbonate + 200L water) dropwise, keep the internal temperature not exceeding 25°C, keep the internal temperature at 0-5°C and stir for 8 hours after the addition. Filter under reduced pressure, and wash the filter cake with water twice. The filter cake was collected to obtain compound SM2-3, and the wet product was directly used in the next step. MS ESI calcd for C14H16BrNS2 [M+ H ; M+2+H] + 342; 344, found 342; 344 .
步骤2：化合物SM2-4的合成Step 2: Synthesis of compound SM2-4
在10℃下，将DCM(600L)，水(100L)，化合物SM2-3(104.35kg，304.83mol，1eq)，浓盐酸(12M，127.01L，5eq)加入2000L反应釜。开始滴加NaClO(1134.59kg，1.22kmol，937.68L，8％水溶液，4eq)，搅拌下持续6小时滴完。静置分液，有机相用水洗涤3次，每次500L。At 10°C, DCM (600L), water (100L), compound SM2-3 (104.35kg, 304.83mol, 1eq), concentrated hydrochloric acid (12M, 127.01L, 5eq) were added to a 2000L reactor. NaClO (1134.59kg, 1.22kmol, 937.68L, 8% aqueous solution, 4eq) was started to be added dropwise and continued to drop for 6 hours under stirring. Let stand to separate the liquid, and wash the organic phase with water 3 times, 500L each time.
将有机相加入1000L反应釜，降温至10℃，加入二苄胺(60.14kg，304.83mol，58.38L，1eq)和三乙胺(30.85kg，304.83mol，42.43L，1eq)，维持内温不超过25℃，反应液在25℃下搅拌1小时。有机相用水(300L)洗涤一次，有机相加入稀盐酸(30kg浓盐酸+300L水)搅拌，析出固体，减压过滤，滤饼用DCM洗涤，滤液静置分液，取有机相，有机相再用水(300L)洗涤一次。减压浓缩至干，加入乙醇(40L)再减压浓缩至干，剩余物转移到500L反应釜，在40℃下加入100L乙醇和300L石油醚，搅拌下缓慢降温至0-5℃，析出固体，在0～5℃继续搅拌6小时，减压过滤，滤饼用乙醇/石油醚(体积比1:4，100L)淋洗，滤饼于40℃下真空干燥12小时，即得到化合物SM2-4(40kg)。MS ESI计算值C 17H 15BrN 2O 2S 2[M+H；M+2+H] +423；425，实测值423；425。 Add the organic phase to a 1000L reactor, cool down to 10°C, add dibenzylamine (60.14kg, 304.83mol, 58.38L, 1eq) and triethylamine (30.85kg, 304.83mol, 42.43L, 1eq) to maintain the internal temperature Over 25°C, the reaction solution was stirred at 25°C for 1 hour. Wash the organic phase with water (300L) once, add dilute hydrochloric acid (30kg concentrated hydrochloric acid + 300L water) to the organic phase and stir to precipitate a solid, filter under reduced pressure, wash the filter cake with DCM, let the filtrate stand for liquid separation, take the organic phase, and re- Wash once with water (300 L). Concentrate to dryness under reduced pressure, add ethanol (40L) and concentrate to dryness under reduced pressure, transfer the residue to a 500L reactor, add 100L ethanol and 300L petroleum ether at 40°C, slowly cool down to 0-5°C while stirring, and precipitate a solid , continue stirring at 0-5°C for 6 hours, filter under reduced pressure, rinse the filter cake with ethanol/petroleum ether (volume ratio 1:4, 100L), and vacuum-dry the filter cake at 40°C for 12 hours to obtain compound SM2- 4 (40kg). MS ESI calcd for C17H15BrN2O2S2 [ M + H ; M+2+ H ] + 423; 425, found 423; 425.
步骤3：化合物SM2-6的合成Step 3: Synthesis of compound SM2-6
在室温下，将甲苯(400L)加入500L反应釜，氮气鼓泡0.5小时，将化合物SM2-4(35kg，82.67mol，1eq)，化合物SM2-5(10kg，107.36mol，1.30eq)，碳酸铯(53.87kg，165.35mol，2eq)，Xantphos(2.39kg，4.13mol，0.05eq)，Pd 2(dba) 3(1.89kg，2.07mol，0.025eq)加入反应釜，氮气保护下109℃回流15小时。降温至50℃，加入食盐水(54kg氯化钠+200L水)，搅拌后过滤，滤液静置分液，取有机相，水相用100L乙酸乙酯萃取，取有机相。有机相合并后减压浓缩。 At room temperature, toluene (400L) was added to a 500L reactor, and nitrogen gas was bubbled for 0.5 hours. (53.87kg, 165.35mol, 2eq), Xantphos (2.39kg, 4.13mol, 0.05eq), Pd 2 (dba) 3 (1.89kg, 2.07mol, 0.025eq) were added to the reactor, and refluxed at 109°C for 15 hours under nitrogen protection . Cool down to 50°C, add saline solution (54kg sodium chloride + 200L water), stir and filter, leave the filtrate to separate liquids, take the organic phase, extract the water phase with 100L ethyl acetate, and take the organic phase. The combined organic phases were concentrated under reduced pressure.
将剩余物加入500L反应釜，降温至5℃，加入DCM(200L)，分批缓慢加入浓H 2SO 4(140kg，1.43kmol，76.09L，17.27eq)，30℃下搅拌6小时。静置分液，分别收集DCM相和浓硫酸相。向1000L反应釜中加入400L水，降温至5℃，分批缓慢加入浓硫酸相，再加入DCM相，保持内温不超过30℃。滴加氨水(浓度约25％)调节水相pH为9～10，析出固体。0～5℃下搅拌9小时，减压过滤，滤饼用水冲洗2次，滤饼于50℃下真空干燥12小时，即得到化合物SM2-6(16kg)。MS ESI计算值C 5H 9N 3O 3S 3[M+H] +256，实测值256。 1H NMR(400MHz,DMSO-d6)δppm 7.82(s,2H),7.23(s,1H),3.37-3.34(m,6H)。 The residue was added to a 500L reactor, cooled to 5°C, DCM (200L) was added, concentrated H 2 SO 4 (140kg, 1.43kmol, 76.09L, 17.27eq) was slowly added in batches, and stirred at 30°C for 6 hours. Set aside for liquid separation, and collect the DCM phase and the concentrated sulfuric acid phase respectively. Add 400L of water into the 1000L reactor, cool down to 5°C, slowly add the concentrated sulfuric acid phase in batches, and then add the DCM phase, keeping the internal temperature not exceeding 30°C. Aqueous ammonia (concentration about 25%) was added dropwise to adjust the pH of the aqueous phase to 9-10, and solids were precipitated. Stir at 0-5°C for 9 hours, filter under reduced pressure, wash the filter cake twice with water, and vacuum-dry the filter cake at 50°C for 12 hours to obtain compound SM2-6 (16kg). MS ESI calcd . for C5H9N3O3S3 [M+H] +256 , found 256 . 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (s, 2H), 7.23 (s, 1H), 3.37-3.34 (m, 6H).
