Refining method of raltitrexed intermediate

Abstract

The invention discloses a refining method of a raltitrexed intermediate as shown in a formula I. The method comprises the following steps: quenching a reaction solution containing a compound as shown in the formula I, extracting, extracting and washing an organic phase by using an acidic aqueous solution and an alkaline aqueous solution, adsorbing the organic phase by using silica gel, filtering, concentrating and pulping to prepare the high-purity compound as shown in the formula I. The method is simple to operate, low in cost, mild in condition and easy for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for refining a raltitrexed intermediate. Background Art

[0002] Raltitrexed is a thymidylate synthase inhibitor, mainly used for the treatment of colorectal cancer. Compared with the previously widely used anti-cancer drug of the same kind, 5-fluorouracil, raltitrexed has the advantages of convenient administration, low toxicity and side effects, and mild adverse reactions, and has become a first-line drug for the treatment of advanced colorectal cancer.

[0003] At present, for the synthesis method of raltitrexed, the mainstream synthesis route is the synthesis route reported in the literature Quinazoline Antifolate Thymidylate Synthase Inhibitors: Heterocyclic Benzoyl Ring Modifications, J. Med. Chem., 1991, 34(5), 1594 - 1605) and the patent specification (US4992550, 1991): .

[0004] Most of the other synthesis routes are improvements on the synthesis method of the early intermediates on this route. For example, as reported in CN1216883C, using 2,5-thiophenedicarboxylic acid as the starting material, first introducing a protecting group and then introducing a methyl group to obtain the compound of formula IV. Another example is that reported in CN106957296B, constructing the compound of formula III through nitro reduction, etc. But no matter which method, ultimately, after synthesizing the compound of formula I, raltitrexed is prepared through a hydrolysis reaction. The specific structure of the compound of formula I is shown as follows: .

[0005] And for the preparation of the compound of formula I, the currently common method is also that reported in the literature Quinazoline Antifolate Thymidylate Synthase Inhibitors: Heterocyclic Benzoyl Ring Modifications, J. Med. Chem., 1991, 34 (5), 1594 - 1605, which is prepared by alkylation reaction using the compound of formula III and the compound of formula II. The synthesis route is shown as follows: .

[0006] The specific process is as follows: The compound of formula III and the compound of formula II are subjected to an alkylation reaction under the conditions of using 2,6-dimethylpyridine as the base and N,N-dimethylformamide (DMF) as the solvent. There are many impurities in this reaction system, and the HPLC purity is only about 75%. The main reasons are as follows: The conversion rate of this reaction is low, and there are residues of both the reaction raw materials of formula II and formula III, with a residual amount of about 2%. Moreover, overreaction impurities V and VI as shown below are easily generated, with contents of about 4% respectively. At the same time, the raw material of formula II is usually prepared by a radical bromination reaction, which will introduce multi-site bromination impurities. Due to the high content of the above impurities and the difficulty in removing them, a post-treatment process of column chromatography purification is usually adopted.

[0007]

[0008] Column chromatography purification is cumbersome, requires a large amount of solvent, and generates a lot of three wastes, which is not conducive to industrial scale-up production. Moreover, the inventor found that when using column chromatography purification, impurities V and VI are very close to the product in polarity, with great separation difficulty and poor operational reproducibility.

[0009] Patent CN105111197A reported a post-treatment method of purification using a mixed solvent of ethyl acetate and petroleum ether, but its preparation route introduced an expensive bromoquinazolinone unit in the starting materials, greatly increasing the production cost. Patent CN101088997A reported that recrystallization using a methanol / ether system was used to replace column chromatography. However, when the inventor tried this process, it was found that this post-treatment method had basically no effect on removing impurities V and VI (see Comparative Example 1), and this process uses ether, which has a high EHS risk. Summary of the Invention

[0010] The object of the present invention is to provide a purification and refinement method for the raltitrexed intermediate shown in formula I, which is simple in operation, mild in conditions, low in cost, and easy to be industrially scaled up, aiming at the above-mentioned defects of the prior art.

