CN111004235A - Synthetic method of ATX inhibitor Ziritaxestat - Google Patents
Synthetic method of ATX inhibitor Ziritaxestat Download PDFInfo
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Abstract
The invention belongs to the field of medicinal chemistry, and relates to a synthetic method of an ATX inhibitor Ziritaxestat, in particular to a preparation method of the ATX inhibitor Ziritaxestat based on a pyridylimidazole parent nucleus, and a synthetic method of an intermediate for preparing the inhibitor. The method relates to eight-step reaction, and the final product Ziritaxestat is obtained through cyclization reaction, ester hydrolysis, Curtius rearrangement, methylation, debenzylation protection, N-arylation, Buchwald-Hartwig coupling and N-alkylation. The invention is a brand new synthesis method of Ziritaxestat, the raw materials needed by the whole reaction are cheap and easy to obtain, the use of highly toxic reagents such as sodium cyanide, isonitrile and the like is avoided, the reaction condition is mild, the operation is simple and easy to implement, and the method is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a synthetic method of an ATX inhibitor Ziritaxestat, in particular to a preparation method of the ATX inhibitor Ziritaxestat based on a pyridylimidazole parent nucleus, and a synthetic method of an intermediate for preparing the inhibitor.
Background
Ziritaxestat (GLPG-1690,9), molecular formula: c30H33FN8O2S, exact molecular weight: 588.24. ziritaxestat is an imidazopyrimidine compound, which mainly inhibits the function of ATX hydrolysis phosphate bond (lysophosphatidylcholine LPC → lysophosphatidic acid LPA) and reduces the tissue concentration of LPA by selectively combining with Autotaxin (ATX), so as to achieve the effect of improving or inhibiting fibrotic diseases, and is currently in the clinical stage III. The structural formula is as follows:
currently, references to the process of preparation of Ziritaxestat include: documents (J.Med.chem.2017,60,3580-3590), (J.Med.chem.2017,60,17,7371-7392), WO2014202458A1, WO2014139882A 1. No synthesis process research aiming at the medicine exists in China. The core of the preparation of Ziritaxestat provided in these references is the construction of the imidazopyridine core, using a three-component ring-closure strategy of aminopyrimidine, propionaldehyde, and a cyano (isonitrile) -containing substrate. The first cyclization method is to take 1 as the starting material, firstly react with propionaldehyde and benzotriazole in toluene, then add ethanol and virulent potassium cyanide, and finally cyclize to obtain 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-amine (b 3). The cyclization strategy introduces virulent potassium cyanide, so that the danger of the reaction is greatly increased, and the labor production is not facilitated; and the yield of the step-cyclization reaction is only 29% (total yield is 10.96%), which further makes it unsuitable for industrial production. The second cyclization strategy also takes 1 and propionaldehyde as starting materials, and obtains 6-bromo-2-ethyl-8-methyl-N- (2,4, 4-trimethylpentan-2-yl) imidazo [1,2-a ] pyridin-3-amine (c2) by introducing virulent 1,1,3, 3-tetramethylbutylisonitrile (c1) into an N-butanol solvent to perform three-component reaction under the catalysis of anhydrous magnesium chloride. The disadvantages of the second cyclization strategy are the following two points: firstly, the isonitrile intermediate c1 is a highly toxic substance, is not beneficial to industrial production operation, is expensive, and has doubled manufacturing cost in the whole route if large-scale industrial production is realized; secondly, three deprotection reactions will be involved in the whole route, which is not well in line with the atom economy principles of the reaction. Based on the above analysis, the present invention has devised a new synthetic route.
Disclosure of Invention
The invention aims to overcome the obvious problems of high toxicity of raw materials, high production cost and the like in the above route, a two-component cyclization strategy is adopted to obtain a pyridylimidazole parent nucleus, Curtius rearrangement is further carried out, and benzyloxycarbonyl protection is removed to obtain a key intermediate 6-bromo-2-ethyl-N, 8-dimethylimidazo [1,2-a ] pyridine-3-amine (6), so that the preparation method of the Ziritaxestat is mild in reaction conditions, simpler and more efficient in post-treatment, lower in cost and higher in route feasibility.
In order to realize the purpose of the invention, the invention takes 2-amino-3-methyl-5-bromopyridine (1) and 2-bromopropionylacetic acid ethyl ester (a1) as initial raw materials, and screens and optimizes a reaction substrate, a solvent, a catalyst, a reagent, reaction time, reaction temperature and a post-treatment purification method, thereby successfully finding a synthetic method which has convenient operation, high selectivity, high yield, simple post-treatment and suitability for industrial production.
