CN110746439A - Preparation method of thienopyrimidinedione compound - Google Patents

Preparation method of thienopyrimidinedione compound Download PDF

Info

Publication number
CN110746439A
CN110746439A CN201910993121.3A CN201910993121A CN110746439A CN 110746439 A CN110746439 A CN 110746439A CN 201910993121 A CN201910993121 A CN 201910993121A CN 110746439 A CN110746439 A CN 110746439A
Authority
CN
China
Prior art keywords
compound
formula
ethyl
oxazol
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201910993121.3A
Other languages
Chinese (zh)
Other versions
CN110746439B (en
Inventor
张军波
齐晓昕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Ruijie Medical Technology Co Ltd
Original Assignee
Nanjing Ruijie Medical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Ruijie Medical Technology Co Ltd filed Critical Nanjing Ruijie Medical Technology Co Ltd
Priority to CN201910993121.3A priority Critical patent/CN110746439B/en
Publication of CN110746439A publication Critical patent/CN110746439A/en
Application granted granted Critical
Publication of CN110746439B publication Critical patent/CN110746439B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The invention provides a process for the preparation of compounds of the general formula c, wherein the substituents are as defined in the description

Description

Preparation method of thienopyrimidinedione compound
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of a thienopyrimidinedione compound.
Background
Obesity is a health crisis for a large group. The health burden of obesity, measured by the years of quality-adjusted life (quality-adjusted life-years) lost by each adult, has outweighed smoking, and is the most serious and preventable cause of death. In the united states, about 34% of adults suffer from obesity, up to 31% from 1999 and about 15% from 1960 to 1980. Obesity increases the mortality rate of men and women of all ages and races for all reasons. Obesity also leads to social deprecations and discrimination, which significantly reduces the quality of life. Chronic disease due to obesity costs the us economy more than 1500 billion dollars per year on weight-related medical bills. In addition, about half of the obese population and 25% of the general population suffer from metabolic syndrome, i.e., conditions associated with abdominal obesity, hypertension, increased plasma triglycerides, decreased HDL cholesterol, and insulin resistance, which increases the risk of type 2 diabetes (T2DM), stroke, and coronary heart disease. (Harwood, Expert opin. Ther. targets 9: 267, 2005).
Diet and exercise, even when used in conjunction with current drug therapies, do not provide the sustainable weight loss required for long-term health benefits. Currently, only a few anti-obesity drugs, orlistat (fat absorption inhibitor), the 5-HT2C antagonist rocacilin (lorcaserin), and the combination therapy phentermine/topiramate (phenotropimine/topiramate), are approved for use in the united states. Unfortunately, poor efficacy and adverse gastrointestinal side effects limit the use of orlistat. Surgery may be effective, but is limited to patients with very high Body Mass Index (BMI), and lower surgical throughput limits the impact of this approach to about 20 million patients per year. Most of the obesity drugs in clinical development are designed to reduce caloric intake via central action in the CNS (e.g., anorectics and satiety agents). However, the FDA has adopted an objection to CNS active agents due to their less than significant efficacy and observed/potential side effect profile.
The continuing and increasing problem of obesity and the current lack of safe and effective drugs to treat it highlight the urgent need for new drugs to treat this condition and its underlying cause.
Another persistent problem is the lack of antifungal agents that are active against a broad spectrum of fungal pathogens. Generally, a given antifungal drug is active against one fungal species, but lacks activity against other (even closely related) species such as Candida albicans (Candida albicans), Candida krusei (Candida krusei), and Candida parapsilosis (Candida parapsilosis).
