CN111377988A - Capecitabine intermediate - Google Patents

Abstract

The invention belongs to the field of medicine synthesis, discloses a capecitabine intermediate (V) and also discloses a preparation method thereof, wherein the preparation method comprises the following steps: coupling the Fmoc-protected 5-deoxy-D-ribose derivative (III) of 2, 3-hydroxyl and activated 5-fluorocytosine (IV) under the action of a catalyst to obtain a capecitabine intermediate (V). The method has the advantages of simple operation, simple post-treatment and high product purity, and is suitable for industrial production.

Description

Capecitabine intermediate

Technical Field

The invention belongs to the field of medicine synthesis, and particularly relates to a capecitabine intermediate and a preparation method thereof.

Background

Capecitabine (capecitabine) with the chemical name of 5' -deoxy-5-fluoro-N- [ (pentyloxy) carbonyl ] cytidine has the structural formula shown in the formula I:

capecitabine is a novel 5-fluorocytosine prodrug developed by roche, and is an oral cytotoxic preparation with selective activity on tumor cells; the compound has no cytotoxicity, is converted into 5-fluorouracil (5-Fu) in tumor cells through a unique three-step enzymatic reaction in vivo to play a highly selective anti-tumor role, has obvious cell targeting and pharmacokinetic characteristic of simulating continuous 5-Fu intravenous drip, and has stronger activity on various solid tumors. FDA approval in the united states was obtained at 9 months in 1998 for the clinical treatment of advanced primary or metastatic breast cancer that is ineffective against drugs such as paclitaxel and doxorubicin, and marketed in japan with the same indications at 4 months in 2003. In 2001 FDA approved this for the treatment of metastatic colorectal cancer. Capecitabine can also be combined with various medicines, and has good therapeutic effect.

The synthesis route of capecitabine mainly comprises the following steps:

route one; [ Nobou Shimma et al, Bioorganic & medicinal Chemistry,2000(8)1697-

The method comprises the steps of reacting triacetyl-5-deoxyribose with activated 5-fluorocytosine under the catalysis of stannic chloride to obtain an intermediate 1, reacting the intermediate 1 with n-amyl chloroformate under the alkaline condition provided by pyridine to obtain an intermediate 2, and removing a protecting group from the intermediate 2 under the alkaline condition to obtain the target product capecitabine. CN106478751A discloses the route, which improves the use of K in the synthesis of intermediate 2 from intermediate 1₃PO₄Is a condensing agent. CN102977169A discloses that 2 '3' -di-O-acetyl-5 '-deoxy-5-fluorocytidine and N-amyl chloroformate are subjected to amidation reaction to obtain 2' 3 '-di-O-acetyl-5' -deoxy-5-fluoro-N4- (pentyloxycarbonyl) cytidine, wherein anhydrous sodium carbonate or anhydrous potassium carbonate is used as an alkali, a quaternary ammonium salt is used as a phase transfer catalyst, 4-substituent pyridine is used as a catalyst. CN104744537A also improves the synthesis of intermediate 2 under the catalysis of dimethylaminopyridine by using potassium carbonate or sodium carbonate as an acid-binding agent. The process does not give much indication of the spatial configuration of the product.

With respect to the above routes, US20080300399 and CN108440623A disclose that intermediate 2 is obtained by directly reacting 5-fluorocytosine and 1,2, 3-tri-O-acetyl-5-deoxyribose with tin tetrachloride, titanium tetrachloride, iron trichloride or zinc chloride as lewis acids without further silylation reagent HMDS, but since amino group and hydroxyl group in 5-fluorocytosine are very sensitive to oxidation and substitution reaction during glycosylation, amino group and hydroxyl group are generally protected by silylation reagent. Otherwise, a large amount of impurities are generated. CN102190695A discloses a preparation method of 5' -deoxy-2 ', 3 ' -diacetyl-5-fluorocytidine, wherein a 5-fluorocytosine protective agent is unstable, so that 5-fluorocytosine generates impurity N-isomeride in the reaction, and the conversion rate of 5-fluorocytosine is low.

