CN107162913B

CN107162913B - Novel deuterated phenylpropionic acid derivative, preparation method thereof and application thereof as medicine

Info

Publication number: CN107162913B
Application number: CN201710545646.1A
Authority: CN
Inventors: 黄文龙; 钱海; 刘春霞; 李政; 杨建勇; 毕昕洲; 蔡星光
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2017-06-29
Filing date: 2017-06-29
Publication date: 2021-04-30
Anticipated expiration: 2037-06-29
Also published as: CN107162913A

Abstract

The invention relates to a novel deuterated phenylpropionic acid derivative shown in a general formula (I), a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a medicament for treating diabetes and metabolic syndrome. The deuterated phenylpropionic acid derivative has excellent in-vivo hypoglycemic activity, and can be used for preparing a medicament for preventing or treating diabetes.

Description

Novel deuterated phenylpropionic acid derivative, preparation method thereof and application thereof as medicine

Technical Field

The invention relates to the field of pharmacology related to diabetes, in particular to a novel deuterated phenylpropionic acid derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a medicine for treating diabetes and metabolic syndrome. The structure of the deuterated phenylpropionic acid derivative has uniqueness and novelty in structural modification of the compound, and the deuterated technology is skillfully applied to block the metabolic sites of the existing drugs, so that the pharmacokinetic property is improved.

Background

Diabetes mellitus is a metabolic disease characterized by persistent hyperglycemia, and is classified into type 1 diabetes (insulin-dependent diabetes mellitus) and type 2 diabetes (non-insulin-dependent diabetes mellitus). Currently, about 4.15 million people worldwide suffer from diabetes, and another 3.18 million people are hidden with high risk of diabetes. By 2040 years, 6.42 million people worldwide are expected to suffer from diabetes. Chinese diabetic patients are 1.096 hundred million and are located at the first position of the world, wherein 2-type diabetic patients account for about 90-95% of the total number of diabetic patients.

Diabetes can be treated by diet regulation and exercise. When these fail to alleviate symptoms, medication is required. Current therapeutic agents for diabetes include: biguanides, such as metformin, are capable of reducing glucose formation in the liver; sulfonylureas, such as glibenclamide, and benzoic acid derivatives, such as repaglinide, can stimulate pancreatic beta cells to secrete more insulin; thiazolidinediones such as pioglitazone, enhance the biological effectiveness of insulin by activating the peroxisome proliferator-activated receptor gamma (PPAR- γ); alpha-glucosidase inhibitors, such as acarbose, capable of inhibiting the production of glucose in the intestinal tract; glucagon-like peptide-1 (GLP-1) analogs, such as liraglutide, which promote insulin secretion from the beta cells of the pancreas; dipeptidyl peptidase IV (DPP-IV) inhibitors, such as sitagliptin, are capable of inhibiting GLP-1 degradation in vivo. However, the existing methods for treating diabetes have certain defects. Such as insulin injections and sulfonylureas, may cause hypoglycemic and weight gain side effects; metformin, alpha-glucosidase inhibitors and GLP-1 analogues may cause gastrointestinal side effects; PPAR-gamma agonists may cause weight gain and edema side effects; DPP-IV inhibitors may cause suprapharyngeal inflammation, headache and infection side effects. Research is being conducted in various fields to bring a safer and more effective novel hypoglycemic agent to diabetic patients.

Free Fatty Acid Receptors (FFARs) are G protein-coupled receptors (GPCRs) that have been de-orphaned in recent years. The free fatty acid receptors identified so far are the G protein-coupled receptor 40(GPR40) family, including GPR40 (also known as free fatty acid receptor 1, FFA1), GPR41 (also known as free fatty acid receptor 3, FFA3), GPR43 (also known as free fatty acid receptor 2, FFA2) and the other families of GPR84, GPR 120. GPR40 is an orphan GPCR discovered in the search for a new somatropin neuropeptide-galanin receptor (GALR) subtype, highly expressed in pancreatic beta cells and insulin secreting cell lines. GPR40 can bind fatty acids in blood plasma such as palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid to achieve a variety of physiological functions. For example, long chain free fatty acids are activated upon binding to GPR40, inducing an increase in intracellular calcium levels, enhancing glucose-stimulated insulin secretion (GSIS). GPR40 modulators exert incretin action to promote GISI and may additionally be used in combination with a variety of diabetes-treating drugs. Based on the above, GPR40 agonists are useful for the treatment of diabetes and related indications, particularly type 2 diabetes, obesity insulin resistance, glucose intolerance, and other metabolic syndrome conditions. GPR40 is used as a potential therapeutic target, and the discovery and modification of the compound with GPR40 agonistic activity have important research value and application prospect.

A series of patent applications for GPR40 agonists have been disclosed, including WO2004041266, WO2005087710, WO2005051890, WO2006083781, WO2007013689, W02008066097, WO2009054390, WO2010085525, WO2015024448, WO2015088868, and the like. The compound 1 (the structure is shown in the following) reported by the martian company has good hypoglycemic activity, but the phenylpropionic acid structure is unstable, beta oxidation metabolism is easy to occur in vivo to generate phenylpropenoic acid and further generate benzoic acid, and the metabolite has no hypoglycemic activity. Deuterium atoms are introduced to the alpha position of phenylpropionic acid of the compound 1, so that the metabolic sites of the compound can be blocked, the metabolic stability of the compound is improved, and the hypoglycemic activity is improved.

Deuterium is a stable nonradioactive isotope of hydrogen and has a weight of 2.0144. There are two main routes for deuterium incorporation into a compound, one is by proton exchange with hydrogen; and secondly, the synthesis is carried out by using deuterated raw materials. The second method is currently used. The deuterium content in the generated deuterated compound is far higher than the content of 0.015% in the natural world, so that the deuterated compound can be regarded as a novel compound. Deuteration has been widely used in human clinical studies and pharmacokinetic studies in drug development.

The invention relates to a deuterated phenylpropionic acid derivative with a novel structure, which has excellent GPR40 agonistic activity and in-vivo hypoglycemic activity. Therefore, the deuterated phenylpropionic acid derivative and the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof can be potentially used for treating or preventing diabetes and related diseases, and have wide development prospects.

