CN105111197B - Synthesis method of raltitrexed - Google Patents
Synthesis method of raltitrexed Download PDFInfo
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- CN105111197B CN105111197B CN201510527881.7A CN201510527881A CN105111197B CN 105111197 B CN105111197 B CN 105111197B CN 201510527881 A CN201510527881 A CN 201510527881A CN 105111197 B CN105111197 B CN 105111197B
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Abstract
The invention provides two methods for preparing a compound shown in a formula 4, wherein in the first scheme, 5-bromothiophene-2-methyl formate is used as a raw material to react with 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1) to prepare 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl]The-aminothiophene-2-methyl formate is hydrolyzed in an aqueous solution of alkali and then undergoes a condensation reaction with L-diethyl glutamate to prepare a compound shown in a formula 4; in the second scheme, 5-bromothiophene-2-formic acid is used as a raw material and is condensed with L-glutamic acid diester to prepare N- (5-bromothiophene-2-yl) diethyl glutamate, and then the N- (5-bromothiophene-2-yl) diethyl glutamate reacts with the compound of the formula 1 to prepare a compound of a formula 4; the invention also provides a method for preparing raltitrexed, wherein the compound in the formula 4 is hydrolyzed in aqueous solution of alkali, and then is acidified by hydrochloric acid to prepare the raltitrexed. The synthesis route adopted by the invention has the advantages of few reaction steps, simple and convenient operation, little environmental pollution and high product yield.
Description
Technical Field
The invention relates to synthesis of an anti-tumor drug, in particular to a synthesis method of raltitrexed.
Background
Raltitrexed (Raltitrexed) is an antitumor drug developed by Zeneca pharmaceutical company, england, in the late 80 s of the 20 th century, with the chemical name N- [5- [ N- [ (3, 4-dihydro-2-methyl-4-oxo-6-quinazolinyl) -methyl ] -N-methylamino ] -2-thienyl ] -L-glutamic acid hydrochloride, and the structural formula is shown below:
the synthesis method of raltitrexed reported in literature mainly includes two kinds, one is that 5-nitro-2-thiophenecarboxylic acid (2) is used as initial raw material, esterification and nitro reduction are carried out, then esterification reaction is carried out on the initial raw material and acetic anhydride to obtain 5- (N-acetyl amino thiophene-2-methyl formate (5), methylation reaction is carried out on the compound (5) and methyl iodide under the action of potassium carbonate, deprotection is carried out in hydrochloric acid, esterification reaction is carried out again to obtain 5- (N-methyl) -amino thiophene-2-methyl formate (8), the compound (8) and 2-methyl-6-bromomethyl-3-hydrogen-quinazoline-4-ketone are condensed, hydrolyzed and acyl-chlorinated under alkaline condition to obtain compound (11), substitution reaction is carried out on the compound (11) and L-dimethyl glutamate, Obtaining the raltitrexed I after hydrolysis. The reaction formula is shown as follows:
in the synthetic route, the nitro group on the thiophene ring needs to be reduced by iron powder, so that the post-treatment is difficult; methyl iodide is required to be used for introducing methyl on the N atom, and the methyl iodide is relatively high in toxicity and is not suitable for industrial production; and the carboxyl on the raw material (2) needs to be esterified and hydrolyzed twice, the synthesis steps are complicated and long, and the reaction time is also long.
The second method is that the target product raltitrexed I is prepared by the condensation and hydrolysis of N- [5- (N-methylamino) -2-thenoyl ] -L-glutamic acid diethyl ester and 2-methyl-6-bromomethyl-3-hydrogen-quinazoline-4-ketone. The key intermediate N- [5- (N-methylamino) -2-thenoyl ] -L-glutamic acid diethyl ester is prepared by taking 2, 5-thiophenedicarboxylic acid as a raw material through condensation, rearrangement reaction, N methylation and deprotection. The reaction formula is shown as follows:
in the synthetic route, the defects are that methyl iodide or dimethyl sulfate and other raw materials are used for the methylation reaction of nitrogen, and the raw materials are not easy to obtain, have high toxicity and are not suitable for industrial production; in the deprotection process, the protecting group needs to be removed in a strong acid environment of trifluoroacetic acid, and industrial production is difficult to realize.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method of an anticancer drug raltitrexed, which overcomes the defects of difficult raw material acquisition, large environmental pollution, complex and long synthesis step, long reaction time and the like in the prior art and improves the total reaction yield.