The synthetic route of the invention is as follows:
wherein the content of the first and second substances,
R1hydrogen, C1-C6 alkyl, 5-10-membered aryl substituted C1-C6 alkyl, halogenated C1-C6 alkyl and C3-C6 cycloalkyl are selected;
if R is1When the H is H, the hydrolysis reaction can be omitted;
R2one of hydrogen, C1-C6 alkyl, 5-10-membered aryl substituted C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, cyano, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 sulfonamide, C1-C6 ester, C1-C4 amide, carbamoyl and the like is selectedOr a plurality of the compounds, and the substitution number and the substitution position are not limited;
x is chlorine, bromine or iodine;
the preparation method comprises the following specific steps:
(1) and (3) cyclization reaction: the compound 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylic ester (2) is prepared by the reaction of 2-amino-3-methyl-5-bromopyridine (1) and 2-halopropionylacetate (a1) in an organic solvent without a catalyst by a retaining ring reaction;
(2) and (3) hydrolysis reaction: in the mixed solvent, 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylic acid ester (2) is subjected to the action of alkali to obtain 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylic acid (3);
(3) curtius rearrangement: in a solvent, 6-bromo-2-ethyl-8-methylimidazo [1,2-a ]]Pyridine-3-carboxylic acid (3) and benzyl alcohol (a2) are reacted under the action of alkali catalyst and diphenyl phosphorazidate (DPPA) to prepare R2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Pyridin-3-yl) carbamate (4);
(4) n-methylation: in a dry solvent, under the catalysis of alkali, benzyl (6-bromo-2-ethyl-8-methylimidazole [1,2-a ]]Reaction of pyridin-3-yl) carbamic acid ester (4) with a methylating agent to produce R2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Pyridin-3-yl) (methyl) carbamate (5);
(5) debenzylation protection: r2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Debenzylation of pyridin-3-yl) (methyl) carbamate (5) under HBr/HOAc (33%) to yield the key intermediate 6-bromo-2-ethyl-N, 8-dimethylimidazo [1,2-a ]]Pyridin-3-amine (6).
(6) N-aromatic alkylation: n is a radical of2Under protection, in a solvent, a key intermediate 6-bromo-2-ethyl-N, 8-dimethylimidazo [1,2-a ]]Pyridine-3-amine (6) reacts with 2-chloro-4- (4-fluorophenyl) thiazole-5-carbonitrile (a3) under the action of alkali to obtain 2- ((6-bromo-2-ethyl-8-methylimidazo [1, 2-a)]Pyridin-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile (7).
(7) Buchwald-Hartwig coupling: n is a radical of2Under the protection, in a solvent and under the alkaline condition, under the action of a phosphine ligand and a palladium catalystThe intermediate 2- ((6-bromo-2-ethyl-8-methylimidazo [1, 2-a)]Pyridine-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile (7) and anhydrous piperazine (a4) are subjected to C-N coupling reaction to obtain an intermediate 2- ((2-ethyl-8-methyl-6- (piperazine-1-yl) imidazo [1, 2-a)]Pyridin-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile (8).
(8) N-alkylation reaction: in a solvent, under the catalysis of a base, an intermediate 2- ((2-ethyl-8-methyl-6- (piperazine-1-yl) imidazo [1,2-a ] pyridine-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile (8) reacts with 2-chloro-1- (3-hydroxyazetidin-1-yl) ethane-1-ketone (a5) to obtain Ziritaxestat (9).