步骤4：化合物SM2的合成Step 4: Synthesis of compound SM2
将二氯甲烷(20L)、化合物SM2-6(3.5kg，13.72mol，1.0eq)和三乙胺(4.16kg，41.16mol，3.0eq)依次加入反应釜A，开始搅拌，调节反应釜A温度至5～10℃，将叔丁基二甲基硅基三氟甲基磺酸酯(3.99kg，15.09mol，1.1eq)加入反应釜A，20～30℃下搅拌1小时。Add dichloromethane (20L), compound SM2-6 (3.5kg, 13.72mol, 1.0eq) and triethylamine (4.16kg, 41.16mol, 3.0eq) into reactor A in sequence, start stirring, and adjust the temperature of reactor A To 5-10°C, add tert-butyldimethylsilyl trifluoromethanesulfonate (3.99kg, 15.09mol, 1.1eq) into reaction kettle A, and stir at 20-30°C for 1 hour.
将二氯甲烷(50L)、三苯基膦(4.86kg，18.52mol，1.35eq)和六氯乙烷(4.87kg，20.58mol，1.5eq) 依次加入反应釜B中，开始搅拌，调节反应釜B温度至35～40℃，搅拌0.5小时。调节反应釜B温度至20～30℃，向反应釜B中加入三乙胺(4.16kg，41.16mol，3.0eq)，搅拌0.5小时。调节反应釜温度至0～10℃，将反应釜A的反应液加入到反应釜B中，温度控制在0～10℃。加料完毕后，继续搅拌0.5小时。向反应釜B中加入化合物SM2-7(2.28kg，15.09mol，1.1eq)，搅拌1小时。Add dichloromethane (50L), triphenylphosphine (4.86kg, 18.52mol, 1.35eq) and hexachloroethane (4.87kg, 20.58mol, 1.5eq) into reactor B in sequence, start stirring, and adjust the reactor B temperature to 35 ~ 40 ℃, stirring for 0.5 hours. Adjust the temperature of the reactor B to 20-30° C., add triethylamine (4.16 kg, 41.16 mol, 3.0 eq) into the reactor B, and stir for 0.5 hours. Adjust the temperature of the reaction kettle to 0-10°C, add the reaction liquid in the reaction kettle A to the reaction kettle B, and control the temperature at 0-10°C. After the addition was complete, stirring was continued for 0.5 hours. Compound SM2-7 (2.28kg, 15.09mol, 1.1eq) was added to Reactor B and stirred for 1 hour.
向反应釜B中加入水(18L)，再加浓盐酸调节pH至5～6，搅拌1小时。Water (18 L) was added to reaction kettle B, and concentrated hydrochloric acid was added to adjust the pH to 5-6, and stirred for 1 hour.
再向反应釜B中加入6M氢氧化钠水溶液调节pH至11～13，静置分液，分别收集有机相和水相，有机相用2M氢氧化钠水溶液(10L*2)萃取(水相pH值应为11～13)。合并所有分液的水相，用二氯甲烷(15L)洗涤，丢弃有机相，水相用浓盐酸调节pH至6～7后用二氯甲烷(30L*2)萃取。合并有机相，减压浓缩至约5L悬浊液，加入叔丁基甲基醚(5L)，于25～30℃下，打浆搅拌1小时，过滤，滤饼用叔丁基甲基醚(1L)洗涤，滤饼于40℃下真空干燥12小时，即得到化合物SM2(3.1kg)。MS ESI计算值C 14H 20N 4O 3S 3[M+H] +389，实测值389。 Then add 6M aqueous sodium hydroxide solution to the reaction kettle B to adjust the pH to 11-13, let stand to separate the liquids, collect the organic phase and the aqueous phase respectively, and extract the organic phase with 2M aqueous sodium hydroxide solution (10L*2) (the pH of the aqueous phase The value should be 11~13). All the separated aqueous phases were combined, washed with dichloromethane (15L), and the organic phase was discarded. The aqueous phase was adjusted to pH 6-7 with concentrated hydrochloric acid and extracted with dichloromethane (30L*2). Combine the organic phases, concentrate under reduced pressure to about 5 L of suspension, add tert-butyl methyl ether (5 L), beat and stir for 1 hour at 25-30 ° C, filter, wash the filter cake with tert-butyl methyl ether (1 L), filter The cake was vacuum-dried at 40° C. for 12 hours to obtain compound SM2 (3.1 kg). MS ESI calcd. for C14H20N4O3S3 [ M+H]+ 389 , found 389 .
实施例3：式(I)化合物的合成Embodiment 3: the synthesis of formula (I) compound
Figure PCTCN2022134644-appb-000023
Figure PCTCN2022134644-appb-000023
步骤1：化合物1-1的合成Step 1: Synthesis of compound 1-1
将乙腈(24L)、化合物SM2(3kg，7.72mol，1.0eq)、化合物SM1(2.49kg，8.49mol，1.1eq)和碳酸铯(5.03kg，15.44mol，2.0eq)依次加入反应釜，调节反应釜温度至35～45℃，搅拌4小时。Acetonitrile (24L), compound SM2 (3kg, 7.72mol, 1.0eq), compound SM1 (2.49kg, 8.49mol, 1.1eq) and cesium carbonate (5.03kg, 15.44mol, 2.0eq) were added to the reactor in sequence to adjust the reaction The temperature of the kettle was raised to 35-45°C, and stirred for 4 hours.
向反应釜中加入水(50L)，搅拌1小时。减压抽滤，滤饼用水(5L)洗涤。滤饼于40℃下真空干燥24小时。Water (50 L) was added to the reaction kettle and stirred for 1 hour. Suction filtration under reduced pressure, and the filter cake was washed with water (5 L). The filter cake was dried under vacuum at 40°C for 24 hours.