And a second route: [ Raghavendacharyuu Venkata Palle et, US20100130734 ]

The method comprises the steps of taking 5-deoxy-D-ribose 5 as a starting material, reacting with 2, 2-dimethoxypropane to protect hydroxyl at 2, 3-position, then protecting the hydroxyl at 1-position with acetyl to obtain an intermediate 2, reacting the intermediate 2 with N, O-bis (trimethylsilyl) protected 5-fluorocytosine under the catalysis of stannic chloride to obtain an intermediate 4, reacting with N-amyl chloroformate to obtain an intermediate 5, and removing protection with Amberlyst15 catalyst to obtain capecitabine. The synthetic route adopts the 5-fluorocytosine reaction protected by silicon base, the stereoselectivity is good, and the protecting group is removed by adopting the recyclable catalyst, and the technologies are all improvements to the prior art.

And a third route: CN102212095A

The method comprises the steps of taking a compound 3 as an initial raw material, protecting by hydroxyl to generate a compound 4 shown in a formula, then sulfonylating to generate a compound 5 shown in the formula, iodinating the compound 5, reducing and deiodinating by hypophosphorous acid or hypophosphite to obtain a compound 2, then deisopropylidene protecting and acetylating the compound 2 to obtain a compound 6, and carrying out glycosylation, acylation at the N4-position and deprotection on the compound 6 to obtain capecitabine. The route avoids the use of metal catalysts and reduces pollution.

And a fourth route: [ Motohiro Arasaki et al, US5472949 ]

The route takes 5' -deoxy-5-fluorocytidine as an initial raw material, acetyl is used for protecting two hydroxyl groups at 2,3 positions and then the hydroxyl groups react with n-amyl chloroformate, and then the target product capecitabine is obtained by removing the protection in a methanol solution of sodium hydroxide. The separation of the intermediate in the route mostly adopts a column chromatography method, and is not suitable for industrial production.

The four synthetic routes adopt different starting materials, and the target product capecitabine is finally obtained through different steps.

The acetyl furanoside synthesized by Helvetica Chimica Acta 65 (Nr.149), fasc.5.1982, 1531 is racemic mixture of α -and β -triacetyl-5-deoxyribose CN102241721 discloses that the introduction of the phenyl acyl group at the 2,3, 5-position of the sugar, especially the 5-position macro group, can effectively avoid the generation of α isomer by using 1-O-acetyl-2, 3, 5-tri-benzoyl-D-ribose and N- [ (N-pentyloxy) carbonyl ] 5-fluorocytosine, but the subsequent reaction needs to deoxidize the 5-position of the sugar, so that the yield is low in practical production, the cost is high, and the method is not suitable for industrial production.

CN102190695A provides a new preparation method of 5' -deoxy-2 ', 3 ' -diacetyl-5-fluorocytidine, which is prepared by adjusting the addition sequence of Lewis acid, especially anhydrous stannic chloride in the reaction and adopting the direct mixing mode of the anhydrous stannic chloride and 2-trimethylsiloxy-4-trimethylsilylamino-5-fluoropyrimidine, thereby avoiding the harsh low-temperature reaction conditions in the prior art, obviously improving the reaction yield, achieving the molar yield of more than 95 percent, and having high product purity which can achieve more than 98 percent. In particular, the production of N-isomerized impurities is reduced, the N-isomerides being as follows:

it can be seen that in the preparation of capecitabine, for the preparation of glycosyl, the activity of the leaving group at the C-1 position of 5-deoxy-D-ribose is taken into consideration, the proportion of products α -and β -at the C-1 position of the glycosyl protecting compound is taken into consideration, and the influence of the steric size of the protecting groups at the C-2 position and the C-3 position on the proportion of β/α isomers of the product is also taken into consideration.

In the case of 5-fluorocytidine derivatives, steric hindrance and stability of the protecting group on 5-fluorocytidine also affect the N-isomerization of the product, such as the N-isomerized analog generated by coupling on another N group of the pyrimidine ring as described above.

In the prior art, in the process of generating glycosidic bonds, due to a steric effect and an electronic effect, substituents at the 2-position and the 3-position on a sugar ring influence the proportion of β/α isomers, and the problem that the proportion synthesis route for improving β isomers is urgently needed to be solved is searched.

Disclosure of Invention

The invention provides a capecitabine intermediate V and a preparation method thereof, wherein a 5-deoxy-D-ribose derivative (III) is used as a starting material and activated 5-fluorocytosine are subjected to coupling reaction under the action of a catalyst, and then purified to obtain a target compound.

