CN111377988B - Capecitabine intermediate - Google Patents
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- CN111377988B CN111377988B CN201811648327.4A CN201811648327A CN111377988B CN 111377988 B CN111377988 B CN 111377988B CN 201811648327 A CN201811648327 A CN 201811648327A CN 111377988 B CN111377988 B CN 111377988B
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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Abstract
The invention belongs to the field of medicine synthesis, and discloses a capecitabine intermediate (V), and also discloses a preparation method thereof, wherein the preparation method comprises the following steps: the Fmoc-protected derivative (III) of the 5-deoxy-D-ribose of the 2, 3-hydroxyl and activated 5-fluorocytosine (IV) are coupled under the action of a catalyst to obtain the 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
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), the chemical name of which is 5' -deoxy-5-fluoro-N- [ (pentyloxy) carbonyl ] cytidine, has the structural formula shown in formula I:
capecitabine is a novel 5-fluorocytosine prodrug developed by roche company, and is an oral cytotoxic agent with selective activity on tumor cells; it has no cytotoxicity, and can be converted into 5-fluorouracil (5-Fu) in tumor cells through three unique enzymatic reactions in vivo, so that the tumor has high selectivity of anti-tumor effect, obvious cell targeting and pharmacokinetics characteristic of simulating continuous 5-Fu intravenous drip, and has stronger activity on various solid tumors. The FDA approval was obtained in 9 1998, and clinical use was made in japan for the treatment of advanced primary or metastatic breast cancer, which was not effective with drugs such as paclitaxel and doxorubicin, and 4 months 2003 for the same indications. The FDA approved this product for the treatment of metastatic colorectal cancer in 2001. The capecitabine can be combined with various medicines for application, and has good curative effect.
The synthesis route of capecitabine mainly comprises the following steps:
route one; [ Nobou Shimma etal, bioorganic & Medicinacal Chemistry,2000 (8) 1697-1706 ]
The method adopts triacetyl-5-deoxyribose and activated 5-fluorocytosine to react under the catalysis of stannic chloride to obtain an intermediate 1, the intermediate 1 reacts with n-amyl chloroformate under the alkaline condition provided by pyridine to obtain an intermediate 2, and the intermediate 2 is subjected to removal of a protecting group under the alkaline condition to obtain the target product capecitabine. CN106478751A discloses this route, improving the use of K in the synthesis of intermediate 2 from intermediate 1 3 PO 4 Is condensing agent. CN102977169A discloses that 2' -3 ' -di-O-acetyl-5 ' -deoxy-5-fluorocytidine and n-amyl chloroformate are subjected to amidation reaction by using anhydrous sodium carbonate or anhydrous potassium carbonate as base, quaternary ammonium salt as phase transfer catalyst and 4-substituent pyridine as catalyst to obtain 2' 3' -di-O-acetyl-5 ' -deoxy-5-fluoro-N4- (pentyloxycarbonyl) cytidine. CN104744537a also improves the synthesis of intermediate 2 under catalysis of dimethylaminopyridine using potassium carbonate or sodium carbonate as an acid-binding agent. The method does not show much of the stereo configuration of the product.
For the above routes, US20080300399 and CN108440623a disclose the direct reaction of 5-fluorocytosine and 1,2, 3-tri-O-acetyl-5-deoxyribose with lewis acid being tin tetrachloride, titanium tetrachloride, ferric trichloride or zinc chloride to intermediate 2 without the use of silylating reagent HMDS, however, in the glycosylation process, since the amino and hydroxyl groups in 5-fluorocytosine are very sensitive to oxidation and substitution reactions, commonly silylating reagents are used to protect the amino and hydroxyl groups. Otherwise, a large amount of impurities are generated. CN102190695a discloses a process for preparing 5' -deoxy-2 ',3' -diacetyl-5-fluorocytidine, wherein the 5-fluorocytidine protecting agent is unstable, resulting in the formation of impurity N-isomer of 5-fluorocytidine in the reaction, which results in low conversion of 5-fluorocytidine.
