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WO2011079772A1 - Procédé de préparation d'un composé de thiophène 2,5-disubstitué - Google Patents

Procédé de préparation d'un composé de thiophène 2,5-disubstitué Download PDF

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Publication number
WO2011079772A1
WO2011079772A1 PCT/CN2010/080357 CN2010080357W WO2011079772A1 WO 2011079772 A1 WO2011079772 A1 WO 2011079772A1 CN 2010080357 W CN2010080357 W CN 2010080357W WO 2011079772 A1 WO2011079772 A1 WO 2011079772A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
glucopyranosyl
amino
methyl
Prior art date
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Ceased
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PCT/CN2010/080357
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English (en)
Chinese (zh)
Inventor
柳永建
吴明军
肖新强
唐桂军
黄英豪
张容霞
李海泓
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Topharman Shanghai Co Ltd
Topharman Shandong Co Ltd
Original Assignee
Topharman Shanghai Co Ltd
Topharman Shandong Co Ltd
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Publication of WO2011079772A1 publication Critical patent/WO2011079772A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is in the field of medicinal chemistry, and more particularly, the present invention relates to a process for the preparation of a 2,5-disubstituted thiophene compound of the formula I and a process for the preparation of a compound of the formula V.
  • the disadvantages of the above methods include: (1) 2-aryl substituted thiophene is not easy to obtain, and is prepared by Suzuki coupling reaction, which is catalyzed by expensive palladium reagent; (2) A1C1 3 is flammable in water, and the aluminum salt formed after the reaction is not easy to be obtained. Removal, which leads to cumbersome and inefficient operations in industrial production.
  • This reaction is cyclized with compound II with a leaving group to form a compound of formula I, such as 2-bromoacetophenone and 3-dimethylamino-1-phenyl-2- Reaction of propylene-1-thioaldehyde to 2-phenyl-5-benzimidylthiophene (Comptes Rendus des Seances de l'Academie des
  • the disadvantage of the above method is that the source of the compound XI is not easy, and the yield is low, only 50% to 55%. Therefore, it is particularly important to find a preparation method of the compound of the general formula I which is easy to obtain raw materials, mild in reaction conditions, simple in operation, high in yield, and suitable for industrial production.
  • an object of the present invention is to provide a new, simple, safe, high-efficiency, high-yield, low-cost, low-pollution environment, suitable for industrial mass production of the general formula I, A method for synthesizing a 5-disubstituted thiophene compound.
  • the present invention synthesizes Compound I by a one-pot method in the presence of a sulfur reagent using the following Compound II and Compound III. Specifically, it is shown by the following reaction scheme (1):
  • the sulfur reagent is selected from the group consisting of Na 2 S, Na 2 S'93 ⁇ 40, Li 2 S, K 2 S, A1 2 S 3 , P 4 Si 0 , Lawesson reagent, Davy reagent and japanese reagent, preferably Na 2 S, Na 2 S-9H 2 0 or Lawesson's reagent, most preferably Na 2 S or Na 2 S'93 ⁇ 40 ;
  • the solvent used for the reaction is an aprotic solvent such as hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, dioxane, tetrahydrofuran, benzene, toluene, xylene, ethyl acetate, chloroform, Dichloromethyl Alkane, acetonitrile, dimethyl sulfoxide, etc., preferably hydrazine, hydrazine-dimethylformamide;
  • reaction temperature is room temperature to 90 ° C, preferably room temperature to 70 ° C; reaction time is 1 hour to 8 hours; ⁇ ⁇ ⁇ ⁇ 2 is the same or different selected from chlorine, bromine and iodine;
  • the oxime and ring B are each independently an optionally substituted aryl group, an optionally substituted unsaturated monocyclic heterocyclic ring or an optionally substituted unsaturated fused heterobicyclic ring;
  • the aryl group is an aryl group having an aromatic hydrocarbon ring having 6 to 10 carbon atoms, such as a phenyl group or a naphthyl group;
  • the unsaturated monocyclic heterocyclic ring is an unsaturated hydrocarbon ring containing one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and preferably contains a nitrogen atom, an oxygen atom and a sulfur atom.
  • a 4 to 7 membered unsaturated hydrocarbon ring of one or more heteroatoms such as: pyridine, pyrimidine, uracil, pyrazine, pyridazine, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole , thiazole, isothiazole, oxadiazole, thiadiazole, triazole, tetrazole, etc.;
