CN108059607B - Sulfonylacetic acid or sulfonyl acetic acid derivative, and pharmaceutical composition, preparation method and application thereof - Google Patents
Sulfonylacetic acid or sulfonyl acetic acid derivative, and pharmaceutical composition, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a sulfoxide acetic acid or sulfone acetic acid derivative with a structure shown in a general formula (I), pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the derivative and a preparation method thereof. The sulfoxide acetic acid or the sulfone acetic acid derivative has high agonistic activity on a GPR40 receptor and can be used for preparing a medicament for treating diabetes and/or metabolic syndrome.
Description
Technical Field
The invention relates to a sulfoxide acetic acid or sulfone acetic acid derivative, a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the derivative and a preparation method thereof. The invention also relates to the application of the sulfoxide acetic acid or sulfone acetic acid derivative, and pharmaceutically acceptable salts thereof or a pharmaceutical composition containing the derivative in the preparation of G protein coupled receptor 40(GPR40) agonists and in the preparation of medicaments for treating diseases such as diabetes, metabolic syndrome and the like.
Background
Diabetes mellitus is a chronic metabolic disease caused when the human body cannot produce enough insulin or cannot effectively utilize insulin. The hyperglycemia existing in the diabetic patients for a long time can cause the dysfunction of various tissues, particularly chronic damage of eyes, kidneys, hearts, blood vessels and nerves. According to the published up-to-date statistics of the International Diabetes Federation (International Diabetes Federation), there are 4.15 billion adult diabetic patients worldwide (20-79 years) in 2015, with an estimated increase to 6.42 billion in 2040. Among them, 1.09 million of diabetic patients exist in China, and the number of diabetic patients is the first to live in the world, and is predicted to increase to 1.50 million in 2040 years. The rapid growth of diabetes in China and other developing countries has placed a very heavy burden on the social and economic development of these countries. The worldwide cost for treating diabetes and preventing complications is estimated to reach 7950 to 1404 million. Therefore, the situation of preventing and treating diabetes at home and abroad is very severe.
At present, the drugs for resisting the type II diabetes mainly comprise insulin sensitizers, such as metformin and thiazolidinediones. Reduce renal glucose reabsorption, such as glucose cotransporter 2(SGLT2) inhibitors. Insulin secretion promoters, such as sulfonylureas, glinides, glucagon-like peptide-1 (GLP-1) s. However, most drugs reduce blood sugar and are accompanied by the risk of hypoglycemia, and some drugs cause side effects such as weight gain, gastrointestinal discomfort, edema, increased fracture risk and the like.
GPR40, also known as the free fatty acid 1(FFA1) receptor, belongs to the family of G-protein coupled receptors (GPCRs) with a classical seven-transmembrane structure that is distributed primarily in the pancreatic islet beta cell enteroendocrine cells. Endogenous agonists of GPR40 are medium and long chain fatty acids, such as capric acid, oleic acid, docosahexaenoic acid. After binding of endogenous agonist to GPR40, activated GPR40 binds to heterotrimeric G protein Gq/11, promoting phospholipase c (plc) hydrolysis of phosphatidylinositol 4, 5-diphosphate (PIP2) to inositol triphosphate (IP3) and Diacylglycerol (DAG). IP3 acts on IP3R to release calcium ions in the endoplasmic reticulum calcium reservoir and promote insulin secretion 8; meanwhile, DAG may also directly activate protein kinase C or activate exocytosis of insulin granules to secrete insulin by activating DAG-sensitive protein kinase D1(PrKD1) to polymerize fibrillar Actin (F-Actin). The GPR40 receptor is also a blood glucose dependent insulinotropic secretion target. That is, the drug promotes insulin secretion only when the blood glucose concentration is too high; when the blood glucose concentration is normal, the insulin secretion amount does not increase even when the drug is administered. This greatly reduces the risk of hypoglycemia. Based on the above, GPR40 agonists can be used to treat type II diabetes and related indications. Therefore, the discovery and modification of GPR40 agonists are of great importance for scientific research and clinical application.
A series of patent applications for GPR40 agonists are currently disclosed, including WO2011069958, US2011053974, WO2016019863, WO2010085525, US2012004166, US20150148347, WO 0202015184, WO2014073904, and WO2015088868, among others.
Although a series of patent applications for GPR40 agonists have been published, there is still a need to develop new compounds with better potency. The invention designs sulfoxide acetic acid or sulfone acetic acid derivatives with the structure shown in the general formula (I) and can stimulate GPR40 receptor and reduce blood sugar activity.
Disclosure of Invention
The invention aims to provide sulfoxide acetic acid or sulfone acetic acid derivatives shown as a general formula (I), racemes, enantiomers or diastereomers thereof, or pharmaceutically acceptable salts thereof. The compounds show high agonistic activity to GPR40 receptor and can be used as medicaments for treating diabetes and/or metabolic syndrome.
Still another object of the present invention is to provide a method for preparing the above-mentioned sulfoxideacetic acid or sulfoneoacetic acid derivatives represented by the general formula (I).
Still another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of sulfoxylacetic acids or sulfoxylacetic acid-based derivatives represented by the general formula (I) according to the present invention and pharmaceutically acceptable salts thereof as an active ingredient. The pharmaceutical composition optionally may further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
Still another object of the present invention is to provide the use of the above-mentioned sulfoxy acetic acid or sulfuryl acetic acid derivatives, racemates, enantiomers or diastereomers, or pharmaceutically acceptable salts thereof, or the use of a pharmaceutical composition containing the above-mentioned sulfoxy acetic acid or sulfuryl acetic acid derivatives, racemates, enantiomers or diastereomers, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating diabetes and/or metabolic syndrome.
Still another object of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of one or more selected from the group consisting of sulfoxy acetic acid or sulfoxy acetic acid derivatives represented by the general formula (I), racemates, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof according to the present invention as an active ingredient and other pharmaceutically acceptable therapeutic agents, particularly other drugs for treating diabetes. The pharmaceutical composition optionally may further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
It is still another object of the present invention to provide a method for treating diabetes and/or metabolic syndrome, which comprises administering a therapeutically effective amount of one or more selected from the group consisting of sulfoxyacetic acid or sulfoxyacetic acid derivatives represented by the general formula (I) according to the present invention, racemates, enantiomers or diastereomers thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to the present invention comprising a therapeutically effective amount of one or more selected from the group consisting of compounds according to the present invention and pharmaceutically acceptable salts thereof as an active ingredient, to a patient in need of such treatment.
In a first aspect of the present invention, there is provided a sulfoxylacetic acid or sulfurylacetic acid derivative, its racemate, enantiomer or diastereomer, or a pharmaceutically acceptable salt thereof, represented by general formula (I):
wherein: r3Is composed of
The R is4Is hydroxy, amino, -NHOH or
n is 1 or 2;
y is-O-, -O-CH2-，-NH-CH2-，-CH2-O-，-CH2-NH-or-C ≡ C-;
ring C is a benzene ring, a thiophene ring or a pyridine ring;
ring A is a benzene ring, a thiophene ring, a thiazole ring, a pyridine ring, an indene ring or a tetrahydroindene ring;
R2is hydrogen, halogen, cyano, hydroxy, nitro, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C10Carbocyclic radical or C3-C10C is a carbocyclic group1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C10Carbocyclyl, C3-C10The carbocyclic group is optionally further substituted with one or more substituents selected from halogen, cyano, hydroxy;
ring B is a benzene ring, a pyridine ring, a pyrazole ring, a pyrimidine ring, an isoxazole ring or is absent;
R1and R5Is a substituent on the ring B, and is independently selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C10Carbocyclic radical or C3-C10C is a carbocyclic group1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C10Carbocyclic radical or C3-C10The carbocyclic group is optionally further substituted with one or more substituents selected from halogen, cyano, or hydroxy;
preferably, the first and second electrodes are formed of a metal,
R3is composed of
Wherein R is4Is hydroxy, -NHOH or
n is 1 or 2;
y is-O-, -O-CH2-，-CH2-O-or-C ≡ C-;
ring C is a benzene ring or a thiophene ring;
ring A is a benzene ring, a thiazole ring or a tetrahydroindene ring;
R2is hydrogen, halogen or C1-C6Alkyl radical, said C1-C6Alkyl is further substituted with one or more substituents selected from halogen, cyano or hydroxy;
ring B is independently selected from a benzene ring, a pyridine ring, a pyrazole ring, an isoxazole ring or is absent;
R1and R5Is a substituent on the ring B and is independently selected from hydrogen, halogen, cyano, C1-C6Alkyl or C1-C6Alkoxy radical, said C1-C6Alkyl is further substituted with one or more substituents selected from halogen, cyano or hydroxy;
it is further preferred that the first and second liquid crystal compositions,
R3is composed of
Wherein R is4Is hydroxy, -NHOH or
n is 1 or 2;
y is-O-, -O-CH2-、-CH2-O-or-C ≡ C-;
ring C is a benzene ring or a thiophene ring;
ring A is a benzene ring, a thiazole ring or a tetrahydroindene ring;
R2is hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl;
ring B is a benzene ring, a pyridine ring, a pyrazole ring, an isoxazole ring or is absent;
R1and R5Is a substituent on ring B and is each independently selected from hydrogen, fluoro, chloro, bromo, methyl or methoxy.
In a preferred embodiment of the present invention, the compound of the general formula (I) is a compound represented by one of the following general formulae:
wherein, ring A, ring B, ring C, R1，R2And R5The same as defined in the general formula (I).
In a preferred embodiment of the invention, the compounds of formula (I) are inventive compounds preferably selected from the following compounds:
or a racemate, an enantiomer, a diastereomer, and a pharmaceutically acceptable salt thereof.
The compounds of the invention may contain one or more asymmetric centers and may thus occur as racemates and as single enantiomers, mixtures of diastereomers and as single diastereomers. The compounds of the invention may have one asymmetric center at the sulfoxide functionality, and other asymmetric centers may occur depending on the nature of the substituents in the molecule. Such asymmetric centers will each independently produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds.
In a second aspect of the invention, there is also provided a process for the preparation of a compound of formula (I) according to the invention, said process being one of the following schemes.
The first scheme is as follows:
wherein ring A, ring B, ring C, R1、R2And R5Is as defined in formula (I), and the PG may be an ethyl group or a tert-butyl group.
