CN102212095A - Preparation methods of capecitabine and intermediate thereof - Google Patents
Preparation methods of capecitabine and intermediate thereof Download PDFInfo
- Publication number
- CN102212095A CN102212095A CN2010101417042A CN201010141704A CN102212095A CN 102212095 A CN102212095 A CN 102212095A CN 2010101417042 A CN2010101417042 A CN 2010101417042A CN 201010141704 A CN201010141704 A CN 201010141704A CN 102212095 A CN102212095 A CN 102212095A
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- Prior art keywords
- preparation
- methyl
- ribofuranose
- isopropylidene
- formula
- Prior art date
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- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 title claims abstract description 32
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960004117 capecitabine Drugs 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 7
- 239000011630 iodine Substances 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 13
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- 238000004519 manufacturing process Methods 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
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- 238000005858 glycosidation reaction Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 5
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- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 3
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种新的卡培他滨的制备方法：以D-核糖为起始原料，经羟基保护、5-位对甲苯磺酰化、碘取代、次磷酸脱碘、乙酰化得关键中间体12，3-三-O-乙酰基-5-脱氧-β-D-呋喃核糖，再与5-氟胞嘧啶进行糖苷化，最后N-4位酰化、脱除保护得卡培他滨，本发明不需要使用金属催化剂参与反应，反应条件温和，且收率较高，经济有效，适于大规模的工业化生产。The invention discloses a new preparation method of capecitabine: D-ribose is used as the starting material, and the key is obtained through hydroxyl protection, 5-position p-toluenesulfonylation, iodine substitution, hypophosphorous acid deiodination, and acetylation. Intermediate 12, 3-tri-O-acetyl-5-deoxy-β-D-ribofuranose, then glycosylated with 5-fluorocytosine, and finally N-4 acylated, deprotected to obtain Capecart Coast, the present invention does not need to use metal catalysts to participate in the reaction, the reaction conditions are mild, and the yield is high, economical and effective, and suitable for large-scale industrial production.
Description
Technical field
The present invention relates to capecitabine and intermediates preparation technology field thereof.
Background technology
Capecitabine is the ucleosides cancer therapy drug by Switzerland Roche Holding Ag research and development, 1998 through U.S. food and the approval of drug safety management board in U.S.'s listing, be used for the treatment of metastatic colorectal cancer, with docetaxel (trade(brand)name: docetaxel,
) drug combination treatment metastatic breast cancer, calendar year 2001 goes on the market in China.In August, 2008, Chinese food and Drug Administration ratify its treatment for advanced gastric carcinoma.There is more than 100 country using capecitabine to treat above-mentioned several cancer at present.
The chemical name of capecitabine is 5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl] cytidine, structure is as follows:
Capecitabine synthetic is divided into two parts:
One, 1,2, the preparation of 3-three-O-ethanoyl-5-deoxidation-β-D-ribofuranose (6)
This step key is reduction.Bibliographical information (Sairam P; Puranik R; Rao BS; et al.Synthesis of 1; 2; 3-tri-O-acetyl-5-deoxy-D-ribofuranose from D-ribose.Carbohydrate Research; 2003; be starting raw material 338:303-306) with D-ribose (3); through 1-position methyl glycosidation, 2, the protection of 3-position isopropylidene, 5-position sulfonylation, metal hydride reduction, acidolysis and acetylize make 1,2; 3-three-O-ethanoyl-5-deoxidation-β-D-ribofuranose (6), yield is 56%.Wherein the metal hydride document has used sodium borohydride, two (2-methoxyethoxy) sodium alanate, three tert.-butoxy lithium aluminum hydrides and tetrahydrochysene lithium aluminium, and yield is 20～89%.
The present inventor at first uses the lower sodium borohydride of price instead and reduces, and yield and document are suitable.Secondly, because the reduction of the sulfonates compounds of sugar often is accompanied by the fracture of O-S key, have hydrolysising by-product in the product, needing influences the yield of product through column chromatography for separation.According to document (Fei XS, Wang JQ, Miller KD, et al.Synthesis of[
18F]-xeloda as a novel potential PET radiotracer for imaging enzymes in cancers[J] .Nuclear Medicineand Biology, 2004,31:1033-1041.), the present inventor at first is converted into the iodo thing with high yield with the sulfonic acid esters derivative, by reduce product and can avoid production of by-products, avoided column chromatography for separation.