The compounds of patent CN106905346B, filed by gillider, are effective as inhibitors of acetyl-CoA carboxylase (ACC) and are useful in the treatment of a variety of diseases, disorders or conditions associated with the modulation of fatty acid production or oxidation. The patent discloses a synthetic route of the compound, and a 2- (tributylstannyl) -1, 3-oxazole reagent is adopted in the synthetic process, so that the compound has extremely high toxicity, does not meet the requirements of environmental protection, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to solve the technical problem of providing a thienopyrimidinedione ACC inhibitor compound prepared by a preparation method which is low in toxicity, green, high in yield and suitable for industrial production.
In order to solve the technical problems, the technical scheme is as follows:
a process for the preparation of a compound of formula (c):
wherein R is1And R2Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R1And R2Together with the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group;
R3and R4Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R3And R4Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R1And R3Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R2And R4Together with the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group;
R5and R6Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R1And R5Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R2And R6Together with the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group;
n is 0, 1;
m is 0, 1;
the method comprises the following steps:
s1, adding the compound of formula (d) into the solution of the compound of formula (a) for reaction to obtain an intermediate compound of formula (b),
Figure BDA0002238903040000031
wherein R is7Is C1-6 alkyl, R8Is C3-6An alkyl group;
s2, hydrolyzing the compound of formula (b) to obtain the compound of formula (c)
Figure BDA0002238903040000032
The compound of formula (c') is obtained by the preparation of formula (c)
In certain embodiments, the solution of the compound of formula (a) in step S1 is a solution of the compound of formula (a) in N, N-dimethylformamide, tetrahydrofuran, toluene.
In some embodiments, one or more of palladium acetate, cuprous iodide, cesium fluoride, and n-butyl di (1-adamantyl) phosphine (cataCxium a) are also added in step S1.
In certain embodiments, (a) the compound: palladium acetate: cuprous iodide: cesium fluoride: mass ratio of n-butyldi (1-adamantyl) phosphine of 1: 0.1-1.9: 0.4-0.5: 2.2-3: 0.18 to 0.22.
In certain embodiments, step S1 is performed at 100 ℃ to 150 ℃. Preferably, step S1 is performed at 120 ℃.
In certain embodiments, the compound of formula (b) obtained in step S1 is polyethylene: ethyl acetate ═ 3: 1 by flash chromatography on silica gel.
In certain embodiments, the compound of formula (d) in step S1 is 2- (tripropylsilyl) oxazole and 2- (tributylsilyl) oxazole.
In certain embodiments, the compound of formula (d) in step S1 is 2- (triisopropylsilyl) oxazole.
In certain embodiments, 2- (triisopropylsilyl) oxazole and 2- (tributylsilyl) oxazole are prepared from oxazoles.
The compound of formula (c) is selected from:
(R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid;
1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid;
(R) -1- ((1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxa-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) methyl) cyclopropane-1-carboxylic acid;
(R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxa-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid;
(R) -1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropane-1-carboxylic acid;
2- (1- ((R) -2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxa-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid;
(R) -2- (1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropyl) acetic acid.
1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopentane-1-carboxylic acid
The compound of formula (c') is selected from:
(R) -1- (1- (2- (2- (2-methoxyphenyl) -2-) ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxa-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropane-1-carboxamide