The organic solvent in the step (1) is selected from one or more of methanol, ethanol, acetonitrile, acetic acid, n-butanol, acetone and tetrahydrofuran;
selecting one of methanol/water, ethanol/water, acetonitrile/water, acetone/water and tetrahydrofuran/water as the mixed solvent in the step (2); the alkali is selected from one of potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide and cesium carbonate;
the organic solvent in the step (3) is one or more of toluene, benzene, acetonitrile, THF and DMF; the base catalyst is organic base triethylamine, DIPEA and N-methylmorpholine;
the drying solvent in the step (4) is one or more selected from methanol, ethanol, acetonitrile, acetic acid, n-butanol, acetone and tetrahydrofuran; the alkali is selected from one of sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the methylation reagent is selected from one of methyl iodide, diazomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate and methyl trifluoromethanesulfonate;
the solvent in the step (6) is one or a mixed system of anhydrous DMF, THF, acetonitrile and DMSO; the alkali is selected from one of sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium carbonate or sodium carbonate;
the solvent in the step (7) is one or a mixed system of toluene, xylene, THF, DME, dioxane, DMF, NMP and DMSO; the base is metal-containing base selected from sodium tert-butoxide, potassium tert-butoxide,Sodium methoxide, sodium carbonate, potassium carbonate, cesium carbonate; phosphine ligand selection Xanphos, DavePhos, John Phos, etc.; pd (OAc) as the palladium catalyst2、Pd2(dba)3、Pd(PPh3)4Etc.;
selecting one or a mixed system of dry DMF, THF, acetonitrile and DMSO as the solvent in the step (8); the alkali is selected from one of potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide and cesium carbonate;
in the step (1), the 2-amino-3-methyl-5-bromopyridine (1) and 2-halopropionylacetate (a1) are subjected to a retaining ring reaction to prepare 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylate (2), wherein the molar ratio of 1 to a1 is 1: (1.1-1.3), the reaction temperature is 66-120 ℃, and the reaction time is 3-15 h.
In step (3), 3 and R2Preparation of R from substituted benzyl alcohol (a2) under base catalysis and mediation of Diphenylphosphorylazide (DPPA)2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Pyridin-3-yl) carbamate 4; wherein the ratio of 3 to a2 to alkali is 1: (1.2-2.5): (1.5-3.2), the reaction temperature is 60-125 ℃, and the reaction time is 2-10 h.
In step (5), 5 removes R under the action of HBr/HOAc (33%)2The substituted benzyl group is used for obtaining a key intermediate 6-bromo-2-ethyl-N, 8-dimethyl imidazo [1,2-a ]]And (3) pyridine-3-amine 6, wherein the reaction time is 2-18 h, and the molar ratio of 5 to HBr is 1: (3-20).
In the step (7), under the protection of nitrogen, the reaction temperature of 7-120 ℃ and the reaction time of 2-5 h, wherein the C-N coupling of 7 and anhydrous piperazine (the introduction and the removal of Boc protecting groups are avoided) is directly carried out. The molar ratio of 7 to the anhydrous piperazine, the palladium catalyst, the phosphine ligand and the alkali is 1: (1.2-1.8): (0.05-0.08): (0.06-0.1): (1.5-2.5).
The invention further provides R2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Pyridin-3-yl) carbamate (4) and R2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Pyridin-3-yl) (methyl) carbamates (5) and processes for their preparation, and also the use of compounds 4 and 5 for the preparation of Ziritaxestat,wherein R is2As previously described.
Compared with the prior art route, the invention has the advantages that: (1) a brand-new synthetic route is designed, and the imidazopyridine ATX inhibitor GLPG-1690 is prepared by taking 2-amino-3-methyl-5-bromopyridine (1) and 2-bromopropionyl acetate (a1) as raw materials, so that the use of an expensive and virulent isonitrile intermediate c1 and virulent potassium cyanide is effectively avoided, the production cost is obviously reduced, and the large-scale preparation is easy; (2) meanwhile, a reasonable synthon can be provided for methylation in one step by a Curtius rearrangement strategy on the premise of introducing 3-amino at the parent nucleus of the imidazopyridine, the conditions of repeated protection and deprotection are avoided, the production cost is obviously reduced, the reaction condition is mild, and the operation is simple and convenient; (3) the intermediate 7 directly performs C-N coupling reaction with anhydrous piperazine, thereby avoiding the introduction and removal of a tert-butyloxycarbonyl (Boc) protecting group and greatly saving time and economic cost; (4) the step reaction yield (> 72%) and the total yield (20.3%) are high, the product quality is stable, the purity is high and reaches more than 99%, and the method is beneficial to industrial production.
