CN107629069B - Preparation method of acetyl coenzyme A carboxylase inhibitor - Google Patents

Preparation method of acetyl coenzyme A carboxylase inhibitor Download PDF

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CN107629069B
CN107629069B CN201711079888.2A CN201711079888A CN107629069B CN 107629069 B CN107629069 B CN 107629069B CN 201711079888 A CN201711079888 A CN 201711079888A CN 107629069 B CN107629069 B CN 107629069B
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methyl
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dihydrothieno
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pyrimidin
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温小安
李恩芹
秦鹿柘
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China Pharmaceutical University
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Abstract

The invention relates to the field of pharmacy, in particular to a preparation method of an acetyl coenzyme A carboxylase inhibitor. The method comprises the steps of reacting 2- (6-halo-5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropanoic acid tert-butyl ester (II) with halogenated o-methoxyacetophenone, hydrolyzing, protecting carboxyl with silicon, reducing, halogenating, replacing halogen atoms with alcohol to obtain a key intermediate 2- (6-halo-1- (2- (2-methoxyphenyl) -2-alkoxy) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropanoic acid silicon ester (VIII), and finally carrying out Stille coupling and desiliconyl protecting group removal to obtain the target compound. The method has the advantages of less side reaction, low cost and simple operation, and is suitable for industrial production.

Description

Preparation method of acetyl coenzyme A carboxylase inhibitor
Technical Field
The invention relates to the field of pharmacy, and in particular relates to a preparation method of 2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazole-2-yl) -2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidine-3 (2H) -yl) -2-methylpropanoic acid and derivatives thereof.
Background
acetyl-CoA carboxylase (ACC) inhibitors are useful for the treatment of obesity, dyslipidemia, hyperlipidemia, and the like. 2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazole-2-yl) -2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropanoic acid shown in formula (1) and derivatives thereof are ACC inhibitors, wherein a compound GS-0976 of Gilead company is currently in II clinical research and is expected to be developed into a safe and effective non-alcoholic steatohepatitis treatment drug.
Figure BDA0001458811710000011
Wherein R is independently hydrogen or optionally substituted from the group consisting of: aliphatic alkyl of 1 to 6 carbons, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
So far, only the Nimbus company patent US009453026B2 discloses a process for the preparation of compounds of formula I, the key intermediate 2- (6-bromo-1- (2- (2-methoxyphenyl) -2- (tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid tert-butyl diphenylsilyl ester, is synthesized by first hydrolyzing tert-butyl 2- (6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid to carboxylic acid, then protecting the carboxyl group with TBDPS group, and then by a mitsunobutation reaction.
The patent discloses a new method for preparing a compound shown in formula I, namely, tert-butyl 2- (6-halo-5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionate (II) is firstly reacted with halo-o-methoxyacetophenone, then hydrolyzed into carboxylic acid, then silicon-based is used for protecting carboxyl, then carbonyl of a lower chain is reduced into hydroxyl, the hydroxyl is halogenated, halogen atoms are substituted by alkoxy groups to obtain a key intermediate 2- (6-halo-1- (2- (2-methoxyphenyl) -2-alkoxy) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionate (VIII), and finally Stille coupling and silicon-based protecting groups are removed to prepare the compound shown in formula I.
Disclosure of Invention
The invention provides a novel method for preparing a compound shown in a formula I, which has the following chemical reaction formula:
Figure BDA0001458811710000021
r of formula I is independently hydrogen or optionally substituted from: C1-C6 aliphatic alkyl, 3-C8 saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-C10 bicyclic aromatic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
The specific steps of the reaction include:
step (1): 2- (6-halo-5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d)]Pyrimidin-3 (2H) -yl) -2-methylpropionic acid tert-butyl ester(s) (II) substitution reaction with 2-halogeno-o-methoxyacetophenone, X in formula II 1 Optionally selected from bromine, chlorine, iodine atoms, preferred 2-halogenated o-methoxyacetophenones include but are not limited to bromo-o-methoxyacetophenone, chloro-o-methoxyacetophenone, iodo-o-methoxyacetophenone, fluoro-o-methoxyacetophenone, preferred reaction solvents include but are not limited to DMF, DMA, CH 3 CN, DMSO, HMPA, preferred inorganic bases include but are not limited to K 2 CO 3 、LiOH、NaOH、KOH、CsOH、Ca(OH) 2 、Na 2 CO 3 、CS 2 CO 3 . The molar ratio of II to 2-halogenated o-methoxyacetophenone is in the range of 1-1.5.