(R) -2- (1- (1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2 yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropyl) acetamide
1- (1- (2- (2-methoxyphenyl) -2-E-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopentane-1-carboxamide.
Detailed Description
The following further describes the technical means adopted by the invention to achieve the predetermined purpose by combining the chemical formula and the preferred embodiment of the invention.
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagent materials used in the following examples are all commercially available products unless otherwise specified.
The general synthetic routes described in the present application can be varied by replacing the starting materials with other materials having similar structures, resulting in different products accordingly. The following synthetic description gives a number of examples of how the starting materials may be varied to give the corresponding products.
General procedure
The synthesis of the compound of formula (a) is carried out using methods known in the prior art and in patents CN106905346B, CN 108699078A.
Synthesis of intermediate 1.7:
Figure BDA0002238903040000061
method A
Compound 1.2 was synthesized.
A round bottom flask was placed a solution of ethyl 3-oxobutyrate, sulfur and ethyl 2-cyanoacetate in ethanol. Thereafter morpholine was added dropwise with stirring, and the resulting solution was stirred. The solids were filtered off. By H2The solution was diluted O, the solid was collected by filtration, and the filter cake was washed with EtOH. Purification afforded 1.2 as a yellow solid.
Synthesis of Compound 1.3
To a three-neck round bottom flask purged with inert nitrogen and maintained under an inert nitrogen atmosphere was placed 1.2 and dichloromethane. After which bistrichloromethyl carbonate is added. Thereafter TEA was added dropwise with stirring, and the resulting solution was stirred. To which f is added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of water. The resulting mixture was concentrated under vacuum. The crude product was recrystallized from EA/PE to give 1.3 as a yellow solid.
Synthesis of Compound 1.4
To a three-necked round-bottomed flask purged with inert nitrogen and maintained under an inert nitrogen atmosphere was placed 1, 4-dioxane. After which sodium hydride is added. The resulting solution was stirred. Followed by addition of NH4The reaction was quenched with Cl (saturated aqueous solution). The resulting solution was extracted with ethyl acetate and the organic layers were combined and concentrated in vacuo. The crude product was recrystallized from EA and PE. Purification afforded 1.4 as a white solid.
Synthesis of Compound 1.5
To a three-necked round bottom flask, 1.4, sodium hydroxide, water and methanol were placed, and the resulting solution was stirred. The resulting mixture was concentrated under vacuum. The pH of the solution was adjusted to 2 with hydrogen chloride. The resulting solution was extracted with ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.5 as a white solid.
Synthesis of Compound 1.6
Adding 1.5 parts of potassium carbonate and CH into a three-neck round-bottom flask3COOAg and NMP. The resulting solution was stirred. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate/petroleum ether. Purification afforded 1.6 as a white solid.
Synthesis of Compound 1.7
1.6 and CH are placed in a three-neck round-bottom flask3COONa and acetic acid. After which Br was added dropwise with stirring2. The resulting solution was stirred at room temperature, concentrated under vacuum and washed with H2O wash gave 1.7 as a white solid.
Synthesis of intermediate 2.6:
Figure BDA0002238903040000081
method B
Synthesis of Compound 2.2
DMSO was placed into a three-necked round bottom flask under nitrogen. Subsequently NaH was added. The mixture was stirred at room temperature. To this was added trimethyl sulfoxide iodide in portions at room temperature. The resulting solution was stirred. To this mixture was added compound 2.1 dropwise and the reaction was stirred at room temperature and then quenched by the addition of NH4Cl (aq). The resulting solution was extracted with EtOAc and the organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give 1.2 as a yellow oil.