The specific technical scheme of the invention is as follows:

the invention provides a capecitabine intermediate V, which has the following structural formula:

the preparation method of the capecitabine intermediate V comprises the following steps:

step d: activation of 5-fluorocytosine; refluxing and dissolving 5-fluorocytosine in toluene, Hexamethyldisilazane (HMDS) and trimethylchlorosilane, and removing the solvent by evaporation under reduced pressure to obtain an intermediate IV of a 5-fluorocytosine activation product;

step e: carrying out condensation reaction on a 5-deoxy-D-ribose derivative (III) and a 5-fluorocytosine intermediate IV activated by hexamethyldisilazane under the action of a catalyst, and purifying to obtain a capecitabine intermediate V;

the synthetic route is as follows:

in step d, the scheme of the prior art can be used, or the molar ratio of the 5-fluorocytosine, the HMDS and the trimethylchlorosilane is as follows: 1: 1-2: 0.1 to 0.15.

In the step e, the molar charge ratio of the 5-deoxy-D-ribose derivative (III) to the 5-fluorocytosine activated product IV is 1: 1.3 to 1.5.

In the step e, the reaction catalyst is one of anhydrous stannic chloride and TMSOTf, preferably TMSOTf; the molar feed ratio of the 5-deoxy-D-ribose derivative (III) to the catalyst is 1: 0.9 to 1.3.

In the step e, the reaction solvent is one or more of dichloromethane, chloroform, 1, 2-dichloroethane and acetonitrile, preferably acetonitrile; the reaction temperature is-10 to 30 ℃, preferably 0 to 10 ℃.

In a preferable scheme, during the post-treatment in the step e, after the reaction is finished, adding an extracting agent into the reaction liquid, washing with water, adjusting the pH value of the system to 7-8, standing, and separating liquid; washing the organic phase with saturated brine; drying the organic phase; filtering, evaporating the solvent under reduced pressure, dissolving the residue in a benign solvent, then dropwise adding the solution into a poor solvent, stirring, crystallizing, filtering, washing, and drying under reduced pressure to obtain the capecitabine intermediate V.

Wherein the benign solvent is one or more of ethyl acetate, methyl acetate and isopropyl acetate, preferably ethyl acetate; the poor solvent is one or more of petroleum ether, n-hexane, cyclohexane and heptane, preferably n-hexane; the extractant is chloroform or dichloromethane.

In a preferred embodiment, the mass-to-volume ratio of the 5-deoxy-D-ribose derivative (III) to the benign solvent at the time of the post-treatment in step e is 1: 3-8 g/mL; the mass-to-volume ratio of the 5-deoxy-D-ribose derivative (III) to the poor solvent is 1: 12-18 g/mL.

The reaction route for preparing capecitabine by using the capecitabine intermediate V is as follows:

step (f), condensation reaction: reacting the intermediate V with n-amyl chloroformate in a solvent in the presence of an organic base to prepare an intermediate VI;

step (h), deprotection reaction: and carrying out deprotection reaction on the intermediate VI in the presence of organic base to obtain a final product, namely capecitabine.

Specifically, the reaction temperature in the step (f) is-20 ℃ to 10 ℃, and preferably-15 ℃ to 0 ℃.

In the step (f), the alkaline condition is provided by one or more of pyridine, DMAP, TMEDA, triethylamine and DIPEA. Further preferably one or more of pyridine, triethylamine and DIPEA. More preferably pyridine.

In the step (f), the feeding molar ratio of the intermediate V to the organic base is 1: 1.5-1: 2.5, preferably 1: 1.8-1: 2.2.

in the step (f), the feeding molar ratio of the intermediate V to the n-amyl chloroformate is 1: 1.0-1: 1.5, preferably 1: 1.2-1: 1.3.

in the step (f), the reaction solvent is one or more of dichloromethane, toluene or chloroform, preferably dichloromethane.

In the step (h), the solvent for dissolving the capecitabine intermediate VI is pyridine; the feeding mass-volume ratio of the capecitabine intermediate VI to the pyridine is 1: 2-3, and g/mL.

