WO2017162204A1 - Procédé de fabrication d'un analogue de benzofurane et d'une forme intermédiaire et cristalline de celui-ci - Google Patents

Procédé de fabrication d'un analogue de benzofurane et d'une forme intermédiaire et cristalline de celui-ci Download PDF

Info

Publication number
WO2017162204A1
WO2017162204A1 PCT/CN2017/078078 CN2017078078W WO2017162204A1 WO 2017162204 A1 WO2017162204 A1 WO 2017162204A1 CN 2017078078 W CN2017078078 W CN 2017078078W WO 2017162204 A1 WO2017162204 A1 WO 2017162204A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
solvent
ether
toluene
Prior art date
Application number
PCT/CN2017/078078
Other languages
English (en)
Chinese (zh)
Inventor
付志飞
张杨
陈曙辉
Original Assignee
常州寅盛药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 常州寅盛药业有限公司 filed Critical 常州寅盛药业有限公司
Publication of WO2017162204A1 publication Critical patent/WO2017162204A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to a process for the preparation of benzofuran analogs, as well as intermediates and crystal forms thereof.
  • HCV is one of the major human pathogens, with an estimated 170 million chronic HCV infections worldwide, five times the number of human immunodeficiency virus type 1 infections. People with chronic HCV infection develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Therefore, chronic HCV infection is the leading cause of death in patients worldwide due to liver disease.
  • HCV is a single-stranded positive-strand RNA virus. It belongs to the genus of the Flaviviridae family. All members of the Flaviviridae are enveloped virions containing a positive-stranded RNA genome that encodes all known virus-specific proteins by translation of a single uninterrupted open reading frame (ORF).
  • ORF open reading frame
  • the nucleotides of the HCV genome and the encoded amino acid sequence are quite heterogeneous. At least 6 major genotypes and more than 50 sub-genotypes have been identified. The main genotypes of HCV are distributed globally. Although a large number of genotypes have been studied for pathogenesis and therapeutic effects, the clinical importance of HCV genetic heterogeneity remains unclear.
  • the invention provides a preparation method of the compound 1,
  • R is selected from Me, Et,
  • B is selected from alkali TMPMgCl ⁇ LiCl, TMP 2 Mg ⁇ 2LiCl, i-PrMgCl, i-PrMgCl ⁇ LiCl, LDA, n-butyllithium;
  • the cyanation reagent is selected from the group consisting of TsCN,
  • the molar ratio of compound 8 to base B is selected from 1:1 to 3;
  • the molar ratio of the compound 8 to the cyanation reagent is selected from 1:1 to 3;
  • the solvent B is selected from a single ether solvent or a mixed solvent of an ether solvent and toluene.
  • the solvent B is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tert-butyl ether, isopropyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether.
  • the solvent B is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tert-butyl ether, isopropyl ether, methyl tert-butyl ether, a mixed solvent of ethylene glycol dimethyl ether and toluene.
  • the molar ratio of the above compound 8 to base B is selected from the group consisting of 1: 1.2 to 2.5.
  • the molar ratio of the above compound 8 to the cyanating agent is selected from the group consisting of 1:1.2 to 2.
  • the molar ratio of the above compound 8 to the cyanating agent is selected from the group consisting of 1:1.3 to 1.6.
  • the above compound 11 is prepared by the following steps,
  • X is selected from the group consisting of F, Cl, Br, and I.
  • the above preparation method further includes the following steps,
  • the condensing agent is selected from the group consisting of: HATU, HBTU, CDI, HOBT, EDCI, DCC, DIC, PyBOP, DPP-Cl;
  • the base A is selected from the group consisting of K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , NaOH, KOH, TEA, DIPEA, pyridine;