  • the unsaturated fused heterobicycle is a hydrocarbon ring composed of a saturated or unsaturated hydrocarbon ring condensed with the above unsaturated monocyclic heterocycle, wherein the saturated hydrocarbon ring and the unsaturated hydrocarbon ring are optionally contained within the ring.
  • Suitable amino and hydroxy protecting groups are known to those skilled in the art and include benzyl, benzoyl, methylbenzoyl, nitrobenzoyl, chlorobenzoyl, acetyl, propionyl, methyl Sulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, Trityl group, etc.;
  • R 2 is hydrogen or 1 to 3 are each independently selected from a halogen atom (fluorine, chlorine, bromine, iodine), a nitro group, an amino group, a cyano group, a hydroxyl group, a decyl group, a carboxyl group, a C1-C4 alkyl group, a C1-C4 halogenated alkane.
  • a halogen atom fluorine, chlorine, bromine, iodine
  • each substituent may be further substituted by these substituents; preferably, it is hydrogen Or 1 to 3 each independently selected from a halogen atom, a nitro group, an amino group, a cyano group, a hydroxyl group, a decyl group, a carboxyl group, a C1-C4 alkyl group, a C1-C4 halogenated alkyl group, a C1-C4 alkoxy group,
  • a substituent in the oxy group a C1-C4 alkylamino group, a di(C1-C4 alkyl)amino group, a C1-C4 alkanoylamino group, and a carbamoyl group.
  • both Ring A and Ring B are benzene rings as shown in Reaction Scheme (2) below:
  • the compound ⁇ -a and the compound ⁇ -a are synthesized in a one-pot method in the presence of a sulfur reagent, wherein the Xi, X 2 , R 2 and sulfur reagents are the same as defined above.
  • the reaction conditions are the same as in the scheme (1).
  • Compound ⁇ -b and compound ⁇ -b are synthesized in a one-pot synthesis of compound Ib in the presence of a sulfur reagent, wherein a is selected from the group consisting of bromine, iodine, nitro, amino, protected amino, carbamoyl, D-glucopyranosyl a hydroxy-protected D-glucopyranosyl group, a methyl-D-glucopyranosyl group, and a hydroxy-protected methyl-D-glucopyranose group;
  • the compound II can be obtained commercially or by a literature method, and the compound III is obtained by reacting the corresponding ethyl ketone compound XII with hydrazine, hydrazine-dimethylformamide (DMF) and phosphorus trihalide.
  • DMF hydrazine-dimethylformamide
  • Another object of the present invention is to provide a use of a compound of the above formula I, which is useful for the synthesis of a compound of the formula V.
  • the compound of the formula V is an insulin-dependent diabetes mellitus (type I diabetes mellitus) caused by hyperglycemia by inhibiting the sodium-glucose cotransporter 2 (SGLT2), insulin-independent diabetes mellitus type, etc.
  • SGLT2 sodium-glucose cotransporter 2
  • a preventive or therapeutic agent for diseases such as diabetes, diabetic complications, and obesity.
  • the synthesis method is carried out by the following reaction scheme (4);
  • R 3 is hydrogen or 1 to 3 are each independently selected from the group consisting of fluorine, chlorine, C1-C4 alkyl, D-glucopyranosyl a substituent in a C1-C4 alkoxy group, a C1-C4 haloalkyl group, and a C1-C4 haloalkoxy group.
  • both ring A and ring B are benzene rings, ie the reaction is
  • R 2 and R 3 are the same as the reaction scheme (4 the most preferred embodiment of the invention is:
  • R la is selected from the group consisting of bromine, iodine, nitro, amino, protected amino, carbamoyl, D-glucopyranosyl, hydroxy protected D-glucopyranosyl, methyl-D-glucopyranosyl and The hydroxy-protected methyl-D-glucopyranosyl group;
  • Compound Vb a candidate compound for the treatment of type 2 diabetes, Canagliflozin (T3063), is currently undergoing Phase II clinical trials.
  • Step b) Compound IV is awakened by reaction with 2,3,4,6-tetra-O-trimethylsilyl gluconic acid under the action of n-butyllithium to give intermediate VI, which is directly added without methyl sulfonate.
  • the acid and methanol react to form methyl-l- C- [3-[[5-(4-fluorophenyl)-2-thiophene]methyl]-4-methylphenylhydrazine- ⁇ -D-glucopyranose ( VII);
  • Step c) Compound VII is reacted under triethylsilane and boron trifluoride diethyl ether to give the target Canagliflozin (Vb).
  • the compound Ib-2 can be obtained by the three routes described in the Scheme Scheme 1 to obtain the key intermediate 5-(4-fluorophenyl)-2-(5-bromo() in the above 1.1). Or iodine)-2-methyl-1-phenylmethyl)thiophene (IV), compound IV, further prepared by the steps b) and c) of the above 1.1) compound Canagliflozin (Vb);
  • Step d) Reduction of the nitro group of 5-(4-fluorophenyl)-2-(5-nitro-2-methyl-1-benzophenone)thiophene (Ib-2) to 5-(4-fluorobenzene) -2-(5-amino-2-methyl-1-benzophenone)thiophene (Ib-3);
  • Step e) reducing the carbonyl group of the compound I-b-3 to give 5-(4-fluorophenyl)-2-(5-amino-2-methyl-1-phenylmethyl:)thiophene (IX);