In the step (h), the deprotected organic base is provided as triethylamine; the feeding mass-volume ratio of the capecitabine intermediate VI to the triethylamine is 1; 2-3 g/mL.

The reaction temperature in the step (h) is room temperature.

Wherein, the 5-deoxy-D-ribose derivative (III) is prepared by the following synthetic route:

the technical advantages of the invention are as follows:

1. the capecitabine intermediate V and the preparation method thereof have high yield and purity.

2. When the capecitabine intermediate V is further used for preparing capecitabine, the yield is over 80 percent, the purity is over 99.6 percent, and the method is simple and is suitable for industrial production.

Detailed Description

The benefits of the present invention will now be further illustrated by the following examples, which are intended for the purpose of illustration only and should not be construed as limiting the invention, and all such obvious modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention.

The detection method of the capecitabine intermediate (V) comprises the following steps: HPLC method

Liquid chromatograph: waters e2695 high performance liquid chromatograph

Chromatographic column Waters Xbridge Amide column (4.6 × 250mm,3.5 μm)

Mobile phase: 0.05mol/L ammonium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid): acetonitrile 1: 4

Flow rate: 1.0mL/min

Detection wavelength: 220nm

Sample introduction amount: 20 μ l

Column temperature: 30.0 deg.C

Test solution: weighing about 12.5mg of capecitabine intermediate V, placing the weighed capecitabine intermediate V into a 25mL measuring flask, adding purified water, ultrasonically dissolving, diluting to a scale, shaking up, and filtering to obtain the capecitabine intermediate V.

Measuring 20 mul of test solution, injecting into a liquid chromatograph, and recording the retention time of the chromatogram until the main peak is 4.5 times. And calculating the content of the main peak in the chromatogram of the test solution according to a normalization method.

Example 1

Synthesis of 5-fluorocytosine IV activated by hexamethyldisilazane

Adding 258g (2mol) of 5-fluorocytosine, 728mL of toluene, 421g (2.6mol) of HMDS and 14.3g (0.13mol) of trimethylchlorosilane into a 3000mL three-necked bottle, stirring and heating to 100 ℃, reacting for 3-4 hours, and after the reaction is finished, evaporating the solvent under reduced pressure until the solvent is dried to obtain white solid particles with the yield of 90%. Directly used for the next reaction.

Synthesis of capecitabine intermediate V

Under the protection of nitrogen, 620g (1mol) of 5-deoxy-D-ribose derivative (III) and 1.3mol of acetonitrile suspension prepared by IV 357.5g (1.3mol) of hexamethyldisilazane activated 5-azacytosine generated by the previous reaction are added into a 5000mL three-necked bottle, 1000mL of acetonitrile is added, a reaction system is kept at 5 ℃ under stirring, a solution of 200g of TMSOTf (0.9mol) and 400mL of acetonitrile is added dropwise, and the reaction progress is detected by TLC; after the reaction, 1.5L of chloroform was added to the reaction solution, and the reaction solution was washed with 2L of water for 2 times; adjusting pH to 7.5 with saturated solution of sodium bicarbonate, standing, and separating;washing an organic phase with 2L of saturated saline solution, drying the organic phase with anhydrous sodium sulfate for 3-4 hours, filtering, evaporating the solvent under reduced pressure to obtain a light yellow foamy solid, adding 3100mL of ethyl acetate to dissolve the solid, slowly adding the ethyl acetate solution into 9300mL of N-hexane under stirring, stirring and crystallizing for 2 hours, performing suction filtration, and drying under reduced pressure to obtain a white-like solid which is a capecitabine intermediate V, wherein the yield is 95.6%, the HPLC purity is 99.7%, the maximum single impurity content is 0.05%, the α configuration is not detected, the N-isomer is not detected, EIS-MS, M/z is 690.22[ M + H ], (M + H)]⁺。