In order to achieve the purpose, the synthetic method route of the raltitrexed provided by the invention is as follows:
the first scheme is as follows: 5-bromothiophene-2-methyl formate is used as a raw material
The first scheme takes 5-bromothiophene-2-methyl formate as a raw material, and specifically comprises the following synthesis steps:
(1) taking 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline as a raw material to perform substitution reaction with methylamine aqueous solution to prepare 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1);
(2) reacting the compound 1 with a raw material 5-bromothiophene-2-methyl formate in the presence of alkali, a catalyst and a ligand to prepare 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] -aminothiophene-2-methyl formate (a compound 2);
(3) the compound 2 is hydrolyzed in aqueous solution of alkali or organic solvent to prepare 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] -aminothiophene-2-formic acid (compound 3);
(4) carrying out condensation reaction on L-diethyl glutamate and a compound 3 under the action of a condensing agent to obtain 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] -amino-2-thiophenyl-L-diethyl glutamate (a compound 4);
(5) and the compound 4 is subjected to hydrolysis reaction in an alkali aqueous solution, and then is acidified by hydrochloric acid to prepare the raltitrexed.
The methylamine water solution in the step (1) has a content of 40% and is purchased from Aladdin reagent Co.Ltd; the molar feed ratio of methylamine to 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline is controlled to be 9: 1-11: 1.
The alkali in the step (2) is potassium phosphate, potassium carbonate, cesium carbonate, a composite alkali of potassium phosphate and cesium carbonate or a composite alkali of potassium phosphate and sodium carbonate, preferably the composite alkali of potassium phosphate and sodium carbonate; the molar ratio of potassium phosphate to sodium carbonate is 1: 2-2: 1; in addition, the amount of the base added was 3 times the equivalent of methyl 5-bromothiophene-2-carboxylate.
The catalyst in the step (2) is cuprous iodide, cuprous chloride or cuprous bromide, preferably cuprous iodide; the molar ratio of the cuprous iodide to the 5-bromothiophene-2-methyl formate is 1: 20-1: 5, preferably 1: 20.
The ligand in the step (2) is N, N-dimethylethanolamine, trans- (1R,2R) -N, N \ \ '-dimethyl 1, 2-cyclohexanediamine or 1, 10-o-phenanthroline, preferably trans- (1R,2R) -N, N \ \' -dimethyl 1, 2-cyclohexanediamine; the molar ratio of the ligand to the catalyst is 2: 1-4: 1.
The solvent used in step (2) is N, N-dimethylformamide, toluene, acetonitrile, 1, 4-dioxane or tetrahydrofuran, preferably 1, 4-dioxane.
The temperature selected in step (2) is 80 deg.C, 100 deg.C, 110 deg.C, preferably 80 deg.C.
The aqueous solution of the alkali described in the steps (3) and (5) is an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably an aqueous solution of lithium hydroxide.
The condensing agent in the step (4) is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT), the solvent is dry N, N-Dimethylformamide (DMF), and a certain amount of base is added, wherein the commonly used base is N, N-Diisopropylethylamine (DIPEA), triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBop), and preferably N, N-Diisopropylethylamine (DIPEA).
Scheme II takes 5-bromothiophene-2-formic acid as raw material
The second scheme takes 5-bromothiophene-2-formic acid as a raw material, and specifically comprises the following synthesis steps:
(1) condensing L-diethyl glutamate and a raw material 5-bromothiophene-2-formic acid in a solvent under the action of a condensing agent to prepare N- (5-bromothiophene-2-yl) diethyl glutamate (a compound 5);
(2) taking 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline as a raw material to perform substitution reaction with methylamine aqueous solution to prepare 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1);
(3) carrying out substitution reaction on the compound 5 and the compound 1 in the presence of alkali, a catalyst and a ligand to obtain 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] -amino-2-thiophenyl-L-glutamic acid diethyl ester (a compound 4);
(4) and the compound 4 is subjected to hydrolysis reaction in an alkali aqueous solution, and then is acidified by hydrochloric acid to prepare the raltitrexed.
The condensing agent in the step (1) is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT), the solvent is dry N, N-Dimethylformamide (DMF), and a certain amount of alkali is added, wherein the common alkali is N, N-Diisopropylethylamine (DIPEA), triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBop), and preferably N, N-Diisopropylethylamine (DIPEA).
The content of the methylamine water solution in the step (2) is 40 percent, and the methylamine water solution is purchased from Aladdin reagent company Limited; the molar feed ratio of methylamine to 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline is controlled to be 9: 1-11: 1.
The step (1) and the step (2) are not in sequence.
The alkali in the step (3) is potassium phosphate, potassium carbonate, cesium carbonate, a composite alkali of potassium phosphate and cesium carbonate or a composite alkali of potassium phosphate and sodium carbonate, preferably the composite alkali of potassium phosphate and sodium carbonate; the molar ratio of potassium phosphate to sodium carbonate is 1: 2-2: 1; in addition, the amount of the base added was 3 times the equivalent of methyl 5-bromothiophene-2-carboxylate.