The first scheme comprises the following steps:
(a) the alcohol compound (IV) can be obtained by dissolving the boric acid compound (II) and the bromo-compound (III) in a solvent, and reacting at 70-100 ℃ in the presence of alkali and under the catalysis of a palladium catalyst. Wherein the palladium catalyst is selected from tetrakis (triphenylphosphine) palladium, palladium chloride, palladium acetate, palladium trifluoroacetate, tris (dibenzylideneacetone) dipalladium, bis (acetonitrile) palladium chloride and the like, preferably tetrakis (triphenylphosphine) palladium; the alkali is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium monohydrogen phosphate and the like, and is preferably sodium carbonate; the solvent is one or more selected from tetrahydrofuran, 1, 4-dioxane, isopropanol and water, and is preferably a mixed solvent of 1, 4-dioxane and water in a volume ratio of 1: 3-1: 4;
(b) reacting the obtained alcohol compound (IV) under the action of carbon tetrabromide or carbon tetrachloride (preferably carbon tetrabromide) and triphenylphosphine to obtain a bromo compound (V);
(d) then carrying out SN2 affinity reaction on the bromo compound (V) and the thioether compound (VIII) under the action of alkali to obtain a compound (IX), wherein the alkali is selected from organic alkali and inorganic alkali, the organic alkali is selected from triethylamine, diisopropylamine and the like, and the inorganic alkali is selected from potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium monohydrogen phosphate and the like; preferably potassium carbonate;
(c) compound (VIII) can be prepared by reacting compounds (VI) and (VII) under basic conditions, the base being selected from organic bases selected from triethylamine, diisopropylamine, etc., and inorganic bases;
(e) compound (IX) is oxidizable to compound (X) at room temperature with an oxidizing agent selected from the group consisting of hydrogen peroxide, m-chloroperoxybenzoic acid, peroxyacetic acid, and the like, most preferably m-chloroperoxybenzoic acid;
(f) compound (IX) can be oxidized to compound (XI) by an oxidizing agent selected from hydrogen peroxide, m-chloroperoxybenzoic acid, peroxyacetic acid, and the like, most preferably m-chloroperoxybenzoic acid, at-20 ℃;
(g) compound (X) or compound (XI) is hydrolyzed under basic conditions to give compounds (XIII) and (XII), respectively, the base being selected from organic bases and inorganic bases selected from potassium hydroxide, sodium hydroxide, lithium hydroxide monohydrate, and the like, preferably lithium hydroxide monohydrate.
Scheme II:
compound (XIV) forms negative ions in the presence of butyllithium, and its reaction with sulfur powder and compound (VII) also gives compound (IX).
Wherein ring A, ring B, ring C, R1、R2And R5Is as defined in formula (I), PG may be ethyl or tert-butyl.
The second scheme comprises the following steps:
(h) forming negative ions by the compound (XIV) in the presence of a lithium reagent, and then further reacting with sulfur powder and the compound (VII) to obtain a compound (IX); the lithium reagent is selected from n-butyllithium and tert-butyllithium, preferably n-butyllithium;
(e) compound (IX) can be oxidized to compound (XI) by an oxidizing agent selected from hydrogen peroxide, m-chloroperoxybenzoic acid, peroxyacetic acid, and the like, most preferably m-chloroperoxybenzoic acid, at-20 ℃;
(f) compound (IX) is oxidizable to compound (X) at room temperature with an oxidizing agent selected from the group consisting of hydrogen peroxide, m-chloroperoxybenzoic acid, peroxyacetic acid, and the like, most preferably m-chloroperoxybenzoic acid;
(g) compound (X) or compound (XI) is hydrolyzed under basic conditions to give compound (XIII) or (XII), respectively, the base being selected from organic bases and inorganic bases selected from potassium hydroxide, sodium hydroxide, lithium hydroxide monohydrate, and the like, preferably lithium hydroxide monohydrate.
The third scheme is as follows:
chiral resolution route of sulfoxide compounds:
wherein ring A, ring B, ring C, R1、R2And R5Is as defined in formula (I), PG may be ethyl or tert-butyl.
The third scheme comprises the following steps:
(i) hydrolyzing the compound (IX) under alkaline conditions to obtain a compound (XV), wherein the base is selected from organic bases and inorganic bases, the inorganic bases are selected from potassium hydroxide, sodium hydroxide, lithium hydroxide monohydrate and the like, and lithium hydroxide monohydrate is preferred;
(j) condensing the compound (XV) with a chiral auxiliary reagent (such as (L) -menthol) under the action of a condensing agent and alkali to obtain a compound (XVI), wherein the condensing agent is selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), Dicyclohexylcarbodiimide (DCC) and the like, preferably EDCI; the base is selected from triethylamine, diisopropylamine, N-dimethyl-4-pyridylamine and the like, and is preferably N, N-dimethyl-4-pyridylamine;
(k) oxidizing the compound (XVI) under an oxide to obtain (XVII); the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid, peroxyacetic acid and the like, and is optimally m-chloroperoxybenzoic acid;
(l) Diastereoisomer (XVII) is resolved by chiral column to obtain optically pure compound (XVIII) and compound (XIX);
(m) Compound (XVIII) or Compound (XIV) is then hydrolyzed under basic conditions, respectively, to give Compound (XX) or Compound (XXI), the base being selected from organic bases and inorganic bases selected from potassium hydroxide, sodium hydroxide, lithium hydroxide monohydrate, etc., preferably lithium hydroxide monohydrate.
And the scheme is as follows:
wherein ring A, ring B, ring C, R1、R2And R5Is as defined in formula (I), PG may be ethyl or tert-butyl.
The fourth scheme comprises the following steps:
(n) reacting the compound (XI) synthesized in the first scheme with hydroxylamine hydrochloride under alkaline conditions to obtain a compound (XXII), wherein the base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide monohydrate and the like, and is preferably potassium hydroxide;
(o) condensing the compound (XII) synthesized in the first scheme with glycine ethyl ester hydrochloride under the action of alkali and a condensing agent to obtain a compound (XXIII), wherein the condensing agent is selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), Dicyclohexylcarbodiimide (DCC) and the like, preferably EDCI; the base is selected from triethylamine, diisopropylamine, N, N-dimethyl-4-pyridylamine and the like, and is preferably N, N-dimethyl-4-pyridylamine;
(p) Compound (XXIII) is hydrolyzed under basic conditions to give Compound (XXIV), the base being selected from organic bases and inorganic bases selected from potassium hydroxide, sodium hydroxide, lithium hydroxide monohydrate, etc., preferably lithium hydroxide monohydrate.
For the compounds of the present invention, there may be an asymmetric center at the sulfoxide functionality, resulting in a racemic mixture of enantiomers. Methods for preparing chiral compounds are provided in the examples, and mixtures of enantiomers can be separated into individual isomers by various methods such as salt formation and crystallization with chiral bases, chiral chromatography, and the like.
The term "protecting group" or "PG" in the present invention means a substituent which is usually used to block or protect a particular functionality when it reacts with other functional groups. For example, "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typical carboxyl protecting groups include cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like.
Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the preparation of a GPR40 receptor agonist.
Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diabetes and/or metabolic syndrome.
Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (e.g., diluent, excipient, etc.) therefor.
In some embodiments, the pharmaceutical composition further comprises an anti-diabetic agent, an anti-hyperglycemic agent, an anti-obesity agent, an anti-platelet agent, an anti-atherosclerotic agent, or a combination thereof.
Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for the treatment of diabetes and/or metabolic syndrome.
Drawings
FIG. 1 the hypoglycemic effect of compound S2 of the present invention on the OGTT model of C57/BL6 mouse;
FIG. 2 hypoglycemic effect of Compound S2 of the present invention on the C57/BL6 mouse OGTT model (TAK-875 as control).
Detailed Description
The invention is further described below with reference to the preparation examples, without restricting the invention.
Process for preparing compounds1HNMR data testing Using Varian Mercury-300Hz or Varian Mercury-400Hz nuclear magnetic resonance with deuterated chloroform (CDCl)3) As solvent, Tetramethylsilane (TMS) was used as internal standard and chemical shift units were ppm. Specific rotation was determined by a P-1030(A012360639) autosterometer. All reaction solvents were purified by conventional methods. Silica gel (200-300 mesh) for column chromatography is produced by the Qingdao ocean chemical industry sub-plant; the TLC silica gel plate is an HSGF-254 thin-layer chromatography silica gel plate produced by a cigarette bench chemical plant, and the thickness of the chromatography plate used for the thin-layer chromatography is 0.2 +/-0.03 mm. Developing by ultraviolet, iodine, potassium permanganate and other methods. The organic solvent was distilled off under reduced pressure in a rotary evaporator. Starting materials such as (2, 6-dimethylphenyl) boronic acid, palladium tetrakistriphenylphosphine, etc., are generally available from commercial sources such as Aldrich Chemicals Co. and Acros Organics, organic solvents petroleum ether (boiling range 60-90 deg.C), methylene chloride, ethyl acetate, methanol, all of analytical purity, supplied by Shanghai Tantake technology, Inc. or national drug group Chemicals, Inc., all of which are not specifically treated except as otherwise indicated.
Preparation of example 1
2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
Reaction reagents and conditions: i) (2, 6-dimethylphenyl) boronic acid, palladium tetratriphenylphosphine, sodium carbonate, water, 1, 4-dioxane; ii) triphenylphosphine, carbon tetrabromide, dichloromethane; iii) ethyl 2-bromoacetate, triethylamine, dichloromethane; iv) potassium carbonate, acetone; v) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃ to room temperature; vi) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Synthesis procedure
Step 1(2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methanol
A sealed reflux condenser flask set-up was charged with magnetons, (2, 6-dimethylphenyl) boronic acid (780mg, 5mmol), (3-bromophenyl) methanol (500. mu.L, 4.17mmol), tetrakistriphenylphosphine palladium (241mg, 0.21mmol), and sodium carbonate (884mg, 8.34 mmol). The reaction was carried out overnight by purging three times and injecting 37.5mL of 1, 4-dioxane and 12.5mL of water. Extraction with dichloromethane, drying over anhydrous sodium sulfate and passage through a silica gel column with ethyl acetate/petroleum ether gave 447mg of a colourless oil.