Example 2

Synthesis of 5-fluorocytosine IV activated by hexamethyldisilazane

The preparation reaction is the same as example 1

Synthesis of capecitabine intermediate V

Under the protection of nitrogen, adding 620g (1mol) of 5-deoxy-D-ribose derivative (III) and 412.5g (1.5mol) of acetonitrile prepared from 5-azacytosine activated by hexamethyldisilazane generated in the previous step into a 5000mL three-necked bottle, adding 1000mL of acetonitrile, stirring, keeping the reaction system at 0 ℃, dropwise adding a solution of 288.6g of TMSOTf (1.3mol) and 500mL of acetonitrile, detecting the reaction process by TLC, after the reaction is finished, adding 1.5L of chloroform into the reaction liquid, washing for 2 times by using 2L of water-carbonate saturated solution, adjusting the pH to 7.5, standing, separating, washing the organic phase by using 2L of saturated saline, drying the organic phase by using anhydrous sodium sulfate for 3-4 hours, filtering, evaporating under reduced pressure to remove the solvent to obtain a pale yellow foamy solid, adding 3100mL of ethyl acetate for dissolution, slowly adding the ethyl acetate solution into 9300mL of N-hexane under stirring, separating out crystals for 2 hours, drying under reduced pressure to obtain a white solid, detecting the EIZ-IV isomer, detecting the maximum yield of the intermediate, and the EIZ, detecting the purity of the EIZ, wherein the EIZ is 97.7.3-7.3-7.7.7.7.7.7.7.7.3% of the isomer by using HPLC]⁺。

Example 3

Synthesis of 5-fluorocytosine IV activated by hexamethyldisilazane

The preparation reaction is the same as example 1

Synthesis of capecitabine intermediate V

Under the protection of nitrogen, adding acetonitrile suspension prepared by 620g (1mol) of 5-deoxy-D-ribose derivative (III) and 385g (1.4mol) of 5-azacytosine activated by hexamethyldisilazane generated in the previous step into a 5000mL three-necked bottle, adding 1000mL of acetonitrile, stirring, keeping the reaction system at 5 ℃, dropwise adding a solution of 222.2g of TMSOTf (1.0mol) and 500mL of acetonitrile, detecting the reaction process by TLC, after the reaction is finished, adding 1.5L of chloroform into the reaction liquid, washing for 2 times by using 2L of water-carbonate saturated solution, adjusting the pH to 7.5, standing, separating, washing the organic phase by using 2L of saturated saline, drying the organic phase by using anhydrous sodium sulfate for 3-4 hours, filtering, evaporating under reduced pressure to remove the solvent to obtain a light yellow foamy solid, adding 3100mL of ethyl acetate for dissolving, slowly adding the ethyl acetate solution into 9300mL of N-hexane under stirring, separating the crystal for 2 hours, drying under reduced pressure to obtain a white solid, detecting the maximum yield of the intermediate of IBS, EIZ-S, detecting the purity of 358.8%, and the purity of the intermediate of IBM, and the HPLC, wherein the purity is detected by HPLC, and the yield of the intermediate is equal to 99.8.8.8-95% and the yield of the HPLC]⁺。

Example 4

Synthesis of 5-fluorocytosine IV activated by hexamethyldisilazane

The preparation reaction is the same as example 1

Synthesis of capecitabine intermediate V

Under the protection of nitrogen, 620g (1mol) of 5-deoxy-D-ribose derivative (III) and 385g (1.4mol) of 5-azacytosine activated by hexamethyldisilazane generated in the previous step are added into a 5000mL three-necked bottle to prepare acetonitrile suspension, 1000mL of acetonitrile is added, a reaction system is kept at 30 ℃ under stirring, a solution prepared from 222.2g of TMSOTf (1.0mol) and 500mL of acetonitrile is added dropwise, and the reaction process is detected by TLC; after the reaction, 1.5L of chloroform was added to the reaction solution, and the reaction solution was washed with 2L of water for 2 times; adjusting pH to 7.5 with saturated solution of sodium bicarbonate, standing, and separating; the organic phase was washed with 2L of saturated brine; drying the organic phase for 3-4 hours by using anhydrous sodium sulfate; filtering, evaporating the solvent under reduced pressure to obtain a yellowish foamy solid, and adding 3100mL of methyl acetate for dissolution; the methyl acetate solution described above was slowly added to 9300mL of cyclohexane under stirring,after the addition, the mixture is stirred and crystallized for 2 hours, is filtered, is dried under reduced pressure to obtain a white solid which is a capecitabine intermediate V, has the yield of 92.6 percent, the HPLC purity of 99.6 percent, the maximum single impurity of 0.08 percent, no α configuration, no N-isomeride, EIS-MS, and M/z of 690.22M + H]⁺。