Disclosure of Invention

The invention aims to provide a compound shown as a general formula (I) and a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof:

wherein:

ring A is selected from aryl or heteroaryl;

ring B is selected from aryl or heteroaryl;

R₁，R₂and R₃Each independently selected from hydrogen, halogen, alkyl, alkoxy, cycloalkoxy, wherein said alkyl, cycloalkyl, alkoxy is optionally further substituted with one or more groups selected from halogen, methyl sulfoneate;

R₄selected from hydrogen, alkyl;

R₅selected from hydrogen, halogen;

in a preferred embodiment of the present invention, the compound is preferably selected from the group consisting of compounds represented by the general formula (I):

wherein:

ring A is preferably selected from a benzene ring, an isoxazole ring;

ring B is preferably selected from benzene ring, thiazole ring;

R₁，R₂and R₃Each independently selected from hydrogen, halogen, alkyl, alkoxy, cycloalkoxy, wherein the alkyl, cycloalkyl, alkoxy is optionally further substituted with one or more groups selected from halogen, methyl sulfoneateSubstituted with a group of (a);

R₄selected from hydrogen, alkyl;

R₅selected from hydrogen, halogen;

preferably from compounds of formula (I) and pharmaceutically acceptable esters or pharmaceutically acceptable salts thereof:

wherein:

ring A is preferably selected from a benzene ring, an isoxazole ring;

ring B is preferably selected from benzene ring, thiazole ring;

R₁，R₂and R₃Each independently selected from hydrogen, halogen, alkyl, alkoxy, cycloalkoxy, wherein said alkyl, alkoxy is optionally further substituted with one or more groups selected from methyl sulfoneate;

R₄selected from hydrogen, methyl;

R₅selected from hydrogen, fluorine, chlorine, bromine;

more preferred compounds of formula (I) and pharmaceutically acceptable esters or pharmaceutically acceptable salts thereof:

wherein:

ring a is preferably selected from a benzene ring or:

ring B is preferably selected from a benzene ring or:

R₁，R₂and R₃Each independently selected from hydrogen, fluoro, methyl, trifluoromethyl, ethoxy, propoxy, isobutoxy, cyclopropylmethoxy, methyl sulphonate propoxy;

R₄selected from hydrogen, methyl;

R₅selected from hydrogen, fluorine;

more preferred compounds of the invention having general formula (I) or a pharmaceutically acceptable salt thereof, are selected from:

3- (4- ((2 '-methyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-1);

3- (4- ((4 '-ethoxy-2', 6 '-dimethyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-2);

3- (4- ([1, 1' -biphenyl ] -3-ylmethoxy) phenyl) -2, 2-dideuteropropionic acid (I-3);

3- (4- ((2 ', 6' -dimethyl-4 '- (3- (methylsulfonyl) propoxy) - [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-4);

3- (4- ((2- (4-fluorophenyl) -4-methylthiazol-5-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-5);

3- (4- ((2- (3-fluorophenyl) -4-methylthiazol-5-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-6);

3- (4- ((2 ' -chloro-4 ' -methyl- [1, 1 ' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-7);

3- (4- ((4 '- (cyclopropylmethoxy) -2', 6 '-dimethyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-8);

3- (4- ((2 ', 6' -dimethyl-4 '-propoxy- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-9);

3- (4- ((2 ' -methyl-4 ' -propoxy- [1, 1 ' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuterepropanoic acid (I-10);

3- (4- ((4 '-isobutoxy-2', 6 '-dimethyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-11);

3- (4- ((2 '-fluoro- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-12);

3- (4- ((4 ' -ethoxy-2 ' -methyl- [1, 1 ' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-13);

3- (4- ((3- (3, 5-dimethylisoxazol-4-yl) benzyl) oxy) phenyl) -2, 2-dideuteropropionic acid (I-14);

3- (4- ((3-phenoxybenzyl) oxy) phenyl) -2, 2-dideuteropropionic acid (I-15);

3- (4- ((5-methyl-2-phenylthiazol-4-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-16);

3- (4- ((4 '-ethoxy-2', 6 '-dimethyl- [1, 1' -biphenyl ] -3-yl) methoxy) -2-fluorophenyl) -2, 2-dideuteropropionic acid (I-17);

3- (2-fluoro-4- ((2 '- (trifluoromethyl) - [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-18);

3- (4- ((2 '- (trifluoromethyl) - [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuterepropanoic acid (I-19);

3- (4- ((3- (2- (methoxyimino) -2-phenylethoxy) benzyl) oxy) phenyl) -2, 2-dideuteropropionic acid (I-20);

3- (4- ((3- (3, 5-dimethylisoxazol-4-yl) benzyl) oxy) -2-fluorophenyl) -2, 2-dideuteropropionic acid (I-21);

3- (4- ((4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) methoxy) phenyl) propanoic acid-2, 2-diester acid-2, 2-dideuteropropanoic acid (I-22);

another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof, together with a suitable carrier, diluent or excipient.

The invention also relates to the application of the compound and pharmaceutically acceptable ester or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicaments for treating diabetes and metabolic syndrome.

Detailed description of the invention

Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.

"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Preferably an alkyl group having 1 to 10 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, even more preferably an alkyl group having 1 to 3 carbon atoms, and most preferably a methyl group. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like, as well as various branched chain isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like

"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.

The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably 5 to 10 membered. Heteroaryl is preferably 5-or 6-membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring.

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

"alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, in admixture with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the absorption of the active ingredients by organisms and to facilitate the active ingredients to exert biological activity in organisms.

The compound of the general formula (I) can be synthesized by the following steps:

the compound represented by the general formula (II) and the compound represented by the general formula (III) react with each other in the presence of a base to obtain a compound represented by the general formula (IV), and the compound represented by the general formula (IV) is hydrolyzed to obtain a compound represented by the general formula (I).

Wherein W is a leaving group, R₁～R₅The definition of (A) is shown in the general formula (I).

W represents a leaving group, and there may be mentioned, for example, Cl, Br, I, optionally halogenated C₁-C₆Alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy, trichloromethylsulfonyl), C optionally having substituents₆-C₁₀Arylsulfonyloxy (e.g., phenylsulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, etc.), and the like.

As the base, inorganic bases and organic bases are included, and as the inorganic bases, there can be mentioned, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as potassium bicarbonate and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; as the organic base, there may be mentioned, for example, triethylamine, pyridine, lutidine, n-butyllithium, potassium t-butoxide and the like.