Route two: [ Raghavendracharyulu Venkata Palle etal, US20100130734 ]
The route comprises the steps of taking 5-deoxy-D-ribose 5 as a starting material, reacting with 2, 2-dimethoxy propane to protect 2, 3-hydroxyl, then acetyl to protect 1-hydroxyl to obtain an intermediate 2, reacting the intermediate 2 with N, O-bis (trimethylsilyl) protected 5-fluorocytosine under the catalysis of stannum tetrachloride to obtain an intermediate 4, reacting with N-amyl chloroformate to obtain an intermediate 5, and then removing the protection by Amberlyst15 catalyst to obtain capecitabine. The synthetic route adopts a silicon-based protected 5-fluorocytosine reaction, the stereoselectivity is good, and finally, the protecting group is removed by adopting a recyclable catalyst, and the technologies are all improvements of the prior technology.
Route three: CN102212095A
The method takes a compound 3 as an initial raw material, a compound 4 of a formula is generated through hydroxyl protection, then a compound 5 of a formula 5 is generated through sulfonylation, a compound 2 is obtained through reduction deiodination by hypophosphorous acid or hypophosphite after the compound 5 is iodized, a compound 6 is obtained through deisopropylidene protection and acetylation of the compound 2, and capecitabine is obtained through glycosylation, N4-position acylation and deprotection of the compound 6. The route avoids the use of metal catalysts and reduces pollution.
Route four: [ Motohiro Arasaki etal, US5472949 ]
The route takes 5' -deoxy-5-fluorocytidine as a starting material, acetyl is used for protecting two hydroxyl groups at 2,3 positions and then reacts with n-amyl chloroformate, and then the target product capecitabine is obtained by deprotection in a methanol solution of sodium hydroxide. The separation of the route intermediates mostly adopts a column chromatography method, which 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.
Helvetica Chimica Acta, volume 65 (Nr.149), fasc.5.1982, page 1531, the synthetic acetylfuranosides are racemic mixtures of α -and β -triacetyl-5-deoxyribose. CN102241721 discloses that the reaction of 1-O-acetyl-2, 3, 5-tri-benzoyl-D-ribose with N- [ (N-pentyloxy) carbonyl ] 5-fluorocytosine, the 2,3, 5-phenylacyl of the sugar, especially the introduction of the 5-position bulky group, can effectively avoid the production of the alpha isomer, but the subsequent reaction requires the deoxygenation of the 5-position of the sugar, which has low yield in practical production and high cost, and is not suitable for industrial production.
CN102190695a provides a new preparation method of 5' -deoxy-2 ',3' -diacetyl-5-fluorocytidine, by adjusting the adding sequence of lewis acid, especially anhydrous tin tetrachloride in the reaction, the preparation is carried out by adopting a direct mixing mode of anhydrous tin tetrachloride and 2-trimethylsiloxy-4-trimethylsilyl amino-5-fluoropyrimidine, thereby avoiding the harsh low temperature reaction condition in the prior art, obviously improving the reaction yield, having the molar yield of more than 95 percent, and having the product purity of more than 98 percent. In particular, the production of N-isomerised impurities is reduced, the N-isomerides being as follows:
it can be seen that in the preparation of capecitabine, both the activity of the leaving group at the C-1 position of 5-deoxy-D-ribose and the ratio of the alpha-and beta-products at the C-1 position of the glycosyl protecting compound are considered for the preparation of glycosyl. It is also contemplated that the protecting groups at the C-2 and C-3 positions on the sugar ring may be sterically sized to affect the beta/alpha isomer ratio of the product.
For 5-fluorocytidine derivatives, the steric hindrance and stability of the protecting group on 5-fluorocytidine also affects the N-isomerisation of the product, as described above for the N-isomerised analogues produced by coupling on another N group of the pyrimidine ring.
In the prior art, in the process of generating glycosidic bonds, 2-position substituent groups and 3-position substituent groups on sugar rings influence the proportion of beta/alpha isomers due to a stereoscopic effect and an electronic effect; the search for a synthetic route to increase the proportion of the beta isomer is an urgent problem to be solved.