1H NMR(300MHz,CDCl3)7.46–7.29(m,2H),7.10(t,J＝11.1Hz,5H),4.73(d,J＝5.7Hz,2H),2.01(s,6H)。
Step 23 '- (bromomethyl) -2, 6-dimethyl-1, 1' -biphenyl
(2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methanol (447mg, 2.1mmol) was dissolved in 20mL of dichloromethane. Triphenylphosphine (829mg, 3.16mmol) and carbon tetrabromide (1.047g, 3.16mmol) were added while cooling on ice. After 1h of reaction, concentration and passage through a silica gel column with ethyl acetate/petroleum ether gave 500mg of a colorless oil.
1H NMR(300MHz,CDCl3)7.43–7.32(m,2H),7.20–7.04(m,5H),4.52(s,2H),2.02(s,6H)。
Step 32- ((4-hydroxyphenyl) mercapto) acetic acid ethyl ester
4-Hydroxythiophenol (300mg, 2.378mmol) was weighed out and dissolved in 10mL of dichloromethane. Triethylamine (1.6mL, 11.89mmol) and ethyl 2-bromoacetate (248. mu.L, 2.615mmol) were added and the reaction was allowed to proceed for two hours. And (5) extracting and spin-drying.
1H NMR(300MHz,CDCl3)7.33(d,J＝8.3Hz,2H),6.73(d,J＝8.3Hz,2H),4.12(q,J＝7.1Hz,2H),3.47(s,2H),1.20(t,J＝7.4Hz,3H)。
Step 42- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) mercapto) acetic acid ethyl ester
Ethyl 2- ((4-hydroxyphenyl) mercapto) acetate (800mg, 3.769mmol) prepared in step 3 was weighed out and dissolved in 10mL of acetone, and potassium carbonate (1.42g, 10.228mmol) was added. After stirring for 30min, 3'- (bromomethyl) -2, 6-dimethyl-1, 1' -biphenyl (943mg, 3.426mmol) was added and reacted overnight. Extraction with dichloromethane, drying over anhydrous sodium sulfate, and passing through silica gel column with ethyl acetate/petroleum ether gave 285mg of colorless oil.
1H NMR(400MHz,CDCl3)7.50–7.34(m,4H),7.22–7.07(m,5H),6.92(d,J＝8.7Hz,2H),5.10(s,2H),4.23–4.11(m,2H),3.51(s,2H),2.01(s,6H),1.21(t,J＝7.1Hz,3H)。
Step 52 Ethyl- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetate
Ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) mercapto) acetate (285mg, 0.701mmol) was weighed out and dissolved in 5mL of dichloromethane. Cooled to-20 ℃ and 86.38% (140mg, 0.701mmol) of m-chloroperoxybenzoic acid was dissolved in 3mL of dichloromethane and slowly poured into the system. After 1h, warm to room temperature. Extraction with dichloromethane, drying over anhydrous sodium sulfate and passage through silica gel column with ethyl acetate/petroleum ether gave 166mg of white solid.
1H NMR(300MHz,CDCl3)7.63(d,J＝8.8Hz,2H),7.52–7.35(m,2H),7.24–7.03(m,7H),5.17(s,2H),4.13(t,J＝6.5Hz,2H),3.87(d,J＝13.5Hz,1H),3.62(d,J＝13.5Hz,1H),2.01(s,6H),1.21(t,J＝7.2Hz,3H)。
Step 62- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
Ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate (166mg, 0.393mmol) was weighed out and dissolved in 2mL of tetrahydrofuran, followed by addition of 2mL of methanol and 1mL of water. Lithium hydroxide monohydrate (50mg,1.179mmol) was added, reacted for 30min, and then made acidic with dilute hydrochloric acid. Extraction with dichloromethane, drying over anhydrous sodium sulfate, concentration and recrystallization from petroleum ether gave 130mg of a white solid.
1H NMR(400MHz,CDCl3)7.64(d,J＝8.8Hz,2H),7.49(t,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.25–7.08(m,7H),5.19(s,2H),3.87(d,J＝14.6Hz,1H),3.69(d,J＝14.5Hz,1H),2.03(s,6H)。
Preparation of example 2
(S) -2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetic acid (S2)
Reaction reagents and conditions: (i) lithium hydroxide monohydrate, tetrahydrofuran, methanol and water; (ii) (L) -menthol, 4-dimethylaminopyridine, dichloromethane; (iii) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃; (iv) lithium hydroxide monohydrate, tetrahydrofuran, methanol and water.
Synthesis procedure
Step 12- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) mercapto) acetic acid
The procedure for the synthesis of 2- ((4- ((2',6' -dimethyl- [1,1 '-biphenyl ] -3-yl) methoxy) phenyl) mercapto) acetic acid was the same as that for the synthesis of 2- ((4- ((2',6 '-dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid
Step 22- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) mercapto) acetic acid L-menthyl ester
2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) mercapto) acetic acid (366mg,0.967mmol), L-menthol (454mg, 2.901mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (556mg, 2.901mmol) and 4-Dimethylaminopyridine (DMAP) (59mg, 0.484mmol) were weighed out and dissolved in 10mL of anhydrous dichloromethane and reacted overnight at room temperature. Extraction with dichloromethane, drying over anhydrous sodium sulfate and passage through silica gel column with ethyl acetate/petroleum ether gave 438mg of a colorless oil.
1H NMR(400MHz,CDCl3)7.51–7.39(m,4H),7.22(t,J＝2.4Hz,1H),7.20–7.16(m,1H),7.16–7.09(m,3H),6.97–6.90(m,2H),5.11(s,2H),4.69(td,J＝10.9,4.4Hz,1H),3.54(s,2H),2.04(s,6H),1.98–1.90(m,1H),1.77(dtd,J＝14.1,7.0,2.7Hz,1H),1.67(ddt,J＝16.3,6.4,3.2Hz,2H),1.55–1.41(m,1H),1.41–1.31(m,1H),1.10–1.01(m,1H),1.00–0.94(m,1H),0.91(d,J＝6.6Hz,4H),0.86(d,J＝7.0Hz,4H),0.71(d,J＝6.9Hz,3H)。
Step 32- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid L-menthol ester
Weighing 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl)]-3-yl) methoxy) phenyl) mercapto) acetic acid L-menthyl ester (438mg, 0.848mmol) was dissolved in 10mL of dichloromethane. The temperature was reduced to-20 ℃ and m-chloroperoxybenzoic acid (70%) (209mg, 0.848mmol) was dissolved in 5mL of dichloromethane and slowly poured into the supernatant. And reacting for 1 h. Extracting, spin-drying and passing through a column. Chiral resolution was then performed at room temperature using a xylonite IC 10mmx250mm chiral column eluting with ethanol: hexane (25:75) at a flow rate of 4 mL/min. At the time of peak111 minutes, t2At 13 minutes, two colorless oils were obtained, component one (230mg) and component two (230mg), respectively.
1H NMR(300MHz,CDCl3)7.64(d,J＝8.7Hz,2H),7.51–7.33(m,2H),7.23–7.03(m,7H),5.15(s,2H),4.67(td,J＝11.0,4.5Hz,1H),3.89(d,J＝13.4Hz,1H),3.64(d,J＝13.2Hz,1H),2.01(s,6H),1.79(dd,J＝8.3,5.4Hz,2H),1.66(d,J＝11.5Hz,2H),1.28(dt,J＝8.6,5.9Hz,3H),1.13–0.91(m,1H),0.87(dd,J＝6.6,2.8Hz,8H),0.72(d,J＝7.0Hz,3H)。
Step 4(S) -2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S2)
Weigh fraction one prepared in step 3 (220mg, 0.520mmol) in 4mL tetrahydrofuran, and add 4mL methanol and 2mL water. Lithium hydroxide monohydrate (65mg, 1.56mmol) was added, and after 30min of reaction, the mixture was made acidic with dilute hydrochloric acid, respectively. Extraction with dichloromethane, drying over anhydrous sodium sulfate, concentration and recrystallization from petroleum ether gave 100mg of a white solid.
1H NMR(400MHz,CDCl3)7.64(d,J＝8.8Hz,2H),7.49(t,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.25–7.08(m,7H),5.19(s,2H),3.87(d,J＝14.6Hz,1H),3.69(d,J＝14.5Hz,1H),2.03(s,6H)。[α]20 D＝-104.554(c＝0.5,CH3OH)。
Preparation of example 3
(R) -2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S3)
Component two (220mg, 0.520mmol) prepared from L-menthyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxido) acetate in example 2 was weighed and dissolved in 4mL of tetrahydrofuran, followed by addition of 4mL of methanol and 2mL of water. Lithium hydroxide monohydrate (65mg, 1.56mmol) was added, and after 30min of reaction, the mixture was made acidic with dilute hydrochloric acid, respectively. Extraction with dichloromethane, drying over anhydrous sodium sulfate, concentration and recrystallization from petroleum ether gave 110mg of a white solid.
1H NMR(400MHz,CDCl3)7.64(d,J＝8.8Hz,2H),7.49(t,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.25–7.08(m,7H),5.19(s,2H),3.87(d,J＝14.6Hz,1H),3.69(d,J＝14.5Hz,1H),2.03(s,6H)。[α]20 D＝101.787(c＝0.5,CH3OH)。
The absolute configuration of the compound is determined to be R type through crystallization and single crystal diffraction experiments.
Preparation of example 4
2- ((3- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetic acid (S4)
The synthesis procedure is as in example 1
1H NMR(400MHz,CDCl3)7.50–7.36(m,3H),7.26–7.06(m,7H),5.14(s,2H),3.75(br,2H),2.05(d,J＝23.8Hz,6H)。
Preparation of example 5
2- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) sulfoxy) acetic acid (S5)
Reaction reagents and conditions: i) sodium borohydride, methanol; ii) ethyl 2- ((4-hydroxyphenyl) mercapto) acetate, diethyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0 ℃ to room temperature; iii) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃; iv) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Synthesis step 14-chloro-2, 3-dihydro-1H-inden-1-ol
Weighing 4-chloro-2, 3-dihydro-1H-inden-1-one (200mg, 1.2mmol) and dissolving in 10mL of methanol, adding sodium borohydride (46mg, 1.2mmol) and reacting at room temperature for 1H. Extraction, drying over anhydrous sodium sulfate, and concentration to give 4-chloro-2, 3-dihydro-1H-inden-1-ol (100 mg).