The GPR40 agonistic activity and in vivo hypoglycemic activity of the compounds of the present invention can be determined by using an assay system as described below.

The following description of the biological test example illustrates the present invention.

The experimental procedures for the specific conditions in the test examples of the present invention are generally carried out under conventional conditions or under conditions recommended by commercial manufacturers. Reagents with no specific source are indicated, and are commonly purchased in the market.

Test example 1 agonistic Activity of the Compounds of the present invention on hGPR40-CHO stably transfected cells

The present invention uses the following method to determine the agonist activity of hGPR40 of the compounds of the present invention:

hGPR40-CHO stably transfected cells at 3X 10⁴The density of each well was inoculated into a 96-well plate and placed at 37 ℃ in 5% CO₂The cell culture box is used for overnight culture; discarding the culture medium, adding 100ul HBSS into each well, cleaning, adding 100ul Fluo-4 dye solution containing Probenecid, and incubating at 37 deg.C for 90 min; after the incubation is finished, absorbing the Fluo-4 dye solution, adding 100ul of HBSS buffer solution, and washing off the dye; adding 100 μ l HBSS containing Probenecid into each well, and incubating at 37 deg.C for 10 min; drugs were added at different concentrations to each well of a 96-well plate and read using flipr (molecular devices) according to the parameter set-up table. And analyzing the experimental result. Agonistic activity ═ (compound well fluorescence value-blank well fluorescence value)/(linoleic acid well fluorescence value-blank well fluorescence value) × 100%, the results are shown in table 1.

Table 1: hGPR40 receptor agonistic activity

And (4) conclusion: all the compounds of the invention have obvious agonist activity on GPR40, wherein I-1, I-4, I-5, I-14, I-15 and I-19 have stronger GPR40 agonist activity.

Test example 2 the in vivo hypoglycemic activity of the compounds of the invention can be determined by using an assay system as described below:

normal mouse Oral Glucose Tolerance Test (OGTT): 10-week-old Kunming clean-grade mice, 18-22 g in body weight and males, wherein the Kunming clean-grade mice are randomly divided into 7 groups, a blank control group (blank solvent: 0.5% sodium carboxymethylcellulose solution), a positive drug control group (TAK-875: 20mg/kg), a test compound group (20mg/kg), 8 mice in each group, the mice are fasted for 12 hours before an experiment, the mice are orally administrated by gastric gavage, blood is taken after tail breakage, and the blood sugar value is measured (recorded as-30 min). Then, respectively gavage and administering a blank solvent, TAK-875 and a test compound, measuring the blood sugar value after 30min and recording as 0min, immediately administering a glucose solution with the concentration of 2g/10ml according to 10ml/kg, and measuring the blood sugar value at 15, 30, 60 and 120 min. The results are shown in Table 2.

Table 2: influence of preferred Compounds on oral glucose tolerance in Normal mice: (

n＝8)

Note: p ≦ 0.05 for Student's t test results relative to the blank control.

The oral glucose tolerance test of the normal mice shows that: all the compounds in the invention have hypoglycemic activity, wherein the compounds I-4, I-14 and I-15 can also obviously improve the oral glucose tolerance of normal mice in vivo, the compounds I-4 and I-15 are superior to a positive control TAK-875, and the compounds 1 to 14 have equivalent activity to the positive control, thereby showing better hypoglycemic effect.

Test example 3 the pharmacokinetic properties of the compounds of the invention for improving the oxidation of the beta position of the phenylpropionic acid structure in compound I can be determined by using an assay system as described below:

male SD rats weighing 180-220 g, 6 per group, fasted for 12h, were gavaged with compounds I (10mg/kg), I-1 and I-4(10mg/kg) and were bled at the fundus vein for 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h. 100 μ L of blood was placed in a centrifuge tube containing heparin at 10000rpm min^-1Centrifuging for 5min, collecting 50 μ L plasma, adding 1% formic acid/water 50 μ L, vortexing for 2min, and precipitating with 200 μ L acetonitrile. Vortex for 3min, 14000rpm min^-1Centrifuging for 15min, taking 8 μ L of supernatant, detecting mass spectrum peak area of compound by LC-MS, calculating compound concentration by using standard curve, and calculating related drug-induced parameters by using DAS V2.1.

Table 3: pharmacokinetic parameters of preferred Compounds

The results show that the pharmacokinetics of the compound is obviously improved after two deuterons are introduced into the alpha position of the phenylpropionic acid. Wherein, compared with the compound I, the plasma clearance rate of I-1 is reduced by 9 times, the peak concentration of the compound is improved by 6 times, the area under the curve is improved by 10 times, the half-life period is improved by 3 times, the plasma clearance rate of I-4 is reduced by 16 times, the peak concentration of the compound is improved by 15 times, the area under the curve is improved by 23 times and the half-life period is improved by 4 times, which shows that the deuteration technology can block the beta oxidation of the metabolic site, thereby improving the pharmacokinetic property.

Detailed Description

The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.

Example 1

3- (4-hydroxyphenyl) -2, 2-dideuteropropionic acid

The first step is as follows: p-hydroxybenzaldehyde (1g, 8.26mmol) was dissolved in 30ml of water, cyclopropyl (ylidene) malonate (1.2g, 8.32mmol) was added, the reaction was heated at 75 ℃ for two hours to obtain a yellow turbid liquid, suction filtration was carried out to obtain 2.3g of a yellow solid, the yield of the crude product was 113%, and the crude product was dried overnight under an infrared lamp.

The second step is that: the crude product (1g, 4.04mmol) was dissolved in 30ml (tetrahydrofuran/methanol, 1: 1, v/v) of a mixed solvent, and NaBH was slowly added under ice-bath₄(0.45g, 6.06mmol), reacting at room temperature for 1 hour, detecting by TLC after the reaction is completed, diluting with 50ml of water, extracting with ethyl acetate (40 ml. times.4), combining organic phases, washing with saturated NaCl solution (20 ml. times.2), drying the obtained organic phase with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent to obtain 0.8g of white solid, and obtaining the crude product with the yield of 72%.

The third step: the solid obtained in the previous step (0.5g, 2mmol) was dissolved in 12.6ml of DMF, 1.4ml of heavy water was added, and the resulting mixture was reacted at room temperature for 1 hour and heated at 100 ℃ for 3 hours. After completion of the TLC detection reaction, 1N HCl80ml was added for dilution, ethyl acetate (80 ml. times.3) was extracted, the combined organic phases were washed with a saturated NaCl solution (80 ml. times.2), the resulting organic phase was dried over anhydrous sodium sulfate, suction filtration was conducted, and the solvent was distilled off under reduced pressure to obtain 0.3g of a yellow oily liquid in a yield of 89%.