Disclosure of Invention
The invention provides a capecitabine intermediate (V). The invention also provides a preparation method of the capecitabine intermediate (V), which takes the 5-deoxy-D-ribose derivative (III) as a starting material and activated 5-fluorocytosine, and the target compound is obtained by performing coupling reaction under the action of a catalyst and purifying.
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; reflux-dissolving 5-fluorocytosine in toluene, hexamethyldisilazane (HMDS) and trimethylchlorosilane, and evaporating the solvent under reduced pressure to obtain a 5-fluorocytosine activated product Intermediate (IV);
step e: the 5-deoxy-D-ribose derivative (III) and the 5-fluorocytosine Intermediate (IV) activated by hexamethyldisilazane are subjected to condensation reaction and purification under the action of a catalyst to obtain a capecitabine intermediate (V);
the synthetic route is as follows:
in step d, the prior art scheme may be used, or alternatively, the molar ratio of 5-fluorocytosine, HMDS and trimethylchlorosilane is: 1: 1-2: 0.1 to 0.15.
In step e, the molar feed ratio of 5-deoxy-D-ribose derivative (III) to 5-fluorocytosine activation 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 preferred scheme, when the post-treatment is performed in the step e, after the reaction is finished, an extractant is added into the reaction liquid, water is used for washing, the pH value of the system is adjusted to 7-8, and the reaction liquid is kept stand and separated; the organic phase was washed with saturated brine; drying the organic phase; filtering, evaporating the solvent under reduced pressure, dissolving the residue in benign solvent after evaporating the solvent under reduced pressure, then dripping the solution into poor solvent, stirring for crystallization, filtering, washing, and drying under reduced pressure to obtain 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 5-deoxy-D-ribose derivative (III) to benign solvent in the post-treatment of step e is 1: 3-8,g/ml; the mass volume ratio of the 5-deoxy-D-ribose derivative (III) to the poor solvent is 1: 12-18 g/ml.
The route for preparing the capecitabine by using the capecitabine intermediate (V) is as follows:
step (f), condensation reaction: reacting the intermediate (V) with n-amyl chloroformate in the presence of an organic base in a solvent to obtain an intermediate (VI);
step (h), deprotection reaction: the intermediate (VI) is subjected to deprotection reaction in the presence of organic base to obtain the final product capecitabine.
Specifically, the reaction temperature in the step (f) is-20-10 ℃, preferably-15-0 ℃.
In step (f), alkaline conditions are provided by organic bases including one or more of pyridine, DMAP, TMEDA, triethylamine, DIPEA. Further preferred are one or more of pyridine, triethylamine, DIPEA. Pyridine is more preferred.
In the step (f), the feeding mole ratio of the intermediate (V) to the organic base is 1:1.5 to 1:2.5, preferably 1:1.8 to 1:2.2.
in the step (f), the feeding mole ratio of the intermediate (V) to the n-amyl chloroformate is 1:1.0 to 1:1.5, preferably 1:1.2 to 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 mass volume ratio of capecitabine intermediate (VI) to pyridine is 1:2-3, g/ml.
In step (h), the organic base providing deprotection is 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 invention has the technical advantages that:
1. provides a preparation method of capecitabine intermediate (V), and has high yield and purity.
2. When the compound is used for further preparing capecitabine, the yield is more than 80%, the purity is more than 99.6%, and the method is simple and suitable for industrial production.
Detailed Description
The advantages of the invention will now be further described by the following examples, which are given for illustrative purposes only and are not to be construed as limiting the invention, since obvious improvements and modifications to the invention will be apparent to those skilled in the art and are 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 (4.6X105 mm,3.5 μm)
Mobile phase: 0.05mol/L monoammonium phosphate solution (pH adjusted to 3.0 with phosphoric acid): acetonitrile= (20:80)
Flow rate: 1.0ml/min
Detection wavelength: 220nm
Sample injection amount: 20 μl of
Column temperature: 30.0 DEG C
Test solution: taking about 12.5mg of capecitabine intermediate V, precisely weighing, placing into a 25ml measuring flask, adding purified water, ultrasonically dissolving, diluting to scale, shaking, and filtering.
20 μl of the sample solution was precisely measured, and injected into a liquid chromatograph, and the chromatogram was recorded until the retention time of the main peak was 4.5 times. The content of the main peak in the chromatogram of the sample solution is calculated according to a normalization method.