The catalyst in the step (3) is cuprous iodide, cuprous chloride or cuprous bromide, preferably cuprous iodide; the molar ratio of the cuprous iodide to the 5-bromothiophene-2-methyl formate is 1: 20-1: 5, preferably 1: 20.
The ligand in the step (3) is N, N-dimethylethanolamine, trans- (1R,2R) -N, N \ \ '-dimethyl 1, 2-cyclohexanediamine or 1, 10-o-phenanthroline, preferably trans- (1R,2R) -N, N \ \' -dimethyl 1, 2-cyclohexanediamine; the molar ratio of the ligand to the catalyst is 2: 1-4: 1.
The solvent used in step (3) is N, N-dimethylformamide, toluene, acetonitrile, 1, 4-dioxane or tetrahydrofuran, preferably 1, 4-dioxane.
The temperature selected in step (3) is 80 deg.C, 100 deg.C, 110 deg.C, preferably 80 deg.C.
The aqueous solution of the alkali in the step (4) is an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably an aqueous solution of lithium hydroxide.
Compared with the prior art, the invention has the following advantages:
(1) and the synthetic route is short. The technological process in the prior art is 11-step reaction and 6-step reaction respectively, while the starting raw materials selected in the scheme I and the scheme II of the invention are different from the prior art, and the synthesis route redesigned according to new starting raw materials only needs 5-step reaction and 4-step reaction respectively;
(2) due to the improvement of the synthetic route of the scheme I and the scheme II, the process does not use methyl iodide with high toxicity, thereby solving the problems of toxicity and safety; the nitro group is reduced without using iron powder, so that the problem of difficult post-treatment is avoided;
(3) the total yield is higher than that of the prior art. The total yield of the synthetic route provided by the scheme I and the scheme II is respectively 35.3 percent and 32.2 percent, and is respectively 12.4 percent higher and 14.1 percent higher than the total yield of the prior art.
As used herein, cat refers to catalyst, Base refers to Base, Ligand refers to Ligand, and Temp refers to temperature.
In this application nARefers to the amount of the raw material 5-bromothiophene-2-methyl formate, nBaseMeans the amount of base, nCat.Means the amount of the substance of the catalyst, nLigandMeans the amount of substance of the ligand, nCuIRefers to the amount of cuprous iodide material.
In this application nBase/nAThe molar ratio of the alkali to the raw material 5-bromothiophene-2-methyl formate, K3PO4/ Na2CO3Refers to the molar ratio of potassium phosphate to sodium carbonate, nCat./nAThe mol ratio of the catalyst to the raw material 5-bromothiophene-2-methyl formate, nCuI./nAThe mol ratio of cuprous iodide to the raw material 5-bromothiophene-2-methyl formate, nLigand/nAThe mol ratio of the ligand to the raw material 5-bromothiophene-2-methyl formate is shown.
Detailed Description
The present invention will be specifically described below by way of examples.
In the invention, L-glutamic acid diethyl ester is prepared from an initial raw material L-glutamic acid diethyl ester hydrochloride, and the specific operation method comprises the steps of firstly adjusting the pH of the L-glutamic acid diethyl ester hydrochloride to be =9 by using saturated sodium bicarbonate, extracting by using ethyl acetate, and evaporating to dryness to obtain the L-glutamic acid diethyl ester, wherein the appearance of the L-glutamic acid diethyl ester is yellow liquid.
Example one Experimental conditions screening of the preparation method of the invention
Now, the process of the synthesis process study of the intermediate compound 1 of the present invention will be mainly exemplified.
(1) Preparation of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (Compound 1)
The reaction step is amination reaction, and the raw material 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline reacts with methylamine to prepare 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1). In the research, firstly, a solvent is screened, small molecular alcohol is used as the solvent, and experimental results show that the reaction is rapid in an alcohol solvent, and when 10-20 minutes, the TLC detection raw material 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline completely reacts, but the impurities are numerous and complex. In addition, according to experience, the addition amount of the methylamine aqueous solution has certain influence on the product yield and quality, in the reaction, methylamine is used as a reaction raw material and also used as an acid-binding agent to neutralize HBr generated in the reaction process, if the addition amount of methylamine is not enough, the reaction of the raw material 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline is incomplete, the product yield is reduced, a disubstituted product can be generated, and impurities are introduced; if too much methylamine is added, the excessive methylamine is not easy to remove, so that the post-treatment operation is complicated, the raw material waste is caused, and the production cost is increased. Therefore, we examined the effect of the molar charge ratio of 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline to methylamine on the reaction through experiments, and the results are shown in table 1.