Detailed Description
The foregoing summary of the invention is provided to further illustrate the invention by the following detailed description of the preferred embodiments, in order to better practice the invention. It should not be understood to those skilled in the art that the scope of the above-described subject matter of the present invention is limited to the following description of the methods; all the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1:
(1) preparation of 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylic acid ester
266g of ethyl 2-bromopropionylacetate (1.2mol) are dissolved in 1200mL of ethanol in a 3L three-necked flask equipped with mechanical stirring, 186g of 5-bromo-3-methylpyridin-2-amine (1mol) are added to the solution and the reaction is refluxed for 3h with stirring and monitored by TLC. After the reaction is finished, cooling, evaporating ethanol to dryness, dissolving in EA, performing vacuum filtration, washing with water and bromine, drying, and evaporating to dryness to obtain 240.3g of yellow solid with the yield of 77.5%. 99.16% by HPLC (%), 311.32[ M +1 ] by MS]+,313.36[M+3]+,1H NMR(400MHz,DMSO)δ9.20(s,1H),7.55(s,1H),4.37(q,J＝7.1Hz,2H),3.01(q,J＝7.5Hz,2H),2.52(s,3H),1.36(t,J＝7.1Hz,3H),1.26(t,J＝7.5Hz,3H).
(2) Preparation of 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylic acid
In a 1000mL round bottom flask, 93g of 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] was placed]Pyridine-3-carboxylic ester (0.3mol) is dissolved in 200mL ethanol, 200mL aqueous solution of sodium hydroxide (0.8mol, 4N) is added into the solution, the mixture is stirred at room temperature and heated to 60 ℃ for stirring reaction for 2h (when the temperature is heated to 45 ℃, 6-bromo-2-ethyl-8-methylimidazo [1,2-a ]]Pyridine-3-carboxylate was completely dissolved in ethanol), monitored by TLC. After the reaction was complete, the organic solvent was evaporated, the pH adjusted to 4 with 2N HCl, filtered, the filter cake washed with water and dried to give 61.3g of a pale yellow solid with a yield of 72.1%. 99.49% by HPLC (%), and 281.38[ M-1 ] by MS]-,1HNMR(400MHz,DMSO)δ9.28(s,1H),7.52(s,1H),3.02(dd,J＝14.7,7.2Hz,2H),2.53(s,3H),1.26(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO)δ162.48,156.81,145.24,129.62,128.06,125.64,112.93,108.08,23.03,16.65,13.99.
(3) Preparation of 3, 5-dichlorobenzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ] pyridin-3-yl) carbamate
In a 1000mL round bottom flask, 42.3g of 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] was placed]Pyridine-3-carboxylic acid (0.15mol) was dissolved in 300mL of dry toluene, and 45.5g of triethylamine (0.45mol) and 49.5g of diphenylphosphorylazide (0.18mol) were added to the solution, and after stirring and reacting at 80 ℃ for 30min, 31.9g of 3, 5-dichlorobenzyl alcohol (0.18mol) was added, and the reaction was stirred under reflux for 2 hours. After TLC monitoring reaction, toluene was evaporated, 500mL of water was added, and after stirring and suction filtration, the liquid layer was discarded, the upper solid was added to 300mL of acetonitrile, and after stirring and suction filtration, the filter cake was washed with acetonitrile (3X 100mL) and dried to obtain 53.5g of white solid, the yield was 78.3%. 95.21% by HPLC (%), 456.40[ M +1 ] by MS]+,458.41[M+3]+,1H NMR(400MHz,DMSO)δ9.59(s,1H),8.27(s,1H),7.61(s,1H),7.55(s,2H),7.29(s,1H),5.19(s,2H),2.63(q,J＝7.5Hz,3H),2.48(s,3H),1.20(t,J＝6.6Hz,3H).
(4) Preparation of 3, 5-dichlorobenzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ] pyridin-3-yl) (methyl) carbamate
In a 500mL three-necked flask, 36.4g of 3, 5-dichlorobenzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ] was placed]Pyridin-3-yl) carbamate 4(0.08mol) was dissolved in 220mL dry DMF, cooled to 0 ℃ in an ice bath, and 8.2g sodium hydride (0.2mol) was added to the solution in portions, stirred at room temperature for reaction for 30min, then 22.9g methyl iodide (0.16mol) was slowly added dropwise, and stirred at room temperature for reaction for 2 h. After TLC monitoring reaction, slowly adding 800ml of ammonium chloride aqueous solution, stirring for 30min, then carrying out suction filtration, washing a filter cake with water, and drying to obtain 34.3g of light yellow solid with the yield of 91.1%. MS 470.38[ M +1 ]]+,472.40[M+3]+,1H NMR(400MHz,DMSO)δ8.44(s,1H),7.61(s,0.26H),7.56(s,0.49H),7.50(s,0.71H),7.26(s,1H),7.12(s,1.44H),5.22(s,0.59H),5.06(s,1.49H),3.28(s,0.67H),3.22(s,2.43H),2.65–2.56(m,2H),2.47(s,3H),1.18(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO)δ154.98,142.27,141.09,140.62,134.45,128.05,127.89,126.64(2C),126.59,126.28,121.46,120.70,106.83,65.65,37.33,20.40,16.24,13.51.