Example 2

2 '-methyl- [1, 1' -biphenyl ] -4-carbaldehyde

The raw material 2-bromotoluene (0.5g, 2.6mmol) was dissolved in 42ml of a mixed solvent (toluene/ethanol/water, 3: 1: 3, v/v/v), and the raw materials 3-formylphenylboronic acid (0.3g, 2.6mmol), triphenylphosphine palladium (0.15g, 0.13mmol) and anhydrous sodium carbonate (0.69g, 6.5mmol) were added, and the mixture was heated at 60 ℃ for reaction for 24 hours under the protection of nitrogen. After the reaction, the reaction mixture was cooled to room temperature, diluted with 20ml of water, filtered with celite, the filter cake was washed with ethyl acetate (15ml × 3), the filtrate was extracted with ethyl acetate (30ml × 4), the combined organic phases were washed with saturated NaCl solution (20ml × 2), the resulting organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate, 70: 30, v/v) to give 0.35g of an off-white solid in 63% yield.

Example 3

3- (4- ((2 '-methyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-1)

The first step is as follows: dissolving a raw material II-1(0.2g, 1.18mmol) in a solution of 20ml of a mixed solvent (tetrahydrofuran/methanol, 1: 1, v/v), slowly adding sodium borohydride (0.1g, 2.4mmol) under ice bath, adding 20ml of water to quench the reaction after the reaction under ice bath is finished, extracting with ethyl acetate (30ml multiplied by 3), combining organic phases, washing with a saturated NaCl solution (20ml multiplied by 2), drying the obtained organic phase with anhydrous sodium sulfate, performing suction filtration, decompressing the filtrate to remove the solvent, and directly using the filtrate for the next reaction without purification.

The second step is that: dissolving the compound obtained in the previous step in 20ml of dichloromethane, slowly dripping 0.5ml of thionyl chloride, adding 1 drop of DMF, heating to react at 25 ℃, and evaporating the solvent under reduced pressure after the reaction is finished to obtain a light yellow oily substance II-2. II-2(0.2g, 0.92mmol) was dissolved in 20ml acetonitrile, the starting materials 3- (4-hydroxyphenyl) -2, 2-dideuteropropionic acid (0.25g, 1.37mmol), anhydrous potassium carbonate (0.5g, 3.62mmol), catalytic amount of KI were added, heated to 60 ℃ to react for 8h, filtered, the solvent was distilled off under reduced pressure, the residue was dissolved in 30ml water, ethyl acetate (20 ml. times.3) was extracted, the organic phases were combined, washed with saturated brine (15 ml. times.2), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure from the filtrate, and the residue was purified by column chromatography (petroleum ether/ethyl acetate, 4: 1, v/v) to give 0.26g of white solid II-3.

The third step: the product II-3 from the previous step was dissolved in 14ml of a mixed solvent (THF/MeOH/H)₂O, 3: 1, v/v/v), adding LiOH (0.07g, 2.79mmol), reacting at room temperature for 8h, evaporating tetrahydrofuran and methanol under reduced pressure, dropwise adding 1N diluted hydrochloric acid in an ice water bath to adjust PH 2-3, separating out a white solid, performing suction filtration, and drying to obtain a white powdery solid I-30.25g, a melting point of 123-.

¹H NMR(300MHz，DMSO-d₆)δ：12.15(s，1H)，7.48-7.43(m，2H)，7.38(s，1H)，7.29-7.25(m，4H)，7.22-7.18(m，1H)，7.14(d，J＝8.4Hz，2H)，6.93(d，J＝8.4Hz，2H)，5.13(s，2H)，2.74(s，2H)，2.20(s，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.22，157.94，157.04，140.83，137.87，136.96，134.04，133.47，129.58，129.10，126.21，115.23，113.69，69.57，29.85，21.15，19.53；ESI-MS m/z：347.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₃H₂₀D₂O₃: c, 79.28; h, 6.94; measured value: c, 79.24; h, 6.95.

Example 4

3- (4- ((4 '-ethoxy-2', 6 '-dimethyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-2)

The synthesis method is the same as I-1, and 0.28g of white solid is obtained, the melting point is 118-.

¹H NMR(300MHz，DMSO-d₆)δ：12.13(s，1H)，7.45-7.41(m，2H)，7.16-7.11(m，4H)，6.91(d，J＝7.8Hz，2H)，6.67(s，2H)，5.15(s，2H)，4.00(q，J＝5.1Hz，2H)，2.73(s，2H)，1.90(s，6H)，1.31(t，J＝5.1Hz，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.31，157.65，157.01，140.80，137.86，136.96，134.01，133.45，129.60，129.12，126.25，115.20，113.61，69.51，63.19，29.82，21.20，15.21；ESI-MS m/z：405.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₆H₂₆D₂O₄: c, 76.82; h, 7.44; measured value: c, 76.85; h, 7.43.

Example 5

3- (4- ([1, 1' -biphenyl ] -3-ylmethoxy) phenyl) -2, 2-dideuteropropionic acid (I-3)

The synthesis method is the same as I-1, 0.21g of white solid is obtained, the melting point is 113-.

¹H NMR(300MHz，DMSO-d₆)δ：12.13(s，1H)，7.82-7.57(m，4H)，7.47-7.40(m，5H)，7.15(d，J＝7.8Hz，2H)，6.91(d，J＝7.8Hz，2H)，5.14(s，2H)，2.74(s，2H)；¹³C NMR(75MHz，DMSO-d₆)δ：176.47，156.25，141.23，140.80，131.26，129.42，129.12，128.43，127.65，127.26，126.75，126.25，114.21，71.47，29.82，21.35；ESI-MS m/z：333.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₂H₁₈D₂O₃: c, 79.02; h, 6.63; measured value: c, 79.06; h, 6.62.

Example 6

3- (4- ((2 ', 6' -dimethyl-4 '- (3- (methylsulfonyl) propoxy) - [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-4)

The synthesis method is the same as I-1, 0.23g of white solid is obtained, the melting point is 150-.

