Disclosure of Invention
In order to solve the problems of low yield, high production cost, instability and low purity of pemetrexed disodium in the prior art, the invention provides a pemetrexed disodium intermediate II-1, a preparation method thereof and a preparation method of pemetrexed disodium IV.
The technical scheme adopted by the invention is as follows:
in one aspect, the invention provides a pemetrexed disodium intermediate II-1 and a preparation method thereof.
The chemical name of the intermediate II-1 is as follows: 4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid, having the formula:
the preparation method of the pemetrexed disodium intermediate II-1 comprises the following steps:
4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidine-5-yl) ethyl ] benzoic acid is used as a starting material, and is subjected to acylation reaction in acetic acid and acetic anhydride, and after the reaction is finished, the intermediate II-1 is obtained through treatment.
The reaction route is as follows:
specifically, the preparation method of the pemetrexed disodium intermediate II-1 comprises the following steps:
adding 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidine-5-yl) ethyl ] benzoic acid into acetic acid, heating to 30 ℃, stirring for dissolving, dropwise adding acetic anhydride, heating to 40-50 ℃, preserving heat for reacting for 1 hour, decompressing and evaporating the acetic acid, adding pure water, stirring, adjusting the pH value to 5-6 by using a 5% sodium hydroxide solution, crystallizing, filtering, and drying to obtain an intermediate II-1.
Preferably, the molar ratio of 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid to acetic anhydride is 1:1-2, more preferably, the molar ratio is 1: 1.2.
The chemical name of the intermediate I is as follows: l-glutamic acid diethyl ester, the structural formula is as follows:
the preparation method of the intermediate I comprises the following steps: taking L-glutamic acid diethyl ester hydrochloride as an initial material, potassium carbonate as a deacidification agent, and dichloromethane as a solvent to carry out deacidification reaction to obtain a light yellow oily intermediate I, namely L-glutamic acid diethyl ester.
The synthetic route is as follows:
on the other hand, the invention also provides a preparation method of pemetrexed disodium, which comprises the following steps:
taking the intermediate I and the intermediate II-1 as raw materials, carrying out condensation reaction under the action of N, N-carbonyldiimidazole, then reacting with p-toluenesulfonic acid to obtain an intermediate III-1N- {4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl } -L-glutamic acid diethyl ester tosylate, then removing the p-toluenesulfonic acid from the intermediate III-1 in a sodium hydroxide solution, carrying out ester hydrolysis and amide hydrolysis, and then forming sodium salt to obtain pemetrexed disodium.
The synthetic route is as follows:
specifically, the preparation method of pemetrexed disodium comprises the following steps:
(1) preparation of intermediate III-1:
adding DMF into the intermediate II-1, stirring and dissolving, adding N, N-carbonyldiimidazole, reacting for 2 hours at 50-60 ℃, adding the intermediate I, heating to 70-80 ℃, reacting for 3 hours, evaporating to dryness under reduced pressure, adding dichloromethane for dissolving, pouring into a mixed solution of pure water and triethylamine, stirring and separating liquid, separating out an organic phase, washing, drying and evaporating to dryness, adding absolute ethyl alcohol, stirring and dissolving, adding p-toluenesulfonic acid, reacting for 1 hour, cooling and crystallizing, performing suction filtration, and drying to obtain an intermediate III-1;
(2) preparation of pemetrexed disodium:
and mixing the intermediate III-1 with a sodium hydroxide solution, dropwise adding a 10% hydrochloric acid solution after complete dissolution to adjust the pH to 2-3, stirring for crystallization, performing suction filtration, adding absolute ethyl alcohol into a filter cake, heating to 50-60 ℃, stirring for dissolution, adjusting the pH to 6-7 with a 20% sodium hydroxide solution, stirring for crystallization, performing hot filtration, adding a 50% sodium hydroxide solution into a filtrate for crystallization, performing suction filtration, and performing vacuum drying to obtain pemetrexed disodium.
Preferably, the mole ratio of the intermediate II-1 to the intermediate (I) is 1:1-2, more preferably 1: 1.2.
Preferably, the mole ratio of the intermediate II-1 to the p-toluenesulfonic acid in the preparation method of the pemetrexed disodium is 1:1-2, more preferably 1: 1.2.