(5) Preparation of 6-bromo-2-ethyl-N, 8-dimethylimidazo [1,2-a ] pyridin-3-amine
150mL of HBr in glacial acetic acid (33%) was added to a 500mL eggplant-shaped bottle at room temperature, and 32.8g of 3, 5-dichlorobenzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ] was added slowly in portions with stirring]Pyridin-3-yl) (methyl) carbamate 5(0.07mol) was reacted with stirring at room temperature for 3 h. After completion of the reaction monitored by TLC, 500mL of water was slowly added, and the mixture was extracted with 200mL of dichloromethane, the organic layer was discarded, the pH of the aqueous layer was adjusted to 10 with 2N sodium hydroxide solution, and the aqueous layer was extracted with dichloromethane (3 × 150mL), and the organic layers were combined, washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, and then dichloromethane was evaporated to dryness to obtain 16.9g of a pale yellow solid, which was 89.1% yield. 97.27% by HPLC (%), 268.0[ M +1 ] by MS]+,270.0[M+3]+,1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.03(s,1H),3.65(m,1H),2.85–2.78(q,2H),2.81(s,3H),2.59(s,3H),1.34(t,J＝7.6Hz,3H).13C NMR(101MHz,CDCl3)δ139.21,129.72,127.48,127.38,126.28,120.41,106.72,35.69,20.33,16.56,14.54.
(6) Preparation of 2- ((6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridin-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
N2Under protection, 16.1g of 6-bromo-2-ethyl-N, 8-dimethylimidazo [1,2-a ] was placed in a 500mL three-necked flask]Pyridine-3-amine 6(0.06mol) is dissolved in 120mL dry THF, the temperature is reduced to 0 ℃ under ice bath, 6.2g sodium hydride (0.15mol) is added into the solution in batches, the solution is heated to 90 ℃ to react for 1h, then the temperature is reduced to 40 ℃, 17.9g 2-chloro-4- (4-fluorophenyl) thiazole-5-carbonitrile (a3, 0.075mol) is slowly added, and after the addition, the reaction is stirred at 90 ℃ for 2 h. After TLC monitoring reaction, slowly adding ammonium chloride aqueous solution 50mL to quench reaction, adding water 500mL, extracting water layer with dichloromethane (3X 120mL), combining organic layers, washing with saturated saline solution and water in turn, evaporating dichloromethane, adding oily matter into 100mL acetonitrile, stirring for 30min, suction filtering, washing filter cake with acetonitrile, drying to obtain yellow solid 23.4g, yield 83.1%. MS 470.69[ M +1 ]]+,472.71[M+3]+,1H NMR(400MHz,DMSO)δ8.61(s,1H),8.07(dd,J＝8.1,5.6Hz,2H),7.42(t,J＝8.9Hz,2H),7.38(s,1H),3.59(s,3H),2.66(q,J＝7.6Hz,2H),2.52(s,3H),1.25(t,J＝7.6Hz,3H).
(7) Preparation of 2- ((2-ethyl-8-methyl-6- (piperazin-1-yl) imidazo [1,2-a ] pyridin-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
In a 500mL eggplant-shaped bottle, 18.8g of 2- ((6-bromo-2-ethyl-8-methylimidazo [1, 2-a)]Pyridin-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile 7(0.04mol) was dissolved in 100mL of dry toluene, and 5.2g of anhydrous piperazine (0.06mol), 7.7g of sodium tert-butoxide (0.08mol), 1.2g of John Phos ligand (0.004mol) and finally 1.83g of Pd were added to the solution successively under stirring2(dba)3(0.002mol)，N2Heating to 115 ℃ for reaction for 2h under protection. After TLC monitoring reaction, pad kieselguhr suction filtration, ethyl acetate rinse kieselguhr, filtrate evaporation to dryness, adding 100mL acetonitrile, stirring for 30min, suction filtration, filter cake washing with acetonitrile (3X 20mL) and discarding, acetonitrile layer evaporation to dryness to obtain light yellow solid 15.7g, yield 82.7%. 99.70% HPLC (%), and 476.62[ M +1 ] MS]+,1H NMR(400MHz,CDCl3)δ8.12(s,2H),7.28(s,1H),7.11(s,2H),7.05–6.90(m,1H),4.70(s,1H),3.59(s,3H),3.31(m,8H),2.75(s,2H),2.59(s,3H),1.26(s,3H).