Example 1
Synthesis of hexamethyldisilazane activated 5-fluorocytosine (IV)
To a 3000ml three-necked flask, 258g (2 mol) of 5-fluorocytosine, 728ml of toluene, 421g (2.6 mol) of HMDS and 14.3g (0.13 mol) of trimethylchlorosilane were added, the mixture was stirred and heated to 100℃for 3 to 4 hours, after the completion of the reaction, the solvent was distilled off under reduced pressure to dryness to obtain white solid particles, and the yield was 90%. Directly used in the next reaction.
Synthesis of capecitabine intermediate (V)
Under the protection of nitrogen, 620g (1 mol) of 5-deoxy-D-ribose derivative (III) and 357.5g (1.3 mol) of acetonitrile suspension prepared by hexamethyldisilazane activated 5-aza cytosine (IV) generated by the previous reaction are added into a 5000ml three-mouth bottle, 1000ml of acetonitrile is added, and under stirring, 200g of TMSOTF (0.9 mol) and 400ml of acetonitrile solution are added dropwise into the reaction system at 5 ℃, and the TLC detects the reaction progress; after the completion of the reaction, 1.5L of chloroform was added to the reaction mixture, and the mixture was washed with 2L of water for 2 times; regulating pH to 7.5 with saturated sodium bicarbonate solution, standing, and separating; the organic phase was washed with 2L of saturated saline; the organic phase is dried with anhydrous sodium sulfate for 3 to 4 hours; filtering, evaporating the solvent under reduced pressure to obtain a pale yellow foaming solid, and adding 3100ml of ethyl acetate for dissolution; slowly adding the ethyl acetate solution into 9300ml of n-hexane under stirring, stirring for crystallization for 2 hours after the addition, filtering, and drying under reduced pressure to obtain an off-white solid which is capecitabine intermediate (V); the yield was 95.6%; HPLC purity: 99.7%, maximum mono-impurity 0.05%, undetected alpha configuration, undetected N-isomer, EIS-MS, m/z 690.22[ M+H ]] + 。
Example 2
Synthesis of hexamethyldisilazane activated 5-fluorocytosine (IV)
Preparation reaction was carried out as in example 1
Synthesis of capecitabine intermediate (V)
Under the protection of nitrogen, 620g (1 mol) of 5-deoxy-D-ribose derivative (III) and 412.5g (1.5 mol) of acetonitrile suspension prepared by hexamethyldisilazane activated 5-aza cytosine (IV) generated by the previous reaction are added into a 5000ml three-mouth bottle, 1000ml of acetonitrile is added, the reaction system is stirred, 288.6g of TMSOTF (1.3 mol) and 500ml of acetonitrile are dropwise added at the temperature of 0 ℃ under stirring, and the TLC detects the reaction progress; after the completion of the reaction, 1.5L of chloroform was added to the reaction mixture, and the mixture was washed with 2L of water for 2 times; regulating pH to 7.5 with saturated sodium bicarbonate solution, standing, and separating; the organic phase was washed with 2L of saturated saline; the organic phase is dried with anhydrous sodium sulfate for 3 to 4 hours; filtering, evaporating the solvent under reduced pressure to obtain a pale yellow foaming solid, and adding 3100ml of ethyl acetate for dissolution; slowly adding the ethyl acetate solution into 9300ml of n-hexane under stirring, stirring for crystallization for 2 hours after the addition, filtering, and drying under reduced pressure to obtain an off-white solid which is capecitabine intermediate (V); the yield was 97.6%; HPLC purity: 99.7%, maximum mono-impurity 0.07%, no alpha configuration detected, no N-isomer detected, EIS-MS, m/z 690.22[ M+H ]] + 。
Example 3
Synthesis of hexamethyldisilazane activated 5-fluorocytosine (IV)
Preparation reaction was carried out as in example 1
Synthesis of capecitabine intermediate (V)