Example 5

Synthesis of 5-fluorocytosine IV activated by hexamethyldisilazane

The preparation reaction is the same as example 1

Synthesis of capecitabine intermediate V

Under the protection of nitrogen, adding acetonitrile suspension prepared by 620g (1mol) of 5-deoxy-D-ribose derivative (III) and 385g (1.4mol) of 5-azacytosine activated by hexamethyldisilazane generated in the previous step into a 5000mL three-necked bottle, adding 1000mL of acetonitrile, stirring, keeping the reaction system at-10 ℃, dropwise adding a solution of 222.2g of TMSOTf (1.0mol) and 500mL of acetonitrile, detecting the reaction progress by TLC, after the reaction is finished, adding 1.5L of chloroform into the reaction liquid, washing for 2 times by using 2L of water-carbonate saturated solution, adjusting the pH to 7.5, standing, separating, washing an organic phase by using 2L of saturated saline, drying the organic phase by using anhydrous sodium sulfate for 3-4 hours, filtering, evaporating the solvent under reduced pressure to obtain a light yellow foamy solid, adding 0mL of isopropyl acetate for dissolution, slowly adding the isopropyl acetate solution into 11160mL of petroleum ether under stirring, precipitating for 2 hours by stirring, drying under reduced pressure to obtain a white solid, performing suction filtration, detecting the isomeric solid, obtaining an EIZ-III intermediate, and culturing the EIZ-III isomer, wherein the purity is equal to the maximum yield is 358%, and the purity of the pure isomer of the pure product is detected by HPLC, the pure isomer is detected by 0.3-95% of the isomer]⁺。

Example 6

Synthesis of 5-fluorocytosine IV activated by hexamethyldisilazane

The preparation reaction is the same as example 1

Synthesis of capecitabine intermediate V

Under the protection of nitrogen, 620g (1mol) of 5-deoxy-D-ribose derivative (III) and 385g (1.4mol) of 5-azacytosine prepared by hexamethyldisilazane activated by the previous reaction are added into a 5000mL three-necked bottle to suspend chloroformAdding 1000mL of trichloromethane, stirring, keeping the reaction system at 5 ℃, dropwise adding 260.5g (1.0mol) of anhydrous stannic chloride, detecting the reaction process by TLC, after the reaction is finished, adding 1.5L of chloroform into the reaction solution, washing for 2 times by using 2L of water, adjusting the pH to 7.5 by using a sodium bicarbonate saturated solution, standing, separating, washing an organic phase by using 2L of saturated saline, drying the organic phase for 3-4 hours by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain a yellowish foamy solid, adding 4960mL of isopropyl acetate for dissolving, slowly adding the isopropyl acetate solution into 7440mL of heptane under stirring, stirring for crystallizing for 2 hours, filtering, drying under reduced pressure to obtain a white-like solid which is a capecitabine intermediate V, wherein the yield is 97.8%, the purity HPLC is 99.8%, the maximum monohetero is 0.03%, the configuration of α is not detected, and the N-isomer, EIS-MS, M/z is 690.22M + H]⁺。

Example 7

Synthesis of intermediate I

268g of 5-deoxy-D-ribose and 3216mL of anhydrous methanol are added into a 5000mL three-necked bottle, and the mixture is stirred at room temperature of 25 ℃ until the solid is completely dissolved, so that the system is a yellowish transparent solution. 950mL of 1% HCl-methanol solution was added dropwise through a constant pressure funnel; after the completion of the dropwise addition, the mixture was stirred for 1 hour. TLC detection, after the reaction was completed, 120mL of pyridine was added and stirring was continued for 30 minutes. Suction filtration, reduced pressure evaporation to dryness to obtain oily intermediate I, yield 97.9%, HPLC purity 99.6%.

Synthesis of intermediate II

Under the protection of nitrogen, 290g (1.96mol) of the intermediate I, 1600mL of chloroform and 387.1g (5mol) of pyridine are added into a dry 5000mL three-necked bottle, the temperature in the reaction system is controlled between-15 ℃ and 10 ℃, mixed liquid of 1216.9g of Fmoc-Cl (4.7mol) and 1700mL of chloroform is dripped, and the reaction is placed at room temperature for reaction after the dripping is finished. TLC detection, after the reaction is finished, pouring the mixture into 6L of ice water under rapid stirring, stirring for 20 minutes, standing and separating, and washing an organic phase with 2.4L of 5% HCl solution, 2.4L of saturated sodium bicarbonate solution and 2.4L of saturated saline solution; anhydrous Na₂SO₄Drying, and evaporating the solvent under reduced pressure to dryness to obtain oily liquid as intermediate II with yield of 93.1% and HPLC purity of 99.5%.