¹H NMR(300MHz，DMSO-d₆)δ：12.15(s，1H)，7.45-7.41(m，2H)，7.14-7.06(m，4H)，6.91(d，J＝8.1Hz，2H)，6.71(s，2H)，5.11(s，2H)，4.13-4.09(m，2H)，3.28(t，J＝6.9Hz，2H)，3.03(s，3H)，2.73(s，2H)，2.16-2.12(m，2H)，1.91(s，6H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.53，157.85，157.39，140.69，137.78，137.07，134.56，129.60，129.04，128.63，126.84，126.61，115.21，113.74，69.50，63.15，51.02，43.85，29.82，22.53，21.19，15.21；ESI-MS m/z：497.2[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₈H₃₀D₂O₆S: c, 67.45; h, 6.87; measured value: c, 67.41; h, 6.86.

Example 7

4-methyl-2-phenylthiazole-5-carboxylic acid ethyl ester

P-fluorobenzamide (1.0g, 7.3mmol) and ethyl 2-chloroacetoacetate (1.4g, 8.6mmol) are dissolved in 20ml of ethanol, a catalytic amount of sodium carbonate is added, heating reflux is carried out for 6h, the reaction is finished, the temperature is cooled to room temperature, insoluble matters are filtered, filtrate is concentrated under reduced pressure, saturated sodium bicarbonate solution is added to be alkalescent, ethyl acetate (20ml multiplied by 3) is extracted, organic phases are combined, the organic phases are washed by saturated saline water (15ml multiplied by 2), anhydrous sodium sulfate is dried, the filtrate is filtered, the solvent is removed by reduced pressure evaporation, and the residue is purified by column chromatography (petroleum ether/ethyl acetate, 5: 1, v/v) to obtain 1.2g of white solid with the melting point of 74-76 ℃ and the yield of 72.8 percent.

Example 8

3- (4- ((2- (4-fluorophenyl) -4-methylthiazol-5-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-5)

Starting material III-1(0.80g, 3.23mmol) was dissolved in 15ml THF and NaBH was added portionwise₄(0.31g, 8.0mmol), after the addition, 0.5ml of methanol is dropwise added under heating and refluxing, the reflux is continued for about 30min after the dropwise addition, the stirring is stopped, the reaction solution is cooled to the room temperature, the reaction solution is poured into 20ml of ice water, ethyl acetate (20ml × 3) is extracted, organic phases are combined, the organic phases are washed by saturated saline water (15ml × 2), dried by anhydrous sodium sulfate and filtered, the filtrate is decompressed and evaporated to remove the solvent, 0.54g of off-white solid is obtained, the off-white solid is directly used for the next reaction without purification, the off-white solid is added into 5ml of pre-cooled thionyl chloride in batches under ice bath, the mixture is heated to 60 ℃ after being uniformly stirred and reacts for 1h, the reaction solution is decompressed and evaporated to remove the redundant thionyl chloride, the obtained brown oily substance III-2 is dissolved in 20ml of THF, the raw materials 3- (4-hydroxyphenyl) -2, 2-dideuterio propionic acid (0.50g, 2.74mmol), anhydrous potassium carbonate (1.15g, heating to 60 deg.C for 8H, filtering, evaporating solvent under reduced pressure, dissolving the residue in 30mL water, extracting with ethyl acetate (20mL × 3), combining organic phases, washing with saturated brine (15mL × 2), drying with anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure, purifying the residue by column chromatography (petroleum ether/ethyl acetate, 4: 1, v/v) to obtain 0.76g white solid III-3, dissolving in 14mL mixed solvent (THF/MeOH/H)₂O, 3: 1, v/v/v), adding LiOH (0.1g, 3.99mmol), reacting at room temperature for 8h, evaporating tetrahydrofuran and methanol under reduced pressure, dropwise adding 1N diluted hydrochloric acid in an ice water bath to adjust PH 2-3, separating out a white solid, performing suction filtration, and drying to obtain a white powdery solid I-50.61g, a melting point of 124-.¹H NMR(300MHz，DMSO-d₆)δ：12.11(s，1H)，7.94(d，J＝8.8Hz，2H)，7.31(d，J＝8.8Hz，2H)，7.16(d，J＝8.4Hz，2H)，6.97(d，J＝8.4Hz，2H)，5.26(s，2H)，2.73(s，2H)，2.42(s，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.25，156.50，151.73，134.02，129.62，128.65，128.00，116.82，116.53，115.41，62.01，29.82，21.20，15.51；ESI-MS m/z：372.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₀H₁₆D₂FNO₃S: c, 64.33; h, 5.40; n, 3.75; measured value: c, 64.36; h, 5.41; n, 3.74.

Example 9

3- (4- ((2- (3-fluorophenyl) -4-methylthiazol-5-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-6)

The synthesis method is the same as I-5, 0.15g of white solid is obtained, the melting point is 132-.

¹H NMR(300MHz，DMSO-d₆)δ：7.73-7.68(m，2H)，7.55，7.50(dd，J＝7.5，13.7Hz，1H)，7.33-7.28(m，1H)，7.16(d，J＝8.1Hz，2H)，6.97(d，J＝8.1Hz，2H)，5.28(s，2H)，2.94(s，2H)，2.43(s，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.31，157.65，157.01，140.80，137.86，136.96，134.01，129.60，129.12，126.25，115.20，113.61，63.19，29.82，21.20，15.21；ESI-MS m/z：372.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₀H₁₆D₂FNO₃S: c, 64.33; h, 5.40; n, 3.75; measured value: c, 64.31; h, 5.41; and N, 3.76.

Example 10

3- (4- ((2 ' -chloro-4 ' -methyl- [1, 1 ' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-7)

The synthesis method is the same as I-1, 0.16g of white solid is obtained, the melting point is 113-.

¹H NMR(300MHz，DMSO-d₆)δ：12.23(s，1H)，7.48-7.44(m，3H)，7.41-7.32(m，2H)，7.26-7.20(m，2H)，7.13(d，J＝8.5Hz，2H)，6.93(d，J＝8.5Hz，2H)，5.11(s，2H)，2.75(s，2H)，2.34(s，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：173.81，156.59，141.65，138.72，137.21，136.56，133.02，131.15，130.88，130.06，129.17，128.61，128.04，126.72，114.62，68.95，29.34，20.22，13.52；ESI-MS m/z：381.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₃H₁₉D₂ClO₃: c, 72.15; h, 6.05; measured value: c, 72.12; h, 6.04.