Under the protection of nitrogen, 620g (1 mol) of 5-deoxy-D-ribose derivative (III) and 385g (1.4 mol) of acetonitrile suspension prepared by hexamethyldisilazane activated 5-azacytosine (IV) generated in the previous reaction are added into a 5000ml three-mouth bottle, 1000ml of acetonitrile is added, a solution of 222.2g TMSOTF (1.0 mol) and 500ml acetonitrile is dropwise added into the reaction system under stirring at the temperature of 5 ℃, and the TLC detects the reaction progress; after the completion of the reaction, 1.5L of chloroform was added to the reaction mixture, and the mixture was washed with 2L of water for 2 times; regulating pH to 7.5 with saturated sodium bicarbonate solution, standing, and separating; the organic phase was washed with 2L of saturated saline; the organic phase is dried with anhydrous sodium sulfate for 3 to 4 hours; filtering, evaporating the solvent under reduced pressure to obtain a pale yellow foaming solid, and adding 3100ml of ethyl acetate for dissolution; 9300ml of water under stirringSlowly adding the ethyl acetate solution into hexane, stirring for crystallization for 2 hours after the addition, carrying out suction filtration, and drying under reduced pressure to obtain an off-white solid which is capecitabine intermediate (V); yield 98.4%; HPLC purity: 99.8%, maximum mono-impurity 0.04%, undetected alpha configuration, undetected N-isomer, EIS-MS, m/z 690.22[ M+H ]] + 。
Example 4
Synthesis of hexamethyldisilazane activated 5-fluorocytosine (IV)
Preparation reaction was carried out as in example 1
Synthesis of capecitabine intermediate (V)
Under the protection of nitrogen, 620g (1 mol) of 5-deoxy-D-ribose derivative (III) and 385g (1.4 mol) of acetonitrile suspension prepared by hexamethyldisilazane activated 5-aza cytosine (IV) generated in the previous reaction are added into a 5000ml three-mouth bottle, 1000ml of acetonitrile is added, a solution prepared by 222.2g TMSOTF (1.0 mol) and 500ml acetonitrile is dropwise added into a reaction system under stirring at 30 ℃, and the TLC detects the reaction progress; after the completion of the reaction, 1.5L of chloroform was added to the reaction mixture, and the mixture was washed with 2L of water for 2 times; regulating pH to 7.5 with saturated sodium bicarbonate solution, standing, and separating; the organic phase was washed with 2L of saturated saline; the organic phase is dried with anhydrous sodium sulfate for 3 to 4 hours; filtering, evaporating the solvent under reduced pressure to obtain a pale yellow foaming solid, and adding 3100mL of methyl acetate for dissolution; slowly adding the methyl acetate solution into 9300mL of cyclohexane under stirring, stirring for crystallization for 2h after the addition, filtering, and drying under reduced pressure to obtain an off-white solid which is capecitabine intermediate (V); yield 92.6%; HPLC purity: 99.6%, maximum mono-impurity 0.08%, undetected alpha configuration, undetected N-isomer, EIS-MS, m/z 690.22[ M+H ]] + 。
Example 5
Synthesis of hexamethyldisilazane activated 5-fluorocytosine (IV)
Preparation reaction was carried out as in example 1
Synthesis of capecitabine intermediate (V)
Under the protection of nitrogen, 620g (1 mol) of 5-deoxy-D-ribose derivative (III) and the activated hexamethyldisilazane generated by the previous reaction are added into a 5000ml three-mouth bottle385g (1.4 mol) of 5-azacytosine (IV) and 1000ml of acetonitrile are added, and a solution of 222.2g TMSOTF (1.0 mol) and 500ml acetonitrile is dropwise added to the reaction system at-10 ℃ under stirring, and the TLC detects the progress of the reaction; after the completion of the reaction, 1.5L of chloroform was added to the reaction mixture, and the mixture was washed with 2L of water for 2 times; regulating pH to 7.5 with saturated sodium bicarbonate solution, standing, and separating; the organic