[0011] To achieve the object of the present invention, the present invention provides the following implementation schemes: In one implementation scheme, a refinement method for a raltitrexed intermediate of the present invention is characterized in that it includes the following process: Water is added to the reaction solution containing the compound of formula I obtained by the alkylation reaction of the compound of formula III and the compound of formula II for quenching, and then extracted with ethyl acetate. The organic phase is separated, and the organic phase is washed with an aqueous solution of an acid, and then the organic phase is separated. The organic phase is washed with an aqueous solution of a base, and then the organic phase is separated. Silica gel is added to the organic phase for adsorption, and then filtered. The filter cake is washed with a solvent. The filtrate is concentrated, slurried, filtered, and dried to obtain the compound of formula I.

[0012] Furthermore, in the above refinement method of the present invention, the volume ratio of water to the reaction solution is 1 to 20:1, preferably 1 to 10:1.

[0013] Further, in the purification method of the present invention described above, the volume ratio of ethyl acetate to the reaction solution is 5 to 30:1, preferably 5 to 15:1.

[0014] Further, in the purification method of the present invention described above, the aqueous solution of acid is selected from aqueous citric acid solution, aqueous hydrochloric acid solution, aqueous sulfuric acid solution and aqueous phosphoric acid solution, preferably aqueous citric acid solution or aqueous phosphoric acid solution. Further, the volume ratio of the aqueous solution of acid to the reaction solution is 1 to 30:1, preferably 5 to 15:1.

[0015] Further, in the purification method of the present invention described above, the aqueous solution of base is selected from aqueous sodium carbonate solution, aqueous sodium bicarbonate solution, aqueous sodium hydroxide solution, aqueous potassium carbonate solution and aqueous potassium bicarbonate solution, preferably aqueous sodium carbonate solution, aqueous sodium bicarbonate solution or aqueous potassium carbonate solution. Further, the volume ratio of the aqueous solution of base to the reaction solution is 1 to 30:1, preferably 5 to 15:1.

[0016] Further, in the purification method of the present invention described above, the silica gel is 100 to 500 mesh, preferably 100 to 400 mesh. Further, the dosage of silica gel is 1 to 20 times, preferably 3 to 10 times, of the theoretical content of the compound of formula I in the reaction solution.

[0017] Further, in the purification method of the present invention described above, the solvent for washing the filter cake is one or more of ethyl acetate, dichloromethane, tetrahydrofuran and methanol, preferably ethyl acetate or a mixed solvent of ethyl acetate and dichloromethane or methanol.

[0018] Further, in the purification method of the present invention described above, the pulping temperature is 20 to 65 °C, preferably 45 to 65 °C.

[0019] Further, in the purification method of the present invention described above, the pulping time is 1 to 8 hours, preferably 1 to 3 hours.

[0020] The beneficial effects of the present invention: By utilizing the characteristics of the compound of formula II being an amphoteric compound, the present invention adopts the method of extraction and washing with acidic aqueous solution and basic aqueous solution to remove the compound of formula II and the impurities introduced thereby; adopts simple silica gel adsorption to remove the over-reacted impurities V and VI; removes the residue of the compound of formula III by pulping, and finally obtains a high-purity product. The whole process does not require column chromatography, greatly reduces the operation difficulty, reduces the solvent waste, is green and environmentally friendly, and has mild conditions and small safety risks, and is suitable for large-scale industrial production. Specific Embodiments

[0021] The following examples are only representative and are used to help understand and illustrate the essence of the present invention, but do not limit the scope of the present invention in any way.

[0022] The reaction solution containing the compound of formula I used in the following examples can be prepared by reacting the compound of formula III and the compound of formula II under the conditions of using 2,6-dimethylpyridine as the base and DMF as the solvent. The HPLC purity of the reaction solution is about 75%, the theoretical content of the compound of formula I is 0.1 g / ml, the residues of the compound of formula III and the compound of formula II are about 2% respectively, and the contents of the impurity of formula V and the impurity of formula VI are about 4% respectively.

