WO2017161555A1 - Intermédiaire de malaxage d'un composé 5-hydroxyl-1,7-naphtyridine substitué par un groupe aryle ou hétéroaryle, et son procédé de préparation - Google Patents

Intermédiaire de malaxage d'un composé 5-hydroxyl-1,7-naphtyridine substitué par un groupe aryle ou hétéroaryle, et son procédé de préparation Download PDF

Info

Publication number
WO2017161555A1
WO2017161555A1 PCT/CN2016/077327 CN2016077327W WO2017161555A1 WO 2017161555 A1 WO2017161555 A1 WO 2017161555A1 CN 2016077327 W CN2016077327 W CN 2016077327W WO 2017161555 A1 WO2017161555 A1 WO 2017161555A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
reaction
methyl
iii
phenyl
Prior art date
Application number
PCT/CN2016/077327
Other languages
English (en)
Chinese (zh)
Inventor
周云隆
蔡遂雄
焦玲玲
景羽
郭明
温剑锋
蔡民民
季风华
Original Assignee
沈阳三生制药有限责任公司
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 沈阳三生制药有限责任公司 filed Critical 沈阳三生制药有限责任公司
Priority to PCT/CN2016/077327 priority Critical patent/WO2017161555A1/fr
Priority to CN201680082549.7A priority patent/CN108884047B/zh
Publication of WO2017161555A1 publication Critical patent/WO2017161555A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation

Definitions

  • the present invention relates to the field of synthesis, in particular, the present invention relates to an intermediate for the preparation of a 5-hydroxy-1,7-naphthyridine compound substituted with an aryl or heteroaryl group for inhibiting HIF proline hydroxylase and Preparation.
  • EPO erythropoietin
  • EPO As a macromolecular glycoprotein, EPO also has low bioavailability, short half-life in the organism, and is easily hydrolyzed by the enzymes in the gastrointestinal tract. Therefore, EPO must be administered frequently, which limits the patient's own medication. The possibility of giving the patient a lot of inconvenience. 3, industrial synthetic EPO still can not avoid the problem of immunogenicity, the product has a certain risk of medication.
  • CN 201510141555.2 filed by the present applicant provides a 5-hydroxy-1,7-naphthyridine compound or a salt thereof having the structure of the following formula (I) for inhibiting aryl or heteroaryl substitution of HIF proline hydroxylase :
  • R 1 and R 2 are each independently hydrogen; R 3 is hydrogen or C 1-3 alkyl; and Ar is an aromatic or aromatic heterocyclic ring selected from the group consisting of a naphthalene ring, a pyridine ring, a thiophene ring, a furan ring and a substituted benzene ring. .
  • Another object of the invention is to provide a process for the preparation of said intermediate compounds.
  • Ar is an aromatic ring or an aromatic heterocyclic ring selected from the group consisting of a naphthalene ring, a pyridine ring, a thiophene ring, a furan ring, and a substituted benzene ring;
  • R 3 is hydrogen or C 1-3 alkyl.
  • Ar is a naphthyl group.
  • the most preferred compound is a compound of the formula (HIF117-04):
  • the present invention provides a process for the preparation of a compound of formula (VI) which can be synthesized according to Synthetic Scheme 1:
  • the present invention relates to a process for the preparation of a compound of the following formula (VI),
  • Step 1 Make the compound of the formula
  • N,N-dimethylformamide dimethyl acetal is heated and refluxed to carry out a condensation reaction to form a compound of the following formula (III)
  • Step 2 Condensing the intermediate (III) obtained in the step 1 with an R3-substituted methyl acyl acetate having the following formula,
  • Step 3 bromination of the methyl or methylene group of the intermediate (IV) obtained in the step 2 to obtain a bromo intermediate (V)
  • Step 4 Substituting the intermediate (V) obtained in the step 3 with methyl toluenesulfonyl glycinate to obtain a p-toluenesulfonyl intermediate (VI)
  • the above step 2 is to heat-condense 3-dimethylamino-1-(4-methoxyphenyl)-propenone (III) and methyl acetoacetate in the presence of an ammonium salt and a catalyst to form 6-(4- Chloro-phenyl)-2-methyl-nicotinic acid methyl ester (IV).
  • Preferred ammonium salts include ammonium carbonate, ammonium hydrogencarbonate, ammonium chloride, ammonium acetate, etc.
  • Preferred catalysts include cerium (III) chloride, Sn (IV) Cl 4 , Ti (IV) Cl 4 , Zn (II) Cl 2 , Al (III) Cl 3 , boron trifluoride etherate and other Lewis acid, a preferred Lewis acid enhancer is sodium iodide, the preferred reaction solvent is ethanol, methanol, isopropanol, tert-butanol, etc., the reaction is reflux Go on.
  • the above step 3 is a free radical bromination of the 2-position methyl group of pyridine on methyl 6-(4-chloro-phenyl)-2-methyl-nicotinate (IV).
  • the bromination reagent is preferably N-bromosuccinimide, dibromohydantoin, copper (II) bromide, liquid bromine, etc.
  • the initiator of the bromination reaction is preferably azobisisonitrile (AIBN), benzoyl peroxide.
  • AIBN azobisisonitrile
  • the solvent for the bromination reaction is preferably carbon tetrachloride, dichloromethane or chloroform.
  • the reaction is carried out under reflux to give the bromo intermediate 2-bromomethyl-6-(4-chlorophenyl)-nicotinic acid methyl ester (V).
  • Step 4 above is to replace methyl 2-bromomethyl-6-(4-chlorophenyl)-nicotinic acid (V) with p-toluenesulfonyl glycine methyl ester under the catalysis of a base to obtain 6-(4) ⁇ Chloro-phenyl) ⁇ 2 ⁇ [methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-methyl ⁇ -methylnicotinate (VI).
  • Preferred bases are potassium carbonate, cesium carbonate, sodium carbonate, and preferred reaction solvents are N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, dimethyl sulfoxide, etc.
  • the preferred reaction temperature is 20 to 80 °C.
  • step i) reacting 3-dimethylamino-1-naphthalen-1-yl-propenone (HIF117-01) obtained in step i) with methyl acetoacetate in the presence of ammonium acetate and acetic acid to give 2-methyl- 6-naphthalen-1-yl-nicotinic acid methyl ester (HIF117-02);
  • the solvent used in step iii) is carbon tetrachloride; the solvent used in step iv) is dimethylformamide.
  • the intermediate of the present invention can be used to prepare a compound of the following formula (I) which inhibits HIF proline hydroxylase:
  • R 1 and R 2 are each independently hydrogen; R 3 is hydrogen or C 1-3 alkyl; and Ar is an aromatic or aromatic heterocyclic ring selected from the group consisting of a naphthalene ring, a pyridine ring, a thiophene ring, a furan ring and a substituted benzene ring. .
  • the preparation process is as shown in the following synthesis scheme 3:
  • the synthesis scheme includes the following steps:
  • the intermediate (VI) of the present invention is first deprotonated on a methylene group to form a carbanion under basic conditions, and then the carbanion undergoes intramolecular attack on the methyl ester group on the pyridine ring to form a ketone, and under alkaline conditions Rapid removal of p-toluenesulfonyl group to form methyl 5-hydroxy-1,7-naphthyridinecarboxylate intermediate (VII)
  • step A) is 6-(4-chlorophenyl)-2-( ⁇ methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-methyl ⁇ -methyl nicotinate (VI) intramolecular cyclization under basic conditions, with the removal of p-toluenesulfonyl group to form 2-(4-chlorophenyl)-5-hydroxy-[1,7]naphthyridin-6-carboxylic acid Methyl ester (VII).
  • Preferred bases are sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide; preferred reaction solvents are N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide , dimethyl sulfoxide, methanol, ethanol, tetrahydrofuran, etc.; preferred reaction temperature is 0 to 40 ° C; a preferred reaction time is 0.5 to 3 hours.
  • step B) is to treat methyl 2-(4-chlorophenyl)-5-hydroxy-[1,7]naphthyridin-6-carboxylate (VII) in a closed heating system under alkaline conditions.
  • Glycine is exchanged directly in methyl 2-(4-chlorophenyl)-5-hydroxy-[1,7]naphthyridin-6-carboxylate
  • Preferred bases are sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide and the like; preferred reaction solvents are methanol, ethanol, isopropanol and n-butanol; preferred reaction temperatures are from 80 to 140 °C.