Step (2): 2- (6-halo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d) prepared in the step (1)]Hydrolysis of t-butyl pyrimidin-3 (2H) -yl) -2-methylpropionate (III) to carboxylic acid using a catalyst including but not limited to trifluoroacetic, formic, oxalic, methanesulfonic, p-toluenesulfonic, benzenesulfonic or tartaric acid and a solvent including but not limited to DCM, DCE, THF, DMF, CH 3 CN。
And (3): reacting the 2- (6-halo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropanoic acid (IV) prepared in step (2) with halosilanes to protect carboxyl groups, wherein the halosilanes include, but are not limited to, TBDPSCl, TBDPSBr, TBDPSI, TBSCl, TBSBr, TBSI, TMSCl, TMSBr and TMSI.
And (4): reducing 2- (6-halo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionate (V) prepared in the step (3), wherein the reducing agent comprises but is not limited to sodium borohydride, lithium aluminum hydride and sodium triacetyl borohydride, and the reaction solvent comprises but is not limited to tetrahydrofuran, methanol, ethanol and 1,4-dioxane.
And (5): 2- (6-halo-1- (2-hydroxy-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d) prepared in the step (4)]Pyrimidin-3- (2H) -yl) -2-Halogenating the methyl propionic acid silicone ester (VI), wherein the halogenating reagent used in the reaction comprises but is not limited to NBS, dibromohydantoin and Br 2 、CBr 4 、PBr 3 、Cl 2 、NCS、PCl 5 、PCl 3 Dichloro hydantoin, NIS, I 2 The molar ratio of halogenating agent to VI is in the range of from 2 to 4.
And (6): 2- (6-halo-1- (2-halo-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d) prepared in the step (5)]The pyrimidine-3 (2H) -yl) -2-methylpropionate silicon ester (VII) and alcohol (R-OH) are subjected to substitution reaction, the base used in the reaction can be inorganic base or organic base, and the preferred inorganic base comprises but is not limited to MgO and Al 2 O 3 CaO, znO, preferred organic bases include, but are not limited to, 2,6-lutidine, 4-dimethylaminopyridine, pyridine, triethylamine, DIPEA.
And (7): 2- (6-halo-1- (2- (2-methoxyphenyl) -2-alkoxy) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d) prepared in the step (6)]Stille coupling reaction of pyrimidine-3 (2H) -yl) -2-methylpropionate (VIII) and 2- (tributylstannyl) -1,3-oxazole (VIII), wherein the solvent used in the reaction comprises but is not limited to toluene, 1,4-dioxane and DMF, and the catalyst used in the reaction comprises but is not limited to Pd (PPh) 3 ) 4 ，Pd(PPh 3 ) 2 Cl 2 ，Pd(dppf)Cl 2 ，Pd(OAc) 2 ，Pd 2 (dba) 3 。
And (8): 2- (1- (2- (2-methoxyphenyl) -2-alkoxy) ethyl) -5-methyl-6- (oxazole-2-yl) -2,4-dioxo-1,4-dihydrothieno [2,3-d) prepared in the step (7)]Pyrimidin-3 (2H) -yl) -2-methylpropionic acid silyl protecting group (IX) is deprotected from a group comprising but not limited to tetrabutylammonium fluoride, trifluoroacetic acid, sulfuric acid, hydrochloric acid, formic acid, acetic acid using a solvent including but not limited to THF, DCM, DCE, CH 3 CN, 1,4-dioxane.
Drawings
Figure 1 is a nuclear magnetic resonance hydrogen spectrum of formula I (R = tetrahydro-2H-pyran-4-yl).