Two, the introducing of side chain
1,2,3-three-O-ethanoyl-5-deoxidation-β-D-ribofuranose (6) makes capecitabine by glucosidesization, N-acidylate, deprotection.
In sum, capecitabine has good prospect in medicine, but develop one not only economical, but also the method for preparing capecitabine of safety be still one of technical problem that those skilled in the art need to be resolved hurrily.
Summary of the invention
The purpose of this invention is to provide a kind of novel method for preparing capecitabine, use this method synthesize capecitabine to overcome the above-mentioned defective of prior art, be fit to suitability for industrialized production, yield is than prior art height, and avoided the use of metal catalyst, reduced cost, reduced pollution.
Another object of the present invention provides a kind of capecitabine intermediate 1-O-methyl-2, the new preparation process of 3-O-isopropylidene-5-deoxidation-D-ribofuranose (2).
The present inventor has found a suitable capecitabine preparation method through repeatedly experiment, utilizes this method to prepare capecitabine, not only stable reaction, yield height, and reaction conditions gentleness, economical and effective.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose, this method is with formula 1 compound (1-O-methyl-2,3-O-isopropylidene-5-deoxidation-5-iodo-D-ribofuranose) is dissolved in the non-protonic solvent, in the presence of alkaline reagents, Hypophosporous Acid, 50 or its salt, by the radical initiator effect, reduction is taken off iodine and is obtained:
Above-mentioned non-protonic solvent is 1,4-dioxane, acetonitrile, N, and the mixing of one or more in dinethylformamide, toluene or the dimethylbenzene, preferred solvent is 1,4-dioxane or acetonitrile.
Wherein, described alkaline reagents is one or more the mixing in sodium hydroxide, potassium hydroxide, triethylamine or the N-ethylpiperidine, preferred triethylamine.
Wherein, described Hypophosporous Acid, 50 or its salt are the Hypophosporous Acid, 50 aqueous solution, N-ethylpiperidine hypophosphite, the preferred Hypophosporous Acid, 50 aqueous solution.
Wherein, described radical initiator is an azo compound, be diisopropyl azodiformate, diethyl azodiformate, azoformic acid dibenzyl ester, tert-butyl azodicarboxylate, azo two (hexanaphthene formonitrile HCN), 4, the mixing of one or more in 4-azo-(4-cyanopentanoic acid) or the Diisopropyl azodicarboxylate, preferred Diisopropyl azodicarboxylate.The consumption of described azo compound is 0.1-1 a times of formula 1 compound molar weight.
Above-mentioned 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose under the radical initiator effect general back flow reaction 0.5-2 hour, reacts completely.
The preparation method of capecitabine; may further comprise the steps: at first with formula 3 compounds through hydroxyl protection production 4 compounds; then with formula 4 compound sulfonylation productions 5 compounds; take off iodine with Hypophosporous Acid, 50 or hypophosphite reduction behind the formula 5 compound iodos and obtain formula 2 compounds; again formula 2 compounds are taken off isopropylidene protection, acetylize gets formula 6 compounds, formula 6 compounds are through glucosidesization, N
4-position acidylate and deprotection get capecitabine (compound 11):
In the above-mentioned production 4 compound steps, 3 obtain 1-position methyl glycosidation product with the mixing solutions reaction of mixing solutions, the vitriol oil and the methyl alcohol of hydrogen chloride methanol solution, concentrated hydrochloric acid and the methyl alcohol of 0.1%-10%, reaction product is dissolved in the acetone, adds acid reagent and dewatering agent and obtains 4.Wherein acid reagent is concentrated hydrochloric acid, the vitriol oil; Dewatering agent is anhydrous cupric sulfate, anhydrous magnesium sulfate.Document (Sairam P, Puranik R, Rao BS, et al.Synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose from D-ribose.Carbohydrate Research, 2003, be starting raw material 338:303-306), under tin protochloride and sulphuric acid catalysis with D-ribose (3), with methyl alcohol, acetone one pot reaction, yield is 88%.The present invention uses concentrated hydrochloric acid or the vitriol oil instead as catalyzer, has simplified operation, avoids the use of tin protochloride (metal object).