  • reaction solution was diluted with 10 ml of water and extracted with three portions of ethyl acetate (60 ml), and then the organic layer was concentrated to give the residue, which was subjected to column chromatography, ethyl acetate / petroleum ether (1:10 to 1:1). 6-(4-Chloro-phenyl)-2- ⁇ 1-[methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-ethyl ⁇ -nicotinic acid methyl ester as a white solid, 67.6%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified, then, eluent, ethyl acetate/ petroleum ether (1:50) - Methyl nicotinate white solid, 53.1%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified, then, eluent, ethyl acetate/ petroleum ether (1:50) to give a mixture of 3.0 g of 2-ethyl-6-(4-methoxy-phenyl) - Methyl nicotinate white solid, 55.4%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified, then, eluent, ethyl acetate/ petroleum ether (1:50) to give 3 g of 2-ethyl-6-(3-methoxy-phenyl) - Methyl nicotinate yellow liquid, 55.3%.
  • the reagent was ethyl acetate/petroleum ether (1:50) to give 1.5 g of methyl 6-(1-bromoethyl)-2-(3-methoxyphenyl)-5-carboxylate as a pale yellow solid, 57.0% .
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified and purified with ethyl acetate / petroleum ether (1:50) to give 4.5 g of 6-ethyl-[2,3']bipyridin-5- Methyl carboxylate yellow solid, 61.9%.
  • reaction solution was diluted with 10 ml of water and extracted with three portions of ethyl acetate (60 ml), and then the organic layer was concentrated, and the residue was subjected to column chromatography.
  • the eluent was ethyl acetate / petroleum ether (1:10 to 1:1). 6-(1-(N-(2-Methoxy-2-oxoethyl)-4-methylbenzenesulfonylamino)propan-2-yl)-[2,3']bipyridin-5 Methyl carboxylate yellow oil, 27.3%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified and then evaporated to ethyl acetate/ petroleum ether (1:50) to give a mixture of 2.2 g of 6-(3-bromo-phenyl)-2-methyl- Methyl ester yellow liquid, 67.7%.
  • reaction mixture was diluted with 10 ml of water and extracted with EtOAc EtOAc EtOAc EtOAc EtOAc 6-(3-Chloro-phenyl)-2- ⁇ 1-[methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-methyl ⁇ -nicotinic acid methyl ester yellow oil , 31.9%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified, then, eluent, ethyl acetate/ petroleum ether (1:50) to give 3.7 g of 6-(3-bromo-phenyl)-2-ethyl- Methyl ester yellow liquid, 60.4%.
  • reaction solution was diluted with 10 ml of water and extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc: EtOAc 6-(3-Bromo-phenyl)-2- ⁇ 1-[methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-ethyl ⁇ -nicotinic acid methyl ester yellow oil 91.6%.
  • reaction mixture was diluted with 10 ml of water and extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) 6-(3-Chloro-phenyl)-2- ⁇ 1-[methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-ethyl ⁇ -nicotinic acid methyl ester as a yellow solid, 31.9%.
  • reaction solution was diluted with 10 ml of water and extracted with three portions of ethyl acetate (60 ml), and the organic layer was concentrated to give a residue, which was subjected to column chromatography, ethyl acetate/ petroleum ether (1:10 to 1:1).
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified, then, eluent, ethyl acetate/ petroleum ether (1:50) to give 4.7 g of 6-(4-bromo-phenyl)-2-methyl- Acid methyl ester yellow solid, 78.33%.
  • reaction mixture was diluted with 10 ml of water and extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) 6-(4-Bromo-phenyl)-2- ⁇ [methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-methyl ⁇ -nicotinic acid methyl ester yellow oil, 25.5 %.
  • EtOAc EtOAc 6-(4-Bromo-phenyl) 6-(4-Bromo-phenyl)-2- ⁇ [methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-methyl ⁇ -nicotinic acid methyl ester yellow oil, 25.5 %.
  • reaction mixture was diluted with 10 ml of water and extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc: EtOAc 2- ⁇ [Methoxycarbonylmethyl-(4-methylphenylsulfonyl)-amino]-methyl ⁇ -6-naphthalen-1-yl-nicotinic acid methyl ester as a white solid, 23.6%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and purified by column chromatography, ethyl acetate / petroleum ether (1:50) to give 6-(3-methoxy-phenyl)-2-methyl- Acid methyl ester brown yellow liquid 6.0 g, 80.0%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified with ethyl acetate / petroleum ether (1:50) to give 2-methyl-6-thiophen-2-yl-nicotinic acid methyl ester as white solid 2.0 grams, 28.6%.
  • reaction mixture was directly subjected to column chromatography, eluent ethyl acetate / petroleum ether (1: 50) 2-Chloromethyl-6-thiophen-2-yl-nicotinic acid methyl ester yellow liquid 2.0 g, 74.1%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and then purified with ethyl acetate / petroleum ether (1:50) to give 2-methyl-6-naphthalen-2-yl-nicotinic acid methyl ester as a solid. 2.0 grams, 28.6%.
  • reaction solution was cooled, suction filtered, and the filtrate was concentrated and purified by column chromatography, ethyl acetate / petroleum ether (1:50) to give 6-(4-cyano-phenyl)-2-ethyl-nicotinic acid Methyl ester yellow solid 800 mg.
  • the organic phase was combined, and the pH was adjusted to neutral with a large amount of saturated aqueous sodium hydrogencarbonate (a large amount of gas was formed).
  • the liquid phase was separated, and the organic phase was dried and then thoroughly dried.
  • the residue was dissolved in an appropriate amount of methanol, and a solution of saturated HCl in methanol (4 eq. The methanol was sparged, the residue was added with ethyl acetate, and the mixture was warmed and washed for 1 hour. After cooling, it was filtered to give a pale yellow solid (the hydrochloride salt of the product); if the product was not thoroughly salted, the free residue in the ethyl acetate mother liquor was repeated.
  • the salt formation step is described inorganic acid
  • the obtained solid was dispersed in ethyl acetate, and the pH was adjusted to neutral using a saturated aqueous sodium hydrogencarbonate solution, and the mixture was separated, and the ethyl acetate layer was dried, and then dried to give a trisubstituted pyridine product, which was used.
  • the combined yield is about 50-60%.
  • the crude product obtained was dissolved in dry THF according to the ratio of the dibromo group obtained by LC-MS, and the corresponding amount of diethyl phosphite (5.0 eq.) and DIPEA (5.0 eq.) were added. Room temperature under nitrogen protection The next reaction is about 2-2.5 hours (times are prolonged with impurities) and LC-MS monitoring indicates that the dibromo is almost completely converted to the monobromo.
  • the mixture was evaporated to dryness.
  • the residue was combined with water and ethyl acetate.
  • the mixture was extracted twice, then the organic phase was combined, dried and then evaporated to dryness.
  • the residue was added to 5 times methanol to warm to reflux for 1-2 hours, then to room temperature. After filtration, the turbid yellow solid is used; or column chromatography gives a pale yellow solid.
  • the yield of the two treatments is equivalent, and the purity of the product obtained by column chromatography is slightly better.
  • the total yield of the two-step reaction is about 60%.