Synthesis of Compound 2.3
Tetrahydropyran-4-ol and FeCl3 were added to a three-necked round bottom flask under nitrogen. Subsequently, 2.2 is added dropwise. The reaction was stirred at room temperature. The resulting solution was diluted with H2O and then extracted with EtOAC. The organic layers were combined and the solvent was removed in vacuo. The crude product was purified by column chromatography to give 2.3 as a white solid.
Synthesis of Compound 2.4
To a round bottom flask was added 2.3, toluene, CAL-B and vinyl butyrate. The reaction was stirred at room temperature. The solid was filtered off and the filtrate was concentrated in vacuo to give 2.4 as a colorless oil.
Synthesis of Compound 2.5
To a three-necked round bottom flask was added 2.4, methanol, water, NaOH. The reaction was stirred at room temperature and then quenched by the addition of acetic acid. The resulting mixture was concentrated in vacuo and then extracted with EtOAc. The organic layers were combined and concentrated in vacuo. The crude product was purified by column chromatography to give 2.5 as a white solid.
Synthesis of Compound 2.6
To a round bottom flask under nitrogen was added 2.5, CBr4, CH2Cl2, PPh 3. The reaction was stirred at rt overnight and then concentrated in vacuo. The crude product was purified by column chromatography to give 2.6 as a yellow oil.
Synthesis of a compound of formula (a):
method C
Cesium carbonate was dried in a vacuum oven. Dry cesium carbonate, as well as N-methylpyrrolidone (NMP), was added to glass reactor a in one portion under nitrogen. NMP, compounds 2.6 and 1.7 were added to glass reactor B and the mixture was stirred until complete dissolution was observed. The solution in reactor B was transferred to reactor a and additional NMP was used to wash the residual contents of reactor B to reactor a. The mixture in reactor a was then heated and stirred at that temperature. The temperature was lowered and purified water was added and the entire mixture was transferred to glass reactor C. Additional purified water and methyl tert-butyl ether (MTBE) were added and the mixture was stirred. The phases were separated and the organic phase was washed with purified water. The aqueous phase was returned to the reactor and washed with MTBE and stirred. The combined organic layers were washed with brine and transferred to reactor a. The organic mixture was concentrated in vacuo to volume L. Ethanol was added and the mixture was concentrated in vacuo, and ethanol was added and concentration was repeated multiple times. The mixture was heated and stirred until complete dissolution was observed. The temperature is lowered. The solid formed was vacuum filtered and washed with ethanol. The resulting solid was dried in a vacuum oven to give a.
Synthesis of a Compound of formula (d):
Figure BDA0002238903040000092
method D
Taking oxazole and the compound e, adding into THF, stirring, drying, filtering and purifying to obtain the compound of the formula (d).
A process for the preparation of a compound of formula (c):
Figure BDA0002238903040000101
wherein R is1And R2Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R1And R2With themThe bonded carbon atoms together form a 3 to 6 membered cycloalkyl group;
R3and R4Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R3And R4Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R1And R3Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R2And R4Together with the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group;
R5and R6Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R1And R5Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R2And R6Together with the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group;
n is 0, 1;
m is 0, 1;
the method comprises the following steps:
s1, reacting a compound of formula (a) in N, N-dimethylformamide with one or more of (d) palladium acetate, cuprous iodide, cesium fluoride and N-butyl bis (1-adamantyl) phosphine (cataCxium a), wherein (a) the compound: palladium acetate: cuprous iodide: cesium fluoride: the amount ratio of cataCxium a species is 1: 0.1-1.9: 0.4-0.5: 2.2-3: 0.18-0.22, at 100-150 deg.C. Preferably, step S1 is performed at 120 ℃. Extracting with ethyl acetate, collecting organic layer, and collecting Na2SO4Dried, filtered and concentrated. The polyethylene is adopted: ethyl acetate ═ 3: 1, purifying by silica gel flash chromatography to obtain an intermediate compound shown as a formula (b);
Figure BDA0002238903040000111
wherein, R is7Is C1-6Alkyl radical, R8Is C3-6An alkyl group;
the compound of formula (d) may be 2- (tripropylsilyl) oxazole, 2- (tributylsilyl) oxazole.
S2, hydrolyzing the compound of formula (b) in sodium hydroxide/methanol solution or sodium hydroxide/ethanol solution to obtain the compound of formula (c).
Figure BDA0002238903040000112
The hydrolysis of step S2 is performed in a sodium hydroxide/methanol solution or a sodium hydroxide/ethanol solution. Step S2 is carried out at 50 ℃ -100 ℃. Preferably, step S2 is performed at 60 ℃. The reaction mixture was adjusted to pH 7 with 5% aqueous HCl solution, extracted with ethyl acetate, and the organic layer was collected and Na was added2SO4Dried, filtered and concentrated. Purification by preparative high performance liquid chromatography gave the compound of formula (c) of step S2.
The compound of formula (c') is prepared according to formula (c).
Figure BDA0002238903040000113
To a solution of compound c in DCM, EDCI (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride) and DMAP (4-dimethylaminopyridine) and NH4Cl were added. The reaction mixture was stirred. After TLC showed no starting material remained, water was added and the separated organic layer was purified over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative HPLC to give compound c' as a white solid.
In certain embodiments, the compounds of formula (c) and formula (c') of the present invention are selected from:
Figure BDA0002238903040000121
Figure BDA0002238903040000131
example 1
Figure BDA0002238903040000132
To a solution of Compound a-1(15mg) in DMF (2mL) was added 2- (triisopropylsilyl) oxazole (11mg), Pd (OAc)2(10mg), CuI (2mg), CsF (8mg) and cataCxium A (2 mg). The reaction mixture was then stirred at 120 ℃ for 4 hours. The reaction mixture was cooled to room temperature and washed with H2O (10mL) was diluted and extracted with EA (10 mL. times.2). The combined organic layers were washed with brine (10mL) and Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA ═ 3/1) to give compound b-1(0.54mg) as a white solid.
MS found: 610[ M + H ]]+
Figure BDA0002238903040000141
To a solution of compound b-1(100mg, N) in EtOH (6mL) and water (1mL) was added NaOH (33 mg). The reaction mixture was stirred at 60 ℃ for 2 hours. The reaction mixture was adjusted to pH 7 with 5% aqueous HCl and then extracted with EA (50 mL. times.2). The combined organic layers were washed with brine (10mL) and Na2SO4Dried, filtered and concentrated. The crude residue was purified by preparative HPLC to give compound c-1(31.2mg, 32% yield) as a white solid.
MS found: 600.1[ M +18 ]]+
1HNMR(400MHz,CD3OD)δ8.02(d,J＝0.8Hz,1H),7.56-7.54(m,1H), 7.34-7.29(m,2H),7.05-7.00(m,2H),5.45-5.42(m,1H),3.88(s,3H),3.86-3.83(m, 2H),3.64-3.62(m,2H),3.50-3.46(m,1H),3.44-3.36(m,2H),2.99-2.90(m,1H), 2.80(s,3H),2.55-2.45(m,2H),2.38-2.33(m,1H),2.21-2.13(m,1H),1.92-1.86(m, 2H),1.78-1.74(m,1H),1.60-1.52(m,2H).
Example 2
Figure BDA0002238903040000142
To a solution of Compound a-2(100mg) in DMF (2mL) was added 2- (triisopropylsilyl) oxazole (59.9mg), Pd (OAc)2(3.6mg)，CuI(12.4mg)，CsF (75mg) and cataCxium A (11.7 mg). The reaction mixture was then stirred at 120 ℃ for 4 hours. The reaction mixture was cooled to room temperature and washed with H2O (10mL) was diluted and extracted with EA (10 mL. times.2). The combined organic layers were washed with brine (10mL) and Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA ═ 3/1) to give compound b-2(31mg, yield 32%) as a white solid.
MS found: 598[ M + H ]]+
Figure BDA0002238903040000151