Example 11

3- (4- ((4 '- (cyclopropylmethoxy) -2', 6 '-dimethyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-8)

The synthesis method is the same as I-1, 0.18g of white solid is obtained, the melting point is 124-.

¹H NMR(300MHz，DMSO-d₆)δ：7.45-7.41(m，2H)，7.13-7.03(m，4H)，6.91(d，J＝8.1Hz，2H)，6.67(s，2H)，5.10(s，2H)，3.79(d，J＝6.3Hz，2H)，2.73(s，2H)，1.89(s，6H)，1.32-1.21(m，1H)，0.56(d，J＝6.3Hz，2H)，0.31(d，J＝3.4Hz，2H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.57，157.76，156.99，140.81，137.85，136.94，133.98，133.53，129.60，129.11，126.24，115.18，113.64，72.23，69.50，29.90，21.20，10.70，3.55；ESI-MS m/z：431.2[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₈H₂₈D₂O₄: c, 77.75; h, 7.46; measured value: c, 77.71; h, 7.45.

Example 12

3- (4- ((2 ', 6' -dimethyl-4 '-propoxy- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-9)

The synthesis method is the same as I-1, 0.22g of white solid is obtained, the melting point is 103-.

¹H NMR(300MHz，DMSO-d₆)δ：12.16(s，1H)，7.48-7.34(m，2H)，7.15-7.10(m，3H)，7.03(d，J＝6.8Hz，1H)，6.90(d，J＝8.4Hz，2H)，6.67(s，2H)，5.09(s，2H)，3.89(t，J＝6.4Hz，2H)，2.73(s，2H)，1.90(s，6H)，1.75-1.65(m，2H)，0.97(t，J＝7.3Hz，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.30，157.83，157.02，140.84，137.83，136.95，133.99，133.44，129.58，129.08，126.20，115.15，113.60，69.51，69.13，29.85，22.60，21.17，10.87；ESI-MS m/z：419.2[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₇H₂₈D₂O₄: c, 77.11; h, 7.67; measured value: c, 77.15; h, 7.66.

Example 13

3- (4- ((2 ' -methyl-4 ' -propoxy- [1, 1 ' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-10)

The synthesis method is the same as I-1, and 0.26g of white solid is obtained, the melting point is 83-85 ℃, and the yield is 55%.

¹H NMR(300MHz，DMSO-d₆)δ：12.18(s，1H)，7.42-7.35(m，3H)，7.24(d，J＝4.4Hz，1H)，7.16-7.08(m，4H)，6.92(d，J＝8.1Hz，2H)，6.85(s，1H)，6.83-6.75(m，1H)，5.06(s，2H)，3.92(t，J＝6.2Hz，2H)，2.74(s，2H)，2.18(s，3H)，1.68-1.70(m，2H)，0.97(t，J＝7.1Hz，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.30，157.76，156.99，140.81，137.85，136.94，133.98，133.53，129.60，129.11，126.24，115.18，113.64，111.92，72.23，69.50，29.90，21.20，10.70，3.55；ESI-MS m/z：405.2[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₆H₂₆D₂O₄: c, 76.82; h, 7.44; measured value: c, 76.86; h, 7.43.

Example 14

3- (4- ((4 '-isobutoxy-2', 6 '-dimethyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-11)

The synthesis method is the same as I-1, 0.18g of white solid is obtained, the melting point is 135-.

¹H NMR(300MHz，DMSO-d₆)δ：12.10(s，1H)，7.48-7.35(m，2H)，7.14-7.10(m，3H)，7.04(d，J＝7.1Hz，1H)，6.91(d，J＝8.5Hz，2H)，6.68(s，2H)，5.11(s，2H)，3.73(d，J＝6.5Hz，2H)，2.73(s，2H)，2.13-1.95(m，1H)，1.91(s，6H)，0.96(d，J＝6.7Hz，6H)；¹³C NMR(75MHz，DMSO-d₆)δ：173.84，162.66，157.08，155.12，141.58，137.59，135.08，133.25，130.80，129.91，129.64，128.67，127.82，126.49，115.15，74.63，69.52，29.91，22.60，20.55；ESI-MS m/z：433.2[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₈H₃₀D₂O₄: c, 77.39; h, 7.89; measured value: c, 77.35; h, 7.88.

Example 15

3- (4- ((2 '-fluoro- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-12)

The synthesis method is the same as I-1, 0.20g of white solid is obtained, the melting point is 106 ℃ and the yield is 57%.

¹H NMR(300MHz，DMSO-d₆)δ：12.14(s，1H)，7.62(s，1H)，7.54-7.49(m，4H)，7.43-7.39(m，1H)，7.33-7.27(m，2H)，7.15(d，J＝8.5Hz，2H)，6.94(d，J＝8.5Hz，2H)，5.13(s，2H)，2.75(s，2H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.27，161.16，157.90，157.10，138.16，135.67，133.55，131.21，130.09，129.67，129.17，128.52，127.50，125.39，116.70，116.40，115.12，69.49，29.86；ESI-MS m/z：351.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₂H₁₇D₂FO₃: c, 74.98; h, 6.01; measured value: c, 74.94; h, 6.02.

Example 16

3- (4- ((4 ' -ethoxy-2 ' -methyl- [1, 1 ' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-13)

The synthesis method is the same as I-1, and 0.21g of white solid is obtained, the melting point is 91-92 ℃, and the yield is 64%.

¹H NMR(300MHz，DMSO-d₆)δ：12.16(s，1H)，7.43-7.34(m，3H)，7.24(d，J＝6.8Hz，1H)，7.14-7.09(m，3H)，6.93(d，J＝8.6Hz，2H)，6.87-6.77(m，2H)，5.11(s，2H)，4.03(q，J＝6.9Hz，2H)，2.74(s，2H)，2.18(s，3H)，1.33(t，J＝6.9Hz，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.25，158.19，157.12，141.60，137.61，136.52，133.89，133.49，131.01，129.63，128.76，126.18，116.68，115.15，112.34，69.58，63.40，29.86，20.83，15.16；ESI-MS m/z：391.2[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₅H₂₄D₂O₄: c, 76.50; h, 7.19; measured value: c, 76.55; h, 7.18.