TABLE 16 influence of bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline on the reaction with the methylamine molar charge ratio
According to the experimental result, when the molar charge ratio of methylamine to 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline is less than or equal to 7:1, the reaction is incomplete, and the yield is low; when the molar charge ratio of methylamine to 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline is more than 7:1, TLC detection shows that the reaction is complete, and the yield is about 70%. According to the comprehensive experiment result, the molar charge ratio of the methylamine and the 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline is controlled to be 9: 1-11: 1, preferably 9:1, under the molar ratio, the 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline as the raw material completely reacts, the residual methylamine is less and is easy to remove, and the post-treatment operation is relatively simple.
We also investigated the reaction conditions of the key step 2-substituted-5-bromothiophene with 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline.
(2) Study of reaction of 2-substituted-5-bromothiophene with 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline
In order to examine the feasibility of the experimental scheme in the step, a reaction of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1) and 5-bromothiophene-2-methyl formate is taken as a template, and a research and development staff takes copper iodide (CuI)/N, N-dimethylethanolamine as a catalytic system and potassium carbonate (K) according to experience2CO3) For the base, N, N-Dimethylformamide (DMF) was used as a solvent to conduct preliminary experiments at 80 ℃.
To a 500mL reaction flask was added 100mL of N, N-Dimethylformamide (DMF), 20.7g of potassium carbonate (K)2CO3) 0.95g of cuprous iodide (CuI), 0.89g N, N-dimethylethanolamine, 12.18g of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline, 11.05g of 5-bromothiophene-2-carboxylic acid methyl ester is added in portions under the stirring condition, the temperature is increased to 80 ℃ after stirring for 15 minutes, the reaction is carried out for 4 hours, and TLC detection is carried out to obtain 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ester]7.0g of methyl (E) -aminothiophene-2-carboxylate, yield 40.8%. Next we screened the reaction conditions. The effect of different bases on the reaction was first investigated and the results are shown in table 2.
TABLE 2 Effect of different bases on the reaction
As can be seen from Table 2, the yield was the highest at 60.5% when potassium phosphate and sodium carbonate complex base was used as the base, and therefore, potassium phosphate and sodium carbonate complex base was used as the base in this step.
Then, the effect of the molar ratio of potassium phosphate to sodium carbonate was investigated, and the results are shown in Table 3.
TABLE 3 influence of different molar ratios of potassium phosphate and sodium carbonate on the reaction
As can be seen from Table 3, the yield was high when the molar ratio of potassium phosphate to sodium carbonate was 1:2 to 2:1, and therefore, the molar ratio of potassium phosphate to sodium carbonate was selected to be 1:2 to 2: 1.
On this basis, we used 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1, 1.2 equivalents) and methyl 5-bromothiophene-2-carboxylate (1.0 equivalent) as reactants, potassium phosphate and sodium carbonate complex base (K)3PO4/Na2CO31:2) base (3.0 equiv.), N, N-dimethylethanolamine (0.2 equivalent)Amount) as a ligand, and N, N-Dimethylformamide (DMF) as a solvent, and reacted at 80 ℃ for 4 hours, and the influence of different catalysts and the content thereof on the reaction was studied, and the experimental results are shown in Table 4.
TABLE 4 influence of different catalysts and their contents on the reaction
As shown in Table 4, the catalytic effect of cuprous iodide is the best, the reaction effect is good when the molar ratio of cuprous iodide to 5-bromothiophene-2-methyl formate is 1: 20-1: 5, and the molar ratio of cuprous iodide to 5-bromothiophene-2-methyl formate is 1:20 in consideration of the problem of post-treatment.
Next, we examined the influence of N, N-dimethylethanolamine, trans- (1R,2R) -N, N \ \' -dimethyl 1, 2-cyclohexanediamine and 1, 10-o-phenanthroline as ligands on the reaction.
The specific operation is as follows: with 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1, 1.2 equivalents) and methyl 5-bromothiophene-2-carboxylate (1.0 equivalent) as reactants, potassium phosphate and sodium carbonate complex base (K)3PO4/Na2CO31:2) as base (3.0 equiv), cuprous iodide (0.05 equiv) as catalyst, N-Dimethylformamide (DMF) as solvent, at 80 ℃ for 4 hours, the effect of different ligands on the reaction was studied, and the experimental results are shown in table 5.