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of tert-butyl 2- (6-bromo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 ((2H) -yl) -2-methylpropionate (III)
2- (6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d)]T-butyl pyrimidin-3 (2H) -yl 2-methylpropionate (II) (2.24g, 5.55mmol) was placed in an eggplant-shaped bottle, DMF (35 ml), potassium carbonate (2.303g, 16.6 mmol) and 2-bromo-o-methoxyacetophenone (1.336g, 5.83mmol) were sequentially added thereto, and after completion of the addition, the mixture was stirred at room temperature overnight. 5 times of DMF water was added, the mixture was transferred to a separatory funnel, extracted 3 times with ethyl acetate, and the combined organic phases were washed with water and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (petroleum ether: acetone, 40, 1) to obtain white solid of III (2.29 g, yield 75%). 1 H NMR(300MHz,DMSO)δ7.92-7.63(m,2H),7.32(d,J＝8.2Hz,1H),7.14(t,J＝6.8Hz,1H),5.28(s,1H),4.02(s,3H),1.66(s,6H),1.37(s,9H)。MS(ES):m/z 573.1(M+Na) + 。
Example 2
Preparation of 2- (6-bromo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid (IV)
2- (6-bromo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 ((2H) -yl) -2-methylpropanoic acid tert-butyl ester (III) (1.2g, 2.3 mmol) was placed in a solanaceous bottle, dichloromethane (20 ml) and trifluoroacetic acid (4.4 ml) were added sequentially, stirring was done at room temperature for 1H, the solvent was evaporated, and after drying, a off-white solid of III (1.09 g) was obtained.
Example 3
Preparation of 2- (6-bromo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid tert-butyldiphenylsilyl ester (V)
2- (6-bromo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -2-methylpropionic acid (IV) (1.09g, 2.2mmol) was put in a bottle of eggplant shape, tetrahydrofuran (7.7 ml), imidazole (180mg, 2.6 mmol), t-butyldiphenylchlorosilane (774mg, 2.6 mmol) were added in this order, and after the addition, stirring was carried out at room temperature overnight. Then, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was transferred to a separatory funnel, extracted 3 times with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After evaporation of the solvent, purification by silica gel column chromatography (petroleum ether: ethyl acetate, 6:1) gave V as a white solid (1.36 g, yield 83%). 1 HNMR(300MHz,DMSO)δ7.80-7.57(m,6H),7.49-7.22(m,7H),7.08(t,J＝7.4Hz,1H),5.27(s,2H),3.97(s,3H),2.19(s,3H),1.69(s,6H),0.94(s,9H)。MS(ES):m/z 755.1(M+Na) + 。
Example 4
2- (6-bromo-1- (2-hydroxy-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidine
-3- (2H) -yl) -2-methylpropionic acid tert-butyldiphenylsilyl ester (VI)
2- (6-bromo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d]1.058g (1.4 mmol) of t-butyldiphenylsilyl pyrimidin-3 (2H) -yl) -2-methylpropionate (V) was put in a bottle shaped like a eggplant, and 15ml of anhydrous tetrahydrofuran and 164mg (4 mol) of sodium borohydride were sequentially added thereto, and after completion of addition, the mixture was stirred at room temperature for 5.5 hours. Then, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was transferred to a separatory funnel, extracted 3 times with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 15, 1) to obtain a white solid of VI (700 mg, yield 66%). 1HNMR (300mhz, cdcl3) δ 7.78-7.64 (m, 4H), 7.47-7.23 (m, 8H), 6.96 (t, J =7.5hz, 1h), 6.89 (d, J =8.2hz, 1h), 5.35-5.21 (m, 1H), 4.21-4.01 (m, 2H), 3.91 (s, 3H), 3.45 (d, J =7.1hz, 1h), 2.29 (s, 3H), 1.83 (d, J =2.6hz, 6H), 1.08 (s, 9H). MS (ES) M/z757.2 (M + Na) + 。
Example 5
Preparation of 2- (6-bromo-1- (2-bromo-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid tert-butyldiphenylsilyl ester (VII)
2- (6-bromo-1- (2-hydroxy-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d]Pyrimidin-3- (2H) -yl) -2-methylpropionic acid tert-butyl diphenylsilyl ester (VI) (271mg, 0.37mmol) was placed in a three-necked flask, and carbon tetrabromide (610mg, 1.84mmol), N, was added 2 Anhydrous tetrahydrofuran (7ml) was added under protection, a tetrahydrofuran solution of triphenylphosphine (483mg, 1.84mmol) was added dropwise at 0 ℃ and after the addition was complete, the temperature was allowed to rise to room temperature naturally, and the mixture was stirred at room temperature overnight. Then, the reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 15, 1) to obtain a white solid of VII (108 mg, yield 37%).