Landscapes

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

Abstract

La présente invention concerne un composé représenté par la formule (IV), Ar étant un cycle aromatique ou un cycle hétéroaromatique sélectionné parmi un cycle naphtalène, un cycle pyridine, un cycle thiophène, un cycle furane et un cycle benzène substitué, R3 étant un atome d'hydrogène ou un groupe alkyle en C1-3. La présente invention concerne également un procédé de préparation du composé. Le composé est un intermédiaire utilisé pour la préparation d'un composé 5-hydroxyl-1,7-naphtyridine substitué par un groupe aryle ou hétéroaryle, utilisé pour l'inhibition de la prolylhydroxylase.
PCT/CN2016/077327 2016-03-25 2016-03-25 Intermédiaire de malaxage d'un composé 5-hydroxyl-1,7-naphtyridine substitué par un groupe aryle ou hétéroaryle, et son procédé de préparation WO2017161555A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2016/077327 WO2017161555A1 (fr) 2016-03-25 2016-03-25 Intermédiaire de malaxage d'un composé 5-hydroxyl-1,7-naphtyridine substitué par un groupe aryle ou hétéroaryle, et son procédé de préparation
CN201680082549.7A CN108884047B (zh) 2016-03-25 2016-03-25 用于合成被芳基或杂芳基取代的5-羟基-1,7-萘啶化合物的中间体及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2016/077327 WO2017161555A1 (fr) 2016-03-25 2016-03-25 Intermédiaire de malaxage d'un composé 5-hydroxyl-1,7-naphtyridine substitué par un groupe aryle ou hétéroaryle, et son procédé de préparation

Publications (1)

Publication Number Publication Date
WO2017161555A1 true WO2017161555A1 (fr) 2017-09-28

Family

ID=59900965

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/077327 WO2017161555A1 (fr) 2016-03-25 2016-03-25 Intermédiaire de malaxage d'un composé 5-hydroxyl-1,7-naphtyridine substitué par un groupe aryle ou hétéroaryle, et son procédé de préparation

Country Status (2)