TABLE 5 Effect of different ligands on the reaction
As is clear from Table 5, when trans- (1R,2R) -N, N \ '-dimethyl 1, 2-cyclohexanediamine was used as the ligand, the yield was improved from 57.4% to 67.6% as compared with the yield when N, N-dimethylethanolamine was used as the ligand, and therefore, trans- (1R,2R) -N, N \' -dimethyl 1, 2-cyclohexanediamine was used as the ligand.
Research personnel continuously investigate the influence of different solvents on the reaction system, and specifically the influence is 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1, 1.2 equivalents) and methyl 5-bromothiophene-2-carboxylate (1.0 equivalent) as reactants with potassium phosphate and sodium carbonate complex base (K)3PO4/Na2CO31:2) as base (3.0 equiv.), cuprous iodide (0.05 equiv.) as catalyst, trans- (1R,2R) -N, N \ \' -dimethyl 1, 2-cyclohexanediamine (0.2 equiv.) as ligand, reacting at 80 ℃ for 4 hours, and studying the influence of different solvents on the reaction, wherein the experimental results are shown in Table 6.
TABLE 6 Effect of different solvents on the reaction
As is clear from Table 6, the polar aprotic solvent 1, 4-dioxane was selected as the solvent because the yield was the best (76.2%).
Finally, researchers investigated the effect of reaction temperature on the reaction. With 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1, 1.2 equivalents) and methyl 5-bromothiophene-2-carboxylate (1.0 equivalent) as reactants, potassium phosphate and sodium carbonate complex base (K)3PO4/Na2CO31:2) is base (3.0 equivalent), cuprous iodide (0.05 equivalent) is catalyst, trans- (1R,2R) -N, N \' -dimethyl 1, 2-cyclohexanediamine (0.2 equivalent) is ligand, 1, 4-dioxane is solvent, TLC detects reaction process, researches the influence of different reaction temperatures on the reaction, and selects three reaction temperatures of 80 ℃, 100 ℃ and 110 ℃ respectively to react for 4 hours, and the experimental result is shown in Table 7.
TABLE 7 Effect of different reaction temperatures on the reaction
As can be seen from Table 7, the reaction becomes complicated and the reaction yield decreases with an increase in temperature.
After being screened by a series of conditions, the prepared 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl is obtained]-ammoniaOptimum reaction conditions for methylthiophene-2-carboxylic acid methyl ester: potassium phosphate and sodium carbonate complex alkali (K)3PO4/Na2CO31:2) as a base (3.0 equivalents), 0.05 equivalent as a catalyst, 0.2 equivalent as a ligand of trans- (1R,2R) -N, N \' -dimethyl 1, 2-cyclohexanediamine, 1.2 equivalents of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline, and 1, 4-dioxane as a solvent, and reacting at 80 ℃ for 4 hours. The applicability of the reaction of diethyl N- (5-bromothien-2-yl) glutamate (compound 5) with 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1) was investigated with this optimization.
To a 500mL reaction flask was added 100mL of 1, 4-dioxane, 10.60g of potassium phosphate (K)3PO4) 10.60g sodium carbonate (Na)2CO3) 0.48g of cuprous iodide (CuI), 1.42g of trans- (1R,2R) -N, N \' -dimethyl 1, 2-cyclohexanediamine, 12.18g of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline, 19.60g of diethyl N- (5-bromothiophene-2-yl) glutamate are added in batches under the stirring condition, the temperature is raised to 80 ℃ after the addition, the reaction is carried out for 4 hours, the TLC detection reaction is complete, and the 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] is obtained]16.67g of diethyl (E) -amino-2-thiophenyl-L-glutamate with a yield of 64.8%. The experimental results show that this condition applies equally to step (3) of scheme two.
Example two Raltitrexed was prepared using protocol one method
(1) Preparation of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (Compound 1)
Slowly dropwise adding 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (m =25.3g, n =0.1mol) into a 40% methylamine aqueous solution (m =77.50g, n =1mol), controlling the temperature to be minus 10 ℃ to minus 5 ℃, gradually heating to room temperature after dropwise adding, continuing stirring, and determining that the reaction is complete (TLC detection). To the reaction solution was added sodium bicarbonate solution, pH was adjusted to be basic (pH >7), extraction was performed with dichloromethane, the organic phase was washed with saturated aqueous sodium chloride solution, the organic phase was rotary evaporated to remove the solvent, 500mL of water was added and slurried, stirring was performed for 30 minutes, filtration was performed, the filter cake was washed with water (3 × 100mL), and after draining, drying was performed to obtain an off-white solid (14.1g, 69.4%).