phase was washed with 2L of saturated saline; the organic phase is dried with anhydrous sodium sulfate for 3 to 4 hours; filtering, evaporating the solvent under reduced pressure to obtain a light yellow foaming solid, and adding 1860ml of isopropyl acetate for dissolution; slowly adding the isopropyl acetate solution into 11160ml petroleum ether under stirring, stirring for crystallization for 2 hours after the addition, filtering, and drying under reduced pressure to obtain an off-white solid which is capecitabine intermediate (V); yield 91.6%; HPLC purity: 99.8%, maximum mono-impurity 0.03%, undetected alpha configuration, undetected N-isomer, EIS-MS, m/z 690.22[ M+H ]] + 。
Example 6
Synthesis of hexamethyldisilazane activated 5-fluorocytosine (IV)
Preparation reaction was carried out as in example 1
Synthesis of capecitabine intermediate (V)
Under the protection of nitrogen, 620g (1 mol) of 5-deoxidized-D-ribose derivative (III) and 385g (1.4 mol) of prepared chloroform suspension of hexamethyldisilazane activated 5-aza cytosine (IV) generated in the previous reaction are added into a 5000ml three-mouth bottle, 1000ml of chloroform is added, under the stirring, 260.5g (1.0 mol) of anhydrous stannic chloride is dropwise added into the reaction system at the temperature of 5 ℃, and the TLC detects the reaction progress; after the completion of the reaction, 1.5L of chloroform was added to the reaction mixture, and the mixture was washed with 2L of water for 2 times; regulating pH to 7.5 with saturated sodium bicarbonate solution, standing, and separating; the organic phase was washed with 2L of saturated saline; the organic phase is dried with anhydrous sodium sulfate for 3 to 4 hours; filtering, evaporating the solvent under reduced pressure to obtain a light yellow foaming solid, and adding 4960ml of isopropyl acetate for dissolution; slowly adding the isopropyl acetate solution into 7440ml of heptane under stirring, stirring for crystallization for 2h after the addition, filtering, and drying under reduced pressure to obtain an off-white solid which is capecitabine intermediate (V); the yield was 97.8%; HPLC purity: 99.8 percent, the maximum single impurity is 0.03 percentNo alpha configuration was detected, no N-isomer, EIS-MS, m/z 690.22[ M+H ]] + 。
Example 7
Synthesis of intermediate I
268g of 5-deoxy-D-ribose, 3216ml of absolute methanol, were placed in a 5000ml three-necked flask and stirred at 25℃until the solid was completely dissolved, the system being 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, stirring was carried out for 1 hour. After completion of the reaction, 120ml of pyridine was added and stirring was continued for 30 minutes. Suction filtration, reduced pressure evaporation of solvent to dryness gave intermediate I as an oil in 97.9% yield and 99.6% HPLC purity.
Synthesis of intermediate II
Under the protection of nitrogen, 290g (1.96 mol) of intermediate I, 1600ml of chloroform and 387.1g (5 mol) of pyridine are added into a dry 5000ml three-necked flask, the temperature in a reaction system is controlled between minus 15 ℃ and 10 ℃, a mixed solution of 1216.9g of Fmoc-Cl (4.7 mol) and 1700ml of chloroform is added dropwise, and the reaction is placed at room temperature for reaction after the dropwise addition. TLC detection, after the reaction, pouring the mixture into 6L of ice water under rapid stirring, stirring for 20 minutes, standing for separating liquid, and washing an organic phase by using 2.4L of 5% HCl solution, 2.4L of saturated sodium bicarbonate solution and 2.4L of saturated saline; anhydrous Na 2 SO 4 Drying, evaporating the solvent under reduced pressure until the solvent is dried to obtain an oily liquid which is an intermediate II, wherein the yield is 93.1% and the HPLC purity is 99.5%.