Preferably, the mole ratio of the intermediate II-1 to the N, N-carbonyl diimidazole in the preparation method of pemetrexed disodium is 1: 1.2-2.
The invention has the advantages that:
(1) the intermediate II-1 is simple to prepare, and the amidation reaction is carried out by taking 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidine-5-yl) ethyl ] benzoic acid as a raw material, so that the amino is protected, the impurity V generated by the reaction is avoided, the problem of oxidative discoloration caused by unstable amino in the reaction process is solved, the condition is mild, the yield is high, the product is stable, and the method is favorable for actual production.
(2) The intermediate I and the intermediate II-1 are used as raw materials to prepare the intermediate III-1, because the-NH of the intermediate II-12Protected, avoids the self reaction of the intermediate II-1 to generate an impurity V compound, greatly improves the quality and yield of the intermediate III-1, and greatly reduces the production cost.
(3) The intermediate III-1 is used as a raw material to prepare pemetrexed disodium, deacidification, hydrolysis and salt formation can be completed in an ethanol sodium hydroxide solution, the operation is simple, the condition is mild, special deprotection reaction is not needed, but the amino group is protected, so that the oxidative degradation of the amino group is prevented, the quality and the purity of a final product are greatly improved, and the purity is more than 99.85%.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.
Example 1:
preparation of L-glutamic acid diethyl ester:
weighing L-glutamic acid diethyl ester hydrochloride (48g 0.2mol), adding into a 500ml four-mouth bottle, adding 120ml pure water, stirring for dissolving, adding 18g potassium carbonate, reacting for 0.5 hour, adding 100ml dichloromethane, stirring for separating liquid, extracting a water layer with 80ml × 3 pure water for three times, collecting an organic phase, drying, and evaporating to dryness to obtain a product L-glutamic acid diethyl ester (the molar yield is 97.5%, and the purity is 94.3%).
Example 2
Preparation of 4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid:
weighing 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (60g and 0.2mol), adding 200ml acetic acid into a 500ml four-mouth bottle, heating to 30 ℃, stirring and dissolving, dropwise adding acetic anhydride (0.2mol), heating to 40 ℃, keeping the temperature and reacting for 1 hour, drying the acetic acid by evaporation under reduced pressure, adding 300ml pure water, stirring, adjusting the pH to 5 by using a 5% sodium hydroxide solution, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, performing suction filtration, drying to obtain a product 4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (the molar yield is 96.3%, purity 99.2%).
4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) ethyl]Mass Spectrometry of benzoic acid [ M-H]+=341.3。
1H-NMR:1H NMR(400MHz,D2O)δ:
12.12(s,1H);8.15(d,1H,J=8.20Hz);8.15(d,1H,J=8.20Hz);7.58(d,1H,J=8.20Hz);7.58(d,1H,J=8.20H z);7.03(d,1H,J=8.26Hz);7.03(d,1H,J=8.26);6.06(s,1H);2.76(m,2H);2.70(m,2H);2.34(m,2H);1.86( s,1H)。
13C-NMR:13C NMR(400MHz,D2O)δ:179.30,169.34,160.08,148.74,148.53,146.68, 130.43,130.43,128.18,128.18,128.91,127.91,117.14,104.97,37.12,29.43,23.10。
Example 3
Preparation of 4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid:
weighing 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (60g and 0.2mol), adding 200ml acetic acid into a 500ml four-mouth bottle, heating to 30 ℃, stirring and dissolving, dropwise adding acetic anhydride (0.4mol), heating to 50 ℃, keeping the temperature and reacting for 1 hour, drying the acetic acid by evaporation under reduced pressure, adding 300ml pure water, stirring, adjusting the pH to 6 by using a 5% sodium hydroxide solution, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, performing suction filtration, drying to obtain a product 4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (the molar yield is 96.9 percent), purity 99.0%).
4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) ethyl]Mass spectrum of benzoic acid,1H-NMR、13C-NMR is given in example 2
Example 4
Preparation of 4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid:
weighing 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (60g and 0.2mol), adding 200ml acetic acid into a 500ml four-mouth bottle, heating to 30 ℃, stirring and dissolving, dropwise adding acetic anhydride (0.24mol), heating to 50 ℃, keeping the temperature and reacting for 1 hour, drying the acetic acid by evaporation under reduced pressure, adding 300ml pure water, stirring, adjusting the pH to 6 by using a 5% sodium hydroxide solution, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, performing suction filtration, drying to obtain a product 4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (the molar yield is 97.1 percent), purity 99.5%).