  • Solvent A is selected from the group consisting of: dichloromethane, acetonitrile, DMF;
  • compound 12 and compound 19 are reacted under catalyst catalysis, and the catalyst is selected from DMAP;
  • the molar ratio of the compound 12 to the condensing agent is selected from 1:1 to 3;
  • the molar ratio of compound 12 to compound 19 is selected from 1:1 to 1.5;
  • the reaction temperature is selected from 10 ° C to 40 ° C.
  • the above preparation method further comprises the following reaction steps,
  • the base C is selected from the group consisting of K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 ;
  • Solvent C is selected from the group consisting of DMF and CH 3 CN.
  • the above preparation method further comprises the following reaction steps,
  • the base D is selected from the group consisting of K 3 PO 4 , K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 ;
  • the solvent D is selected from the group consisting of THF, DMF, toluene, xylene, 1,4-dioxane, a single solvent of water or a mixed solvent of two solvents;
  • the catalyst is selected from the group consisting of Pd 2 (dba) 3 , Pd (dppf) Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 ;
  • the ligand is selected from the group consisting of no or PPh 3 , tricyclohexylphosphine, tributylphosphine.
  • the solvent D is selected from the group consisting of a mixed solvent of toluene and water, and the volume ratio of toluene to water is selected from 1 to 3:1.
  • the above preparation method further comprises the following reaction steps,
  • the base E is selected from the group consisting of LiOH, NaOH, KOH, Na 2 CO 3 , K 2 CO 3 ;
  • the solvent E is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, and acetonitrile.
  • the method includes the following reaction steps,
  • the invention also provides a compound of the formula: as an intermediate for the preparation of compound 1:
  • the present invention also provides Form A of Compound 1, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 10.58 ⁇ 0.2 °, 20.41 ⁇ 0.2 °, 21.98 ⁇ 0.2 °.
  • the X crystal form of the above Compound 1 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ angles: 5.34 ⁇ 0.2°, 10.58 ⁇ 0.2°, 12.70 ⁇ 0.2°, 20.41 ⁇ 0.2°. , 20.74 ⁇ 0.2 °, 21.16 ⁇ 0.2 °, 21.98 ⁇ 0.2 °, 24.55 ⁇ 0.2 °.
  • the X-form of Form A of Compound 1 above is shown in Figure 1.
  • the analytical data of the XRPD pattern of the A crystal form of the above compound 1 is shown in Table-1:
  • the A crystal form of the compound 1 described above has a differential scanning calorimetry curve having a starting point of an endothermic peak at 212.07 ° C ⁇ 3 ° C.
  • the A crystal form of the above compound 1 has a DSC pattern as shown in FIG.
  • the A crystal form of the above compound 1 has a thermogravimetric analysis curve having a weight loss of 0.3107 ⁇ 0.2% at 120.0 ⁇ 3° C., and a weight loss of 0.2094 ⁇ 0.2% at 232.5 ⁇ 3° C., 233.0 ⁇ 3° C. The weight loss was 0.3501 ⁇ 0.2%.
  • the T crystal of Form A of Compound 1 above is shown in Figure 3.
  • the invention also provides a preparation method of the crystal form A, which comprises adding any one form of the compound 1 to a solvent for recrystallization or beating, wherein the recrystallization solvent or the beating solvent is selected from the group consisting of methanol, ethanol and isopropanol. , dioxane, acetonitrile, tetrahydrofuran, acetone, toluene.
  • the preparation A crystal recrystallization or beating solvent is selected from the group consisting of methanol, ethanol, isopropanol, dioxane, acetonitrile, tetrahydrofuran, acetone, and a mixed solvent of water and water.
  • Another object of the present invention is to provide a use of Form A in the preparation of a medicament for the treatment of a disease associated with HCV.
  • intermediate 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, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • TMPMgCl ⁇ LiCl represents lithium dichloride (2,2,6,6-tetramethylpiperidine);