依次将滤饼、乙腈(17L)加入到反应釜中，调节反应釜温度至55～65℃，搅拌1小时。减压抽滤，滤饼用乙腈(0.5L)洗涤。依次将滤饼、乙腈(14L)加入到反应釜中，调节反应釜温度至55～65℃，搅拌1小时。减压抽滤，滤饼用乙腈(0.5L)洗涤。依次将滤饼、乙腈(11L)加入到反应釜中，调节反应釜温度至55～65℃，搅拌1小时。减压抽滤，滤饼用乙腈(0.5L)洗涤。滤饼于40℃下真空干燥12小时，即得到化合物1-1(1.05kg)。MS ESI计算值C 27H 33N 5O 4S 3[M+H] +588，实测值588。 The filter cake and acetonitrile (17 L) were successively added into the reactor, the temperature of the reactor was adjusted to 55-65° C., and stirred for 1 hour. Suction filtration under reduced pressure, and the filter cake was washed with acetonitrile (0.5 L). The filter cake and acetonitrile (14 L) were successively added into the reactor, the temperature of the reactor was adjusted to 55-65° C., and stirred for 1 hour. Suction filtration under reduced pressure, and the filter cake was washed with acetonitrile (0.5 L). The filter cake and acetonitrile (11 L) were successively added into the reaction kettle, the temperature of the reaction kettle was adjusted to 55-65° C., and stirred for 1 hour. Suction filtration under reduced pressure, and the filter cake was washed with acetonitrile (0.5 L). The filter cake was vacuum-dried at 40° C. for 12 hours to obtain compound 1-1 (1.05 kg). MS ESI calcd. for C27H33N5O4S3 [ M+H] +588 , found 588 .
步骤2：式(I)化合物的合成Step 2: Synthesis of the compound of formula (I)
将二氯甲烷20L、化合物1-1(1kg，1.7mol，1.0eq)依次加入反应釜，调节反应釜温度至0～5℃，将1.0mol/L三氯化硼的二氯甲烷溶液(5.10L，5.1mol，3.0eq)缓慢滴加到反应釜，于0～5℃下搅拌1小时。将反应液缓慢加入到搅拌的碳酸钾(2.11kg)的冰水溶液(40L)和四氢呋喃(20L)中淬灭，静置分液， 有机相用水(40L*2)洗涤，用无水硫酸钠(2kg)干燥，垫硅胶(300g，100-200目)助滤，减压抽滤，滤液在外温40℃下减压浓缩至约1.5L悬浊液。向悬浊液中加入乙腈(1.5L)，于20～30℃下搅拌打浆15分钟，过滤，滤饼用乙腈(300mL)洗涤。滤饼于40℃下真空干燥12小时，即得到式(I)化合物(500g)。MS ESI计算值C 18H 23N 5O 3S 3[M+H] +454，实测值454。 1H NMR(400MHz,DMSO-d 6)δppm 8.42(brs,1H),7.73(brs,2H),7.23(s,1H),6.87(s,1H),3.35(brs,6H),2.78(brt,J＝7.0Hz,4H),2.68(brs,4H),1.93(brt,J＝7.3Hz,4H)。 Add 20L of dichloromethane and compound 1-1 (1kg, 1.7mol, 1.0eq) into the reaction kettle in turn, adjust the temperature of the reaction kettle to 0-5°C, add 1.0mol/L boron trichloride in dichloromethane solution (5.10 L, 5.1mol, 3.0eq) was slowly added dropwise to the reaction kettle, and stirred at 0-5°C for 1 hour. The reaction solution was slowly added to a stirred ice solution (40L) of potassium carbonate (2.11kg) and tetrahydrofuran (20L) to quench, and left to separate the layers. The organic phase was washed with water (40L*2), washed with anhydrous sodium sulfate ( 2kg) to dry, pad silica gel (300g, 100-200 mesh) to aid in filtration, vacuum filtration under reduced pressure, and the filtrate was concentrated under reduced pressure at an external temperature of 40°C to about 1.5L suspension. Add acetonitrile (1.5L) to the suspension, stir and beat at 20-30°C for 15 minutes, filter, and wash the filter cake with acetonitrile (300mL). The filter cake was vacuum-dried at 40° C. for 12 hours to obtain the compound of formula (I) (500 g). MS ESI calcd. for C18H23N5O3S3 [ M+H]+ 454 , found 454 . 1 H NMR (400MHz,DMSO-d 6 )δppm 8.42(brs,1H),7.73(brs,2H),7.23(s,1H),6.87(s,1H),3.35(brs,6H),2.78(brt , J=7.0Hz, 4H), 2.68 (brs, 4H), 1.93 (brt, J=7.3Hz, 4H).
生物测试数据biological test data
实验例1：利用THP-1细胞检测NLRP3拮抗剂的IC 50实验 Experimental example 1: IC 50 experiment of detecting NLRP3 antagonists using THP-1 cells
1.实验原理：本实验利用人源的单核细胞系THP1，来研究NLRP3拮抗剂对细胞IL-1β分泌的抑制活性(IC 50)。利用PMA(巴豆醇-12-十四烷酸酯-13-乙酸酯)分化单核细胞系THP1变成成熟的巨噬细胞，然后利用Toll样受体TLR4的激动剂LPS(脂多糖)来对细胞进行刺激，激活炎症小体NLRP3的转录活性，以及IL-1β前体pro-IL-1β的表达。在此时，加入NLRP3的拮抗剂，然后再加入ATP来使得NLRP3进一步成熟和活化，并激活下游的caspase-1。活化的caspase-1可以对pro-IL-1β进行酶切加工成为可被分泌的成熟IL-1β。NLRP3拮抗剂可以有效抑制ATP诱导的NLRP3的成熟和活化，以及下游caspase-1的活化，从而抑制IL-1β的成熟和分泌。 1. Experimental principle: In this experiment, the human monocyte cell line THP1 was used to study the inhibitory activity (IC 50 ) of NLRP3 antagonists on the secretion of IL-1β. Using PMA (crotyl alcohol-12-myristate-13-acetate) to differentiate monocyte cell line THP1 into mature macrophages, and then using LPS (lipopolysaccharide), an agonist of Toll-like receptor TLR4, to Stimulation of the cells activates the transcriptional activity of the inflammasome NLRP3 and the expression of pro-IL-1β, the precursor of IL-1β. At this time, an antagonist of NLRP3 was added, followed by ATP to further mature and activate NLRP3 and activate downstream caspase-1. Activated caspase-1 can enzymatically process pro-IL-1β into mature IL-1β that can be secreted. NLRP3 antagonists can effectively inhibit the ATP-induced maturation and activation of NLRP3, as well as the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1β.