4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) ethyl]Mass spectrum of benzoic acid,1H-NMR、13C-NMR is given in example 2
Example 5
Preparation of N- {4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl } -L-glutamic acid diethyl ester tosylate:
adding 4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (64.6g and 0.19mol) into a 1L four-mouth bottle, adding 650ml of DMF, stirring and dissolving, heating to 50 ℃, adding 0.228mol of N, N-carbonyl diimidazole, keeping the temperature at 50 ℃ for 2 hours, adding L-glutamic acid diethyl ester (0.19mol), heating to 70 ℃, reacting for 3 hours, evaporating under reduced pressure, adding 800ml of dichloromethane for dissolving, pouring into a mixed solution of 1600ml of pure water and 160ml of triethylamine, stirring and separating to obtain an organic phase, washing 1600ml of pure water multiplied by 2 twice, drying and evaporating to dryness, adding 500ml of anhydrous ethanol, stirring and dissolving, dropwise adding 36g of p-toluenesulfonic acid monohydrate and 200ml of anhydrous ethanol solution under the reflux state, after the addition, the reflux reaction is carried out for 1 hour, the temperature is reduced, the crystallization is carried out, the suction filtration is carried out, and the drying is carried out, thus obtaining the product (the molar yield is 87.0 percent, the purity is 98.9 percent, and the content of the impurity V is 0).
N- {4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) ethyl]Mass spectrum of benzoyl } -L-glutamic acid diethyl ester tosylate: [ M-H ]]-=524.5。
1H-NMR:1H NMR(400MHz,(CD3)2SO)δ:
7.80(d,1H,J=8.26Hz);7.80(d,1H,J=8.26Hz);7.55(m,1H),7.55(m,1H);7.30(d,1H,J=8.28Hz);7.30(d, 1H,J=8.28Hz);7.16(d,1H,J=7.87Hz);7.16(d,1H,J=7.87H);6.52(d,1H,J=2.06Hz);4.43(m,1H);4.09( m,1H);4.09(m,1H);2.93(m,2H);2.93(m,2H);2.44(t,2H,J=7.49Hz,);2.29(s,3H);2.06(m,2H);1.83 (s,3H);1.17(m,3H);1.17(m,3H)。
13C-NMR(400MHz,(CD3)2SO):δ:172.69,172.32,170.32,167.08,157.74,151.06,146.20,144. 98,139.11,138.89,131.70,128.80,128.80,128.68,128.68,127.95,127.95,125.98,125.98,119.53,115. 80,99.48,61.02,60.41,52.45,36.18,27.65,26.17,23.21,21.26,14.54,14.54。
Example 6
Preparation of N- {4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl } -L-glutamic acid diethyl ester tosylate:
adding 4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (64.6g and 0.19mol) into a 1L four-mouth bottle, adding 650ml of DMF, stirring and dissolving, heating to 50 ℃, adding 0.38mol of N, N-carbonyldiimidazole, keeping the temperature at 60 ℃ for 2 hours, adding L-glutamic acid diethyl ester (0.38mol), heating to 80 ℃, reacting for 3 hours, evaporating under reduced pressure, adding 800ml of dichloromethane for dissolving, pouring into a mixed solution of 1600ml of pure water and 160ml of triethylamine, stirring and separating to obtain an organic phase, washing 1600ml multiplied by 2 of pure water twice, drying and evaporating to dryness, adding 500ml of anhydrous ethanol, stirring and dissolving, dropwise adding 72g of p-toluenesulfonic acid monohydrate and 200ml of anhydrous ethanol solution under a reflux state, after the addition, the reflux reaction is carried out for 1 hour, and the product is obtained by cooling crystallization, suction filtration and drying (the molar yield is 88.1%, the purity is 98.3%, and the content of the impurity V is 0).
N- {4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) ethyl]Mass spectrum of benzoyl } -L-glutamic acid diethyl ester tosylate,1H-NMR、13C-NMR is given in example 5.