1H NMR(400MHz,CDCl3)7.33(d,J＝7.8Hz,1H),7.28(d,J＝7.4Hz,1H),7.22(t,J＝7.9Hz,1H),5.35–5.25(m,1H),3.13(ddd,J＝16.7,8.7,4.6Hz,1H),2.94–2.78(m,1H),2.61–2.49(m,1H),2.05–1.94(m,1H)。
Step 22- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) mercapto) acetic acid ethyl ester
The 4-chloro-2, 3-dihydro-1H-inden-1-ol (100mg, 0.593mmol) prepared in step 1, ethyl 2- ((4-hydroxyphenyl) mercapto) acetate (84mg, 0.395mmol) and triphenylphosphine (166mg, 0.632mmol) were weighed out and dissolved in 6mL of tetrahydrofuran, diethyl azodicarboxylate (100. mu.L, 0.632mmol) was injected under ice bath, and the mixture was warmed to room temperature for reaction for 3 hours. Extraction with dichloromethane, drying over anhydrous sodium sulfate, concentration and passage through a silica gel column with petroleum ether/ethyl acetate gave 70mg of a colorless oil.
1H NMR(300MHz,CDCl3)7.44(d,J＝8.7Hz,2H),7.30(dd,J＝7.5,2.4Hz,2H),7.24–7.15(m,1H),6.93(d,J＝8.7Hz,2H),5.76(dd,J＝6.6,4.4Hz,1H),4.16(q,J＝7.1Hz,2H),3.53(s,2H),3.17(ddd,J＝16.3,8.9,5.4Hz,1H),3.08–2.81(m,1H),2.74–2.47(m,1H),2.21(dq,J＝7.4,4.9Hz,1H),1.23(t,J＝7.1Hz,3H)。
Step 32- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) sulfoxy) acetic acid ethyl ester
The synthesis procedure was as for ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate
1H NMR(300MHz,CDCl3)7.66(d,J＝8.7Hz,2H),7.32(t,J＝6.8Hz,2H),7.21(t,J＝7.9Hz,1H),7.12(d,J＝8.6Hz,2H),5.85(dd,J＝6.2,4.4Hz,1H),4.16(q,J＝7.1Hz,2H),3.89(d,J＝13.5Hz,1H),3.65(d,J＝13.5Hz,1H),3.28–3.12(m,1H),3.08–2.92(m,1H),2.72–2.55(m,1H),2.29–2.15(m,1H),1.23(t,J＝7.1Hz,3H)。
Step 42- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) sulfoxy) acetic acid (S5)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(400MHz,CDCl3)7.69(d,J＝8.7Hz,2H),7.35(t,J＝8.7Hz,2H),7.24(t,J＝7.7Hz,1H),7.17(d,J＝8.6Hz,2H),5.87(dd,J＝6.4,4.0Hz,1H),3.90(d,J＝15.9Hz,1H),3.81(d,J＝14.3Hz,1H),3.21(ddd,J＝16.4,8.6,5.5Hz,1H),3.02(ddd,J＝16.8,8.7,5.3Hz,1H),2.71–2.58(m,1H),2.31–2.18(m,1H)。
Preparation of example 6
2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfone) acetic acid (S6)
Reaction reagents and conditions i) m-chloroperoxybenzoic acid, dichloromethane, room temperature; ii) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water;
synthesis procedure
Step 12- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfonyl) acetic acid ethyl ester
Weighing 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl)]-3-yl) methoxy) phenyl) mercapto) acetic acid ethyl ester (135mg, 0.332mmol) was dissolved in 3mL of dichloromethane, m-chloroperoxybenzoic acid (246mg, 0.996mmol) was added to react overnight, extracted, dried, VEthyl acetate/(VEthyl acetate+VPetroleum ether) Silica gel column chromatography of 15/100 gave the product as a white solid, 132 mg.
1H NMR(300MHz,CDCl3)7.87(d,J＝8.8Hz,2H),7.47(t,J＝7.7Hz,1H),7.39(d,J＝7.7Hz,1H),7.23–7.03(m,7H),5.20(s,2H),4.15(q,J＝7.0Hz,2H),4.08(s,2H),2.01(s,6H),1.21(t,J＝7.2Hz,3H)。
Step 22- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfonyl) acetic acid (S6)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(300MHz,CDCl3)7.88(d,J＝8.8Hz,2H),7.47(t,J＝7.6Hz,1H),7.39(d,J＝7.9Hz,1H),7.20(s,1H),7.19–7.05(m,6H),5.20(s,2H),4.12(s,2H),2.00(s,6H)。
Preparation of example 7
2- ((3- ((2',6' -dimethyl- [1,1' -biphenyl ] -4-yl) methoxy) phenyl) sulfoxide) acetic acid (S7)
The synthesis procedure is as in example 1
1H NMR(300MHz,CDCl3)7.48(dd,J＝7.5,4.3Hz,3H),7.37(d,J＝1.1Hz,1H),7.17(dt,J＝14.6,8.0Hz,7H),5.16(s,2H),3.89(d,J＝15.2Hz,1H),3.68(d,J＝14.2Hz,1H),2.03(s,6H)。
Preparation of example 8
2- ((4- ((2-methylphenyl) oxy) phenyl) sulfoxide) acetic acid (S8)
The synthesis procedure is as in example 1
1H NMR(300MHz,CDCl3)7.65(d,J＝8.6Hz,2H),7.38(d,J＝7.2Hz,1H),7.33–7.19(m,4H),7.14(d,J＝8.5Hz,2H),5.09(s,2H),3.85(d,J＝15.0Hz,1H),3.71(d,J＝14.5Hz,1H),2.37(s,3H)。
Preparation of example 9
2- ((4- ((2-methylphenyl) oxy) phenyl) sulfonyl) acetic acid (S9)
The synthesis procedure was as in example 6
1H NMR(400MHz,CDCl3)7.96(d,J＝8.6Hz,2H),7.73(d,J＝8.6Hz,2H),7.53(d,J＝7.5Hz,1H),7.30(ddd,J＝12.9,9.6,3.7Hz,2H),7.22(dd,J＝7.4,1.4Hz,1H),7.19(d,J＝1.2Hz,0H),4.21(s,2H),2.54(s,3H)。
Preparation of example 10
2- ((4- (o-tolylethynyl) phenyl) sulfoxide) acetic acid isomer 1(S10)
Reaction reagents and conditions: i) ethyl 2-bromoacetate, potassium carbonate, N-dimethylformamide; ii) 1-ethynyl-2-toluene, cuprous iodide, palladium dichlorotriphenylphosphine, triethylamine, N-dimethylformamide; iii) lithium hydroxide monohydrateTetrahydrofuran, methanol, water; iv) L-menthol, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N-dimethylaminopyridine, dichloromethane; v) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃; vi) Daxylonite IC 10mmx250mm, VEthanol/(VEthanol+VN-hexane)＝10/100，t114.960 min, t217.224 minutes.
Synthesis procedure
Step 12- ((4-bromophenyl) mercapto) acetic acid ethyl ester
4-Bromobenzothiophenol (644mg, 3.406mmol) was weighed out and dissolved in 10mL of N, N-dimethylformamide, potassium carbonate (1.4g, 10.218mmol) was added, and ethyl 2-bromoacetate (567. mu.L, 5.109mmol) was added and stirred at room temperature overnight. After the reaction is finished, ethyl acetate is used for extraction, drying and petroleum ether is used for passing through a silica gel column.
1H NMR(400MHz,CDCl3)7.42(d,J＝8.6Hz,2H),7.28(d,J＝8.6Hz,2H),4.17(q,J＝7.1Hz,2H),3.61(s,2H),1.23(t,J＝7.1Hz,3H)。
Step 22- ((4- (o-tolylethynyl) phenyl) mercapto) acetic acid ethyl ester
Ethyl 2- ((4-bromophenyl) mercapto) acetate (694mg, 2.522mmol), 1-ethynyl-2-toluene (477. mu.L, 3.783mmol), palladium monochloroditriphenylphosphine (89mg, 0.126mmol) and cuprous iodide (48mg, 0.252mmol) were weighed into a 100mL flask. 20mL of N, N-dimethylformamide and 1.7mL of triethylamine were added, the temperature was raised to 90 ℃ and the reaction was carried out overnight. Extraction, drying and passing through a silica gel column using a mixed solution of ethyl acetate and petroleum ether (V/V. 5/95) gave 669mg as a colorless oil.