  • Step f) Compound IX is first diazotized and then subjected to bromination or iodo reaction to obtain compound IV; gg) Compound Ib-3 is first diazotized and then brominated or iodo-substituted to obtain compound Ib-1; Step h) reducing the carbonyl group of compound Ib-2 to give the compound 5-(4-fluorophenyl)-2-(5-nitro-2-methyl-1-phenylmethyl)thiophene (VIII);
  • Step i) reducing the nitro group of compound VIII to give compound IX;
  • the reducing agent for reducing the nitro group is selected from the group consisting of iron powder, zinc powder, stannous chloride, sodium sulfide, sodium disulfide, sodium sulfite, sodium hydrogen sulfite, ammonium sulfite, ammonium hydrogen sulfite and the like.
  • the reducing agent for reducing the carbonyl group is selected from the group consisting of triethylsilane, borane, zinc amalgam and hydrazine hydrate;
  • the diazotization reaction is compound Ib-3 or compound IX with sodium nitrite and acid at 0
  • the reaction is carried out at a low temperature of ⁇ 5 ° C for 0.5 to 2 hours to form a diazonium salt, wherein the acid may be a mineral acid such as hydrochloric acid or sulfuric acid, or may be an organic acid such as trifluoroacetic acid or the like, the brominated or iodo
  • the reaction is the reaction of the above diazonium salt with bromide or iodide, wherein the iodide may be potassium iodide or sodium iodide, and the bromide may be potassium bromide or sodium bromide;
  • the Hofmann degradation reaction (step k) is a compound Ib-5 which forms a compound Ib-3 under the action of bromine (or chlorine) and a base, and the base may be sodium hydroxide, potassium hydroxide, sodium carbonate and sodium methoxide. ;
  • a is selected from the group consisting of a nitro group, an amino group and a carbamoyl group is specifically: ;-(4-fluorophenyl)-2-(5-nitro-2-methyl- 1 -benzophenone)thiophene
  • the present invention also provides another novel 2,5-disubstituted thiophene compound represented by the following formula XIII.
  • a novel method for synthesizing 2,5-disubstituted thiophene is provided, which is simple and efficient, has a wide range of raw materials, simple synthesis route, simple operation, mild reaction conditions, short reaction time, high recovery, and low synthesis cost. Easy to handle, environmentally friendly, suitable for industrial production.
  • the invention does not require the Suzuki coupling reaction to prepare the compound of the formula V, avoids the use of expensive metal reagents (such as palladium reagent:) catalysis, avoids harsh reaction conditions, and is easy to obtain raw materials, easy to operate, and mild in reaction conditions.
  • the whole process is environmentally friendly and suitable for industrial production.
  • nuclear magnetic resonance was measured by a Bruker AMX-300 nuclear magnetic resonance spectrometer, TMS
  • the chemical shift unit is ppm
  • the mass spectrometer is determined by MAT-711 and MAT-95 mass spectrometer
  • the column chromatography is 200-300 mesh silica gel, produced by Qingdao Ocean Chemical Plant
  • TLC silica gel plate is produced by Yantai Chemical Factory.
  • petroleum ether boiling range is 60-90 ° C
  • UV lamp, iodine cylinder color development unless otherwise specified, the concentration means that the solvent in the preparation compound solution is distilled off by a rotary evaporator; the drying means drying the prepared compound at 60 ° C in a DHG-9240A constant temperature drying oven.
  • Example 16 The compound prepared in Example 16 (100 mg, 0.152 mmol) was dissolved in trifluoroacetic acid / dichloromethane (1:1, v/v, 5 ml) and the mixture was stirred for five minutes. Spin dry to give the product (50 mg, yield 70%).
  • Example 17 The compound obtained in Example 17 (48 mg, 0.1 mmol) was dissolved in tetrahydrofuran (5 ml), and triethylsilane (12 ml) / boron trifluoride diethyl ether (5 ml) was added dropwise. The reaction was carried out at room temperature overnight. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. 5-(4-fluorophenyl)-2-thiophene]methyl]-4-methyl [3 ⁇ 43 ⁇ 4 ⁇ - ⁇ -[ «[ ⁇ 3 ⁇ 4- ⁇ -(3 ⁇ 4*3 ⁇ 4- ⁇ ]]- ]-3-1-3 ⁇ 43 ⁇ 41 -0-0-9 ⁇ ' ⁇
  • Example 20 The compound obtained in Example 20 (48 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 ml), and triethylsilane (10 ml) / boron trifluoride diethyl ether (5 ml) was added dropwise. The reaction was carried out at room temperature overnight. The mixture was stirred for 5 min. -[[5-(4-Fluorophenyl)-2-thiophene]methyl]-4-methylphenylhydrazine- ⁇ -D-glucopyranose (28 mg, yield 82%). The hydrogen spectrum data was the same as in Example 18.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
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Abstract