To a solution of compound b-2(30mg) in MeOH (2mL) and water (1mL) was added NaOH (10 mg). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 7 with 5% aqueous HCl and then extracted with EA (25 mL. times.3). The combined organic layers were washed with brine (10mL), dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC to give c-2(12mg, 41.9% yield) as a white solid.
MS found: 568[ M + H]+
1HNMR(400MHz,CDCl3)δppm:7.73(s,1H),7.52-7.51(m,1H),7.31-7.25 (m,1H),7.20(s,1H),7.02-7.01(m,1H),6.90-6.87(m,1H),5.43(s,1H),3.87-3.80 (m,6H),3.62-3.51(m,2H)3.26(s,3H),2.00(s,3H),2.01-2.02(m,2H),1.70-1.73(m, 2H),1.35-1.25(m,4H),0.88-0.86(m,2H).
Example 3
Figure BDA0002238903040000152
To a solution of Compound a-3(100mg) in DMF (2mL) was added 2- (triisopropylsilyl) oxazole (80.3mg), Pd (OAc)2(3.6mg), CuI (12.5mg), CsF (74.8mg) and cataCxium A (11.8 mg). The reaction mixture was then stirred at 120 ℃ for 4 hours. The reaction was cooled to room temperature and quenched with H2O (15mL) was diluted and extracted with EA (15 mL. times.2). The combined organic layers were washed with brine (10mL) and Na2SO4Drying and filteringAnd concentrated. The residue was purified by flash chromatography on silica gel (PE/EA ═ 3/1) to give compound b-3(52mg) as a white solid.
MS found: 596[ M + H]+
Figure BDA0002238903040000161
To a solution of compound b-3(60mg) in MeOH (2mL) and water (1mL) was added NaOH (20 mg). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 7 with 5% aqueous HCl and then extracted with EA (50 mL. times.3). The combined organic layers were washed with brine (20mL) and Na2SO4Dried, filtered and concentrated. The crude residue was purified by preparative HPLC to give c-3(28mg, 48% yield) as a white solid.
MS found: 581.9[ M + H]+
1HNMR(400MHz,DMSO-d6)δppm:8.23(s,1H),7.49-7.48(m,1H),7.39(s, 1H),7.34-7.29(m,1H),7.06-7.01(m,2H),5.32-5.29(m,1H),4.40(s,2H),4.06(s, 2H),3.81(s,3H),3.60-3.49(m,2H),3.24-3.18(m,2H),2.79(s,3H),1.63-1.62(m, 2H),1.34-1.14(m,2H),1.03(s,2H),0.70-0.68(m,2H).
Example 4
Figure BDA0002238903040000162
A-4(257mg, 0.43mmol), Pd (PPh 3)4(155mg,0.134mmol), 2- (tributylsilyl) oxazole (230mg, 0.86mmol) and toluene (35mL) were poured into a 100mL three-necked round bottom flask, purged and kept under an inert atmosphere of nitrogen 3 times. The solution was stirred in an oil bath at 110 ℃ overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EA ═ 5: 1) to give b-4(150mg, yield 32%) as a white solid.
B-4(150mg, 0.258mmol) was dissolved in a 50mL three-neck round-bottom flask of H2O (5mL), THF (5mL) and MeOH (5mL), LiOH (41mg,1.03 mmol). The mixture was heated to 70 ℃ for 5 hours. The mixture was reacted with 1M HCl to acidify the pH to 2 and extracted with EA, and the organic phase was dried and concentrated. The residue was purified by column chromatography (DCM/MeOH ═ 20/1) to give c-4(45mg, 30%).
Figure BDA0002238903040000172
To a solution of compound c-4(60mg, 0.10mmol) in 1.2mL DCM were added EDCI (27mg, 0.14mmol) and DMAP (25.8mg, 0.211mmol) and NH4Cl (15mg, 0.28 mmol). The reaction mixture was stirred at 40 ℃ for 2 hours. TLC showed no starting material remaining, 5mL water was added and the separated organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to give compound c' -4(28mg, 46.7% yield) as a white solid.
MS found: 567.1[ M + H]+
1H NMR(400MHz,MeOD)δ7.89(d,J＝5.4Hz,1H),7.41(dd,J＝28.9,7.3 Hz,1H),7.20(t,J＝7.7Hz,2H),6.99–6.83(m,2H),5.30-5.37(m,1H),4.57–4.47 (m,1H),3.87–3.66(m,4H),3.44-5.56(m,1H),3.24-3.40(m,2H),2.75(d,J＝9.1 Hz,3H),1.58-1.84(m,4H),0.85-1.48(m,6H).
Example 5
Figure BDA0002238903040000181
In N2Next to a solution of oxazole (1.0g, 14.5mmol) in THF (15mL) at-78 deg.C was added n-butyllithium (11.6mL, 29mmol, 2.5M in hexane) dropwise. After stirring at-78 ℃ for an additional 45 minutes, triisopropylsilyltriflate (6.65g, 21.8mmol) was slowly added to the reaction mixture at-78 ℃. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 12 hours. The reaction mixture was diluted with water (100mL) and extracted with EA (200 mL. times.2). The combined organic layers were washed with brine (50mL) and Na2SO4Dried, filtered and concentrated. Passing the residue through silica gelFlash chromatography purification (PE/EA. RTM. 20/1) afforded the compound 2- (triisopropylsilyl) oxazole (1.1g, 33.7% yield) as a yellow oil.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (17)