Synthesis of 5-deoxy-D-ribose derivative (III)

1081.2g (1.83mol) of intermediate II was dissolved in 2500mL of chloroform, transferred into a 5000mL three-necked flask with mechanical stirring, added with 261.3g (2.56mol) of acetic anhydride, cooled to-15 ℃ and added with 66.2g (0.662mol) of concentrated sulfuric acid. After the dropwise addition, the system was maintained at-15 ℃ for reaction, and monitored by TLC. After the reaction is finished, pouring the mixture into 6L of ice water under rapid stirring, adding chloroform for extraction, and standing for liquid separation; NaHCO for organic phase₃Neutralizing with saturated water solution to neutrality, and adding anhydrous Na₂SO₄Drying, distilling under reduced pressure to remove solvent, cooling the residue to 0-5 ℃, rapidly stirring, dropwise adding 12974mL of purified water, stirring and crystallizing for 4 hours, filtering, washing with diethyl ether, and drying under reduced pressure to obtain a white solid 5-deoxy-D-ribose derivative (III), wherein the yield is 87.7%, the HPLC detection purity is 99.8%, the maximum single impurity content is 0.06%, no α configuration is detected, EIS-MS, and M/z is 621.20[ M + H ] M]⁺。

Example 8

Synthesis of intermediate VI

689g (1mol) of intermediate V, 2000mL of dichloromethane and 142.2g (1.8mol) of pyridine are added into a 5000mL three-necked bottle, stirred and cooled to-15-0 ℃, and a mixed solution of 180.7g (1.2mol) of chloroformic acid n-amyl ester and 500mL of dichloromethane is dripped; after the dropwise addition is finished, keeping the same temperature for reaction; when the TLC monitoring reaction is complete, adding 2000mL of water, stirring for 20min, and standing for layering; the organic phase was separated and washed with water (2000mL x 2); the aqueous phase was back-extracted with dichloromethane (2000mL x 2); the organic phases are combined, dried by anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a yellow oily product which is an intermediate VI with the yield of 99.1 percent.

Synthesis of capecitabine

Adding 796g of intermediate VI and 0mL of pyridine 2070 into a 5L three-necked bottle, stirring at room temperature to dissolve the intermediate VI and the pyridine 2070mL, and then dropwise adding 2070mL of triethylamine; stirring for reaction after the dropwise addition is finished; after the reaction is finished, the solvent is evaporated under reduced pressure to obtain a reddish brown solid; adding 3000mL of dichloromethane and 2000mL of purified water, stirring and dissolving for 1 hour, then dropwise adding concentrated hydrochloric acid, adjusting the pH value to 4-5, standing and layering, and separating out an organic phase. The organic phase was washed with water (2000mL × 2). For aqueous phaseDichloromethane back-extraction (1000mL × 2). The organic phases were combined and anhydrous Na₂SO₄Drying, suction filtering, decompressing and distilling to remove the solvent to obtain a white (yellowish) solid, redissolving the solid in 500mL of dichloromethane, slowly adding 1500mL of normal hexane, stirring for 3 hours, suction filtering, washing the filter cake twice with ether (completely soaking each time), decompressing and drying to obtain capecitabine with the yield of 81.9%. HPLC purity: 99.7 percent and maximum single impurity of 0.04 percent.