In the above-mentioned production 5 compound steps, sulfonylation uses p-methyl benzene sulfonic chloride; The used iodo reagent of formula 5 compound prepared in reaction formulas, 1 compound is potassiumiodide, sodium iodide.
Document (Sairam P, Puranik R, Rao BS, et al.Synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose from D-ribose.Carbohydrate Research, 2003, be with compound 4 and Tosyl chloride reacting generating compound 5 338:303-306), compound 5 directly reduces under sodium borohydride, three tert.-butoxy lithium aluminum hydrides or two (2-methoxyethoxy) sodium alanate effect and generates 2, two step of compound yield is 57.9%.But for the reduction of sulfonates compounds, often be accompanied by the fracture of O-S key, product has a certain proportion of compound 4, need carry out column chromatography for separation, and above-mentioned reagent price is comparatively expensive, should not industrialized the development.The present invention at first is converted into iodo thing 1 with sulfonates compounds 5, by the reduction of iodo thing, can obtain to high purity compound 2.
In the synthesis step of above-mentioned capecitabine; with 1-O-methyl-2; 3-O-isopropylidene-5-deoxidation-D-ribofuranose (2) removes 2 through the one kettle way reaction; the protection of 3-O-isopropylidene, acetylize get 1-O-methyl-2, and 3-O-isopropylidene-5-deoxidation-β-D-ribofuranose (6) is about to compound (2) and is dissolved in back flow reaction in the acidic solution; steaming desolventizes; residual slurry is dissolved in pyridine or the triethylamine, adds acetic anhydride, gets compound (6) through aftertreatment.Acidic solution is dilution heat of sulfuric acid, dilute hydrochloric acid solution in this method.Document (Sairam P, Puranik R, Rao BS, et al.Synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose fromD-ribose.Carbohydrate Research, 2003,338:303-306) in acetic acid, the vitriol oil and acid anhydrides solution, carry out acidolysis, obtain compound 6 through normal hexane-ether recrystallization, yield 48.6%.The present invention has used isopropyl ether instead, sherwood oil carries out crystallization, and yield slightly improves, and is 50.8%.
In the synthesis step of above-mentioned capecitabine, the glucosides catalyst system therefor is Lewis acid common in the nucleosides chemistry etc., is one or more mixing of aluminum chloride, tin tetrachloride, titanium tetrachloride, TMS triflate, boron trifluoride ethyl ether complex, tin protochloride, antimony pentachloride.Described glucosides solvent is one or more mixing of methylene dichloride, ethylene dichloride, chloroform, acetonitrile.
The preparation of compound 10, document (Fei XS, Wang JQ, Miller KD, et al.Synthesis of[
18F] xeloda as anovel potential PET radiotracer for imaging enzymes in cancers.Nuclear Medicine and Biology, 2004,31:1033-1041) product is through column chromatography for separation, yield 73%.The present invention uses sherwood oil, re-crystallizing in ethyl acetate, yield 93%.
The preparation of compound 11, document (Fei XS, Wang JQ, Miller KD, et al.Synthesis of[
18F] xeloda as anovel potential PET radiotracer for imaging enzymes in cancers.Nuclear Medicine and Biology; 2004; 31:1033-1041) used aqueous sodium hydroxide solution to remove ethanoyl on the glycosyl, yield is 82%.The used alkali of deprotection reaction of the present invention is sodium methylate, aqueous sodium hydroxide solution or ammoniacal liquor, and yield is 85%.