1H NMR (400 MHz, DMSO-d 6) δ12.18 (s, 1H), 9.02 (s, 1H), 8.23 (s, 1H), 7.89-7.87 (m, 1H), 7.64-7.63 (m, 1H), 4.25 (s, 2H), 2.57 (s, 3H), 2.36 (s, 3H)。
(2) Preparation of 2- [ N- (2-methyl-4-oxoquinazolin-6-methyl) -N-methyl ] -aminothiophene-2-carboxylic acid methyl ester (Compound 2)
To a 500mL reaction flask was added 200mL of 1, 4-dioxane, 5.30g of potassium phosphate (K)3PO4) 5.30g of sodium carbonate, 0.24g of copper iodide (CuI), 0.72g of trans- (1R,2R) -N, N \' -dimethyl-1, 2-cyclohexanediamine, 6.10g of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline, adding 5.53g of 5-bromothiophene-2-methyl formate in batches under the stirring condition, replacing 3 times by nitrogen, then, the temperature is increased to 80 ℃, the reaction is carried out for 4 hours, the TLC detection shows that the reaction is complete, the reaction liquid is cooled to room temperature, 150mL of ethyl acetate is added, 100mL of ammonium chloride aqueous solution is added, the mixture is stirred, the mixture is kept stand and layered, an organic layer is washed by ammonium chloride aqueous solution until an aqueous phase has no copper ions, anhydrous sodium sulfate is dried, the solvent is removed by rotary evaporation, and the solid is treated by 50mL of petroleum ether: pulping the mixed solvent with the volume ratio of ethyl acetate of 15:1, and filtering to obtain 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl]6.20g of methyl (E) -aminothiophene-2-carboxylate in a yield of 72.3%.
1H-NMR(400MHz, DMSO-d6) δ 9.46 (s, 1H), 8.15-8.14 (m, 1H), 7.99-7.97 (m, 1H), 7.65-7.63 (m, 1H), 7.56-7.54 (m, 1H), 6.01-5.97(m, 1H), 4.36 (s, 2H), 2.56(s, 3H), 2.04 (s, 3H), 0.95(s, 3H)。
(3) Preparation of 2- [ N- (2-methyl-4-oxoquinazolin-6-methyl) -N-methyl ] -aminothiophene-2-carboxylic acid (Compound 3)
6.20g of 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] -aminothiophene-2-carboxylic acid methyl ester is dissolved in 100mL of tetrahydrofuran solvent, 8mL of 3mol/L lithium hydroxide solution is added, stirring is carried out at room temperature, the reaction is detected to be complete, diluted hydrochloric acid is used for adjusting the reaction to be weak acidity, standing and layering are carried out, and the organic phase is dried in a spinning mode to obtain 5.57g of 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] -aminothiophene-2-carboxylic acid, wherein the yield is 93.6%.
1H NMR(400MHz, CDCl3) δ 8.10-8.08 (m, 1H), 7.93-7.91 (m, 1H), 7.64-7.63 (m, 1H), 7.56-7.5 (m, 1H), 6.09-6.07(m, 1H), 4.33 (s, 2H), 2.07 (s, 3H), 0.97(s, 3H)。
(4) Preparation of 2- [ N- (2-methyl-4-oxoquinazolin-6-methyl) -N-methyl ] -amino-2-thiophenyl-L-glutamic acid diethyl ester (Compound 4)
4.06g L-glutamic acid diethyl ester (1.0eq), 7.24g 2- [ N- (2-methyl-4-oxoquinazolin-6-methyl) -N-methyl ] -aminothiophene-2-carboxylic acid (1.1eq), 4.05g HOBT (1.5eq), 7.74g N, N-diisopropylethylamine (DIPEA, 3.0eq), 5.76g EDCI (1.5eq) were added to a reaction flask, 100mL DMF was added, the reaction was stirred at room temperature, TLC followed, after completion of the reaction, 250 mL ethyl acetate was added, washed 5 times with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and the mixture was washed with ethyl acetate: purifying the mixed solvent with the petroleum ether volume ratio of 1:1 to obtain 9.00g of 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] -amino-2-thiophenyl-L-glutamic acid diethyl ester, wherein the yield is 87.4%.
1H NMR(DMSO-d6) δ 10.91-10.89 (m, 1H), 8.13-8.12 (m, 1H), 7.68-7.65 (m, 2H), 7.29-7.27 (m, 1H), 6.53-6.52 (m, 1H), 5.89-5.86 (m, 1H), 4.78-4.74 (m, 1H), 4.59 (s, 2H), 4.22-4.19 (m, 2H), 4.13-4.10 (m, 2H), 3.03 (s, 3H), 2.56 (s, 3H), 2.44-2.42 (m, 2H), 2.27-2.25 (m, 2H), 1.28-1.23 (m, 6H)。
(5) Preparation of raltitrexed
Adding 5.15g (0.01mol) of 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl ] -amino-2-thiophenyl-L-glutamic acid diethyl ester and 15mL of 2mol/L lithium hydroxide solution into a reaction bottle, introducing nitrogen, stirring at room temperature until the reaction is complete, adding dichloromethane into the reaction liquid for extraction, adjusting the pH value of the water phase to weak acidity by using 2mol/L hydrochloric acid, and separating out solids. Filtering, washing the product with distilled water, and drying to obtain 4.25g of raltitrexed with the yield of 85.9%.