Example 7
Preparation of N- {4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl } -L-glutamic acid diethyl ester tosylate:
adding 4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (64.6g and 0.19mol) into a 1L four-mouth bottle, adding 650ml of DMF, stirring and dissolving, heating to 50 ℃, adding 0.38mol of N, N-carbonyldiimidazole, keeping the temperature at 60 ℃ for 2 hours, adding L-glutamic acid diethyl ester (0.48mol), heating to 80 ℃, reacting for 3 hours, evaporating under reduced pressure, adding 800ml of dichloromethane for dissolving, pouring into a mixed solution of 1600ml of pure water and 160ml of triethylamine, stirring and separating to obtain an organic phase, washing 1600ml multiplied by 2 of pure water twice, drying and evaporating to dryness, adding 500ml of anhydrous ethanol, stirring and dissolving, adding 90g of p-toluenesulfonic acid monohydrate and 200ml of anhydrous ethanol solution under a reflux state, after the addition, the reflux reaction is carried out for 1 hour, and the product is obtained by cooling crystallization, suction filtration and drying (the molar yield is 84.7%, the purity is 98.6%, and the content of the impurity V is 0).
N- {4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) ethyl]Mass spectrum of benzoyl } -L-glutamic acid diethyl ester tosylate,1H-NMR、13C-NMR is given in example 5.
Example 8
Preparation of pemetrexed disodium:
weighing 36g of sodium hydroxide, adding into 600ml of pure water, stirring and dissolving, cooling to below 30 ℃, adding N- {4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl } -L-glutamic acid diethyl ester tosylate (112.7g and 0.16mol), stirring and dissolving, dropwise adding 10% hydrochloric acid solution after complete dissolution to adjust the pH to 2, stirring and crystallizing, carrying out suction filtration, adding a filter cake into a 1L four-mouth bottle, adding 500ml of absolute ethyl alcohol, heating to 50 ℃, stirring and dissolving, adjusting the pH to 6 with 20% sodium hydroxide solution, stirring and crystallizing, carrying out heat filtration, pouring the filtrate into the bottle, adding 24g of 50% sodium hydroxide solution, stirring and heating to 50 ℃, carrying out a stirring reaction for 1 hour, cooling to 0 ℃, stirring and crystallizing for 5 hours, filtering, and drying in vacuum to obtain white solid pemetrexed disodium (molar yield 81.5%, purity 99.85%).
Mass spectrum of pemetrexed disodium: [ M-2Na-2.5H2O + H]-426.4。
Method for preparing pemetrexed disodium1H-NMR:1H NMR(400MHz,D2O)δ=7.58(d,1H,J=8.20Hz);7.58(d,1H, J=8.20Hz);7.02(d,1H,J=8.26Hz);7.02(d,1H,J=8.26Hz);6.16(s,1H);4.32(dd,1H, J=4.78Hz);2.59(m,2H);2.59(m,2H);2.34(m,2H);2.18(m,1H);2.06(m,1H)。
Method for preparing pemetrexed disodium13C-NMR:13C NMR(400MHz,D2O)δ:182.33,179.10,169.84,160.88, 151.74,150.53,146.58,130.43,128.18,128.18,126.91,126.91,118.14,114.97,98.72, 56.00,35.12,34.32,28.43,26.71。
Example 9
Preparation of pemetrexed disodium:
weighing 36g of sodium hydroxide, adding into 600ml of pure water, stirring and dissolving, cooling to below 30 ℃, adding N- {4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl } -L-glutamic acid diethyl ester tosylate (112.7g and 0.16mol), stirring and dissolving, dropwise adding 10% hydrochloric acid solution after complete dissolution to adjust the pH to 3, stirring and crystallizing, carrying out suction filtration, adding a filter cake into a 1L four-mouth bottle, adding 500ml of absolute ethyl alcohol, heating to 60 ℃, stirring and dissolving, adjusting the pH to 7 with 20% sodium hydroxide solution, stirring and crystallizing, carrying out heat filtration, pouring the filtrate into the bottle, adding 24g of 50% sodium hydroxide solution, stirring and heating to 50 ℃, carrying out a stirring reaction for 1 hour, cooling to 0 ℃, stirred and crystallized for 5 hours, filtered by suction and dried in vacuum to obtain white solid (molar yield 82.3 percent and purity 99.86 percent).