(8) Preparation of Ziritaxestat
In a 250mL eggplant-shaped bottle, 9.5g of 9(0.02mol) was dissolved in 80mL of acetonitrile, and 6.9g of potassium carbonate (0.05mol) was added thereto under stirring, followed by reflux reaction for 3 hours under stirring. After completion of the TLC monitoring reaction, potassium carbonate was removed by suction filtration, acetonitrile was evaporated under reduced pressure, the residue was dissolved in 200mL of dichloromethane, extracted with 4M hydrochloric acid (2 × 150mL), the organic layer was discarded, the pH of the aqueous layer was adjusted to 10 with 6N sodium hydroxide solution, extracted with dichloromethane (3 × 100mL), the organic layers were combined, washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, and dichloromethane was evaporated to dryness to give 9.8g of a pale yellow solid, with a yield of 83.2%. HPLC (%) (99.60%), MS (589.92M + 1)]+,611.94[M+23]+,587.93[M-1]-,1H NMR(400MHz,DMSO)δ8.11(dd,J＝8.5,5.6Hz,2H),7.43(t,J＝8.8Hz,2H),7.24(s,1H),5.73(s,1H),4.44(s,1H),4.38–4.31(m,1H),4.11–4.01(m,1H),3.91(dd,J＝9.2,4.2Hz,1H),3.65–3.59(m,1H),3.58(s,3H),3.52(d,J＝8.3Hz,1H),3.13(s,4H),2.73(s,4H),2.62(dd,J＝15.1,7.5Hz,2H),2.48(s,3H),1.23(t,J＝7.6Hz,3H).
Claims (10)
1. A method for synthesizing an ATX inhibitor Ziritaxestat is characterized by comprising the following steps:
(1) and (3) cyclization reaction: the compound 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylic acid or carboxylic ester 2 is prepared by the reaction of 2-amino-3-methyl-5-bromopyridine 1 and 2-halopropionylacetate a1 in an organic solvent through a retaining ring reaction;
(2) and (3) hydrolysis reaction: in the mixed solvent, 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylic acid ester 2 is subjected to alkali action to obtain 6-bromo-2-ethyl-8-methylimidazo [1,2-a ] pyridine-3-carboxylic acid 3;
(3) curtius rearrangement: in a solvent, 6-bromo-2-ethyl-8-methylimidazo [1,2-a ]]Pyridine-3-carboxylic acid 3 and benzyl alcohol are treated by diphenyl phosphorazidate under the action of alkali catalystOr sodium azide to obtain R2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Pyridin-3-yl) carbamate 4;
(4) n-methylation: in a dry solvent, under the catalysis of alkali, benzyl (6-bromo-2-ethyl-8-methylimidazole [1,2-a ]]Reaction of pyridin-3-yl) carbamic acid ester 4 with a methylating agent to produce R2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Pyridin-3-yl) (methyl) carbamate 5;
(5) debenzylation protection: r2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]The pyridine-3-yl) (methyl) carbamate 5 is subjected to benzyl removal under the action of HBr/HOAc to obtain 6-bromo-2-ethyl-N, 8-dimethylimidazo [1,2-a ]]Pyridin-3-amine 6;
(6) n-aromatic alkylation: n is a radical of2Under protection, in a solvent, 6-bromo-2-ethyl-N, 8-dimethyl imidazo [1,2-a]Pyridine-3-amine 6 reacts with 2-chloro-4- (4-fluorophenyl) thiazole-5-carbonitrile under the action of alkali to obtain 2- ((6-bromo-2-ethyl-8-methylimidazo [1, 2-a)]Pyridin-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile 7;
(7) Buchwald-Hartwig coupling: n is a radical of2Under protection, in a solvent and under the action of a phosphine ligand and a palladium catalyst, 2- ((6-bromo-2-ethyl-8-methylimidazo [1, 2-a)]Pyridine-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile 7 and anhydrous piperazine are subjected to C-N coupling reaction to obtain 2- ((2-ethyl-8-methyl-6- (piperazine-1-yl) imidazo [1, 2-a)]Pyridin-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile 8;
(8) n-alkylation reaction: in a solvent, under the catalysis of alkali, 2- ((2-ethyl-8-methyl-6- (piperazine-1-yl) imidazo [1,2-a ] pyridine-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile 8 reacts with 2-chloro-1- (3-hydroxyazetidin-1-yl) ethane-1-ketone to obtain Ziritaxestat;
wherein the content of the first and second substances,
R2one or more of hydrogen, C1-C6 alkyl, 5-10-membered aryl substituted C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, cyano, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 sulfonamide, C1-C6 ester group, C1-C4 amide group, carbamoyl and the like are selected, and the substitution number and the substitution position are not limited;
x is chlorine, bromine or iodine.