Beneficial effect of the present invention:
1. the present inventor at first is converted into the iodo thing with high yield with the sulfonic acid esters derivative, by reduce product and can avoid production of by-products, avoided column chromatography for separation.In the reduction reaction, use Hypophosporous Acid, 50/Diisopropyl azodicarboxylate/triethylamine system to carry out free radical first and take off iodine.This method reagent is cheap, and the reaction times is short, convenient post-treatment, and yield is higher to be 90%.Avoid the use of metal catalyst (as sodium borohydride etc.) simultaneously, had certain industrial applications prospect.
2. the present invention is a starting raw material with the lower D-ribose (3) of price; select suitable reaction scheme; earlier through 1-position first glycosidation; 2; the 3-O-isopropylidene protect intermediate 1-O-methyl-2,3-O-isopropylidene-D-ribofuranose (4) is by the sulfonic acid esterification of 5-position; again sulphonate is converted into high yield 5-position iodo thing (1), takes off iodine by Hypophosporous Acid, 50/triethylamine/free radical initiator system again.This route reaction mild condition, step is simple, and the yield height has reduced cost, has reduced pollution, is fit to large-scale industrial production.
Embodiment
Embodiment 1
1-O-methyl-2, the preparation of 3-O-isopropylidene-D-ribofuranose (4):
(20g 133mmol) is dissolved in methyl alcohol (80ml) and the acetone (120ml) D-ribose (3), adds concentrated hydrochloric acid (2ml), mixed-liquor return reaction 3h is put coldly, and making its pH value of solution with the solid sodium bicarbonate neutralization reaction is 6-7, remove solvent under reduced pressure, add entry (60ml) and ethyl acetate (100ml), divide and get organic phase, the water ethyl acetate extraction, the organic phase washing and drying filters, and evaporate to dryness gets oily matter 4 (23.6g, 86.8%), can be directly used in the next step.
Embodiment 2
1-O-methyl-2,3-O-isopropylidene-5-O-are to the preparation of Methyl benzenesulfonyl base-D-ribofuranose (5):
(47g 0.23mol) is dissolved in the methylene dichloride (200ml), adds triethylamine (56ml) with oily matter 4, be cooled to 0-5 ℃, divide six times and add p-methyl benzene sulfonic chloride (62.4g), each about 10min at interval, finish, continue to keep 5 ℃, stir 3h, water (50ml) successively, 1mol/L hydrochloric acid (25ml), saturated sodium bicarbonate aqueous solution (25ml) and water (50ml) are washed, evaporate to dryness with frozen water, stirs, filters, washes, dry solid 5 (60g, 72.7%), mp 80-81 ℃.
Embodiment 3
1-O-methyl-2, the preparation of 3-O-isopropylidene-5-deoxidation-5-iodo-D-ribofuranose (1):
(10g 31.8mmol) is dissolved in the acetonitrile (104ml), adds sodium iodide (12.5g), back flow reaction 12h with compound 5.Put coldly, filter, steaming desolventizes, and adds isopropyl ether and stirs, and filters, and isopropyl ether is washed, and the filtrate decompression evaporate to dryness gets yellow oil 1 (8.5g, 100%).Need not to handle, directly drop into next step reaction.
Embodiment 4
1-O-methyl-2, the preparation of 3-O-isopropylidene-5-deoxidation-D-ribofuranose (2):
With 1-O-methyl-2, (0.9g 3mmol) is dissolved in the dioxane (60ml) 3-O-isopropylidene-5-deoxidation-5-iodo-D-ribofuranose (1), adds triethylamine (2.4ml) and 50%H
3PO
2(1.56ml), under the nitrogen protection, drip and to contain AIBN (0.24g, dioxane 1mmol) (20ml) continue backflow 2-3h, react completely to the raw material point, stop heating, naturally cool to room temperature.Steam and remove the dioxane solvent, residual slurry is dissolved in the ethyl acetate (20ml), washes three times, and saturated sodium bicarbonate is washed, the saturated common salt washing through anhydrous magnesium sulfate drying, is filtered, steaming desolventize 1-O-methyl-2,3-O-isopropylidene-5-deoxidation-D-ribofuranose (2) (0.48g, 90.1%).