Mass spectrometry, 1H-NMR and 13C-NMR of pemetrexed disodium were performed in example 8.
Comparative example 1
Preparation of 4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid:
weighing 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (60g and 0.2mol), adding 200ml acetic acid into a 500ml four-mouth bottle, heating to 30 ℃, stirring and dissolving, dropwise adding acetic anhydride (0.5mol), heating to 50 ℃, keeping the temperature and reacting for 1 hour, drying the acetic acid by evaporation under reduced pressure, adding 300ml pure water, stirring, adjusting the pH to 6 by using a 5% sodium hydroxide solution, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, performing suction filtration, drying to obtain a product 4- [2- (2-acetamido-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (the molar yield is 93.4%), purity 97.6%).
4- [2- (2-acetylamino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) ethyl]Mass spectrum of benzoic acid,1H-NMR、13C-NMR is given in example 2
Comparative example 2
Preparation of N- {4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl } -L-glutamic acid diethyl ester tosylate:
adding 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (64.6g and 0.19mol) into a 1L four-mouth bottle, adding 650ml of DMF, stirring and dissolving, heating to 50 ℃, adding 0.38mol of N, N-carbonyldiimidazole, keeping the temperature at 60 ℃ for 2 hours, adding L-diethyl glutamate (0.38mol), heating to 80 ℃, reacting for 3 hours, evaporating to dryness under reduced pressure, adding 800ml of dichloromethane for dissolving, pouring into a mixed solution of 1600ml of pure water and 160ml of triethylamine, stirring and separating to obtain an organic phase, washing 1600ml of pure water by 2 twice, drying and evaporating to dryness, adding 500ml of anhydrous ethanol, stirring and dissolving, dropwise adding 72g of p-toluenesulfonic acid monohydrate and 200ml of anhydrous ethanol solution under a reflux state, after the addition, the reflux reaction is carried out for 1 hour, the temperature is reduced, the crystallization is carried out, the suction filtration is carried out, and the drying is carried out, thus obtaining 87.2g of crude product (the molar yield is 70.1 percent, the purity is 92.3 percent, and the content of the impurity V is 6.52 percent).
Adding 87.2g of the crude product into a three-mouth reaction bottle, adding 350ml of N, N-dimethylformamide, heating to 40-45 ℃, stirring to dissolve, dropwise adding 700ml of absolute ethyl alcohol after complete dissolution, slowly precipitating a solid, cooling to room temperature, stirring to crystallize for 1-2h, filtering to obtain 69.8g of the solid, wherein the yield is 80.0%. The above refining operation was repeated 1 time to obtain 55.4g of a solid (purity: 98.2%, impurity V content: 0.07%).
Comparative example 3
In a four-necked flask, 55.4g of N- {4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl } -L-glutamic acid diethyl ester tosylate and 200ml of a 2mol/L sodium hydroxide solution were charged, stirred for 1 hour, adjusted to pH 3 with 0.5mol/L hydrochloric acid solution, and the resulting suspension was heated to 65 ℃ for 2.5 hours while controlling the temperature. Cooling to room temperature, filtering, washing the solid with deionized water to obtain N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidine-5-yl) ethyl ] benzoyl) -L-glutamic acid. Adding the N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid obtained in the previous step and 200ml of 0.5mol/L sodium hydroxide into a four-mouth bottle, stirring for 1 hour, filtering to remove insoluble substances to obtain a transparent solution, adjusting the pH to 8 by using 0.5mol/L hydrochloric acid, heating the obtained solution to 50 ℃, stirring for 30 minutes, cooling to room temperature, adding 300ml of a mixed solvent of ethanol and dimethyl sulfoxide (the volume ratio is 10: 1.8), stirring for 10 minutes, stirring for 2 hours at 0 ℃, filtering, washing a solid by using 60ml of the mixed solvent of ethanol and dimethyl sulfoxide (the volume ratio is 10: 1.8), and carrying out vacuum drying at 50 ℃ for 5 hours to obtain pemetrexed disodium, the yield is 60.9 percent, and the purity is 97.5 percent.
Mass spectrometry, 1H-NMR and 13C-NMR of pemetrexed disodium were performed in example 8.