2. The method of synthesis according to claim 1,
in the step (1), the organic solvent is one or more selected from methanol, ethanol, acetonitrile, acetic acid, n-butanol, acetone and tetrahydrofuran; halo is chloro, bromo or iodo; wherein the ratio of 1 to a1 is 1: (0.8-1.5), the reaction temperature is 66-120 ℃, and the reaction time is 3-15 h.
3. The method of synthesis according to claim 1,
in the step (2), the mixed solvent is selected from one of methanol/water, ethanol/water, acetonitrile/water, acetone/water and tetrahydrofuran/water; the alkali is selected from one of potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide and cesium carbonate, R1The hydrolysis reaction can be omitted in the case of hydrogen.
4. The method of synthesis according to claim 1,
in the step (3), the organic solvent is one or more of toluene, benzene, acetonitrile, THF and DMF; the base catalyst is organic base such as triethylamine, DIPEA, N-methylmorpholine, etc.; wherein the ratio of 3 to a2 to the alkali catalyst is 1: (1.2-2.5): (1.5-3.2), the reaction temperature is 60-125 ℃, and the reaction time is 2-10 h.
5. The method of synthesis according to claim 1,
the drying solvent in the step (4) is one or more selected from methanol, ethanol, acetonitrile, acetic acid, n-butanol, acetone and tetrahydrofuran; the alkali is selected from one of sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the methylating agent is one of methyl iodide, diazomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate and methyl trifluoromethanesulfonate.
6. The method of synthesis according to claim 1,
in the step (5), the reaction time is 2-18 h, wherein R2Substituted benzyl (6-bromo-2-ethyl-8-methylimidazol [1,2-a ]]Pyridin-3-yl) (methyl) carbamate to HBr molar ratio was 1: (3-20).
7. The method of synthesis according to claim 1,
selecting one or a mixed system of dry DMF, THF, acetonitrile and DMSO as the solvent in the step (6); the alkali is selected from one of sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium carbonate and sodium carbonate;
selecting one or a mixed system of dry DMF, THF, acetonitrile and DMSO as the solvent in the step (8); the alkali is selected from one of potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide and cesium carbonate.
8. The method of synthesis according to claim 1,
in the step (7), the reaction temperature is 90-120 ℃, and the reaction time is 2-5 h; the base is metal-containing base selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium carbonate, potassium carbonate, and cesium carbonate; phosphine ligand selection Xanphos, DavePhos, John Phos, etc.; pd (OAc) as the palladium catalyst2、Pd2(dba)3、Pd(PPh3)4(ii) a The solvent is one or a mixed system of toluene, xylene, THF, DME, dioxane, DMF, NMP and DMSO; 2- ((6-bromo-2-ethyl-8-methylimidazo [1, 2-a)]Pyridine-3-yl) (methyl) amine) -4- (4-fluorophenyl) thiazole-5-carbonitrile (7) with anhydrous piperazine, palladium catalyst, phosphine ligand, base in a molar ratio of 1: (1.2-1.8): (0.05-0.08): (0.06-0.1): (1.5-2.5).
9. A compound of the following structure, and not limited to the list:
wherein R is2One or more of hydrogen, C1-C6 alkyl, 5-10-membered aryl substituted C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, cyano, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 sulfonamide, C1-C6 ester group, C1-C4 amide group, carbamoyl and the like are selected, and 4-fluorine, 4-chlorine, 2, 3-dichloro, 3, 5-dichloro, 3, 4-difluoro, 2, 4-difluoro, 3-chlorine-4-methoxy and hydrogen are preferably selected.
10. Use of a compound as claimed in claim 9 in the preparation of Ziritaxestat.
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