2.实验材料：2. Experimental materials:
2.1试剂：试剂信息见表1。2.1 Reagents: See Table 1 for reagent information.
表1试剂信息Table 1 Reagent information
名称name 供应商supplier 货号或编号Item number or serial number 储存条件Storage conditions
PMAPMA SigmaSigma 7934679346 -20℃-20°C
LPSLPS InvivoGenInvivoGen tlrl-eblpstlrl-eblps -20℃-20°C
ATPATP -- -- -20℃-20°C
1640培养基1640 Medium GibcoGibco 22400-08922400-089 4℃4°C
FBSFBS HyCloneHyClone SV30087.03SV30087.03 -80℃-80°C
青链霉素Penicillin HyCloneHyClone SV30010SV30010 4℃4°C
β-巯基乙醇β-mercaptoethanol SigmaSigma M3148M3148 室温room temperature
NEAA非必需氨基酸NEAA non-essential amino acids GibcoGibco 1140-0501140-050 4℃4°C
人可溶性蛋白试剂盒Human Soluble Protein Kit BDBD 558265558265 室温room temperature
Human IL-1βFlex SetHuman IL-1βFlex Set BDBD 558279558279 室温room temperature
名称name 供应商supplier 货号或编号Item number or serial number 储存条件Storage conditions
96孔平底板96-well flat bottom plate CorningCorning 35993599 室温room temperature
96孔U底板96-well U-bottom plate CorningCorning 37993799 室温room temperature
2.2仪器：流式细胞仪SRFortessa2.2 Instrument: flow cytometer SRFortessa
2.3实验步骤：2.3 Experimental steps:
(1)将THP1细胞的密度调整到5*10 5细胞/mL，然后加入PMA，并且将终浓度调整为100ng/mL，200μL/孔接种至96孔平底板，37℃、5％CO 2刺激过夜(尽量<16小时)。 (1) Adjust the density of THP1 cells to 5*10 5 cells/mL, then add PMA, and adjust the final concentration to 100 ng/mL, inoculate 200 μL/well into a 96-well flat-bottom plate, stimulate at 37°C, 5% CO 2 Overnight (<16 hours if possible).
(2)第二天，将上清弃掉，然后小心用杜氏磷酸盐缓冲液清洗两次(200μL/次)。(2) The next day, the supernatant was discarded, and then carefully washed twice with Duchenne's phosphate buffered saline (200 μL/time).
(3)用LPS刺激细胞，LPS终浓度为：100ng/mL，200μL/孔加入96孔板，37℃、5％CO 2培养3h。 (3) The cells were stimulated with LPS, the final concentration of LPS was 100ng/mL, 200 μL/well was added to a 96-well plate, and cultured at 37° C., 5% CO 2 for 3 hours.
(4)将测试化合物加入孔内，筛选浓度分别为：5μM、1μM、200nM、40nM、8nM、1.6nM、0.32nM、0.064nM。在37℃、5％CO 2培养箱内孵育1h。 (4) Add test compounds into the wells, and the screening concentrations are: 5 μM, 1 μM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM. Incubate for 1 h at 37°C in a 5% CO 2 incubator.
(5)每孔加入ATP，终浓度为5mM，37℃、5％CO 2培养过夜(>18小时)。 (5) Add ATP to each well with a final concentration of 5 mM, and culture overnight (>18 hours) at 37° C. and 5% CO 2 .
(6)第三天，取出上清5μL，稀释10倍，并利用CBA检测上清中IL-1β的含量。(6) On the third day, 5 μL of the supernatant was taken out, diluted 10 times, and the content of IL-1β in the supernatant was detected by CBA.
3.实验结果：3. Experimental results:
化合物活性结果见表2。The activity results of the compounds are shown in Table 2.
表2化合物NLRP3拮抗剂抑制活性结果Table 2 Compound NLRP3 antagonist inhibitory activity results
化合物compound THP-1细胞IL-1β抑制活性IC 50(nM) IC 50 (nM) of THP-1 cell IL-1β inhibitory activity
式(I)化合物Compound of formula (I) 9.89.8
实验结论：本发明化合物展示了良好的NLRP3抑制活性。Experimental conclusion: the compound of the present invention exhibits good NLRP3 inhibitory activity.
实验例2：化合物药代动力学评价Experimental Example 2: Pharmacokinetic Evaluation of Compounds
实验材料：C57BL/6J小鼠(雄性，6-8周龄)Experimental material: C57BL/6J mice (male, 6-8 weeks old)
实验操作：将试验化合物溶解后得到的澄清溶液分别经尾静脉注射和灌胃(溶媒为10％DMSO/10％solutol/80％水)给予雌性C57BL/6J小鼠体内(过夜禁食，6-8周龄)。给予受试化合物后，静脉注射组(IV)在0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组(PO)在0.25，0.5，1，2，4，6，8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。各参数含义：T 1/2：半衰期，C max：达峰浓度，AUC 0-inf：从0时间到外推至无穷大时的血浆浓度-时间曲线下面积，AUC 0-last：从0时间到最后能检测到药物浓度时的血浆浓度‐时间曲线下面积，F：生物利用度，Vd：表观分布容积，Cl：清除率，T max：达峰时间。测试结果如表3所示： Experimental operation: the clear solution obtained after dissolving the test compound was administered to female C57BL/6J mice via tail vein injection and intragastric administration (vehicle: 10% DMSO/10% solutol/80% water) (overnight fasting, 6- 8 weeks old). After giving the test compound, the intravenous injection group (IV) was treated at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours; and 24 hours, blood was collected from the mandibular vein and centrifuged to obtain plasma. The blood drug concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version6.3 pharmacokinetic software. The meaning of each parameter: T 1/2 : half-life, C max : peak concentration, AUC 0-inf : area under the plasma concentration-time curve from time 0 to extrapolation to infinity, AUC 0-last : time from 0 to The area under the plasma concentration-time curve when the drug concentration can be finally detected, F: bioavailability, Vd: apparent volume of distribution, Cl: clearance rate, T max : peak time. The test results are shown in Table 3:
表3式(I)化合物的药代动力学测试结果The pharmacokinetic test result of table 3 formula (I) compound
Figure PCTCN2022134644-appb-000024
Figure PCTCN2022134644-appb-000024
结论：本发明的化合物具良好的口服生物利用度，较高的暴露量，体内药效性质良好。Conclusion: The compound of the present invention has good oral bioavailability, high exposure, and good pharmacodynamic properties in vivo.