1H NMR(DMSO-d6) δ 12.23 (brs, 1H), 8.13-8.12 (m, 1H), 7.94-7.93 (m, 1H), 7.66-7.65 (m, 1H), 7.57-7.55 (m, 2H), 5.60-5.99 (m, 1H), 4.65 (s, 2H), 4.30-4.27 (m, 1H), 3.04 (s, 3H), 2.33-2.30 (m, 2H), 2.08 (s, 3H), 2.07-2.06 (m, 1H), 2.04-2.03 (m, 1H)。
Example III Raltitrexed preparation by protocol II
(1) Preparation of N- (5-bromothien-2-yl) glutamic acid diethyl ester (Compound 5)
200mL of DMF, 10.15g of 10.15g L-diethyl glutamate (1eq), 11.39g of 5-bromothiophene-2-carboxylic acid (1.1eq), 10.13g of HOBT (1.5eq), 19.35g of 19.35g N, N-diisopropylethylamine (3eq) and 14.40g of EDCI (1.5eq) are added into a reaction flask, the mixture is stirred at room temperature under the protection of nitrogen, 500mL of ethyl acetate is added for extraction after the reaction is completed, the mixed solution is washed with saturated saline solution for 5 times, an organic phase is dried by anhydrous sodium sulfate, filtered, the solvent is evaporated, and the organic phase is dried to obtain 16.50g of diethyl N- (5-bromothiophene-2-yl) glutamate with the yield of 84.2%.
1H NMR (CDCl3) δ7.30-7.27(m, 1H), 7.05-7.03(m, 1H), 7.01-6.98(m, 1H), 4.72-4.68 (m, 1H), 4.24-4.22(m, 2H), 4.13-4.10(m, 2H), 2.52-2.37(m, 2H), 2.31-2.25 (m, 1H), 2.17-2.13 (m, 1H), 1.31-1.29(m, 3H), 1.25-1.22 (m, 3H)。
(2) Preparation of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline (Compound 1)
The preparation method is the same as the two steps (1) of the example, and the yield is 67.8%.
(3) Preparation of 2- [ N- (2-methyl-4-oxoquinazolin-6-methyl) -N-methyl ] -amino-2-thiophenyl-L-glutamic acid diethyl ester (Compound 4);
to a 500mL reaction flask was added 200mL of 1, 4-dioxane, 10.60g of potassium phosphate (K)3PO4) 10.60g sodium carbonate (Na)2CO3) 0.48g of cuprous iodide (CuI), 1.42g of trans- (1R,2R) -N, N \' -dimethyl 1, 2-cyclohexanediamine, 12.18g of 6- ((methylamino) methyl) -3, 4-dihydro-2-methyl-4-oxo-6-quinazoline, 19.60g of diethyl N- (5-bromothien-2-yl) glutamate is added in batches under stirring, after the addition is finished, nitrogen is used for replacing for 3 times, then the temperature is increased to 80 ℃, the reaction is carried out for 4 hours, the TLC detection reaction is completed, the reaction liquid is cooled to room temperature, 300mL of ethyl acetate is added, 50mL of ammonium chloride aqueous solution is added, the mixture is stirred, the mixture is kept stand and layered, the organic layer is washed by ammonium chloride aqueous solution until the aqueous phase has no copper ions, anhydrous sodium sulfate is dried, the solvent is removed by rotary evaporation, the solids were treated with 50mL of petroleum ether: pulping the mixed solvent with the volume ratio of ethyl acetate of 15:1, and filtering to obtain 2- [ N- (2-methyl-4-oxoquinazoline-6-methyl) -N-methyl]16.78g of methyl (E) -aminothiophene-2-carboxylate, yield 65.2%.
1H NMR(400MHz CDCl3) δ10.91-10.89 (m, 1H), 8.13-8.12 (m, 1H), 7.68-7.65 (m, 2H), 7.29-7.27 (m, 1H), 6.53-6.52 (m, 1H), 5.89-5.86 (m, 1H), 4.78-4.74 (m, 1H), 4.59 (s, 2H), 4.22-4.19 (m, 2H), 4.13-4.10 (m, 2H), 3.03 (s, 3H), 2.56 (s, 3H), 2.44-2.42 (m, 2H), 2.27-2.25 (m, 2H), 1.28-1.23 (m, 6H)。
(4) Preparation of raltitrexed
The operation was carried out in the same manner as in step (5) in example, giving a yield of 86.4%.