1H NMR(300MHz,CDCl3)7.51–7.42(m,3H),7.36(d,J＝8.3Hz,2H),7.23(d,J＝4.1Hz,2H),7.20–7.11(m,1H),4.19(q,J＝7.2Hz,2H),3.67(s,2H),2.50(s,3H),1.25(t,J＝7.1Hz,3H)。
Step 32- ((4- (o-tolylethynyl) phenyl) mercapto) acetic acid
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(300MHz,CDCl3)7.52–7.44(m,3H),7.37(d,J＝8.0Hz,2H),7.23(d,J＝2.9Hz,2H),7.20–7.12(m,1H),3.72(s,2H),2.50(s,3H)。
Step 42- ((4- (o-tolylethynyl) phenyl) mercapto) acetic acid (L) -menthyl ester
The synthesis procedure was as for L-menthyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) mercapto) acetate
1H NMR(400MHz,CDCl3)7.49(dd,J＝14.5,7.8Hz,3H),7.38(d,J＝8.4Hz,2H),7.28–7.24(m,2H),7.23–7.15(m,1H),4.72(td,J＝10.9,4.3Hz,1H),3.69(s,2H),2.53(s,3H),1.96(d,J＝12.3Hz,1H),1.81–1.74(m,1H),1.73–1.63(m,2H),1.48(ddd,J＝11.9,8.1,3.6Hz,1H),1.42–1.33(m,1H),1.13–0.94(m,2H),0.92(d,J＝6.5Hz,3H),0.87(d,J＝7.1Hz,3H),0.71(d,J＝6.9Hz,3H)。
Step 52- ((4- (O-methylacetylenyl) phenyl) sulfoxido) acetic acid (L) -menthyl ester
The synthesis procedure was as for ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate
HPLC chiral resolution conditions: dailco IC 10mmx250mm chiral column using mixed solution V of ethanol and hexaneEthanol/(VEthanol+VN-hexane) 10/100, eluted at a flow rate of 4mL/min at the time of peak appearance t114.960 min, t2When 17.224 minutes, two colorless oils were obtained, component one (60mg) and component two (80mg), respectively
The component one:
1H NMR(400MHz,CDCl3)7.77–7.64(m,4H),7.53(d,J＝7.5Hz,1H),7.28(d,J＝13.8Hz,2H),7.25–7.18(m,1H),4.73(td,J＝10.9,4.4Hz,1H),3.91(d,J＝13.5Hz,1H),3.72(d,J＝13.5Hz,1H),2.54(s,3H),1.85(dd,J＝12.5,10.2Hz,2H),1.69(d,J＝13.2Hz,2H),1.53–1.44(m,1H),1.42–1.34(m,1H),1.05(dt,J＝17.3,10.6Hz,1H),0.91(d,J＝6.9Hz,6H),0.86(dd,J＝12.4,4.7Hz,1H),0.77(d,J＝6.9Hz,3H)。
and (2) component two:
1H NMR(400MHz,CDCl3)7.77–7.64(m,4H),7.53(d,J＝7.5Hz,1H),7.28(d,J＝13.8Hz,2H),7.25–7.18(m,1H),4.73(td,J＝10.9,4.4Hz,1H),3.91(d,J＝13.5Hz,1H),3.72(d,J＝13.5Hz,1H),2.54(s,3H),1.85(dd,J＝12.5,10.2Hz,2H),1.69(d,J＝13.2Hz,2H),1.53–1.44(m,1H),1.42–1.34(m,1H),1.05(dt,J＝17.3,10.6Hz,1H),0.91(d,J＝6.9Hz,6H),0.86(dd,J＝12.4,4.7Hz,1H),0.77(d,J＝6.9Hz,3H)。
step 62- ((4- (o-tolylethynyl) phenyl) sulfoxide) acetic acid isomer 1(S10)
The synthesis procedure was the same as 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetic acid (S1), and component one was hydrolyzed to give 40mg of 2- ((4- (o-tolylethynyl) phenyl) sulfoxide) acetic acid isomer 1 (S10).
1H NMR(400MHz,CDCl3)7.71(s,4H),7.52(d,J＝7.4Hz,1H),7.32–7.24(m,2H),7.20(td,J＝7.1,1.7Hz,1H),3.94–3.80(m,2H),2.53(s,3H)。
Preparation of example 11
2- ((4- (o-tolylethynyl) phenyl) sulfoxide) acetic acid isomer 2(S11)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetic acid (S1), and component two from example 10 was hydrolyzed to give 60mg of 2- ((4- (o-tolylethynyl) phenyl) sulfoxide) acetic acid isomer 2 (S11).
1H NMR(400MHz,CDCl3)7.71(s,4H),7.52(d,J＝7.4Hz,1H),7.32–7.24(m,2H),7.20(td,J＝7.1,1.7Hz,1H),3.94–3.80(m,2H),2.53(s,3H)。
Preparation of example 12
2- ((4- (o-methylacetylenyl) phenyl) sulfone) acetic acid (S12)
Reaction reagents and conditions: i) meta-chloroperoxybenzoic acid, dichloromethane, room temperature; ii) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water, 0 ℃.
Step 12- ((4- (o-tolylethynyl) phenyl) sulfonyl) acetic acid (L) -menthyl ester
Ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfone) acetate was synthesized using the product obtained in the 4 th step of example 10 as a starting material.
1H NMR(300MHz,CDCl3)7.88(d,J＝8.8Hz,2H),7.37(d,J＝7.3Hz,1H),7.33–7.19(m,3H),7.11(d,J＝8.9Hz,2H),5.11(s,2H),4.67(td,J＝10.9,3.9Hz,1H),4.08(s,2H),2.37(s,3H),1.91(d,J＝12.6Hz,1H),1.82–1.72(m,1H),1.66(d,J＝9.6Hz,2H),1.41(s,1H),1.37–1.14(m,1H),1.10–0.94(m,2H),0.87(dd,J＝11.3,6.8Hz,6H),0.70(d,J＝6.9Hz,3H)。
Step 22- ((4- (o-tolylethynyl) phenyl) sulfonyl) acetic acid (S12)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfonyl) acetic acid (S6)
1H NMR(400MHz,CDCl3)7.97(d,J＝8.6Hz,2H),7.74(d,J＝8.6Hz,2H),7.54(d,J＝7.7Hz,1H),7.36–7.26(m,2H),7.22(t,J＝7.4Hz,1H),4.20(s,2H),2.55(s,3H)。
Preparation of example 13
2- ((4- (((R) -4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) sulfoxy) acetic acid (S13)
Reaction reagents and conditions: i) triethylamine, formic acid, ruthenium catalyst (RuCl [ (S, S) -Tsdpen ] (mesitylene)); ii) ethyl 2- ((4-hydroxyphenyl) mercapto) acetate, triphenylphosphine, diethyl azodicarboxylate, tetrahydrofuran; iii) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃; iv) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Synthesis procedure
Step 1(S) -4-trifluoromethyl-2, 3-dihydro-1H-inden-1-ol
Formic acid (330. mu.L, 8.743mmol) was slowly added dropwise to triethylamine (1.05mL, 7.494mmol) while cooling on ice. Then, 4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-one (500mg, 2.498mmol) was added at room temperature. After complete dissolution, ruthenium reagent (RuCl [ (S, S) -Tsdpen ] (mesitylene)) (78mg, 0.125mmol) was added at room temperature. The reaction was stirred at room temperature for 3h under nitrogen protection. Extraction with ethyl acetate, washing of the organic layer with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtration, spin-drying, and passage through a silica gel column with ethyl acetate-petroleum ether mixed solvent (V/V-10/90) gave a deep red oil in 85% yield.
1H NMR(300MHz,CDCl3)7.91(d,J＝8.0Hz,1H),7.63–7.41(m,1H),7.32(t,J＝7.8Hz,1H),5.25(t,J＝6.4Hz,1H),3.55(ddd,J＝16.9,8.4,4.5Hz,1H),3.30–3.12(m,1H),2.56(dt,J＝12.3,7.5Hz,1H),2.03–1.92(m,1H)。
Step 2(R) -ethyl 2- ((4- ((4-trifluoromethyl-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) mercapto) acetate
The synthesis procedure was as for ethyl 2- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) mercapto) acetate
1H NMR(300MHz,CDCl3)7.97(d,J＝7.9Hz,1H),7.51(d,J＝7.5Hz,1H),7.46(d,J＝8.8Hz,2H),7.33(t,J＝7.7Hz,1H),6.95(d,J＝8.8Hz,2H),5.81–5.67(m,1H),4.16(q,J＝7.1Hz,2H),3.74–3.55(m,1H),3.46–3.24(m,1H),2.62(td,J＝13.7,7.6Hz,1H),2.31–2.18(m,1H),1.24(t,J＝7.1Hz,3H)。
Step 3 Ethyl (R) -2- ((4- ((4-trifluoromethyl-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) sulphoxide) acetate
The synthesis procedure was as for ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate
1H NMR(300MHz,CDCl3)7.99(d,J＝7.8Hz,1H),7.67(d,J＝8.3Hz,2H),7.52(d,J＝7.6Hz,1H),7.35(t,J＝7.6Hz,1H),7.14(d,J＝8.3Hz,2H),5.82(t,J＝5.6Hz,1H),4.17(q,J＝7.3Hz,2H),3.90(d,J＝14.0Hz,1H),3.65(d,J＝13.4Hz,1H),3.63–3.51(m,1H),3.48–3.28(m,1H),2.78–2.54(m,1H),2.36–2.12(m,1H),1.24(t,J＝7.0Hz,4H)。
Step 42- ((4- (((R) -4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) sulfoxy) acetic acid (S13)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(300MHz,CDCl3)8.01(dd,J＝13.2,8.3Hz,1H),7.68(d,J＝8.2Hz,3H),7.57(dd,J＝27.0,6.8Hz,1H),7.35(t,J＝7.9Hz,1H),7.21–7.10(m,2H),5.82(t,J＝5.3Hz,1H),3.87(d,J＝14.5Hz,1H),3.76(d,J＝14.0Hz,1H),3.69–3.52(m,1H),3.41(dt,J＝19.7,9.2Hz,1H),2.66(dt,J＝12.9,6.8Hz,1H),2.32–2.14(m,1H)。
Preparation of example 14
2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxy) -N-hydroxyacetamide (S14)
Reaction reagents and conditions: i) hydroxylamine hydrochloride, potassium hydroxide and methanol.
Hydroxylamine hydrochloride (66mg, 0.947mmol) was dissolved in 1mL of methanol. Cooled to 0 deg.C, potassium hydroxide (80mg, 1.422mmol) dissolved in 1mL of methanol was added to the supernatant.
Ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) prepared in step 5 of example 1 (100mg, 0.237mmol) was weighed out and dissolved in 1mL of methanol. The supernatant was added slowly to the system. The reaction is carried out for 1h, the pH is adjusted to about 2, dichloromethane is extracted for three times, after low-temperature spin drying, petroleum ether is recrystallized to obtain white solid with the yield of 80%.
1H NMR(400MHz,DMSO-d6)10.71(d,J＝10.4Hz,1H),9.16(s,1H),7.64(dd,J＝17.4,8.8Hz,2H),7.53–7.41(m,2H),7.23(d,J＝8.7Hz,3H),7.13(t,J＝7.8Hz,4H),5.25(s,2H),3.65(d,J＝13.2Hz,1H),3.49(d,J＝13.2Hz,1H),1.94(s,6H)。
Preparation of example 15
2- (2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetamido) acetic acid (S15)
Reaction reagents and conditions: i) glycine hydrochloride, diethyl azodicarboxylate, N-dimethylaminopyridine, dichloromethane; ii) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Step 12- (2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetamido) acetic acid ethyl ester
2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (50mg, 0.127mmol) prepared in step 6 of example 11 was dissolved in 2mL of dichloromethane with glycine hydrochloride (53mg, 0.380mmol), diethyl azodicarboxylate (73mg, 0.380mmol) and N, N-dimethylaminopyridine (16mg, 0.127mmol), and the reaction was stirred at room temperature for 5 hours.