Procédé de préparation d'un composé I de thiophène 2,5-disubstitué et son utilisation pour préparer le composé V. Le procédé selon l'invention comprend la réaction du composé II avec le composé III en présence d'un réactif à base de soufre pour obtenir le composé I d'une manière monotope.
PCT/CN2010/080357 2009-12-31 2010-12-28 Procédé de préparation d'un composé de thiophène 2,5-disubstitué Ceased WO2011079772A1 (fr)

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CN200910247892.4A CN102115468B (zh) 2009-12-31 2009-12-31 一种2,5-二取代噻吩化合物的合成方法
CN200910247892.4 2009-12-31

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103980263A (zh) * 2014-04-17 2014-08-13 海门瑞一医药科技有限公司 卡格列净的合成新工艺
EP2918579A1 (fr) 2014-03-14 2015-09-16 LEK Pharmaceuticals d.d. Synthèse de 2-arylméthyl-5-aryl-thiophène
WO2015101670A3 (fr) * 2014-01-03 2015-12-03 Elexopharm Gmbh Inhibiteurs des 17bêta-hydroxystéroïde déshydrogénases de type 1 et 2
WO2016035042A1 (fr) 2014-09-05 2016-03-10 Mylan Laboratories Ltd Procédé de préparation de canagliflozine
WO2016135747A3 (fr) * 2015-02-27 2016-10-20 Msn Laboratories Private Limited Processus de préparation d'un composé amorphe (1s)-1,5-anhvdro-1-[3- [[5- (4 fluorophényl)-2-thiényl]methvl]-4-méthylphényl]-d-glucitol et de ses formes polymorphes
WO2024040259A3 (fr) * 2022-08-19 2024-03-28 Nimml Institute Dérivés de thiazole à usage thérapeutique