实验例3化合物对MSU诱导的C57BL/6小鼠气囊急性痛风模型的治疗效果评价Evaluation of the therapeutic effect of the compound of Experimental Example 3 on the acute gout model of C57BL/6 mouse air pouch induced by MSU
鼠气囊(Air Pouch)是类似于人滑膜的囊状空间，将尿酸单钠晶体(MSU)注入气囊会引起类似于人类痛风的急性炎症反应。通过对气囊冲洗液(APLV)中的炎性细胞因子IL-6和IL-1β分析，以MCC950为参照化合物，测试本发明化合物在雄性C57BL/6小鼠的MSU诱导的气囊痛风模型中的功效。The mouse air sac (Air Pouch) is a sac-like space similar to the human synovium, and injecting monosodium urate crystals (MSU) into the air sac can cause an acute inflammatory response similar to human gout. By analyzing the inflammatory cytokines IL-6 and IL-1β in the air sac flushing fluid (APLV), using MCC950 as a reference compound, the efficacy of the compound of the present invention in the MSU-induced air sac gout model of male C57BL/6 mice was tested .
1、实验目的：小鼠Air Pouch痛风模型评价本发明化合物的治疗急性痛风的效果。1. Experimental purpose: Mouse Air Pouch gout model evaluates the effect of the compound of the present invention in treating acute gout.
2、实验动物：C57BL/6小鼠,雄性，7-8周龄，北京维通利华实验动物技术有限公司。2. Experimental animals: C57BL/6 mice, male, 7-8 weeks old, Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
3、实验设计：3. Experimental design:
实验用健康小鼠进行编号和分组，当天(Day1)和第4天(Day4)向小鼠背部注射无菌空气产生气囊。在第7天，先给药，1小时后将MSU晶体溶液注入气囊中，7小时后收集气囊冲洗液(APLV)并进行分析。分组及给药方案如表4所示。Healthy mice were used for numbering and grouping in the experiment, and sterile air was injected into the back of the mice on the day (Day1) and day 4 (Day4) to generate air sacs. On day 7, the drug was given first, the MSU crystalloid solution was infused into the air pouch 1 h later, and the air pouch flushing fluid (APLV) was collected 7 h later and analyzed. The grouping and dosing regimen are shown in Table 4.
表4分组及给药方案Table 4 Grouping and dosing regimen
组别group 动物数number of animals 免疫原immunogen 受试药品Test drug 给药剂量和途径Dosage and route of administration 溶媒solvent
11 55 无none NavieNavie -- --
22 88 MSU(3mg)MSU (3mg) VehicleVehicle -- --
33 88 MSU(3mg)MSU (3mg) MCC950MCC950 50mg/kg；po50mg/kg; po 10％DMSO/10％solutol/80％水10%DMSO/10%solutol/80%water
44 88 MSU(3mg)MSU (3mg) 式(I)化合物Compound of formula (I) 50mg/kg；po50mg/kg; po 10％DMSO/10％solutol/80％水10%DMSO/10%solutol/80%water
55 88 MSU(3mg)MSU (3mg) 式(I)化合物Compound of formula (I) 15mg/kg；po,15mg/kg; po, 10％DMSO/10％solutol/80％水10%DMSO/10%solutol/80%water
66 88 MSU(3mg)MSU (3mg) 式(I)化合物Compound of formula (I) 5mg/kg；po5 mg/kg; po 10％DMSO/10％solutol/80％水10%DMSO/10%solutol/80%water
77 88 MSU(3mg)MSU (3mg) Dex.Dex. 10mg/kg；ip10mg/kg; ip 生理盐水normal saline
注：Navie：健康对照组；Vehicle：溶媒对照组；MCC950：参比化合物；Dex.：地塞米松；po：口服给药；ip：腹腔注射给药；Note: Navie: healthy control group; Vehicle: vehicle control group; MCC950: reference compound; Dex.: dexamethasone; po: oral administration; ip: intraperitoneal injection;
4、实验方法与步骤：4. Experimental method and steps:
(1)MSU制备(1) Preparation of MSU
将1g尿酸溶解在0.2升含有6mL 1N氢氧化钠的沸水中，将pH值调节至7.4后，将溶液在室温下逐渐冷却，然后在4℃下放置过夜。通过离心回收MSU晶体，并通过蒸发干燥进行干燥，分配到单个小瓶中(3mg)，并通过高压灭菌进行灭菌。Dissolve 1 g of uric acid in 0.2 L of boiling water containing 6 mL of 1N sodium hydroxide, and after adjusting the pH to 7.4, the solution was gradually cooled at room temperature and then left overnight at 4 °C. MSU crystals were recovered by centrifugation, dried by evaporative drying, dispensed into individual vials (3 mg), and sterilized by autoclaving.
(2)分组和给药以及IL-6和IL-1β检测(2) Grouping and administration and detection of IL-6 and IL-1β
实验用健康C57BL/6小鼠进行编号和分组，分组当天(Day1)和第四天(Day4)通过向小鼠的背部皮下注射5mL无菌空气，产生一个气囊。在第七天(Day7)，分别给予分组小鼠溶媒或者受试物，1小时后，将MSU晶体的悬浮液(盐水，3mg/mL)注入气囊中。6小时后，将收集气囊冲洗液(APLV)，使用ELISA试剂盒测试APLV中IL-6和IL-1β的水平。结果表示为平均值±SEM。统计分析是使用方差分析(ANOVA)的一种方法进行的，随后进行了Dunnett检验，当p＜0.05时，差异被认为是显着的。Healthy C57BL/6 mice were used for numbering and grouping in the experiment. On the day of grouping (Day1) and the fourth day (Day4), 5 mL of sterile air was subcutaneously injected into the back of the mice to generate an air pouch. On the seventh day (Day7), the mice in each group were given the vehicle or the test substance, and 1 hour later, the suspension of MSU crystals (saline, 3 mg/mL) was injected into the air bag. After 6 hours, air pouch flushing fluid (APLV) will be collected, and the levels of IL-6 and IL-1β in APLV will be tested using ELISA kits. Results are expressed as mean ± SEM. Statistical analysis was performed using a method of analysis of variance (ANOVA) followed by Dunnett's test and differences were considered significant when p<0.05.