After the reaction was completed, 10mL of dichloromethane was added, and the mixture was washed three times with a saturated sodium chloride solution. Drying with anhydrous sodium sulfate, concentrating, passing through silica gel column, and eluting with mixed solution of ethyl acetate-petroleum ether (V)Ethyl acetate/VPetroleum ether30: 70). 56mg of the product was obtained as a colorless oil.
1H NMR(300MHz,CDCl3)7.59(d,J＝8.7Hz,2H),7.51–7.35(m,3H),7.23–7.06(m,7H),5.15(s,2H),4.22(q,J＝7.1Hz,2H),4.02(d,J＝5.3Hz,2H),3.70(d,J＝14.1Hz,1H),3.53(d,J＝14.2Hz,1H),2.01(s,6H),1.28(t,J＝7.2Hz,3H)。
Step 22- (2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetamido) acetic acid (S15)
The reaction procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(400MHz,DMSO-d6)8.47(t,J＝5.3Hz,1H),7.63(d,J＝8.8Hz,2H),7.55–7.41(m,2H),7.27–7.06(m,7H),5.25(s,2H),3.78(d,J＝5.2Hz,4H),1.95(s,6H)。
Preparation of example 16
2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -4-yl) methoxy) phenyl) sulfoxide) acetic acid (S16)
The synthesis procedure is as in example 1
1H NMR(300MHz,DMSO-d6)7.68(d,J＝8.7Hz,2H),7.53(d,J＝7.8Hz,2H),7.24(d,J＝8.7Hz,2H),7.20–7.06(m,5H),5.21(s,2H),3.92(d,J＝14.2Hz,1H),3.79(d,J＝14.3Hz,1H),1.95(s,6H)。
Preparation of example 17
2- ((4- ((3- (3-chloropyridin-4-yl) phenyl) oxy) phenyl) sulfoxido) acetic acid (S17)
Reaction reagents and conditions: i) triphenylphosphine, diethyl azodicarboxylate, tetrahydrofuran; ii) 3-chloro-4-pyridinediboronate, (2, 6-dimethylphenyl) boronic acid, palladium tetratriphenylphosphine, sodium carbonate, water, 1, 4-dioxane; iii) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃ to room temperature; iv) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Step 12- ((4- ((3-bromophenyl) oxy) phenyl) mercapto) acetic acid ethyl ester
The synthesis procedure was as for ethyl 2- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) mercapto) acetate
1H NMR(300MHz,CDCl3)7.58(s,1H),7.44(t,J＝9.3Hz,3H),7.33(d,J＝7.5Hz,1H),7.26(d,J＝7.6Hz,1H),6.90(d,J＝8.2Hz,2H),5.01(s,2H),4.14(q,J＝7.2Hz,2H),3.52(s,2H),1.21(t,J＝7.1Hz,3H)。
Step 22- ((4- ((3- (3-Chloropyridin-4-yl) phenyl) oxy) phenyl) mercapto) acetic acid ethyl ester
The synthetic procedure is as for (2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methanol
1H NMR(300MHz,CDCl3)8.68(s,1H),8.53(d,J＝5.0Hz,1H),7.57–7.39(m,6H),7.29(d,J＝4.8Hz,1H),6.93(d,J＝8.8Hz,2H),5.12(s,2H),4.19–4.10(m,2H),3.52(s,2H),1.21(t,J＝7.1Hz,3H)。
Step 32- ((4- ((3- (3-Chloropyridin-4-yl) phenyl) oxy) phenyl) sulfoxy) acetic acid ethyl ester
The synthesis procedure was as for ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate
1H NMR(300MHz,CDCl3)8.68(s,1H),8.53(d,J＝5.0Hz,1H),7.64(d,J＝8.7Hz,2H),7.58–7.41(m,4H),7.29(d,J＝4.9Hz,1H),7.12(d,J＝8.7Hz,2H),5.18(s,2H),4.14(q,J＝7.1Hz,2H),3.87(d,J＝13.5Hz,1H),3.63(d,J＝13.5Hz,1H),1.20(t,J＝7.1Hz,3H)。
Step 42- ((4- ((3- (3-Chloropyridin-4-yl) phenyl) oxy) phenyl) sulfoxido) acetic acid (S17)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(300MHz,CDCl3)8.67(s,1H),8.52(d,J＝5.6Hz,1H),7.66(d,J＝8.3Hz,2H),7.49(dd,J＝17.1,4.1Hz,4H),7.32(d,J＝5.1Hz,1H),7.12(d,J＝8.4Hz,2H),5.18(s,2H),3.79(dd,J＝16.6,12.5Hz,2H)。
Preparation of example 18
2- ((4- ((3- (3, 5-Dimethylisoxazol-4-yl) phenyl) oxy) phenyl) sulfoxy) acetic acid (S18)
Reaction reagents and conditions: i) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃; ii) (2, 6-dimethylphenyl) boronic acid, palladium tetratriphenylphosphine, sodium carbonate, water, 1, 4-dioxane; iii) triphenylphosphine, diethyl azodicarboxylate, tetrahydrofuran; iv) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Step 12- ((4-hydroxyphenyl) sulfoxide) acetic acid ethyl ester
The synthesis procedure was as for ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate
1H NMR(400MHz,CDCl3)7.56(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,2H),4.16(q,J＝7.1Hz,2H),3.97(d,J＝13.7Hz,1H),3.70(d,J＝13.7Hz,1H),1.22(t,J＝7.1Hz,3H)。
Step 2(3- (3, 5-Dimethylisoxazol-4-yl) phenyl) methanol
The synthetic procedure is as for (2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methanol
1H NMR(300MHz,CDCl3)7.43(t,J＝7.5Hz,1H),7.36(d,J＝7.7Hz,1H),7.26(s,1H),7.18(d,J＝7.4Hz,1H),4.75(d,J＝5.5Hz,2H),2.40(s,3H),2.27(s,3H)。
Step 32- ((4- ((3- (3, 5-Dimethylisoxazol-4-yl) phenyl) oxy) phenyl) sulfoxy) acetic acid ethyl ester
The synthesis procedure was as for ethyl 2- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) mercapto) acetate
1H NMR(300MHz,CDCl3)7.65(d,J＝8.8Hz,2H),7.44(dd,J＝15.9,7.4Hz,2H),7.31(s,1H),7.23(s,1H),7.12(d,J＝8.6Hz,2H),5.16(s,2H),4.14(q,J＝7.3Hz,2H),3.88(d,J＝13.5Hz,1H),3.63(d,J＝13.6Hz,1H),2.40(s,3H),2.26(s,3H),1.22(t,J＝7.2Hz,3H)。
Step 42- ((4- ((3- (3, 5-Dimethylisoxazol-4-yl) phenyl) oxy) phenyl) sulfoxy) acetic acid (S18)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(400MHz,CDCl3)7.67(d,J＝8.7Hz,2H),7.51(t,J＝7.7Hz,1H),7.44(d,J＝7.9Hz,1H),7.33(s,1H),7.27(d,J＝7.9Hz,1H),7.16(d,J＝8.6Hz,2H),5.19(s,2H),3.87(d,J＝14.6Hz,1H),3.72(d,J＝14.4Hz,1H),2.42(s,3H),2.28(s,3H)。
Preparation of example 19
2- ((4- ((3- (1-methyl-1H-pyrazol-4-yl) benzyl) oxy) phenyl) sulfoxy) acetic acid (S19)
The synthesis procedure is as in example 1
1H NMR(400MHz,DMSO-d6)8.16(s,1H),7.88(s,1H),7.68(d,J＝8.1Hz,3H),7.54(d,J＝7.6Hz,1H),7.39(t,J＝7.8Hz,1H),7.29(d,J＝7.4Hz,1H),7.24(d,J＝8.5Hz,2H),5.18(s,2H),3.93(d,J＝14.2Hz,1H),3.87(s,3H),3.80(d,J＝14.2Hz,1H)。
Preparation of example 20
2- ((4- ((2- (4-fluorophenyl) -4-methylthiazol-5-yl) methoxy) phenyl) sulfoxy) acetic acid (S20)
Reaction reagents and conditions: i) refluxing Lawson's reagent and tetrahydrofuran; ii) ethyl 2-chloroacetoacetate, ethanol, refluxing; iii) lithium aluminum hydride, diethyl ether; iv) ethyl 2- ((4-hydroxyphenyl) mercapto) acetate, triphenylphosphine, diethyl azodicarboxylate, tetrahydrofuran; v) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃; vi) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Synthesis procedure
Step 14-Fluorothiobenzamide
4-fluorobenzamide (2g, 14.375mmol) and Lawson's reagent (6.395g, 15.813mmol) were dissolved in 45mL of tetrahydrofuran and heated to reflux for 4 h. Recrystallization from petroleum ether and dichloromethane gave 2g of a yellow solid.
1H NMR(400MHz,CDCl3)7.93(dd,J＝8.7,5.2Hz,2H),7.11(t,J＝8.6Hz,2H)。
Step 22- (4-fluorophenyl) -4-methylthiazole-5-carboxylic acid ethyl ester
4-Fluorothiobenzamide (500mg,3.222mmol) and ethyl 2-chloroacetoacetate (1.337mL,9.666mmol) were dissolved in 15mL of ethanol and heated at reflux for 2 h. After concentration, the residue was subjected to silica gel chromatography using a mixed solution of petroleum ether and ethyl acetate (V/V. 10/90) to give 800mg of a colorless oil.
1H NMR(300MHz,CDCl3)7.95(dd,J＝8.7,5.2Hz,2H),7.13(t,J＝8.6Hz,2H),4.35(dd,J＝15.4,8.3Hz,2H),2.77(s,3H),1.38(t,J＝7.2Hz,3H)。
Step 3(2- (4-fluorophenyl) -4-methylthiazol-5-yl) methanol
Ethyl 2- (4-fluorophenyl) -4-methylthiazole-5-carboxylate (1g,3.769mmol) was dissolved in 30mL of diethyl ether and lithium aluminum hydride (430mg,11.308mmol) was added at 0 ℃. The temperature is raised to room temperature, and the reaction is stirred for 3 hours. The mixture solution (V/V-50/50) was passed through a silica gel column. 600mg of a white solid are obtained.