Example 17

3- (4- ((3- (3, 5-dimethylisoxazol-4-yl) benzyl) oxy) phenyl) -2, 2-dideuteropropionic acid (I-14)

The synthesis method is the same as I-1, 0.25g of white solid is obtained, the melting point is 121-.

¹H NMR(300MHz，DMSO-d₆)δ：12.08(s，1H)，7.51-7.37(m，3H)，7.33(d，J＝6.6Hz，1H)，7.14(d，J＝8.0Hz，2H)，6.93(d，J＝8.0Hz，2H)，5.13(s，2H)，2.74(s，2H)，2.37(s，3H)，2.20(s，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.25，165.60，158.52，156.99，138.41，133.55，130.40，129.54，128.53，127.15，116.19，115.16，69.27，29.86，11.72，10.86；ESI-MS m/z：352.2[M-1]^-(ii) a Calculated values of elemental analysis: for C₂₁H₁₉D₂NO₄: c, 71.37; h, 6.56; measured value: c, 71.20; H.6.54.

example 18

(3-Phenoxyphenyl) methanol (IV-1)

The first step is as follows: dissolving 3-phenoxybenzoic acid (1g, 4.67mmol) in 30ml methanol, adding 3ml concentrated sulfuric acid, heating at 60 ℃ for 3 hours, after TLC detection reaction is finished, adding water for dilution, EA extracting (50ml multiplied by 3), combining organic phases, washing with saturated salt water (50ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, decompressing filtrate, evaporating the solvent to obtain 1.02g of white solid, and directly using the white solid in the next step without purification.

The second step is that: the crude product from the previous step (1.02g, 4.47mmol) was dissolved in 15ml THF and NaBH was added portionwise₄(0.31g, 8.0mmol), adding, heating, refluxing, dropwise adding 0.5ml methanol, continuously refluxing for about 30min, stopping stirring, cooling to room temperature, pouring the reaction solution into 40ml ice water, extracting with ethyl acetate (40ml × 3), mixing organic phases, washing with saturated saline (50ml × 2), drying with anhydrous sodium sulfate, filtering, collecting filtrateThe solvent was distilled off under reduced pressure to give 0.80g of a white solid in 80% yield.

Example 19

3- (4- ((3-phenoxybenzyl) oxy) phenyl) -2, 2-dideuteropropionic acid (I-15)

The first step is as follows: dissolving IV-1 (3-phenoxyphenyl) methanol (0.5g, 2.5mmol) obtained in the last step in 30ml dichloromethane, adding SOCl20.2ml, adding 1 drop of DMF as a catalyst, reacting for 2 hours at 25 ℃, and after the reaction is detected by TLC, evaporating the reaction solution under reduced pressure to remove excessive SOCl2 to obtain a light yellow oily substance IV-2 which is directly used for the next step.

The second step is that: dissolving the product IV-2 obtained in the last step in 30mL of acetonitrile, adding the raw material 3- (4-hydroxyphenyl) -2, 2-dideuteropropionic acid (0.50g, 2.74mmol), anhydrous potassium carbonate (1.15g, 8.34mmol) and catalytic amount of KI, heating to 60 ℃ for 8H, reacting, filtering, evaporating the solvent under reduced pressure, dissolving the residue in 30mL of water, extracting with ethyl acetate (20 mL. times.3), combining the organic phases, washing with saturated saline (15 mL. times.2), drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure from the filtrate, purifying the residue by column chromatography (petroleum ether/ethyl acetate, 4: 1, v/v) to obtain 0.76g of white solid IV-3, dissolving in 14mL of mixed solvent (THF/MeOH/H)₂O, 3: 1, v/v/v), adding LiOH (0.1g, 3.99mmol), reacting at room temperature for 8h, evaporating tetrahydrofuran and methanol under reduced pressure, dropwise adding 1N diluted hydrochloric acid in an ice water bath to adjust PH 2-3, separating out a white solid, performing suction filtration, and drying to obtain a white powdery solid I-150.61g, wherein the melting point is 85-87 ℃, and the yield is 80.3%.

¹H NMR(300MHz，DMSO-d₆)δ：12.13(s，1H)，7.38(t，J＝7.9Hz，3H)，7.20(d，J＝7.5Hz，1H)，7.17-7.10(m，3H)，7.09(s，1H)，7.01(d，J＝7.9Hz，2H)，6.95(s，1H)，6.89(d，J＝8.3Hz，2H)，5.05(s，2H)，2.75(s，2H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.28，157.25，156.94，140.03，133.58，130.48，129.64，123.98，122.82，119.16，118.17，117.87，115.13，69.13，29.89；ESI-MS m/z：349.1[M-1]^-(ii) a Calculated values of elemental analysis: for C₂₂H₁₈D₂O₄: c, 75.41; h, 6.33; measured value: c, 75.42; h, 6.32.

Example 20

3- (4- ((5-methyl-2-phenylthiazol-4-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-16)

The synthesis method is the same as I-5, and 0.20g of white solid is obtained, the melting point is 121-.

¹H NMR(300MHz，DMSO-d₆)δ：7.89-7.84(m，2H)，7.52-7.45(m，3H)，7.15(d，J＝8.0Hz，2H)，6.97(d，J＝8.0Hz，2H)，5.09(s，2H)，2.75(s，2H)，2.47(s，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.29，163.59，157.16，148.86，133.53，130.91，130.42，129.64，126.23，115.08，63.86，29.87，11.41；ESI-MS m/z：354.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₀H₁₇D₂NO₃S: c, 67.58; h, 5.95; n, 3.94; measured value: c, 67.53; h, 5.94; and N, 3.93.

Example 21

3- (4- ((4 '-ethoxy-2', 6 '-dimethyl- [1, 1' -biphenyl ] -3-yl) methoxy) -2-fluorophenyl) -2, 2-dideuteropropionic acid (I-17)

The synthesis method is the same as I-1, 0.23g of white solid is obtained, the melting point is 125-.

¹H NMR(300MHz，DMSO-d₆)δ：12.22(s，1H)，7.46-7.37(m，2H)，7.23-7.12(m，2H)，7.05(d，J＝6.8Hz，1H)，6.66-6.84(m，2H)，6.66(s，2H)，5.12(s，2H)，4.00(q，J＝6.7Hz，2H)，2.76(s，2H)，1.90(s，6H)，1.30(d，J＝6.7Hz，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：173.99，162.86，159.64，158.42，157.69，140.90，137.35，136.94，133.96，131.25，129.96，129.33，126.29，119.80，114.11，113.62，111.45，102.99，102.65，69.96，63.29，23.50，21.13，15.10；ESI-MS m/z：423.2[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₆H₂₅D₂FO₄: c, 73.56; h, 6.89; measured value: c, 73.53; h, 6.88.