5、试验结果5. Test results
与健康对照组相比，MSU注射使得小鼠气囊中产生急性炎症反应，表现为APLV中的炎性细胞因子IL-6和IL-1β浓度显著升高。给予化合物MCC950、式(I)化合物和地塞米松治疗后，APLV中的IL-6水平和IL-1β水平迅速降低。其中，式(I)化合物在高、中和低三个剂量下对IL-6的降低效果都优于地塞米松(10mg/kg剂量)，在15mg/kg和50mg/kg给药剂量下对IL-6的降低效果都优于MCC950(50mg/kg剂量)。式(I)化合物对IL-1β的降低效果显著，在15mg/kg和50mg/kg给药剂量下对IL-1β的降低效果都显著优于MCC950(50mg/kg剂量)，IL-1β水平极低，达到地塞米松(10mg/kg)同等效果。APLV中的炎性细胞因子IL-6的抑制实验结果见附图1，APLV中的炎性细胞因子IL-1β的抑制实验结果见附图2，p表示显著性差异，*：p<0.05；**：p<0.01；***p<0.001。Compared with healthy controls, MSU injection induced an acute inflammatory response in the air pouch of mice, manifested by significantly increased concentrations of inflammatory cytokines IL-6 and IL-1β in APLV. After treatment with compound MCC950, compound of formula (I) and dexamethasone, the levels of IL-6 and IL-1β in APLV decreased rapidly. Wherein, formula (I) compound is all better than dexamethasone (10mg/kg dosage) to the reducing effect of IL-6 under high, middle and low three dosages, under 15mg/kg and 50mg/kg administration dosage to The reduction effect of IL-6 is better than that of MCC950 (50mg/kg dose). The reducing effect of the compound of formula (I) on IL-1β is remarkable, and the reducing effect on IL-1β under the dosage of 15mg/kg and 50mg/kg is all significantly better than MCC950 (50mg/kg dose), and the level of IL-1β is extremely Low, reaching the same effect as dexamethasone (10mg/kg). The results of the inhibition test of the inflammatory cytokine IL-6 in APLV are shown in Figure 1, and the results of the inhibition test of the inflammatory cytokine IL-1β in APLV are shown in Figure 2, p means significant difference, *: p<0.05; **: p<0.01; ***p<0.001.
结论：本发明化合物对MSU诱导的C57BL/6小鼠Air Pouch痛风模型有较好的治疗效果，具有治疗痛风等其他与炎性细胞因子相关疾病的潜力。Conclusion: The compound of the present invention has a good therapeutic effect on the MSU-induced C57BL/6 mouse Air Pouch gout model, and has the potential to treat gout and other diseases related to inflammatory cytokines.

Claims (17)

  1. 式(Ⅰ)化合物的制备方法，The preparation method of formula (I) compound,
    Figure PCTCN2022134644-appb-100001
    Figure PCTCN2022134644-appb-100001
    其包含如下步骤：It includes the following steps:
    Figure PCTCN2022134644-appb-100002
    Figure PCTCN2022134644-appb-100002
    其中，in,
    R 1选自H和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个F取代； R 1 is selected from H and C 1-3 alkoxy, said C 1-3 alkoxy is optionally substituted by 1, 2 or 3 F;
    R 2选自OH、C 1-3烷基和-C 1-3烷基-OH，所述C 1-3烷基和-C 1-3烷基-OH分别独立地任选被1、2或3个F取代； R 2 is selected from OH, C 1-3 alkyl and -C 1-3 alkyl-OH, said C 1-3 alkyl and -C 1-3 alkyl-OH are independently optionally replaced by 1, 2 or 3 F replacements;
    n选自1、2和3。n is selected from 1, 2 and 3.
  2. 根据权利要求1所述的制备方法，其中，所述化合物1-1-A的合成包含如下步骤：The preparation method according to claim 1, wherein the synthesis of the compound 1-1-A comprises the following steps:
    Figure PCTCN2022134644-appb-100003
    Figure PCTCN2022134644-appb-100003
    其中，in,
    R 3选自-N＝C＝O和
    Figure PCTCN2022134644-appb-100004
    R 3 is selected from -N=C=O and
    Figure PCTCN2022134644-appb-100004
    R选自H、OCH 3和NO 2； R is selected from H, OCH3 and NO2 ;
    n、R 1和R 2如权利要求1所定义。 n, R1 and R2 are as defined in claim 1.
  3. 根据权利要求1或2所述的制备方法，其中，所述式(I)化合物的制备方法其包含如下步骤：The preparation method according to claim 1 or 2, wherein, the preparation method of the compound of formula (I) comprises the following steps:
    Figure PCTCN2022134644-appb-100005
    Figure PCTCN2022134644-appb-100005
    其中，in,
    碱B-6选自碳酸钾、碳酸钠、碳酸铯、钠氢、LiHMDS、NaHMDS和KHMDS；Base B-6 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen, LiHMDS, NaHMDS and KHMDS;
    试剂R-5选自三氯化硼、三溴化硼、三氟化硼、三氟乙酸、盐酸、氢溴酸、硫酸、Pd/C、Raney Ni、PtO 2、Pd(OH) 2和CAN。 Reagent R-5 is selected from boron trichloride, boron tribromide, boron trifluoride, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, Pd/C, Raney Ni, PtO 2 , Pd(OH) 2 and CAN .
  4. 根据权利要求3所述的制备方法，其中，碱B-6选自碳酸铯，试剂R-5选自三氯化硼，化合物SM1与化合物SM2的当量比为1.0～1.5，试剂R-5与化合物1-1的当量比为2.0～4.0。The preparation method according to claim 3, wherein, base B-6 is selected from cesium carbonate, reagent R-5 is selected from boron trichloride, the equivalent ratio of compound SM1 to compound SM2 is 1.0 to 1.5, and reagent R-5 and The equivalent ratio of compound 1-1 is 2.0-4.0.