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CN104557894A (zh) * 2013-10-18 2015-04-29 上海信谊药厂有限公司 坎格列汀晶型及其制备方法
CN103936725B (zh) * 2014-04-01 2016-07-27 天津大学 卡格列净的c晶型及其结晶制备方法
ES2711804T3 (es) 2014-05-27 2019-05-07 Glenmark Pharmaceuticals Ltd Proceso para preparación de canagliflozina
CN104086523A (zh) * 2014-06-09 2014-10-08 上海方楠生物科技有限公司 一种制备坎格列净中间体2-(4-氟苯基)-5-[(5-卤代-2-甲基苯基)甲基]噻吩的方法
CN105272960A (zh) 2014-07-18 2016-01-27 上海科胜药物研发有限公司 一种坎格列净中间体2-(2-甲基-5-溴苄基)-5-(4-氟苯)噻吩的制备方法
CN104311532B (zh) * 2014-10-31 2016-04-20 山东大学 2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩的制备方法
WO2016098016A1 (fr) * 2014-12-17 2016-06-23 Dr. Reddy’S Laboratories Limited Procédé de préparation d'inhibiteurs de sglt2
CN104926803B (zh) * 2015-06-17 2017-12-22 南通常佑药业科技有限公司 一种新的sglt2抑制剂药物的制备方法
CN104987320A (zh) * 2015-08-03 2015-10-21 沧州那瑞化学科技有限公司 一种坎格列净中间体的制备方法
CN105130952A (zh) * 2015-08-06 2015-12-09 杨海霞 一种医药中间体醛基取代噻吩化合物的合成方法
CN108976182A (zh) * 2017-06-05 2018-12-11 上海奥博生物医药技术有限公司 一种制备达格列净五元环杂质的方法
CN108017612B (zh) * 2017-11-29 2020-06-09 南通常佑药业科技有限公司 一种坎格列净中间体的制备方法
CN110950833A (zh) * 2019-12-11 2020-04-03 台州学院 一种2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩的制备方法
CN116162945B (zh) * 2022-11-28 2023-08-04 安庆奇创药业有限公司 一种利用微反应装置连续电合成卡格列净中间体的方法

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015101670A3 (fr) * 2014-01-03 2015-12-03 Elexopharm Gmbh Inhibiteurs des 17bêta-hydroxystéroïde déshydrogénases de type 1 et 2
US9884839B2 (en) 2014-01-03 2018-02-06 Elexopharm Gmbh Inhibitors of 17Beta-hydroxysteroid dehydrogenases type 1 and type 2
EP2918579A1 (fr) 2014-03-14 2015-09-16 LEK Pharmaceuticals d.d. Synthèse de 2-arylméthyl-5-aryl-thiophène
CN103980263A (zh) * 2014-04-17 2014-08-13 海门瑞一医药科技有限公司 卡格列净的合成新工艺
CN103980263B (zh) * 2014-04-17 2016-08-03 海门瑞一医药科技有限公司 卡格列净的合成工艺
WO2016035042A1 (fr) 2014-09-05 2016-03-10 Mylan Laboratories Ltd Procédé de préparation de canagliflozine
WO2016135747A3 (fr) * 2015-02-27 2016-10-20 Msn Laboratories Private Limited Processus de préparation d'un composé amorphe (1s)-1,5-anhvdro-1-[3- [[5- (4 fluorophényl)-2-thiényl]methvl]-4-méthylphényl]-d-glucitol et de ses formes polymorphes
US10633372B2 (en) 2015-02-27 2020-04-28 Msn Laboratories Private Limited Process for the preparation of amorphous (1S)-1,5-anhydro-1-[3-[[5-(4 fluorophenyl)-2-thienyl]-4-methylphenyl]-D-glucitol and its polymorphs thereof
WO2024040259A3 (fr) * 2022-08-19 2024-03-28 Nimml Institute Dérivés de thiazole à usage thérapeutique

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CN102115468B (zh) 2014-06-11

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