1H NMR(300MHz,DMSO-d6)7.90(dd,J＝8.9,5.4Hz,2H),7.29(t,J＝8.9Hz,2H),5.53(t,J＝5.5Hz,1H),4.61(d,J＝5.5Hz,2H),2.32(s,3H)。
Step 42- ((4- ((2- (4-fluorophenyl) -4-methylthiazol-5-yl) methoxy) phenyl) mercapto) acetic acid ethyl ester
The synthesis procedure was as for ethyl 2- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) mercapto) acetate
1H NMR(300MHz,CDCl3)7.89(dd,J＝8.6,5.4Hz,2H),7.44(d,J＝8.8Hz,2H),7.11(t,J＝8.6Hz,2H),6.92(d,J＝8.8Hz,2H),5.16(s,2H),4.14(q,J＝7.1Hz,2H),3.53(s,2H),2.48(s,3H),1.21(t,J＝7.1Hz,3H)。
Step 52 Ethyl- ((4- ((2- (4-fluorophenyl) -4-methylthiazol-5-yl) methoxy) phenyl) sulfoxy) acetate
The synthesis procedure was as for ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate
1H NMR(400MHz,CDCl3)7.92(dd,J＝8.1,5.6Hz,2H),7.69(d,J＝8.6Hz,2H),7.20–7.07(m,4H),5.26(s,2H),4.17(q,J＝7.1Hz,2H),3.90(d,J＝13.5Hz,1H),3.66(d,J＝13.6Hz,1H),2.53(s,3H),1.24(t,J＝7.1Hz,3H)。
Step 62- ((4- ((2- (4-fluorophenyl) -4-methylthiazol-5-yl) methoxy) phenyl) sulfoxy) acetic acid (S20)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(300MHz,DMSO-d6)7.94(dd,J＝8.3,5.6Hz,2H),7.67(d,J＝8.6Hz,2H),7.31(t,J＝8.8Hz,2H),7.22(d,J＝8.5Hz,2H),5.38(s,2H),3.92(d,J＝14.3Hz,1H),3.78(d,J＝14.3Hz,1H),2.43(s,3H)。
Preparation of example 21
2- ((5- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) thiophen-2-yl) sulfoxy) acetic acid (S21)
Reaction reagents and conditions: i) 3-bromobenzyl alcohol, cuprous iodide, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, cesium carbonate, 80 ℃; ii)2, 6-dimethylphenylboronic acid, tetratriphenylphosphine palladium, sodium carbonate, dioxane-water mixed solution (V/V ═ 3:1), 100 ℃; iii) n-butyllithium, sulfur powder, tert-butyl 2-bromoacetate, tetrahydrofuran, from-78 ℃ to room temperature; iv) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃; v) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Step 12- ((3-bromobenzyl) oxy) thiophene
Cuprous iodide (38mg, 0.2mmol), 3,4,7, 8-tetramethyl-1, 10-phenanthroline (94mg, 0.4mmol) and cesium carbonate (987mg, 3mmol) were placed in a reaction flask under nitrogen protection. 2-iodothiophene (221. mu.L, 2mmol) and 3-bromobenzyl alcohol (1mL, 8.34mmol) were added, heated to 80 ℃ and reacted for 24 h. Cooling to room temperature, filtering through a thin layer of silica gel, rinsing with ethyl acetate, spin-drying, and dissolving in a mixture of dichloromethane and petroleum ether (V)Methylene dichloride/V Petroleum ether10/90) was passed through a silica gel column to give 320mg of a colorless oil.
1H NMR(300MHz,CDCl3)7.58(s,1H),7.47(d,J＝7.4Hz,1H),7.34(d,J＝7.5Hz,1H),7.25(d,J＝15.4Hz,1H),6.71(dd,J＝5.4,3.9Hz,1H),6.58(d,J＝5.8Hz,1H),6.27(d,J＝3.7Hz,1H),5.04(s,2H)。
Step 22- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) thiophene
The synthetic procedure is as for (2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methanol
1H NMR(300MHz,CDCl3)7.50–7.37(m,2H),7.15(dt,J＝20.6,7.3Hz,5H),6.76–6.65(m,1H),6.56(d,J＝5.8Hz,1H),6.27(d,J＝3.7Hz,1H),5.12(s,2H),2.02(s,6H)。
Step 32- ((5- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) thiophen-2-yl) mercapto) acetic acid tert-butyl ester
2- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) thiophene (200mg, 0.679mmol) was weighed out and dissolved in 6mL of anhydrous tetrahydrofuran. After cooling to-78 deg.C, n-BnLi (2.5M) (272. mu.L, 0.679mmol) was added and the reaction stirred for 30 min. Sulfur powder (22mg, 0.679mmol) was added to the reaction solution. After the reaction solution was yellow and transparent, 2-bromoacetic acid tert-butyl ester (100. mu.L, 0.679mmol) was added to the reaction solution, and the mixture was warmed to room temperature and stirred for 30 min. And quenching by saturated ammonium chloride solution. After addition of 20mL of ethyl acetate, the mixture was washed with saturated sodium chloride solution several times, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography using an ethyl acetate-petroleum ether mixed solution (V/V. 5/95) to give 100mg of a colorless oil.
1H NMR(300MHz,CDCl3)7.45(t,J＝7.5Hz,1H),7.38(d,J＝7.6Hz,1H),7.21–7.07(m,5H),6.89(d,J＝3.9Hz,1H),6.13(d,J＝4.0Hz,1H),5.10(s,2H),3.32(s,2H),2.01(s,6H),1.44(s,9H)。
Step 42- ((5- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) thiophen-2-yl) sulfoxy) acetic acid tert-butyl ester
The synthesis procedure was as for ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate
1H NMR(400MHz,CDCl3)7.47(t,J＝7.5Hz,1H),7.39(d,J＝7.7Hz,1H),7.23(d,J＝4.1Hz,1H),7.20(s,1H),7.16(d,J＝7.6Hz,2H),7.11(d,J＝7.4Hz,2H),6.25(d,J＝4.1Hz,1H),5.18(s,2H),4.05(d,J＝13.6Hz,1H),3.74(d,J＝13.6Hz,1H),2.02(s,6H),1.39(s,9H)。
Step 52- ((5- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) thiophen-2-yl) sulfoxy) acetic acid (S21)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(400MHz,CDCl3)7.47(t,J＝7.5Hz,1H),7.38(d,J＝7.5Hz,1H),7.31(d,J＝4.1Hz,1H),7.21–7.14(m,3H),7.11(d,J＝7.3Hz,2H),6.28(d,J＝4.1Hz,1H),5.19(s,2H),3.91(q,J＝14.4Hz,2H),2.01(s,6H)。
Preparation of example 22
2- ((4- ((3- (4, 6-dimethylpyrimidin-5-yl) phenyl) oxy) phenyl) sulfoxido) acetic acid (S22)
Reaction reagents and conditions: i) tetratriphenylphosphine palladium, sodium carbonate, 1, 4-dioxane and water, wherein the temperature is 80 ℃; ii) sodium borohydride, methanol; iii) ethyl 2- ((4-hydroxyphenyl) mercapto) acetate, diethyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0 ℃ to room temperature; iv) m-chloroperoxybenzoic acid, dichloromethane, -20 ℃; v) lithium hydroxide monohydrate, tetrahydrofuran, methanol, water.
Step 13- (4, 6-dimethylpiperidin-5-yl) benzaldehyde
In a 100mL flask was weighed 5-bromo-4, 6-dimethylpyrimidine (500mg, 2.687mmol), (3-formylphenyl) boronic acid (605mg, 4.031mmol), tetrakistriphenylphosphine palladium (311mg, 0.269mmol), and sodium carbonate (855mg, 8.061 mmol). 21mL of dioxane and 7mL of water were added and the reaction was carried out at 80 ℃ for 5 hours. After the reaction, 40mL of ethyl acetate was added, the mixture was washed with saturated sodium chloride solution 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then mixed with ethyl acetate-petroleum ether (V)Ethyl acetate/V Petroleum ether20/80) was passed through a silica gel column to give 600mg of a white solid.
1H NMR(300MHz,CDCl3)10.08(s,1H),8.97(s,1H),7.95(d,J＝7.7Hz,1H),7.67(dd,J＝17.9,9.8Hz,1H),7.50(dd,J＝19.0,8.1Hz,1H),2.26(s,6H)。
Step 23- (4, 6-dimethylpiperidin-5-yl) benzyl alcohol
The synthetic steps are the same as those of 4-chloro-2, 3-dihydro-1H-indene-1-ol
1H NMR(300MHz,CDCl3)8.92(s,1H),7.74–7.36(m,1H),7.19(s,1H),7.09(d,J＝7.5Hz,1H),4.78(s,2H),2.26(s,6H)。
Step 32- ((4- ((3- (4, 6-dimethylpiperidin-5-yl) phenyl) oxy) phenyl) mercapto) acetic acid ethyl ester
The synthesis procedure was as for ethyl 2- ((4- ((4-chloro-2, 3-dihydro-1H-inden-1-yl) oxy) phenyl) mercapto) acetate
1H NMR(400MHz,CDCl3)8.97(s,1H),7.63–7.37(m,3H),7.25(s,1H),7.16(d,J＝7.2Hz,1H),6.94(d,J＝8.7Hz,2H),5.14(s,2H),4.16(q,J＝7.1Hz,2H),3.54(s,2H),2.28(s,6H),1.24(t,J＝7.1Hz,3H)。
Step 42- ((4- ((3- (4, 6-dimethylpiperidin-5-yl) phenyl) oxy) phenyl) sulfoxy) acetic acid ethyl ester
The synthesis procedure was as for ethyl 2- ((4- ((2',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxide) acetate
1H NMR(400MHz,CDCl3)8.98(s,1H),7.67(d,J＝8.7Hz,2H),7.60–7.48(m,2H),7.25(s,1H),7.19(d,J＝7.4Hz,1H),7.14(d,J＝8.7Hz,2H),5.20(s,2H),4.17(q,J＝7.6Hz,2H),3.90(d,J＝13.5Hz,1H),3.65(d,J＝13.5Hz,1H),2.29(s,6H),1.24(t,J＝7.1Hz,3H)。
Step 52- ((4- ((3- (4, 6-dimethylpiperidin-5-yl) phenyl) oxy) phenyl) sulfoxy) acetic acid (S22)
The synthesis procedure was as for 2- ((4- ((2',6' -dimethyl- [1,1' -diphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S1)
1H NMR(400MHz,DMSO-d6)8.89(s,1H),7.67(d,J＝8.7Hz,2H),7.55(d,J＝5.4Hz,2H),7.39(s,1H),7.29(d,J＝5.3Hz,1H),7.23(d,J＝8.8Hz,2H),5.26(s,2H),3.92(d,J＝14.2Hz,1H),3.79(d,J＝14.2Hz,1H),2.18(s,6H)。
Preparation of example 23
2- ((4- ((2' -fluoro-5 ' -methoxy- [1,1' -biphenyl ] -3-yl) methoxy) phenyl) sulfoxy) acetic acid (S23)
The reaction procedure is as in example 1
1H NMR(300MHz,DMSO-d6)7.65(d,J＝8.5Hz,3H),7.50(s,3H),7.23(t,J＝8.2Hz,3H),6.99(ddd,J＝12.3,7.6,4.2Hz,2H),5.23(s,2H),3.91(d,J＝14.0Hz,1H),3.84–3.69(m,4H)。
Preparation of example 24
2- ((4- ((3- (pyridin-4-yl) benzyl) oxy) phenyl) sulfoxido) acetic acid (S24)
The reaction procedure is as in example 18
1H NMR(300MHz,DMSO-d6)8.63(d,J＝4.9Hz,2H),7.90(s,1H),7.83–7.62(m,5H),7.56(s,2H),7.23(d,J＝8.4Hz,2H),5.25(s,2H),3.91(d,J＝14.3Hz,1H),3.78(d,J＝14.3Hz,1H),2.48(s,2H)。
Experimental example 1
In vitro agonism of Compounds of the invention on GPR40 in vitro evaluation of GPR40 agonistic Activity
Agonistic activity of the compounds of the invention on HEK293/hGPR40 cells (HEK 293 cells stably expressing GPR 40/ga 16). Human embryonic kidney cells HEK293 were purchased from the American Standard culture Collection (ATCC).