1H-NMR(CDCl
3，400MHz)δ(ppm)：4.93(s，1H，H-1)，4.62(d，1H，H-3)，4.49(d，1H，H-2)，4.32(q，1H，H-4)，3.33(s，3H，OCH
3)，1.53，1.29(m，6H，C-Me
2)，1.27(d，3H，CH
3)。
Embodiment 5
1-O-methyl-2, the preparation of 3-O-isopropylidene-5-deoxidation-D-ribofuranose (2):
With 1-O-methyl-2; 3-O-isopropylidene-5-deoxidation-5-iodo-D-ribofuranose (1) (0.9g; 3mmol) be dissolved in the dioxane (60ml), add triethylamine (2.4ml) and solid N-ethylpiperidine hypophosphite (2.7g), under the nitrogen protection; dropping contains diisopropyl azodiformate (0.6g; dioxane 3mmol) (20ml) continues backflow 2-3h, reacts completely to the raw material point; stop heating, naturally cool to room temperature.Steam and remove the dioxane solvent, residual slurry is dissolved in the ethyl acetate (20ml), washes three times, and saturated sodium bicarbonate is washed, the saturated common salt washing through anhydrous magnesium sulfate drying, is filtered, steaming desolventize 1-O-methyl-2,3-O-isopropylidene-5-deoxidation-D-ribofuranose (2) (0.5g, 93.1%).
1H-NMR(CDCl
3，400MHz)δ(ppm)：4.93(s，1H，H-1)，4.62(d，1H，H-3)，4.49(d，1H，H-2)，4.32(q，1H，H-4)，3.33(s，3H，OCH
3)，1.53，1.29(m，6H，C-Me
2)，1.27(d，3H，CH
3)。
Embodiment 6
1,2, the preparation of 3-O-ethanoyl-5-deoxidation-β-D-ribofuranose (6):
1-O-methyl-2,3-O-isopropylidene-5-deoxidation-D-ribofuranose (2) (18.5g, 98mmol), the water (120ml) and the vitriol oil (0.2ml)) drop in the 250ml reaction flask, backflow 2h, put cold, regulate pH to 6-7 with solid sodium bicarbonate, evaporated under reduced pressure is dissolved resistates with anhydrous pyridine (200ml), add aceticanhydride (50ml), stirring at room 20h, evaporated under reduced pressure adds entry (80ml) and ethyl acetate (100ml) and extracts, with 0.5N hydrochloric acid (40ml), water (40ml), sodium hydrogen carbonate solution (40ml) and saturated aqueous common salt (40ml) are washed, drying, evaporate to dryness get soup compound (22g, 86%).Add isopropyl ether, petroleum ether and stirring is separated out solid, filter compound 6 (13g, 50.8%).
1H-NMR(CDCl
3，400MHz)δ(ppm)：6.10(s，1H，H-1)，5.31(d，1H，H-3)，5.08(d，1H，H-2)，4.25(m，1H，H-4)，2.09-2.04(m，9H，3
*Ac)，1.35(d，3H，-CH3)。
ESI-MS(m/z)：283(M+Na)，299(M+K)，543(2M+Na)。
Embodiment 7
2 ', 3 '-two-O-ethanoyl-5 '-preparation of deoxidation-5-fluorine cytidine (8):
With 5-flurocytosine (30g; 0.23mol); hexamethyldisilane amine (38g) and toluene (150ml) backflow 3h; remove toluene under reduced pressure; resistates is dissolved in the methylene dichloride (400ml), and adding compound 6 (66g, 0.25mol); be cooled to 0 ℃; add tin tetrachloride (72g), stir 2h, adding sodium bicarbonate (100g) in 0 ℃; frozen water (200ml); stirring at room 0.5h filters, and organic phase is washed with the 1mol/L sodium hydrogen carbonate solution successively; reclaim methylene dichloride to most; add ethyl acetate (150ml), stirring and dissolving drips sherwood oil (450ml); crystallization get solid 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluorine cytidine (8) (60g, yield 78.4%), mp180-183 ℃.