[0023] Example 1 Preparation of Intermediate (I) Take 40 ml of the reaction solution, add 200 ml of water to quench it, extract with 320 ml of ethyl acetate, separate the organic phase, wash the organic phase with 240 ml of 5% aqueous citric acid solution, separate the organic phase, wash the organic phase with 240 ml of 5% aqueous sodium carbonate solution, and separate the organic phase. Add 20.0 g of silica gel with a mesh size of 200-300 to the organic phase, stir and adsorb, filter, and wash the filter cake with ethyl acetate to obtain a filtrate. Concentrate the filtrate to about 120 ml, slurry at 60 °C for 2 hours, filter, and dry to obtain 3.3 g of the compound of formula I, with a yield of 82.5%, a purity of 99.79%, the content of the compound of formula III being 0.02%, the compound of formula II not detected, the content of the impurity of formula V being 0.08%, and the content of the impurity of formula VI being 0.06%.

[0024] Example 2 Preparation of Intermediate (I) Take 40 ml of the reaction solution, add 240 ml of water to quench it, extract with 440 ml of ethyl acetate, separate the organic phase, wash the organic phase with 400 ml of 5% aqueous citric acid solution, separate the organic phase, wash the organic phase with 320 ml of 5% aqueous sodium carbonate solution, and separate the organic phase. Add 12.0 g of silica gel with a mesh size of 100-200 to the organic phase, stir and adsorb, filter, and wash the filter cake with a 1:1 mixed solution of ethyl acetate and dichloromethane to obtain a filtrate. Concentrate the filtrate to about 120 ml, slurry at 55 °C for 2 hours, filter, and dry to obtain 3.4 g of the compound of formula I, with a yield of 85.0%, a purity of 99.83%, the compound of formula III not detected, the compound of formula II not detected, the content of the impurity of formula V being 0.05%, and the content of the impurity of formula VI being 0.04%.

[0025] Example 3 Preparation of Intermediate (I) Take 40 ml of the reaction solution, quench it by adding 400 ml of water, extract with 600 ml of ethyl acetate, separate the organic phase, wash the organic phase with 480 ml of 5% aqueous citric acid solution, separate the organic phase, wash the organic phase with 300 ml of 5% aqueous potassium carbonate solution, and separate the organic phase. Add 40.0 g of silica gel with a mesh size of 300 - 400 to the organic phase, stir and adsorb, filter, wash the filter cake with ethyl acetate to obtain a filtrate. Concentrate the filtrate to about 150 ml, slurry at 60 °C for 3 hours, filter, and dry to obtain 3.3 g of the compound of formula I, with a yield of 82.5%, a purity of 99.84%, a content of the compound of formula III of 0.01%, no detection of the compound of formula II, a content of the impurity of formula V of 0.07%, and a content of the impurity of formula VI of 0.03%.

[0026] Example 4 Preparation of Intermediate (I) Take 40 ml of the reaction solution, quench it by adding 120 ml of water, extract with 360 ml of ethyl acetate, separate the organic phase, wash the organic phase with 300 ml of 2% aqueous phosphoric acid solution, separate the organic phase, wash the organic phase with 200 ml of 5% aqueous sodium bicarbonate solution, and separate the organic phase. Add 20.0 g of silica gel with a mesh size of 200 - 300 to the organic phase, stir and adsorb, filter, wash the filter cake with ethyl acetate to obtain a filtrate. Concentrate the filtrate to about 180 ml, slurry at 60 °C for 1 hour, filter, and dry to obtain 3.5 g of the compound of formula I, with a yield of 87.5%, a purity of 99.82%, a content of the compound of formula III of 0.02%, no detection of the compound of formula II, a content of the impurity of formula V of 0.07%, and a content of the impurity of formula VI of 0.03%.

[0027] Example 5 Preparation of Intermediate (I) Take 0.5 L of the reaction solution, quench it by adding 2.5 L of water, extract with 7.0 L of ethyl acetate, separate the organic phase, wash the organic phase with 3.0 L of 5% aqueous citric acid solution, separate the organic phase, wash the organic phase with 3.0 L of 5% aqueous sodium carbonate solution, and separate the organic phase. Add 300.0 g of silica gel with a mesh size of 200 - 300 to the organic phase, stir and adsorb, filter, wash the filter cake with a mixed solvent of ethyl acetate and methanol at a ratio of 20:1 to obtain a filtrate. Concentrate the filtrate to about 1 L, slurry at 60 °C for 3 hours, filter, and dry to obtain 44.9 g of the compound of formula I, with a yield of 89.8%, a purity of 99.83%, no detection of the compound of formula III, no detection of the compound of formula II, a content of the impurity of formula V of 0.07%, and a content of the impurity of formula VI of 0.04%.