The compounds of the invention were tested for GPR40 agonistic activity using the following method:
and (3) testing the sample: all compounds of the invention, prepared according to the methods in the examples of the invention, respectively;
comparison products: TAK-875, the structural formula of which is
Preparation of hanks balanced salt solution HBSS (special for calcium flux experiments): the hanks balanced salt solution is prepared according to the preparation method reported in the literatures of Glucagon receivers mediums calcium signaling by coating to G alpha q/11 and G alpha i/o in HEK293 cells, J Recept Signal Transmission Res.2009,29(6) and 318-25, wherein the formula is 0.3mmol/L Na2HPO4·12H2O，5.4mmol/L KCl，0.4mmol/L KH2PO4，4.2mmol/L NaHCO3，0.6mmol/L MgSO4，0.5mmol/L MgCl2·6H2O，137mmol/L NaCl，1.3mmol/L CaCl2The pH was adjusted to 7.4 with deionized water.
Preparation of calcium buffer (prepared with HBSS, ready for use): the formulation was 5.6mmol/L D-glucose, 250. mu.M/L of fensulazolone (Sigma, S9509), prepared with HBSS as a solvent.
Preparing Fluo-4AM fluorescent dye solution (prepared by calcium buffer): the formulation was 0.03% (v/v) polyoxyethylene castor oil (Biochemika, 27963) and 2. mu.M/L Fluo-4, AM (Invitrogen, F14202), and the prepared calcium buffer was prepared as a solution.
Compound stocks were prepared and subjected to cellular experiments as reported in the Discovery of DS-1558, A patent and Orally Bioavailable GPR40 Agonist.Acs Med.chem.Lett.,2015,6(3), pp 266-270, and Discovery and Optimization of content GPR40 Full Agonists contacting Tricyclic Spirocycles Acs. chem.Lett.,2013,4(6), pp 551-555 literature.
The flow of compound storage liquid preparation:
the preparation method comprises the following steps: first, a compound was dissolved in dimethyl sulfoxide to prepare a 10mM stock solution, 1. mu.L of the stock solution was added to 9. mu.L of dimethyl sulfoxide to obtain a 1mM solution, then 1. mu.L of the stock solution was added to 9. mu.L of dimethyl sulfoxide to obtain a 100. mu.M solution, and so on to prepare a stock solution of the compound having working concentrations of 100. mu.M, 10. mu.M, 1. mu.M, 100nM, 10nM, 1nM, and 0.1 nM.
After compound gradient dilution, 3. mu.L of each concentration was added to 97. mu.L of calcium buffer and mixed. The blank control was prepared by adding 3. mu.L DMSO to 97. mu.L calcium buffer and mixing.
Cell experiments:
1. cell plating: HEK293 cells stably expressing GPR40/G alpha 16 were plated in 96-well plates at 37 ℃ in 5% CO2The cell culture chamber of (2) was cultured overnight.
2. And (3) dye incubation: the culture medium was aspirated off, 40. mu.L/well of freshly prepared dye was added, and incubation was carried out in an incubator at 37 ℃ for 45 minutes at constant temperature. The dye was aspirated off and discarded, and after washing once with 40 μ L of freshly prepared calcium buffer, 50 μ L of calcium buffer was replaced.
3. Detection signal value: 25 μ L of a stock solution of the pre-prepared compound was added and the fluorescence was measured at 525nm using a Flexitation instrument.
4. Curve fitting the gradient concentration and the corresponding calcium flux signal value by Graphpad Prism 5.0 to calculate the EC of each compound50See table 1.
Table 1: example agonistic activity on GPR40 receptor.
| Compound numbering | EC50(nM) | Compound numbering | EC50(nM) | Compound numbering | EC50(nM) |
| TAK-875 | 35.80 | S1 | A | S2 | A |
| S3 | C | S4 | D | S5 | D |
| S6 | B | S7 | D | S8 | D |
| S9 | C | S10 | C | S11 | D |
| S12 | C | S13 | D | S14 | C |
| S15 | D | S16 | B | S17 | B |
| S18 | C | S19 | D | S20 | C |
| S21 | B | S22 | C | S23 | B |
| S24 | B |
10nM<A<100nM；100nM<B<1μM；1μM<C<10μM；10μM<D。
And (4) conclusion: as can be seen from Table 1, the synthetic compounds were designed to have varying degrees of agonistic activity at the GPR40 receptor, with multiple compounds having higher activity at the GPR40 receptor.
Experimental example 2
Hypoglycemic effect of compound S2 on ICR mouse Oral Glucose Tolerance Test (OGTT) model
C57/BL6 male mice, SPF grade, 8-10 weeks old, body weight around 25g, purchased from Shanghai Si Laike laboratory animals Co. Mice were randomly divided into a blank control group and a dosing group, and the dosing group was divided into two doses (10mg/kg and 30mg/kg), with 7 mice per group. Before the experiment, the mice were starved for 16 hours (i.e. 5 pm to 9 am), and before administration (-30min), fasting blood glucose was measured with a blood glucose strip, and the experimental results were recorded. Then, the drug was administered orally, and the experiment was divided into three groups, with 0.5% sodium carboxymethylcellulose (CMC-Na) as a negative control, and compound S2(10mg/kg and 30mg/kg) as the experimental group. After 30min (0min time point), blood glucose was measured and the results recorded. 1.5g/kg glucose was orally administered immediately after measuring blood glucose. Blood glucose levels were then tested at 15, 30, 60, 90 and 120min respectively and the results recorded. The experimental results show that 10mg/kg of compound S2 has a good effect of improving glucose tolerance, and is repeated once, and the same similar experimental effects are obtained, and the results are as follows:
based on the above results, the above experiment was repeated with 0.5% CMC-Na as a negative control, 20mg/kg compound TAK-875 as a positive control, and 10mg/kg compound S2 as the experimental group. Before the experiment, the mice are starved for 16 hours, before the administration (-60min), fasting blood glucose is measured by a blood glucose test paper, and the experiment result is recorded. Then 20mg/kg of compound TAK-875 is orally taken, and after 30min, a 0.5% CMC-Na negative control group and a 10mg/kg compound S2 experimental group are orally taken respectively. After 30min (0min time point), blood glucose was measured and the results recorded. Glucose was taken orally at 1.5g/kg immediately after the blood glucose measurement, and then blood glucose levels were measured at 15, 30, 60, 90 and 120min and the results were recorded. The experimental results preliminarily show that the compound S2 at 10mg/kg has better effect of improving the glucose tolerance compared with the positive compound TAK-875, and the experimental results are shown in figure 1.
Based on the results shown in FIG. 1, the above experiment was repeated with 0.5% CMC-Na as a negative control, 20mg/kg compound TAK-875 as a positive control, and 10mg/kg compound S2 as the experimental group. Before the experiment, the mice are starved for 16 hours, before the administration (-60min), fasting blood glucose is measured by a blood glucose test paper, and the experiment result is recorded. Then 20mg/kg of compound TAK-875 is orally taken, and after 30min, a 0.5% CMC-Na negative control group and a 10mg/kg compound S2 experimental group are orally taken respectively. After 30min (0min time point), blood glucose was measured and the results recorded. Glucose was taken orally at 1.5g/kg immediately after the blood glucose measurement, and then blood glucose levels were measured at 15, 30, 60, 90 and 120min and the results were recorded. The experimental results preliminarily show that the compound S2 at 10mg/kg has better effect of improving the glucose tolerance compared with the positive compound TAK-875, and the experimental results are shown in figure 2.
Claims (5)
1. The sulfoxide acetic acid derivative comprises a sulfoxide acetic acid derivative and a pharmaceutically acceptable salt thereof, wherein the sulfoxide acetic acid derivative is selected from the following compounds:
2. a pharmaceutical composition comprising a therapeutically effective amount of a sulfoxide acetic acid derivative of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. The pharmaceutical composition according to claim 2, further comprising other antidiabetic agents, other antihyperglycemic agents, antiobesity agents, antiplatelet agents, antiatherosclerotic agents or combinations thereof.
4. Use of the sulfoxide acetic acid derivatives and pharmaceutically acceptable salts thereof according to claim 1 or pharmaceutical compositions according to claims 2 or 3 for the preparation of medicaments for use as GPR40 receptor agonists.
5. Use of the sulfoxide acetic acid derivatives and pharmaceutically acceptable salts thereof according to claim 1 or pharmaceutical compositions according to claim 2 or 3 for the preparation of medicaments for the treatment of diabetes and/or metabolic syndrome.
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