Example 6
Preparation of 2- (6-bromo-1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid tert-butyldiphenylsilyl ester (VIII) (R is tetrahydro-2H-pyran-4-yl)
2- (6-bromo-1- (2-bromo-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -2-methylpropanoic acid tert-butyldiphenylsilyl ester (VII) (881mg, 1.1mmol) was put into a three-necked flask, anhydrous magnesium sulfate (292mg, 2.43mmol), magnesium oxide (98mg, 2.43mmol), and tetrahydropyran-4-ol (2 ml) were sequentially added, and stirring was carried out at 80 ℃ for 10 hours after the end of the addition. Then transferred to a separatory funnel, extracted 3 times with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 25, 1) to give VIII as a white solid (418 mg, yield 46%). 1 HNMR(300MHz,DMSO)δ7.65(d,J＝6.5Hz,4H),7.55-7.20(m,8H),6.98(t,J＝8.3Hz,2H),5.40-5.18(m,1H),3.99(s,2H),3.80(s,3H),3.70-3.58(m,1H),3.55-3.46(m,1H),3.36(dd,J＝8.3,4.6Hz,1H),3.19(ddd,J＝14.7,11.0,1.9Hz,2H),2.16(s,3H),1.70(d,J＝8.7Hz,8H),1.36(dd,J＝13.4,6.5Hz,2H),0.98(s,9H)。MS(ES):m/z 841.2(M+Na) + 。
Example 7
Preparation of 2- (1- (2- (2-methoxyphenyl) -2-9 ((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 tert-butyldiphenylsilicon ester (IX) (R is tetrahydro-2H-pyran-4-yl)
Reacting 2- (6-bromo-1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d)]Pyrimidin-3 (2H) -yl) -2-methylpropanoic acid tert-butyl diphenyl silyl ester (VIII) (R is tetrahydro-2H-pyran-4-yl) (100mg, 0.12mmol) is placed in a Schlenk tube, tetrakistriphenylphosphine palladium (22mg, 0.018mmol), 2- (tributylstannyl) -1,3-oxazole (66mg, 0.183mmol) and toluene (4 ml) are added in sequence, and after finishing addition, the mixture is frozen and pumped out, protected by argon, and stirred at 110 ℃ for 17H. Adding potassium fluoride aqueous solution, stirring overnight, transferring to a separating funnel, extracting with ethyl acetate for 3 times, washing the combined organic phase with water, washing with saturated sodium chloride aqueous solution, and drying with anhydrous sodium sulfate. After the solvent was distilled off, purification was performed by silica gel column chromatography (petroleum ether: acetone, 15, 1) to obtain white solid of IX (40 mg, yield 41%). 1 HNMR(300MHz,CDCl 3 )δ7.82-7.66(m,5H),7.56(d,J＝7.2Hz,1H),7.47-7.27(m,7H),7.21(s,1H),7.00(t,J＝7.4Hz,1H),6.85(d,J＝8.2Hz,1H),5.51-5.33(m,1H),4.08(dd,J＝24.2,7.8Hz,2H),3.85(s,3H),3.79-3.60(m,2H),3.49-3.36(m,1H),3.35-3.19(m,2H),2.75(s,3H),1.84(d,J＝3.5Hz,6H),1.69(d,J＝12.6Hz,2H),1.54(dd,J＝13.7,9.7Hz,2H),1.09(s,9H)。MS(ES):m/z 830.3(M+Na) + 。
Example 8
Preparation of 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 (I) (R is tetrahydro-2H-pyran-4-yl)
2- (1- (2- (2-methoxyphenyl) -2-9 ((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 tert-butyl diphenylsilyl ester (IX) (75mg, 0.09mmol) was put in a bottle of eggplant shape, and tetrahydrofuran (3 ml) and tetrakis were added in this orderN-butylammonium fluoride (29mg, 0.11mmol), and stirred at room temperature overnight. After the reaction solvent was distilled off, purification was performed by silica gel column chromatography (dichloromethane: methanol, 20, 1) to obtain white solid of I (42 mg, yield 79%). 1 HNMR(300MHz,CDCl 3 )δ7.70(s,1H),7.58(d,J＝7.5Hz,1H),7.31(d,J＝8.2Hz,1H),7.23(s,1H),7.03(t,J＝7.4Hz,1H),6.86(d,J＝8.2Hz,1H),5.46-5.35(m,1H),4.12(dd,J＝14.3,7.2Hz,2H),3.86(s,3H),3.81-3.64(m,2H),3.50-3.40(m,1H),3.34(t,J＝9.8Hz,2H),2.84(s,3H),1.84(d,J＝12.6Hz,6H),1.73(dd,J＝8.4,4.4Hz,2H),1.65-1.52(m,1H),1.50-1.40(m,1H)。MS(ES):m/z 592.2(M+Na) + 。