1. A process for the preparation of a compound of formula (c):
wherein R is1And R2Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R1And R2Together with the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group;
R3and R4Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R3And R4Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R1And R3Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R2And R4Together with the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group;
R5and R6Is H, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, or R1And R5Together with the carbon atom to which they are bonded form a 3-to 6-membered cycloalkyl group, or R2And R6To carbon atoms bound theretoTo form a 3 to 6 membered cycloalkyl group;
n is 0, 1;
m is 0, 1;
characterized in that the method comprises the following steps:
s1, adding the compound of formula (d) into the solution of the compound of formula (a) for reaction to obtain an intermediate compound of formula (b),
Figure FDA0002238903030000012
wherein R is7Is C1-6Alkyl radical, R8Is C3-6An alkyl group;
s2, hydrolyzing the compound of formula (b) to obtain the compound of formula (c)
Figure FDA0002238903030000021
2. A process for the preparation of a compound according to claim 1, wherein a compound of formula (c') is prepared from formula (c)
Figure FDA0002238903030000022
3. The method for producing a compound according to claim 1 or 2, wherein the solution of the compound of formula (a) in step S1 is a solution of N, N-dimethylformamide of formula (a), a solution of tetrahydrofuran, or a solution of toluene.
4. The method of claim 3, wherein one or more of palladium acetate, cuprous iodide, cesium fluoride and n-butyl bis (1-adamantyl) phosphine are further added in step S1.
5. The method of claim 4, wherein in step S1 (a) the compound: palladium acetate: cuprous iodide: cesium fluoride: mass ratio of n-butyldi (1-adamantyl) phosphine of 1: 0.1-1.9: 0.4-0.5: 2.2-3: 0.18 to 0.22.
6. The method for preparing a compound according to claim 3, wherein the step S1 is performed at 100 ℃ to 150 ℃.
7. The method for preparing a compound according to claim 6, wherein the step S1 is performed at 120 ℃.
8. The method for preparing the compound according to claim 7, wherein the compound of formula (b) obtained in step S1 is polyethylene: ethyl acetate ═ 3: 1 by flash chromatography on silica gel.
9. The method for preparing a compound according to claim 1, wherein the hydrolysis of step S2 is performed in a sodium hydroxide/methanol solution or a sodium hydroxide/ethanol solution.
10. The method for preparing a compound according to claim 9, wherein the step S2 is performed at 50 ℃ to 100 ℃.
11. The method for preparing a compound according to claim 10, wherein the step S2 is performed at 60 ℃.
12. The method of claim 11, wherein the compound of formula (c) obtained in step S2 is purified by preparative high performance liquid chromatography.
13. The method for producing a compound according to claim 1, wherein the compound of formula (d) is 2- (tripropylsilyl) oxazole or 2- (tributylsilyl) oxazole.
14. The method for producing the compound according to claim 13, wherein the compound of the formula (d) is 2- (triisopropylsilyl) oxazole.
15. The method for preparing a compound according to claim 13, wherein the 2- (tripropylsilyl) oxazole and the 2- (tributylsilyl) oxazole are prepared from oxazol.
16. A process for the preparation of a compound according to claim 1, wherein the compound of formula (c) is selected from:
(R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid;
1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid;
(R) -1- ((1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxa-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) methyl) cyclopropane-1-carboxylic acid;
(R) -3- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxa-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid;
(R) -1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropane-1-carboxylic acid;
2- (1- ((R) -2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxa-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid;
(R) -2- (1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropyl) acetic acid;
1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopentane-1-carboxylic acid.
17. A process for the preparation of a compound according to claim 2, wherein the compound of formula (c') is:
(R) -1- (1- (2- (2- (2-methoxyphenyl) -2-) ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxa-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropane-1-carboxamide;
(R) -2- (1- (1- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2 yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropyl) acetamide;
1- (1- (2- (2-methoxyphenyl) -2-E-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopentane-1-carboxamide.
CN201910993121.3A 2019-10-18 2019-10-18 Preparation method of thienopyrimidinedione compound Active CN110746439B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910993121.3A CN110746439B (en) 2019-10-18 2019-10-18 Preparation method of thienopyrimidinedione compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910993121.3A CN110746439B (en) 2019-10-18 2019-10-18 Preparation method of thienopyrimidinedione compound