1H-NMR(CDCl
3，400MHz)δ(ppm)：8.28，5.80(br?s，2H，NH2)，7.36(s，1H，H-6)，5.96(d，1H，H-1′)，5.30(t，1H，H-3′)，4.98(t，1H，H-2′)，4.21(t，1H，H-4′)，2.10-2.03(m，6H，2Ac)，1.43(s，3H，CH
3)。
ESI-MS(m/z)：352(M+Na)。
Embodiment 8
2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl] preparation of cytidine (10):
2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluorine cytidine (8) (16g; 48.6mmol) be dissolved in the methylene dichloride (160ml); add pyridine (16ml); be cooled to 0 ℃, add n-amyl chlorocarbonate (9) (16g), 0 ℃ is stirred 1h down; slowly pour in the frozen water (100ml); divide and get dichloromethane layer, water extracts with methylene dichloride (100ml), merges organic phase; water (50ml) is washed; anhydrous magnesium sulfate drying, evaporated under reduced pressure adds ethyl acetate (16ml) dissolving; drip sherwood oil (160ml); be stirred to solid and separate out fully, filter, solid chemical compound 2 '; 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl] cytidine (10) (20g, 93%).
1H-NMR(CDCl
3，400MHz)δ(ppm)：7.39(s，1H，H-6)，5.92(d，1H，H-1′)，5.28(t，1H，H-3′)，5.01(t，1H，H-2′)，4.23(m，1H，H-4′)，4.16(m，2H，OCH
2)，2.10-2.07(2s，6H，2Ac)，1.71-1.32(m，9H，-C
4H
9)，0.9(s，3H，CH
3)。ESI-MS(m/z)：466(M+Na)。
Embodiment 9
The preparation of capecitabine (11):
2 ', 3 '-two-O-ethanoyl-5 '-deoxidation-5-fluoro-N-[(pentyloxy) carbonyl] (12g 27mmol) is dissolved in the methyl alcohol (120ml) cytidine (10); add sodium methylate (0.5g); stirring at room 1h, 2mol/L hydrochloric acid regulate pH to neutral, evaporated under reduced pressure; add entry (150ml); ethyl acetate (100ml); divide and get ethyl acetate layer, water layer uses ethyl acetate extraction, merges organic phase; the saturated common salt washing; anhydrous magnesium sulfate drying, evaporated under reduced pressure stir and drip sherwood oil (40ml) down to 20ml; separate out solid; filter, ethyl acetate: the sherwood oil volume ratio was washed in about 1: 3, dry capecitabine (11) (8.2g; 85%), mp 117-119 ℃.
1H-NMR(CDCl
3，400MHz)δ(ppm)：7.77(s，1H，H-6)，5.68(d，1H，H-1′)，5.00-4.26(br?s，3H，OH-2′，3′，NH)，4.19(m，4H，H-2′，3′，-OCH
2)，3.88(d，1H，H-4′)，1.71-1.34(2s，9H，-C
4H
9)，0.90(s，3H，CH
3)。
ESI-MS(m/z)：382(M+Na)。
Claims (14)
1.1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose, this method are dissolved in formula 1 compound in the non-protonic solvent, and in the presence of alkaline reagents, Hypophosporous Acid, 50 or its salt, by the radical initiator effect, reduction is taken off iodine and obtained:
2. as right 1 described 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose, it is characterized in that: said non-protonic solvent is 1,4-dioxane, acetonitrile, N, the mixture of one or more in dinethylformamide, toluene or the dimethylbenzene.
3. as right 2 described 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose is characterized in that: said non-protonic solvent is 1,4-dioxane or acetonitrile.
4. as right 1 described 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose is characterized in that: said alkaline reagents is one or more the mixture in sodium hydroxide, potassium hydroxide, triethylamine or the N-ethylpiperidine.
5. as right 4 described 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose is characterized in that: said alkaline reagents is a triethylamine.
6. as right 1 described 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose is characterized in that: said Hypophosporous Acid, 50 or its salt are the Hypophosporous Acid, 50 aqueous solution, N-ethylpiperidine hypophosphite.