Example 9
2- (6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -2-methylpropionic acid tert-butyl ester (II, X) 1 Preparation of Br)
Figure BDA0001458811710000071
5-amino-3-methylthiophene-2,4-dicarboxylic acid-2,4-diethyl ester (X) (10g, 38.9mmol) was placed in a three-necked flask, N 2 After the protection, anhydrous dichloromethane (35 ml) was added, a dichloromethane solution (15 ml) of bistrichloromethyl carbonate (4.15g, 13.99mmol) was added at 0 ℃, triethylamine (27 ml) was added dropwise in an ice bath after the addition was completed, tributyl 2-amino-2-methylpropionate (8.37g, 42.7 mmol) was added thereto while maintaining the temperature at 0 ℃ for 2 hours, and then the mixture was stirred at room temperature overnight after the addition was completed. The reaction was quenched with water, filtered with suction on a buchner funnel, and the filter cake was washed with ethyl acetate. The filtrate was transferred to a separatory funnel, extracted 3 times with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After evaporation of the solvent, purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate, 4:1) to give 5- (3- (1- (tert-butoxy) -2-methyl-1-oxoprop-2-yl) ureido) -3-methylthiophene-2,4-dicarboxylic acid diethyl ester (XI) as a pale yellow solid (9.2 g, 53% yield).
5- (3- (1- (tert-butoxy) -2-methyl-1-oxoprop-2-yl) ureido) -3-methylthiophene-2,4-dicarboxylic acid diethyl ester (XI) (5.6 g, 13mmol) was placed in a three-necked flask, N 2 Adding under protection in turn1,4-dioxane (50 ml), 60% sodium hydride (1g, 25mmol), and stirring at 90 deg.C for 2h. The reaction was quenched with saturated aqueous ammonium chloride, 5 times the amount of 1,4-dioxane water was added, transferred to a separatory funnel, extracted 3 times with ethyl acetate, the combined organic phases washed with water, saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Evaporating the solvent to obtain 3- (1- (tert-butoxy) -2-methyl-1-oxoprop-2-yl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]White solid (3.7 g) of ethyl pyrimidine-6-carboxylate (XII), which was used in the next step without purification.
Ethyl 3- (1- (tert-butoxy) -2-methyl-1-oxoprop-2-yl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carboxylate (XII) (3.70g, 9.0mmol) was placed in a jar, 95% ethanol (37 ml, an aqueous solution of sodium hydroxide (1.85g, 46.0mmol) (5.5 ml) was added sequentially, stirring was performed at 70 ℃ for 2h, pH was adjusted to 2 with 2N hydrochloric acid, a separatory funnel was transferred for extraction, extraction was performed 3 times with ethyl acetate, the combined organic phase was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a solid of 3- (1- (tert-butoxy) -2-methyl-1-oxoprop-2-yl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 26 ] pyrimidine-6-carboxylate (XIII) which was used for the next purification without further purification.