  5. 根据权利要求4所述的方法，其中，化合物SM1与化合物SM2的当量比为1.1，试剂R-5与化合物1-1的当量比为3.0。The method according to claim 4, wherein the equivalent ratio of compound SM1 to compound SM2 is 1.1, and the equivalent ratio of reagent R-5 to compound 1-1 is 3.0.
  6. 化合物SM2-A的制备方法，The preparation method of compound SM2-A,
    Figure PCTCN2022134644-appb-100006
    Figure PCTCN2022134644-appb-100006
    其包含如下步骤：It includes the following steps:
    Figure PCTCN2022134644-appb-100007
    Figure PCTCN2022134644-appb-100007
    其中，in,
    R 1选自H和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个F取代； R 1 is selected from H and C 1-3 alkoxy, said C 1-3 alkoxy is optionally substituted by 1, 2 or 3 F;
    R 2选自OH、C 1-3烷基和-C 1-3烷基-OH，所述C 1-3烷基和-C 1-3烷基-OH分别独立地任选被1、2或3个F取代； R 2 is selected from OH, C 1-3 alkyl and -C 1-3 alkyl-OH, said C 1-3 alkyl and -C 1-3 alkyl-OH are independently optionally replaced by 1, 2 or 3 F replacements;
    n选自1、2和3。n is selected from 1, 2 and 3.
  7. 根据权利要求6所述的制备方法，其中，化合物SM2-7选自
    Figure PCTCN2022134644-appb-100008
    The preparation method according to claim 6, wherein, compound SM2-7 is selected from
    Figure PCTCN2022134644-appb-100008
  8. 根据权利要求7所述的制备方法，其中，化合物SM2-A选自化合物SM2，所述化合物SM2的合成包含如下步骤：The preparation method according to claim 7, wherein, compound SM2-A is selected from compound SM2, and the synthesis of said compound SM2 comprises the following steps:
    Figure PCTCN2022134644-appb-100009
    Figure PCTCN2022134644-appb-100009
    其中，in,
    R 4为氨基保护基，所述氨基保护基选自TBS、TMS、Boc、Trt和TBDPS； R 4 is an amino protecting group, and the amino protecting group is selected from TBS, TMS, Boc, Trt and TBDPS;
    酸A-2选自硫酸、盐酸和三氟乙酸；Acid A-2 is selected from sulfuric acid, hydrochloric acid and trifluoroacetic acid;
    酸A-3选自盐酸和四丁基氟化铵；Acid A-3 is selected from hydrochloric acid and tetrabutylammonium fluoride;
    碱B-3选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、磷酸钾、醋酸钾、醋酸钠和叔丁醇钠；Base B-3 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, potassium acetate, sodium acetate and sodium tert-butoxide;
    碱B-4选自钠氢、三乙胺、咪唑和二异丙基乙胺；Base B-4 is selected from sodium hydrogen, triethylamine, imidazole and diisopropylethylamine;
    碱B-5选自三乙胺和二异丙基乙胺；Base B-5 is selected from triethylamine and diisopropylethylamine;
    催化剂C-1选自Pd 2(dba) 3、Pd(OAc) 2、Pd(dppf)Cl 2和Pd(PPh 3) 4； Catalyst C-1 is selected from Pd 2 (dba) 3 , Pd(OAc) 2 , Pd(dppf)Cl 2 and Pd(PPh 3 ) 4 ;
    配体L-1选自Xantphos、JohnPhos和dppf；Ligand L-1 is selected from Xantphos, JohnPhos and dppf;
    试剂R-3选自TBSOTf、TBSCl、TMSOTf、TMSCl、(Boc) 2O、TrtCl和TBDPSCl； Reagent R-3 is selected from TBSOTf, TBSCl, TMSOTf, TMSCl, (Boc) 2O , TrtCl and TBDPSCl;
    试剂R-4选自三苯基膦/六氯乙烷、三苯基膦/氯气和二氯三苯基膦。Reagent R-4 is selected from triphenylphosphine/hexachloroethane, triphenylphosphine/chlorine and dichlorotriphenylphosphine.
  9. 根据权利要求8所述的制备方法，其中，R 4选自TBS，酸A-2选自硫酸，酸A-3选自盐酸，碱B-3选自碳酸铯，碱B-4选自三乙胺，碱B-5选自三乙胺，催化剂C-1选自Pd 2(dba) 3，配体L-1选自Xantphos，试剂R-3选自叔丁基二甲基硅基三氟甲基磺酸酯，试剂R-4选自三苯基膦/六氯乙烷，所述三苯基膦与化合物SM2-6的当量比为1.0～2.0，所述六氯乙烷与化合物SM2-6的当量比为1.0～2.0，化合物SM2-5与化合物SM2-4的当量比为1.0～2.0，催化剂C-1与化合物SM2-4的当量比为0.01～0.1，配体L-1与化合物SM2-4的当量比为0.02～0.2，酸A-2与化合物SM2-4的当量比为10～20，试剂R-3与化合物SM2-6的当量比为1.0～2.0，试剂R-4与化合物SM2-6的当量比为1.0～2.0，化合物SM2-7与化合物SM2-6的当量比为1.0～2.0。 The preparation method according to claim 8, wherein, R 4 is selected from TBS, acid A-2 is selected from sulfuric acid, acid A-3 is selected from hydrochloric acid, base B-3 is selected from cesium carbonate, and base B-4 is selected from three Ethylamine, base B-5 is selected from triethylamine, catalyst C-1 is selected from Pd 2 (dba) 3 , ligand L-1 is selected from Xantphos, reagent R-3 is selected from tert-butyldimethylsilyltri Fluoromethylsulfonate, reagent R-4 is selected from triphenylphosphine/hexachloroethane, the equivalent ratio of said triphenylphosphine to compound SM2-6 is 1.0 to 2.0, said hexachloroethane and compound The equivalent ratio of SM2-6 is 1.0-2.0, the equivalent ratio of compound SM2-5 and compound SM2-4 is 1.0-2.0, the equivalent ratio of catalyst C-1 and compound SM2-4 is 0.01-0.1, and the ligand L-1 The equivalent ratio of the compound SM2-4 to the compound SM2-4 is 0.02 to 0.2, the equivalent ratio of the acid A-2 to the compound SM2-4 is 10 to 20, the equivalent ratio of the reagent R-3 to the compound SM2-6 is 1.0 to 2.0, and the reagent R- The equivalent ratio of 4 to compound SM2-6 is 1.0-2.0, and the equivalent ratio of compound SM2-7 to compound SM2-6 is 1.0-2.0.