Publications (2)

Publication Number Publication Date
CN110746439A true CN110746439A (en) 2020-02-04
CN110746439B CN110746439B (en) 2020-10-30

Family

ID=69278881

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910993121.3A Active CN110746439B (en) 2019-10-18 2019-10-18 Preparation method of thienopyrimidinedione compound

Country Status (1)

Country Link
CN (1) CN110746439B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104105485A (en) * 2011-11-11 2014-10-15 尼普斯阿波罗有限公司 Acc inhibitors and uses thereof
WO2017151816A1 (en) * 2016-03-02 2017-09-08 Gilead Apollo, Llc Solid forms of a thienopyrimidinedione acc inhibitor and methods for production thereof
CN108349995A (en) * 2015-11-25 2018-07-31 吉利德阿波罗公司 Pyrazoles ACC inhibitor and application thereof
CN108347939A (en) * 2015-11-25 2018-07-31 吉利德阿波罗公司 Fungicidal composition containing the 2,4- dioxo -1,4- dihydro-thiophenes simultaneously derivative of [2,3-D] pyrimidine
CN108368125A (en) * 2015-10-26 2018-08-03 吉利德阿波罗公司 ACC inhibitor and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104105485A (en) * 2011-11-11 2014-10-15 尼普斯阿波罗有限公司 Acc inhibitors and uses thereof
CN108368125A (en) * 2015-10-26 2018-08-03 吉利德阿波罗公司 ACC inhibitor and application thereof
CN108349995A (en) * 2015-11-25 2018-07-31 吉利德阿波罗公司 Pyrazoles ACC inhibitor and application thereof
CN108347939A (en) * 2015-11-25 2018-07-31 吉利德阿波罗公司 Fungicidal composition containing the 2,4- dioxo -1,4- dihydro-thiophenes simultaneously derivative of [2,3-D] pyrimidine
WO2017151816A1 (en) * 2016-03-02 2017-09-08 Gilead Apollo, Llc Solid forms of a thienopyrimidinedione acc inhibitor and methods for production thereof

Also Published As

Publication number Publication date
CN110746439B (en) 2020-10-30

Similar Documents

Publication Publication Date Title
JP6916968B1 (en) GLP-1 receptor agonist and its use
CN108699077B (en) Heterocyclic compounds as RSV inhibitors
JP5202635B2 (en) Processes and intermediates for the preparation of integrase inhibitors
KR20200032702A (en) Piperazine heteroaryl derivatives, methods for their preparation and uses in medicine
CN104610360A (en) Method for preparing tenofovir disoproxil fumarate
CN108017583A (en) A kind of preparation method for winning U.S.
JP2019510790A (en) Pyrazolo [1,5-a] pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders
KR20240049561A (en) Benzazepine aromatic ring derivatives and their applications in medicine
AU2013243353A1 (en) Fused cyclopentyl antagonists of CCR2
WO2002006284A1 (en) Indoloquinazolinones
KR20180128907A (en) TRICYCLIC COMPOUND SERVING AS IMMUNOMODULATOR, acting as an immunomodulator,
AU2022328556A1 (en) Prodrugs and derivatives of psilocin and uses thereof
EP1847535A1 (en) 1-(piperidin-4-yl)-1h-indole derivative
KR20220097388A (en) Heterocyclic amide compounds, pharmaceutically acceptable salts thereof, and methods and uses thereof
CN101186611B (en) Pyrroline-2-one derivative capable of inhibiting cell to release tumor necrotic factor and its preparation and application
CN110746439B (en) Preparation method of thienopyrimidinedione compound
CN101481323A (en) Benzo cyclohepten derivate, and preparation and medical use thereof
CN102977142B (en) The preparation method of fosaprepitant dimeglumine
CN112243437A (en) Acryloyl group-containing nuclear transport modulators and uses thereof
CN105358551A (en) Octahydro-cyclopentapyrrolyl antagonists of CCR2
JP7314494B2 (en) Pharmaceuticals containing prodrugs of amino acid derivatives
CN113121417A (en) Novel piperidine derivative and pharmaceutical application thereof
CN107737126B (en) Application of coumarin-dithiocarbamate derivative in pharmacy
CN107074780A (en) Method for producing the alcoholic compound of pyrimidine 1 and its intermediate
CN109232222A (en) A kind of preparation method of (E)-octyl- 4- alkene -1,8- diacid

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: A preparation method of thiophene pyrimidine dione compound

Effective date of registration: 20221124

Granted publication date: 20201030

Pledgee: Jiangsu Zijin Rural Commercial Bank Co.,Ltd. Jiangning Development Zone sub branch

Pledgor: NANJING RUIJIE PHARMA Co.,Ltd.

Registration number: Y2022980023326

PE01 Entry into force of the registration of the contract for pledge of patent right
PC01 Cancellation of the registration of the contract for pledge of patent right

Date of cancellation: 20231223

Granted publication date: 20201030

Pledgee: Jiangsu Zijin Rural Commercial Bank Co.,Ltd. Jiangning Development Zone sub branch

Pledgor: NANJING RUIJIE PHARMA Co.,Ltd.

Registration number: Y2022980023326

PC01 Cancellation of the registration of the contract for pledge of patent right