Example 22

3- (2-fluoro-4- ((2 '- (trifluoromethyl) - [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-18)

The synthesis method is the same as I-1, and 0.23g of white solid is obtained, the melting point is 91-93 ℃, and the yield is 60%.

¹H NMR(300MHz，DMSO-d₆)δ：12.21(s，1H)，7.83(d，J＝7.6Hz，1H)，7.72-7.61(m，2H)，7.47-7.38(m，4H)，7.28(d，J＝6.5Hz，1H)，7.23-7.17(m，1H)，6.92-6.74(m，2H)，5.14(s，2H)，2.76(s，2H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.24，162.83，159.61，141.65，139.97，137.06，132.78，131.35，128.64，128.36，127.59，126.35，125.43，123.68，120.37，111.47，102.59，69.91，23.54；ESI-MS m/z：419.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₃H₁₆D₂F₄O₃: c, 65.71; h, 4.79; measured value: c, 65.75; h, 4.78.

Example 23

3- (4- ((2 '- (trifluoromethyl) - [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid (I-19)

The synthesis method is the same as I-1, 0.21g of white solid is obtained, the melting point is 137-139 ℃, and the yield is 64 percent.

¹H NMR(300MHz，DMSO-d₆)δ：12.09(s，1H)，7.83(d，J＝7.7Hz，1H)，7.74-7.62(m，2H)，7.48-7.36(m，4H)，7.27(d，J＝6.7Hz，1H)，7.14(d，J＝8.4Hz，2H)，6.92(d，J＝8.4Hz，2H)，5.11(s，2H)，2.74(s，2H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.30，156.37，141.25，139.97，137.06，132.78，131.35，128.64，128.36，127.59，126.65，123.48，111.47，102.59，69.91，23.54；ESI-MS m/z：401.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₃H₁₇D₂F₃O₃: c, 68.65; h, 5.26; measured value: c, 68.61; h, 5.25.

Example 24

3- (4- ((3- (2- (methoxyimino) -2-phenylethoxy) benzyl) oxy) phenyl) -2, 2-dideuteropropionic acid (I-20)

The synthesis method is the same as I-1, 0.29g of white solid is obtained, the melting point is 117 ℃ and the yield is 62 percent.

¹H NMR(300MHz，DMSO-d₆)δ：12.07(s，1H)，7.54-7，68(m，3H)，7.30-7.41(m，4H)，7.34(d，J＝8.1Hz，2H)，7.12(d，J＝7.5Hz，2H)，6.90(t，J＝8.9Hz，4H)，5.22(s，2H)，4.96(s，2H)，4.00(s，3H)，2.73(s，2H)；¹³C NMR(75MHz，DMSO-d₆)δ：173.35，157.42，153.96，132.83，129.23，128.32，127.66，126.69，115.01，114.44，114.03，68.77，62.23，59.33，29.41；ESI-MS m/z：420.2[M-1]^-(ii) a Calculated values of elemental analysis: for C₂₅H₂₃D₂NO₅: c, 71.24; h, 6.46; measured value: c, 71.22; h, 6.43.

Example 25

3- (4- ((3- (3, 5-Dimethylisoxazol-4-yl) benzyl) oxy) -2-fluorophenyl) -2, 2-dideuteropropionic acid (I-21)

The synthesis method is the same as I-1, 0.16g of white solid is obtained, the melting point is 103-.

¹H NMR(300MHz，DMSO-d₆)δ：7.50(d，J＝6.7Hz，1H)，7.44(d，J＝7.4Hz，2H)，7.33(d，J＝6.9Hz，1H)，7.20(t，J＝8.7Hz，1H)，6.91-6.75(m，2H)，5.15(s，2H)，2.76(s，2H)，2.37(s，3H)，2.20(s，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：173.52，165.12，159.18，157.92，137.40130.85，129.98，128.96，128.17，126.74，115.66，110.85，102.44，102.10，69.19，22.95，11.17，10.32；ESI-MS m/z：370.2[M-1]^-(ii) a Calculated values of elemental analysis: for C₂₁H₁₈D₂FNO₄: c, 67.91; h, 5.97; measured value: c, 67.89; h, 5.99.

Example 26

3- (4- ((4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) methoxy) phenyl) propanoic acid-2, 2-diester acid-2, 2-dideuteropropanoic acid (I-22)

The synthesis method is the same as I-5, 0.24g of white solid is obtained, the melting point is 123-.

¹H NMR(300MHz，DMSO-d₆)δ：8.10(d，J＝8.1Hz，2H)，7.83(d，J＝8.1Hz，2H)，7.17(d，J＝8.3Hz，2H)，6.96(d，J＝8.3Hz，2H)，5.30(s，2H)，2.76(s，2H)，2.46(s，3H)；¹³C NMR(75MHz，DMSO-d₆)δ：174.22，168.35，163.71，156.49，152.16，136.89，134.13，129.97，127.03，126.58，124.63，115.43，62.10，35.94，29.90，15.51；ESI-MS m/z：422.1[M-H]^-(ii) a Calculated values of elemental analysis: for C₂₁H₁₆D₂F₃NO₃S：C, 59.57; h, 4.76; n, 3.31; measured value: c, 59.53; h, 4.75; and N, 3.32.

Example 27

Tablets containing active agent I-4:

sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft mass, sieving, making wet granule, drying at 50-60 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.

The composition also has excellent in-vivo hypoglycemic activity through verification.

Claims

1. A compound selected from the group consisting of:

3- (4- ((2 '-methyl- [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid;

3- (4- ((2 ', 6' -dimethyl-4 '- (3- (methylsulfonyl) propoxy) - [1, 1' -biphenyl ] -3-yl) methoxy) phenyl) -2, 2-dideuteropropionic acid.

2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a suitable carrier.

3. Use of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diabetes and metabolic syndrome.

4. Use of a pharmaceutical composition as defined in claim 2 for the manufacture of a medicament for the treatment of diabetes and metabolic syndrome.