Claims (10)
1. A method of preparing raltitrexed, the method comprising the steps of:
(1) carrying out substitution reaction on 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline and methylamine water solution to prepare a compound shown in a formula 1;
wherein the molar feed ratio of methylamine to 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline is controlled to be 9: 1-11: 1;
(2) reacting the compound shown in the formula 1 with a raw material 5-bromothiophene-2-methyl formate in the presence of alkali, a catalyst and a ligand to obtain a compound shown in the formula 2;
wherein the alkali is a composite alkali of potassium phosphate and sodium carbonate, the molar ratio of the potassium phosphate to the sodium carbonate is 1: 2-2: 1, the catalyst is cuprous iodide or cuprous bromide, the ligand is N, N-dimethylethanolamine or trans- (1R,2R) -N, N \' -dimethyl 1, 2-cyclohexanediamine, the solvent is N, N-dimethylformamide or 1, 4-dioxane, and the temperature is 80 ℃, 100 ℃ or 110 ℃;
(3) the compound of the formula 2 is subjected to hydrolysis reaction in an aqueous solution of alkali to prepare a compound of a formula 3;
(4) carrying out condensation reaction on the compound shown in the formula 3 and L-diethyl glutamate under the action of a condensing agent to obtain a compound shown in a formula 4;
wherein the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, the base is N, N-diisopropylethylamine, and the solvent is dry N, N-dimethylformamide;
(5) the compound of the formula 4 is subjected to hydrolysis reaction in an aqueous solution of alkali, and then is acidified by hydrochloric acid to prepare raltitrexed;
wherein, the alkali aqueous solution in the step (3) and the step (5) is lithium hydroxide aqueous solution.
2. The method of claim 1, wherein the base is added in step (2) in an amount of 3 equivalents of 5-bromothiophene-2-carboxylic acid methyl ester.
3. The process of claim 1, wherein the catalyst in step (2) is preferably cuprous iodide.
4. The method of claim 1, wherein the molar ratio of cuprous iodide to methyl 5-bromothiophene-2-carboxylate in step (2) is 1:20 to 1: 5.
5. The process according to claim 4, wherein the molar ratio of cuprous iodide to methyl 5-bromothiophene-2-carboxylate is preferably 1: 20.
6. The process of claim 1, wherein the ligand in step (2) is preferably trans- (1R,2R) -N, N \ \' -dimethyl 1, 2-cyclohexanediamine.
7. The method of claim 1, wherein the ligand to catalyst molar ratio in step (2) is from 2:1 to 4: 1.
8. The process according to claim 1, wherein the solvent in step (2) is preferably 1, 4-dioxane.
9. The method of claim 1, wherein the temperature in step (2) is preferably 80 ℃.
10. A method of preparing raltitrexed, the method comprising the steps of:
(1) condensing raw materials of 5-bromothiophene-2-formic acid and L-diethyl glutamate in a solvent under the action of a condensing agent to prepare a compound shown in a formula 5;
wherein the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, the base is N, N-diisopropylethylamine, and the solvent is dry N, N-dimethylformamide;
(2) carrying out substitution reaction on 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline and methylamine water solution to prepare a compound shown in a formula 1;
wherein the molar feed ratio of methylamine to 6-bromomethyl-3, 4-dihydro-2-methyl-4-oxo-6-quinazoline is controlled to be 9: 1-11: 1;
(3) carrying out substitution reaction on the compound of the formula 5 and the compound of the formula 1 in the presence of alkali, a catalyst and a ligand to obtain a compound of a formula 4;
wherein the alkali is a composite alkali of potassium phosphate and sodium carbonate, the molar ratio of the potassium phosphate to the sodium carbonate is 1:2, and the addition amount of the alkali is 3 equivalents of the compound shown in the formula 5; the catalyst is cuprous iodide which is 0.05 equivalent of the compound of formula 5; the ligand is trans- (1R,2R) -N, N \ \' -dimethyl 1, 2-cyclohexanediamine which is 0.2 equivalent of the compound of the formula 5; the compound of formula 1 is 1.2 equivalents of the compound of formula 5; the solvent is 1, 4-dioxane, and the temperature is 80 ℃;
(4) the compound of the formula 4 is subjected to hydrolysis reaction in an aqueous solution of alkali, and then is acidified by hydrochloric acid to prepare raltitrexed; the aqueous solution of the alkali is aqueous solution of lithium hydroxide.
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