Country Link
CN (1) CN108884047B (fr)
WO (1) WO2017161555A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114591199A (zh) * 2022-03-17 2022-06-07 诚弘制药(威海)有限责任公司 一种溴乙腈的制备方法
CN114644589A (zh) * 2020-12-17 2022-06-21 鲁南制药集团股份有限公司 一种化合物n-[（4-羟基--1-甲基-3-异喹啉基）羰基]-甘氨酸的制备方法
CN114907836A (zh) * 2022-05-07 2022-08-16 西北工业大学 一种多级光响应型荧光液晶基元及其聚合物及制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105308023A (zh) * 2013-03-28 2016-02-03 宇部兴产株式会社 取代联芳基化合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4030999A1 (de) * 1990-10-01 1992-04-09 Hoechst Ag 4- oder 5-substituierte pyridin-2-carbonsaeuren, verfahren zu deren herstellung sowie deren verwendung als arzneimittel
US6562822B2 (en) * 2000-07-12 2003-05-13 Pharmacia & Upjohn Company Heterocyle carboxamides as antiviral agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105308023A (zh) * 2013-03-28 2016-02-03 宇部兴产株式会社 取代联芳基化合物

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114644589A (zh) * 2020-12-17 2022-06-21 鲁南制药集团股份有限公司 一种化合物n-[（4-羟基--1-甲基-3-异喹啉基）羰基]-甘氨酸的制备方法
CN114591199A (zh) * 2022-03-17 2022-06-07 诚弘制药(威海)有限责任公司 一种溴乙腈的制备方法
CN114591199B (zh) * 2022-03-17 2024-03-12 诚弘制药(威海)有限责任公司 一种溴乙腈的制备方法
CN114907836A (zh) * 2022-05-07 2022-08-16 西北工业大学 一种多级光响应型荧光液晶基元及其聚合物及制备方法
CN114907836B (zh) * 2022-05-07 2023-10-27 西北工业大学 一种多级光响应型荧光液晶基元及其聚合物及制备方法

Also Published As

Publication number Publication date
CN108884047A (zh) 2018-11-23
CN108884047B (zh) 2022-03-08

Similar Documents

Publication Publication Date Title
JP2021508722A (ja) 芳香族ビニルまたは芳香族エチル系誘導体、その製造方法、中間体、薬物組成物および使用
AU2008252380A1 (en) Quinazolin-oxime derivatives as Hsp90 inhibitors
WO2012008563A1 (fr) Dérivé de cycle hétérocyclique aromatique azoté
JP2006528193A (ja) Ｃ−ｆｍｓキナーゼの阻害剤としてのキノリノン誘導体
TWI426074B (zh) ５－（２－胺基－嘧啶－４－基）－２－芳基－１ｈ－吡咯－３－羧醯胺之製造方法
WO2006049232A1 (fr) Dérivé d’acide carboxylique contenant un cycle thiazole et applications pharmaceutiques dudit dérivé
CA2687611A1 (fr) Nouveaux derives de quinoleine et de quinazoline substituee par un sulphoximine et de quinazoline en tant qu'inhibiteurs de kinase
CA2587207A1 (fr) Agonistes des recepteurs de la niacine, compositions contenant ces composes et methodes de traitement
AU2015221343B2 (en) Naphthylamide compound, preparation method and use thereof
CN110066276B (zh) 芳香杂环化合物、其中间体、制备方法、药物组合物和应用
WO2019196945A1 (fr) Nouveau procédé de synthèse d'amides deutérés et de sulfonamides deutérés
WO2017161555A1 (fr) Intermédiaire de malaxage d'un composé 5-hydroxyl-1,7-naphtyridine substitué par un groupe aryle ou hétéroaryle, et son procédé de préparation
CN105524043A (zh) 内酰胺类组蛋白去乙酰化酶抑制剂
WO1999051574A1 (fr) Derives d'indole
KR102575605B1 (ko) B형 간염 코어 단백질 조정제의 제조 방법
CN108727295A (zh) 一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途
WO2016155358A1 (fr) Composé de 5-hydroxy-1,7-naphtyridine substitué par aryle ou hétéroaryle, son procédé de préparation et son utilisation pharmaceutique
WO2019242689A1 (fr) Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, procédé de préparation correspondant et utilisation associée
US20150218113A1 (en) Method for producing 1,4-benzoxazine compound
AU2016288534A1 (en) Bicyclic heterocycle derivatives as bromodomain inhibitors
CN107922375A (zh) 靶向idh2突变的抗肿瘤化合物及其使用方法
TW202239409A (zh) 化合物
CZ20022146A3 (cs) Způsob výroby 4-(heteroarylmethyl)halogen-1(2H)-ftalazinonů
WO2018133159A1 (fr) Méthode de préparation d'un nouveau composé de quinoléine
TWI731540B (zh) 製備磺胺類藥物的方法

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: 16894910

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 16894910

Country of ref document: EP

Kind code of ref document: A1