3- (1- (tert-butoxy) -2-methyl-1-oxoprop-2-yl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]Pyrimidine-6-carboxylic acid (XIII) (3.4g, 9.0mmol) was placed in a eggplant-shaped bottle, and anhydrous N-methylpyrrolidone (60 ml), silver acetate (1.85g, 11mmol), and potassium carbonate (1.53g, 11mmol) were sequentially added thereto, and after completion of addition, stirring was carried out at 110 ℃ for 2 hours. Then, it was filtered with suction using a Buchner funnel, and the filter cake was washed 3 times with ethyl acetate. The filtrate was transferred to a separatory funnel, extracted 3 times with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 20: 1) to obtain 2-methyl-2- (5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d]Solid of t-butyl pyrimidin-3 (2H) -yl) propionate (XIV) (1.79 g, 44% three step yield). 1 HNMR(300MHz,CDCl 3 )δ10.81(s,1H),6.37(s,1H),2.44(s,3H),1.82(s,6H),1.47(s,9H)。MS(ES):m/z 347.1(M+Na) + 。
2-methyl-2- (5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d)]T-butyl pyrimidin-3 (2H) -yl) propionate (XIV) (1.37g, 4mmol) was placed in a jar, and then anhydrous tetrahydrofuran (35 ml) and a tetrahydrofuran solution (15 ml) of N-bromosuccinimide (726mg, 4.08mmol) were added thereto in this order, followed by stirring at room temperature for 45min after completion of the addition. The reaction solution was transferred to a separatory funnel, extracted 3 times with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 20: 1) to give 2- (6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -2-methylpropionic acid tert-butyl ester (II) as a white solid (1.25 g). 1 HNMR(300MHz,DMSO)δ12.07(s,1H),δ2.28(s,3H),1.62(s,3H),1.35(s,9H)。MS(ES):m/z 425(M+Na) + 。

Claims (15)

1. A process for preparing a compound of formula I, having the chemical reaction formula:
Figure FDA0003880359170000011
r of the formula I, i.e. R 1 、R 2 、R 3 Independently hydrogen or optionally substituted from the group: aliphatic alkyl of 1 to 6 carbons, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
x in the formula II 1 Is a halogen radical.
2. The method of claim 1, wherein in step (1), tert-butyl 2- (6-halo-5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionate (II) is subjected to substitution reaction with 2-halo-o-methoxyacetophenone, and the molar ratio of the reaction of formula II with 2-halo-o-methoxyacetophenone is in the range of 1 to 1.5.
3. The method according to claim 2, wherein X in the formula II 1 Optionally selected from bromine, chlorine, and iodine atoms, the 2-halogenated o-methoxyacetophenone is one of bromo-o-methoxyacetophenone, chloro-o-methoxyacetophenone, iodo-o-methoxyacetophenone, and fluoro-o-methoxyacetophenone, and the reaction solvent is DMF, DMA, and CH 3 One of CN, DMSO and HMPA, and K as inorganic base 2 CO 3 、LiOH、NaOH、KOH、CsOH、Ca(OH) 2 、Na 2 CO 3 、CS 2 CO 3 One kind of (1).
4. The process according to claim 1, wherein in step (2), tert-butyl 2- (6-halo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionate (III) obtained in step (1) is hydrolyzed into carboxylic acid.
5. The method according to claim 4, wherein the catalyst used in the reaction is one of trifluoroacetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid or tartaric acid, and the solvent used in the reaction is DCM, DCE, THF, DMF, CH 3 One of CN.
6. The process according to claim 1, wherein in the step (3), 2- (6-halo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid (IV) obtained in the step (2) is reacted with a halosilane to protect the carboxyl group.
7. The method of claim 6, wherein the halosilane is one of TBDPSCl, TBDPSBr, TBDPSI, TBSCl, TBSBr, TBSI, TMSCl, TMSBr, and TMSI.
8. The process according to claim 1, wherein in the step (4), the 2- (6-halo-1- (2- (2-methoxyphenyl) -2-oxoethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionic acid silyl ester (V) obtained in the step (3) is reduced.
9. The method according to claim 8, wherein the reducing agent is one of sodium borohydride, lithium aluminum hydride and sodium triacetyl borohydride, and the reaction solvent is one of tetrahydrofuran, methanol, ethanol and 1,4-dioxane.
10. The method according to claim 1, wherein in the step (5), the 2- (6-halo-1- (2-hydroxy-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3- (2H) -yl) -2-methylpropionate (VI) prepared in the step (4) is halogenated, and the molar ratio of the halogenated agent to VI is in the range of 2 to 4.
11. The process according to claim 10, wherein the halogenating agent is NBS, dibromohydantoin, br 2 、CBr 4 、PBr 3 、Cl 2 、NCS、PCl 5 、PCl 3 Dichloro hydantoin, NIS, I 2 To (3) is provided.
12. The method according to claim 1, wherein in the step (6), 2- (6-halo-1- (2-halo-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropionate (VII) produced in the step (5) is subjected to substitution reaction with an alcohol.
13. The method according to claim 12, wherein the base used in the reaction is an inorganic base or an organic base.
14. The method according to claim 13, wherein the inorganic base is MgO or Al 2 O 3 CaO, znO.
15. The method of claim 13, wherein the organic base is one of 2,6-lutidine, 4-dimethylaminopyridine, pyridine, triethylamine, and DIPEA.
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