  10. 根据权利要求9所述的制备方法，其中，化合物SM2-5与化合物SM2-4的当量比为1.3，试剂R-3与化合物SM2-6的当量比为1.1，三苯基膦与化合物SM2-6的当量比为1.35，六氯乙烷与化合物SM2-6的当量比为1.5，化合物SM2-7与化合物SM2-6的当量比为1.1。The preparation method according to claim 9, wherein the equivalent ratio of compound SM2-5 to compound SM2-4 is 1.3, the equivalent ratio of reagent R-3 to compound SM2-6 is 1.1, triphenylphosphine and compound SM2- The equivalent ratio of 6 is 1.35, the equivalent ratio of hexachloroethane to compound SM2-6 is 1.5, and the equivalent ratio of compound SM2-7 to compound SM2-6 is 1.1.
  11. 根据权利要求8～10任意一项所述的制备方法，所述化合物SM2-4的合成包含如下步骤：According to the preparation method described in any one of claims 8-10, the synthesis of the compound SM2-4 comprises the following steps:
    Figure PCTCN2022134644-appb-100010
    Figure PCTCN2022134644-appb-100010
  12. 根据权利要求11所述的制备方法，所述化合物SM2-3的合成包含如下步骤：The preparation method according to claim 11, the synthesis of the compound SM2-3 comprises the following steps:
    Figure PCTCN2022134644-appb-100011
    Figure PCTCN2022134644-appb-100011
  13. 根据权利要求11或12所述的制备方法，其包含如下步骤：The preparation method according to claim 11 or 12, which comprises the steps of:
    Figure PCTCN2022134644-appb-100012
    Figure PCTCN2022134644-appb-100012
    其中，in,
    试剂R-1选自NBS和液溴；Reagent R-1 is selected from NBS and liquid bromine;
    试剂R-2选自次氯酸钠、氯气和二氯海因；Reagent R-2 is selected from sodium hypochlorite, chlorine and dichlorohydantoin;
    酸A-1选自盐酸和醋酸；Acid A-1 is selected from hydrochloric acid and acetic acid;
    碱B-1选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、磷酸钾、二异丙基乙胺、钠氢和甲醇钠；Base B-1 is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, diisopropylethylamine, sodium hydrogen and sodium methoxide;
    碱B-2选自三乙胺和二异丙基乙胺。Base B-2 is selected from triethylamine and diisopropylethylamine.
  14. 根据权利要求13所述的制备方法，其中，试剂R-1选自NBS，试剂R-2选自8％次氯酸钠水溶液，酸A-1选自盐酸，碱B-1选自碳酸钾，碱B-2选自三乙胺；酸A-1与化合物SM2-3的当量比为1.0～6.0，NaClO与化合物SM2-3的当量比为1.0～6.0，且NaClO的摩尔量小于酸A-1，NH(Bn) 2与化合物SM2-3的当量比为1.0～2.0。 The preparation method according to claim 13, wherein, reagent R-1 is selected from NBS, reagent R-2 is selected from 8% sodium hypochlorite aqueous solution, acid A-1 is selected from hydrochloric acid, base B-1 is selected from potassium carbonate, base B -2 is selected from triethylamine; the equivalent ratio of acid A-1 and compound SM2-3 is 1.0～6.0, the equivalent ratio of NaClO and compound SM2-3 is 1.0～6.0, and the molar weight of NaClO is less than acid A-1, The equivalent ratio of NH(Bn) 2 to compound SM2-3 is 1.0-2.0.
  15. 根据权利要求14所述的制备方法，其中，酸A-1与化合物SM2-3的当量比为5.0，NaClO与化合物SM2-3的当量比为4.0，NH(Bn) 2与化合物SM2-3的当量比为1.0。 The preparation method according to claim 14, wherein, the equivalent ratio of acid A-1 and compound SM2-3 is 5.0, the equivalent ratio of NaClO and compound SM2-3 is 4.0, NH(Bn) 2 and compound SM2-3 The equivalence ratio was 1.0.
  16. 根据权利要求13所述的制备方法，其中，碱B-1选自碳酸钾，化合物SM2-2与化合物SM2-1的当量比为1.0～1.5，试剂R-1选自NBS，NBS与化合物SM2-1的当量比为1.0～2.0。The preparation method according to claim 13, wherein the base B-1 is selected from potassium carbonate, the equivalent ratio of compound SM2-2 to compound SM2-1 is 1.0 to 1.5, and the reagent R-1 is selected from NBS, NBS and compound SM2 The equivalent ratio of -1 is 1.0 to 2.0.
  17. 根据权利要求16所述的制备方法，其中，化合物SM2-2与化合物SM2-1的当量比为1.1，NBS与化合物SM2-1的当量比为1.2。The preparation method according to claim 16, wherein the equivalent ratio of compound SM2-2 to compound SM2-1 is 1.1, and the equivalent ratio of NBS to compound SM2-1 is 1.2.
PCT/CN2022/134644 2021-12-03 2022-11-28 Method for preparing dimethyl sulfinyl imine derivative WO2023098613A1 (en)

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CN111094243A (en) * 2017-07-24 2020-05-01 诺华炎症研究公司 Compounds and compositions for treating conditions associated with NLRP activity
CN112654350A (en) * 2018-07-03 2021-04-13 诺华股份有限公司 Methods of treating a subject resistant to a TNF inhibitor or selecting a treatment for said subject using an NLRP3 antagonist
CN113286784A (en) * 2018-11-16 2021-08-20 诺华股份有限公司 Compounds and compositions for treating conditions associated with NLRP activity
WO2021249337A1 (en) * 2020-06-11 2021-12-16 南京明德新药研发有限公司 Dimethylsulfoximine derivative

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111094243A (en) * 2017-07-24 2020-05-01 诺华炎症研究公司 Compounds and compositions for treating conditions associated with NLRP activity
CN112654350A (en) * 2018-07-03 2021-04-13 诺华股份有限公司 Methods of treating a subject resistant to a TNF inhibitor or selecting a treatment for said subject using an NLRP3 antagonist
CN113286784A (en) * 2018-11-16 2021-08-20 诺华股份有限公司 Compounds and compositions for treating conditions associated with NLRP activity
WO2021249337A1 (en) * 2020-06-11 2021-12-16 南京明德新药研发有限公司 Dimethylsulfoximine derivative

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