Synthesis of 5-deoxy-D-ribose derivative (III)
Intermediate II1081.2g (1.83 mol) was dissolved in 2500ml of chloroform, transferred into a 5000ml three-necked flask with mechanical stirring, 261.3g (2.56 mol) of acetic anhydride was added, and after cooling to a system temperature of-15℃66.2g (0.662 mol) of concentrated sulfuric acid was added dropwise. After the completion of the dropwise addition, the reaction was maintained at-15℃and monitored by TLC. After the reaction is completed, pouring the mixture into 6L of ice water under rapid stirring, adding chloroform for extraction, and standing for liquid separation; naHCO for organic phase 3 Neutralizing the saturated aqueous solution to be neutral, and obtaining anhydrous Na 2 SO 4 Drying, evaporating solvent under reduced pressure, cooling the residue to 0-5 deg.C, rapidly stirring, dripping 12974ml of purified water, stirring for crystallization for 4 hr, filtering, and washing with diethyl etherWashing, drying under reduced pressure to obtain 5-deoxy-D-ribose derivative (III) as off-white solid, yield of 87.7%, purity of 99.8% by HPLC detection, maximum single impurity of 0.06%, undetected alpha configuration, EIS-MS, m/z:621.20[ M+H ]] + 。
Example 8
Synthesis of intermediate (VI)
In a 5000ml three-necked flask, 689g (1 mol) of intermediate (V), 2000ml of dichloromethane, 142.2g (1.8 mol) of pyridine, stirring and cooling to-15 ℃ to 0 ℃, and dropwise adding a mixed solution of 180.7g (1.2 mol) of n-amyl chloroformate and 500ml of dichloromethane; after the dripping is finished, keeping the same temperature for reaction; after TLC monitoring reaction is completed, 2000ml of water is added, and stirring is carried out for 20min, standing and layering are carried out; the organic phase was separated and washed with water (2000 ml x 2); the aqueous phase was back extracted with dichloromethane (2000 ml x 2); the organic phases were combined, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the product as intermediate (VI) as a yellow oil in 99.1% yield.
Synthesis of capecitabine
To a 5L three-necked flask, 796g of intermediate VI and 2070ml of pyridine were added, and after stirring at room temperature to dissolve, 2070ml of triethylamine was added dropwise; after the dripping is finished, stirring and reacting; after the reaction is completed, the solvent is distilled off under reduced pressure to obtain reddish brown solid; adding 3000ml of dichloromethane and 2000ml of purified water, stirring and dissolving for 1 hour, then dropwise adding concentrated hydrochloric acid, regulating the pH to 4-5, standing and layering, and separating out an organic phase. The organic phase was washed with water (2000 ml x 2). The aqueous phase was back extracted with dichloromethane (1000 ml x 2). The organic phases were combined, anhydrous Na 2 SO 4 Drying, suction filtering, vacuum evaporating the solvent to obtain white (yellowish) solid, re-dissolving the solid in 500ml of dichloromethane, slowly adding 1500ml of n-hexane, stirring for 3h, suction filtering, washing the filter cake twice with diethyl ether (each time soaking is complete), and drying under reduced pressure to obtain capecitabine with the yield of 81.9%. HPLC purity: 99.7% and the maximum single impurity is 0.04%.
Comparative example 1
Preparation of 5' -deoxy-2 ',3' -diacetyl-5-fluorocytidine
Under the protection of nitrogen, 1.8kg toluene, 125g 5-fluorocytosine, 2g ammonium sulfate and 247g HMDS are added into a reaction kettle, after the addition, the mixture is heated and refluxed until the mixture is dissolved, the reflux is continued for 3 hours, the solvent is recovered by decompression concentration, the residue is dissolved by 1.40kg dichloromethane, 225g1,2, 3-tri-O-acetyl-5-deoxyribose is added, the mixture is protected by nitrogen, cooled to the temperature of minus 5 ℃, and 155g SnCl is added dropwise 4 /200gCH 2 Cl 2 The temperature of the solution is controlled to be less than or equal to 0 ℃ in the dripping process. After the dripping, naturally heating up to react until the raw material point disappears, cooling to about 5 ℃, adding 400g of sodium bicarbonate, stirring, dripping 187.5g of purified water, and stirring at room temperature. The feed liquid is filtered, and the filter cake is pulped and washed by using 500g of dichloromethane and pumped down. The filtrate was washed twice with 840g of 5% aqueous sodium bicarbonate solution, once with 840g of saturated brine and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, and the solvent is concentrated under reduced pressure to obtain white solid which is 5' -deoxy-2 ',3' -diacetyl-5-fluorocytidine. Adding 500g of absolute ethyl alcohol for dissolution and crystallization, filtering and drying to obtain white solid. Yield 78.0%, HPLC purity 96.1%, α isomer 2%, N-isomerised impurity 0.13%.