  • TMP 2 Mg ⁇ 2LiCl represents two (2,2',6,6' - tetramethylpiperidine) magnesium dichloride;
  • DPP-Cl represents diphenylphosphoryl chloride;
  • i-PrMgCl represents isopropyl magnesium chloride;
  • LDA represents lithium diisopropylamide;
  • TsCN represents 4-toluenesulfonyl nitrile;
  • HATU stands for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;
  • HBTU stands for benzotriazole-N,N,N', N'-tetramethylurea hexafluorophosphate;
  • CDI stands for N,N'-carbonyldiimidazole;
  • DMAP
  • XRPD X-ray powder diffractometer
  • Test method about 10-20 mg sample is used for XRPD detection;
  • Light pipe voltage 40kV
  • light pipe current 40mA
  • Anti-scattering slit 7.10mm;
  • Step diameter 0.02 deg
  • Step size 0.12 seconds
  • DSC Differential Scanning Calorimeter
  • Test method The sample ( ⁇ 1 mg) was placed in a DSC aluminum pan for testing, and the sample was heated from 25 ° C to 300 ° C at a heating rate of 10 ° C / min under 50 mL / min N 2 .
  • TGA Thermal Gravimetric Analyzer
  • Test method A sample (2 to 5 mg) was placed in a TGA platinum pot for testing, and the sample was heated from room temperature to 300 ° C at a heating rate of 10 ° C/min under a condition of 25 mL/min N 2 .
  • the compound A provided by the invention has stable crystal form, good solubility and good wettability, and has good promising prospects.
  • the process for synthesizing compound 1 and its intermediates provided by the invention has the advantages that the raw materials are cheap and easy to obtain, and the disadvantages of the reagents used are large, the reaction conditions are harsh, the separation and purification are difficult, and the industrialization is difficult.
  • the compound 11 was prepared by a one-step reaction from the compound 8, and the post-treatment was simple, and the reaction yield was high.
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form A.
  • Figure 2 is a DSC spectrum of Form A.
  • Figure 3 is a TGA spectrum of Form A.
  • Compound 1 was placed in a 50 mL vial, and an appropriate amount of acetonitrile, tetrahydrofuran, acetone, toluene, dioxane, ethyl acetate, isopropanol, acetone + water and acetonitrile + water were added thereto, and heated to complete dissolution.
  • the mixture was slowly cooled to 0 ° C, and the solid obtained by filtration was subjected to XRPD, and the XRPD results are shown in Table 2.
  • HCV genotype 1a (HCV-1a) and 1b (HCV-1b) stably transfected replicon (replicon)
  • Cell 50 measured values of the anti-HCV compound EC 50 and CC.
  • the genotype 1a replicon is derived from the H77 clone and contains K1691R, K2040R and S2204I adaptive mutations.
  • the genotype 1b replicon is derived from the Con1 clone and contains E1202G, 10T1280I and K1846T adaptive mutations.
  • the HCV 1a (HCV-1a) and 1b (HCV-1b) genotype subgenomic replication subsystems contain the relevant HCV gene subtype non-structural protein genes, the G418 resistance gene NEO and the luciferase gene, making HCV-related proteins and fluorescein
  • the enzyme can be stably expressed in cells.
  • the level of replication of the HCV replicon can be determined by detecting the level of expression of the luciferase gene. Therefore, this system serves as a model for screening the activity of anti-HCV compounds in vitro.
  • HCV replicon cell lines HCV-1a and HCV-1b cells.
  • Cell culture medium DMEM (Invitrogen, Cat. #11960077) culture medium, plus 10% fetal bovine serum (FBS, Sigma, Cat. #12003C) and 1% double antibody (penicillin 5000 IU / mL, streptomycin 10 mg / mL, Hyclone, Cat. #SV30010).
  • the compound powder was dissolved in 100% DMSO. The compound was then diluted 6 points by 5 fold. Echo liquid handler 5 was added to the cell plate. The final concentration of DMSO was 0.5%. Each compound is doubled.
  • HCV-1a or HCV-1b replicon cells Cell culture (HCV-1a or HCV-1b replicon cells):