Comparative example 1

Preparation of 5' -deoxy-2 ', 3 ' -diacetyl-5-fluorocytidine

Under the protection of nitrogen, 1.8kg of toluene, 125g of 5-fluorocytosine, 2g of ammonium sulfate and 247g of HMDS are added into a reaction kettle, the mixture is heated and refluxed until the mixture is clear, the mixture is refluxed for 3 hours continuously, the solvent is recovered by decompression concentration, the residue is dissolved by 1.40kg of dichloromethane, 225g of 1,2, 3-tri-O-acetyl-5-deoxyribose is added, the mixture is cooled to-5 ℃ under the protection of nitrogen, and 155g of SnCl is dropwise added₄/200gCH₂Cl₂The temperature of the solution is controlled to be less than or equal to 0 ℃ in the dripping process, the solution is dripped, the temperature is naturally raised until the raw material point disappears, the temperature is reduced to about 5 ℃, 400g of sodium bicarbonate is added, the solution is stirred, 187.5g of purified water is dripped, the solution is stirred at room temperature, the feed liquid is filtered, a filter cake is beaten and washed by 500g of dichloromethane, the filter cake is drained, the filtrate is washed twice by 840g of 5 percent sodium bicarbonate aqueous solution, 840g of saturated salt is washed once, anhydrous sodium sulfate is dried, a drying agent is removed by filtration, the solvent is concentrated by decompression to obtain a white solid which is 5' -deoxy-2 ', 3 ' -diacetyl-5-fluorocytidine, 500g of absolute ethyl alcohol is added for dissolving and crystallizing, the white solid is filtered and dried to obtain 78.0 percent of yield, the HPLC purity is 96..

Claims (10)

1. A capecitabine intermediate V is characterized in that the intermediate has the following structural formula:

2. a process for the preparation of capecitabine intermediate v according to claim 1, comprising the steps of:

step d: activation of 5-fluorocytosine; carrying out reflux reaction on 5-fluorocytosine in toluene, hexamethyldisilazane and trimethylchlorosilane, and evaporating the solvent under reduced pressure to obtain an intermediate IV of a 5-fluorocytosine activation product; directly used for the next reaction;

step e: carrying out condensation reaction on a 5-deoxy-D-ribose derivative (III) and a 5-fluorocytosine intermediate IV activated by hexamethyldisilazane under the action of a catalyst, and purifying to obtain a capecitabine intermediate V;

the synthetic route is as follows:

3. the process according to claim 2, wherein in step e, the molar ratio of 5-deoxy-D-ribose derivative (III) to 5-fluorocytosine activated product IV is 1: 1.3 to 1.5.

4. The method of claim 2, wherein in step e, the reaction catalyst is one of anhydrous stannic chloride and TMSOTf; the molar feed ratio of the 5-deoxy-D-ribose derivative (III) to the catalyst is 1: 0.9 to 1.3.

5. The preparation method according to claim 2, wherein in the step e, the reaction solvent is one or more of dichloromethane, chloroform, 1, 2-dichloroethane and acetonitrile; the reaction temperature is-10 ℃ to 30 ℃, preferably 0 ℃ to 10 ℃.

6. The preparation method according to claim 2, wherein in the post-treatment in the step e, after the reaction is finished, an extracting agent is added into the reaction solution, the reaction solution is washed by water, the pH value of the system is adjusted to 7-8, and the reaction solution is kept stand and separated; washing the organic phase with saturated brine; drying the organic phase; filtering, evaporating the solvent under reduced pressure, dissolving the residue in a benign solvent, then dropwise adding the solution into a poor solvent, stirring, crystallizing, filtering, washing, and drying under reduced pressure to obtain the capecitabine intermediate V.

7. The method of claim 6, wherein the extractant used in the post-treatment of step e is chloroform or dichloromethane.

8. The method according to claim 6, wherein in the post-treatment in step e, the benign solvent is one or two of ethyl acetate, methyl acetate and isopropyl acetate; the poor solvent is one or two of petroleum ether, n-hexane, cyclohexane and heptane.

9. The process according to claim 6, wherein the mass-to-volume ratio of the 5-deoxy-D-ribose derivative (III) to the benign solvent is 1: 3-8 g/ml; the mass-to-volume ratio of the 5-deoxy-D-ribose derivative (III) to the poor solvent is 1: 12-18 g/ml.

10. A process for the synthesis of capecitabine from capecitabine intermediate v according to claim 1, wherein the reaction scheme of the process is:

step (f), condensation reaction: reacting the intermediate V with n-amyl chloroformate in a solvent in the presence of an organic base to prepare an intermediate (VI);

step (h), deprotection reaction: and carrying out deprotection reaction on the intermediate VI in the presence of organic base to obtain a final product, namely capecitabine.