Claims (11)
1. The capecitabine intermediate V is characterized by having the following structural formula:
2. a process for the preparation of capecitabine intermediate V according to claim 1, characterized in that it comprises the following steps:
step d: activation of 5-fluorocytosine; reflux reaction of 5-fluorocytosine in toluene, hexamethyldisilazane and trimethylchlorosilane, and reduced pressure distillation to eliminate solvent to obtain 5-fluorocytosine activating product intermediate IV; directly used for the next reaction;
step e: the 5-deoxy-D-ribose derivative (III) and the 5-fluorocytosine intermediate IV activated by hexamethyldisilazane are subjected to condensation reaction under the action of a catalyst, and the capecitabine intermediate V is obtained by purification; the synthetic route is as follows:
3. the process according to claim 2, wherein in step e, the molar feed ratio of the 5-deoxy-D-ribose derivative (III) to the 5-fluorocytosine activated product IV is from 1:1.3 to 1.5.
4. The method of claim 2, wherein in step e, the reaction catalyst is one of anhydrous tin tetrachloride and TMSOTf: the molar feed ratio of the 5-deoxy-D-ribose derivative (III) to the catalyst is 1:0.9-1.3.
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, and the reaction temperature is-10 ℃ to 30 ℃.
6. The process according to claim 2 or 5, wherein in step e, the reaction temperature is from 0℃to 10 ℃.
7. The preparation method of claim 2, wherein, when the post-treatment of step e is finished, an extractant is added into the reaction liquid, water is used for washing, the pH of the system is adjusted to 7-8, and the reaction liquid is left to stand and separated; the organic phase was washed with saturated brine; drying the organic phase; filtering, evaporating the solvent under reduced pressure, dissolving the residue in benign solvent, then dripping the solution into poor solvent, stirring for crystallization, filtering, washing, and drying under reduced pressure to obtain capecitabine intermediate V.
8. The process of claim 7, wherein the extractant is chloroform or methylene chloride in the post-treatment of step e.
9. The method of claim 7, wherein the benign solvent is one or two of ethyl acetate, methyl acetate, isopropyl acetate during the post-treatment of step e; the poor solvent is one or two of petroleum ether, n-hexane, cyclohexane and heptane.
10. The process according to claim 7, wherein the mass to volume ratio of the 5-deoxy-D-ribose derivative (III) to the benign solvent is 1:3 to 8,g/m1; the mass-volume ratio of the 5-deoxy-D-ribose derivative (III) to the poor solvent is 1:12-18 g/ml.
11. A process for the preparation of capecitabine according to claim 1, which is characterized in that the reaction route of the process is:
step (f), condensation reaction: reacting the intermediate V with n-amyl chloroformate in the presence of an organic base in a solvent to prepare an intermediate (VI);
step (h), deprotection reaction: and (3) carrying out deprotection reaction on the intermediate VI in the presence of organic base to obtain the final product capecitabine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103288905A (en) * | 2012-02-22 | 2013-09-11 | 北京博时安泰科技发展有限公司 | Novel technology for synthesis of capecitabine |
| CN103739636A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Preparation method of decitabine intermediate |
| CN108440623A (en) * | 2018-04-09 | 2018-08-24 | 重庆三圣实业股份有限公司 | A kind of preparation method and products thereof of capecitabine intermediate |
| CN108864231A (en) * | 2018-07-27 | 2018-11-23 | 上海葆隆生物科技有限公司 | A kind of impurity of capecitabine and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103288905A (en) * | 2012-02-22 | 2013-09-11 | 北京博时安泰科技发展有限公司 | Novel technology for synthesis of capecitabine |
| CN103739636A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Preparation method of decitabine intermediate |
| CN108440623A (en) * | 2018-04-09 | 2018-08-24 | 重庆三圣实业股份有限公司 | A kind of preparation method and products thereof of capecitabine intermediate |
| CN108864231A (en) * | 2018-07-27 | 2018-11-23 | 上海葆隆生物科技有限公司 | A kind of impurity of capecitabine and preparation method thereof |
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