[0028] Comparative Example 1 Preparation of Intermediate (I) Take 23 ml of the reaction solution, remove DMF by distillation under reduced pressure, add 50 ml of water, extract with ethyl acetate (3 × 60 ml), combine the organic layers, wash with saturated brine (2 × 50 ml), dry over anhydrous magnesium sulfate, remove the organic solvent by distillation under reduced pressure, add 6 ml of methanol, dropwise add 30 ml of ether with stirring, crystallize, filter by suction to obtain 2.07 g of the compound of formula I, with a yield of 90%, a purity of 93.32%, the content of the compound of formula III being 0.78%, the content of the compound of formula II being 1.12%, the content of the impurity of formula V being 2.47%, and the content of the impurity of formula VI being 1.89%.

[0029] The above embodiments are typical. Any simple modification or variation made in the spirit and essence of the present invention also falls within the protection scope of the present invention.

Claims

1. A purification method for raltitrexed intermediate shown in Formula I, comprising: ， The compound of Formula III and the compound of Formula II are subjected to an alkylation reaction to obtain a reaction solution containing the compound of Formula I; ， Water is added to the reaction solution for quenching, extracted with ethyl acetate, the organic phase is separated, the organic phase is washed with an aqueous solution of an acid, the organic phase is separated, the organic phase is washed with an aqueous solution of a base, the organic phase is separated, silica gel is added to the organic phase for adsorption, filtered, the filter cake is washed with a solvent, the filtrate is concentrated, slurried, filtered, and dried to obtain the compound of Formula I.

2. According to the purification method described in claim 1, in the quenching, the volume ratio of water to the reaction solution is 1 to 20:1, preferably 1 to 10:

1.

3. According to the purification method described in claim 1, in the extraction, the volume ratio of ethyl acetate to the reaction solution is 5 to 30:1, preferably 5 to 15:

1.

4. According to the purification method described in claim 1, the aqueous solution of the acid is selected from aqueous citric acid solution, aqueous hydrochloric acid solution, aqueous sulfuric acid solution, and aqueous phosphoric acid solution, preferably aqueous citric acid solution or aqueous phosphoric acid solution.

5. According to the purification method described in claim 4, the volume ratio of the aqueous solution of the acid to the reaction solution is 1 to 30:1, preferably 5 to 15:

1.

6. According to the purification method described in claim 1, the aqueous solution of the base is selected from aqueous sodium carbonate solution, aqueous sodium bicarbonate solution, aqueous sodium hydroxide solution, aqueous potassium carbonate solution, and aqueous potassium bicarbonate solution, preferably aqueous sodium carbonate solution, aqueous sodium bicarbonate solution, or aqueous potassium carbonate solution.

7. According to the purification method described in claim 6, the volume ratio of the aqueous solution of the base to the reaction solution is 1 to 15:1, preferably 5 to 10:

1.

8. According to the purification method described in claim 1, the silica gel is 100 to 500 mesh, preferably 100 to 400 mesh.

9. According to the purification method described in claim 8, the dosage of silica gel is 1 to 20 times the theoretical content of the compound of Formula I in the reaction solution, preferably 3 to 10 times.

10. According to the purification method described in claim 1, the solvent for washing the filter cake is one or more of ethyl acetate, dichloromethane, tetrahydrofuran, and methanol, preferably ethyl acetate or a mixed solvent of ethyl acetate and dichloromethane or methanol.

11. According to the purification method described in claim 1, the slurrying temperature is 20 to 65 °C, preferably 45 to 65 °C.

12. According to the purification method described in claim 1, the slurrying time is 1 to 8 hours, preferably 1 to 3 hours.

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