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de fabrication d'un analogue de benzofurane et d'une forme intermédiaire et cristalline de celui-ci.
PCT/CN2017/078078 2016-03-24 2017-03-24 Procédé de fabrication d'un analogue de benzofurane et d'une forme intermédiaire et cristalline de celui-ci WO2017162204A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610173779.6 2016-03-24
CN201610173779 2016-03-24

Publications (1)

Publication Number Publication Date
WO2017162204A1 true WO2017162204A1 (fr) 2017-09-28

Family

ID=59899272

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/078078 WO2017162204A1 (fr) 2016-03-24 2017-03-24 Procédé de fabrication d'un analogue de benzofurane et d'une forme intermédiaire et cristalline de celui-ci

Country Status (2)

Country Link
TW (1) TW201734011A (fr)
WO (1) WO2017162204A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017529401A (ja) * 2014-09-26 2017-10-05 チャーンジョウ インシュヨン ファーマシューティカル カンパニー，リミティド Ｎｓ４ｂ阻害剤としてのベンゾフラン類似体
CN109846878A (zh) * 2017-11-30 2019-06-07 常州寅盛药业有限公司 抗hcv联合用药物
CN109846899A (zh) * 2017-11-30 2019-06-07 常州寅盛药业有限公司 苯并呋喃衍生物与gs-7977联合用药物
CN109846883A (zh) * 2017-11-30 2019-06-07 常州寅盛药业有限公司 苯并呋喃衍生物与tmc435联合用药物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011050284A1 (fr) * 2009-10-23 2011-04-28 Glaxosmithkline Llc Agents antiviraux de pyrazolylpyridine
CN105732602A (zh) * 2015-09-23 2016-07-06 常州寅盛药业有限公司 作为ns4b抑制剂的苯并呋喃类似物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011050284A1 (fr) * 2009-10-23 2011-04-28 Glaxosmithkline Llc Agents antiviraux de pyrazolylpyridine
CN105732602A (zh) * 2015-09-23 2016-07-06 常州寅盛药业有限公司 作为ns4b抑制剂的苯并呋喃类似物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOHN, F.M.: "Hepatitis C replication inhibitors that target the viral NS4B protein", JOURNAL OF MEDICAL CHEMISTRY, vol. 57, no. 5, 19 April 2013 (2013-04-19), pages 2107 - 2120, XP055370833, DOI: 10.1021/jm400125h *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017529401A (ja) * 2014-09-26 2017-10-05 チャーンジョウ インシュヨン ファーマシューティカル カンパニー，リミティド Ｎｓ４ｂ阻害剤としてのベンゾフラン類似体
CN109846878A (zh) * 2017-11-30 2019-06-07 常州寅盛药业有限公司 抗hcv联合用药物
CN109846899A (zh) * 2017-11-30 2019-06-07 常州寅盛药业有限公司 苯并呋喃衍生物与gs-7977联合用药物
CN109846883A (zh) * 2017-11-30 2019-06-07 常州寅盛药业有限公司 苯并呋喃衍生物与tmc435联合用药物

Also Published As

Publication number Publication date
TW201734011A (zh) 2017-10-01

Similar Documents

Publication Publication Date Title
KR102604876B1 (ko) Mcl-1 억제제의 합성
KR102024766B1 (ko) 바이러스 감염 치료를 위한 피리미딘 유도체
WO2017162204A1 (fr) Procédé de fabrication d'un analogue de benzofurane et d'une forme intermédiaire et cristalline de celui-ci
WO2017076286A1 (fr) Forme cristalline, procédé de préparation et intermédiaire d'un composé à cycle dihydropyridine
BR112017015206B1 (pt) Processos para a preparação de 1-((r)-3-(4-amino-3-(4- fenoxifenil)-1h- pirazol[3,4-d]pirimidin-1-il)piperidin-1-il)prop-2- en-1-ona (ibrutinibe) e compostos
WO2017016921A1 (fr) Nouvelles formes cristallines d'acide (6s)-10-méthoxy-6-isopropyl-9-(3-méthoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylique
WO2018126898A1 (fr) Dérivé de thiénopyrimidine, son procédé de préparation et son application dans la fabrication de médicaments antitumoraux
CN114133390B (zh) 一种去氢骆驼蓬碱衍生物及其制备方法和应用
TW201011034A (en) New (poly) aminoalkylaminoalkylamide, alkyl-urea, or alkyl-sulfonamide derivatives of epipodophyllotoxin, a process for preparing them, and application thereof in therapy as anticancer agents
CN110818609A (zh) 3-乙酰基吲哚类brpf1抑制剂的制备方法及其用途
TW201925202A (zh) 新穎哌啶基衍生物、其製備方法及含其之醫藥組合物
JP6021148B2 (ja) Ｌｓｔ−１及び／又はｌｓｔ−２によって輸送される化合物
US10227339B2 (en) Salt form and crystal form of 1,2,5-thiadiazolidin-1,1-dioxide, preparation method thereof and intermediate
WO2020253458A1 (fr) Inhibiteur de kinase cdk
CN109384727B (zh) 酞嗪酮类化合物、其制备方法、药物组合物及用途
WO2017050224A1 (fr) Forme saline et forme cristalline d'un dérivé de quinoléine, procédé de préparation et intermédiaire de celui-ci
CN113845548B (zh) 一种喹唑啉肼二硫代甲酸酯的铂配合物及其制备方法和用途
CN111065635B (zh) 作为mth1抑制剂的新型嘧啶衍生物
Siyu et al. Design, Synthesis, and Antitumor Activity of β-Carboline-Benzimidazole Hybrids
CN117343058A (zh) 取代7-氮杂吲哚-3-羧酸类Mcl-1蛋白抑制剂及制备方法和应用
CN117658932A (zh) 一种含酰胺结构单元的氨基二硫代酯衍生物及其制备方法和应用
CN117586246A (zh) No供体型香豆素曼尼希碱类化合物及其制备方法、用途
CN116063298A (zh) Wnt通路抑制剂的代谢物
CN112745302A (zh) 苯并咪唑类化合物及其医药用途
CN117843638A (zh) 基于rsl3诱导gpx4蛋白降解的双功能分子化合物的制备与应用

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17769481

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17769481

Country of ref document: EP

Kind code of ref document: A1