7. as right 1 described 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose, it is characterized in that: said radical initiator is diisopropyl azodiformate, diethyl azodiformate, azoformic acid dibenzyl ester, tert-butyl azodicarboxylate, azo two (hexanaphthene formonitrile HCN), 4, the mixture of one or more in 4-azo-(4-cyanopentanoic acid) or the Diisopropyl azodicarboxylate.
8. as right 7 described 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose is characterized in that: said radical initiator is a Diisopropyl azodicarboxylate.
9. as right 1 described 1-O-methyl-2, the preparation method of 3-O-isopropylidene-5-deoxidation-D-ribofuranose is characterized in that: the 0.1-1 that said azo type free base initiator mole dosage is formula 1 a compound molar weight doubly.
10. the preparation method of capecitabine; may further comprise the steps: at first with formula 3 compounds through hydroxyl protection production 4 compounds; then with formula 4 compound sulfonylation productions 5 compounds; take off iodine with Hypophosporous Acid, 50 or hypophosphite reduction behind the formula 5 compound iodos and obtain formula 2 compounds; again formula 2 compounds are taken off isopropylidene protection, acetylize gets formula 6 compounds, formula 6 compounds are through glucosidesization, N
4-position acidylate and deprotection get capecitabine:
11. the preparation method of capecitabine as claimed in claim 10, it is characterized in that: in the production 4 compound steps, the hydrogen chloride methanol solution of formula 3 compounds and 0.1%-10%, concentrated hydrochloric acid methanol solution or the reaction of vitriol oil methanol solution obtain 1-position methyl glycosidation product, 1-position methyl glycosidation product is dissolved in the acetone, adds concentrated hydrochloric acid or vitriol oil acid reagent and anhydrous cupric sulfate or anhydrous magnesium sulfate dewatering agent and obtains formula 4 compounds.
12. the preparation method of capecitabine as claimed in claim 10 is characterized in that: in the production 5 compound steps, the sulfonylation agent that sulfonylation uses is p-methyl benzene sulfonic chloride.
13. the preparation method of capecitabine as claimed in claim 10 is characterized in that: the used iodo reagent of iodide reaction is potassiumiodide or sodium iodide in preparation formula 1 compound.
14. the preparation method of capecitabine as claimed in claim 10 is characterized in that: sherwood oil, re-crystallizing in ethyl acetate are used in the aftertreatment of reactant compound 10.
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| CN102690311A (en) * | 2012-05-24 | 2012-09-26 | 上虞市华科化工有限公司 | Preparation method for cytidine |
| CN102977169A (en) * | 2012-12-20 | 2013-03-20 | 齐鲁天和惠世制药有限公司 | Preparation method of 2'3'-di-O-acetyl-5'-desoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine |
| CN103059085A (en) * | 2011-12-27 | 2013-04-24 | 石药集团中奇制药技术（石家庄）有限公司 | Anti-cancer medicament intermediate and preparation method thereof |
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| CN103059085A (en) * | 2011-12-27 | 2013-04-24 | 石药集团中奇制药技术（石家庄）有限公司 | Anti-cancer medicament intermediate and preparation method thereof |
| CN103059085B (en) * | 2011-12-27 | 2015-09-02 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of Anti-cancer medicament intermediate and preparation method thereof |
| CN102690311A (en) * | 2012-05-24 | 2012-09-26 | 上虞市华科化工有限公司 | Preparation method for cytidine |
| CN102977169A (en) * | 2012-12-20 | 2013-03-20 | 齐鲁天和惠世制药有限公司 | Preparation method of 2'3'-di-O-acetyl-5'-desoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine |
| CN103897004A (en) * | 2012-12-27 | 2014-07-02 | 鲁南制药集团股份有限公司 | Synthesis method for capecitabine |
| CN103897004B (en) * | 2012-12-27 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of synthetic method of capecitabine |
| CN103113441A (en) * | 2013-03-13 | 2013-05-22 | 上海龙翔生物医药开发有限公司 | Method for preparing capecitabine |
| CN106478751A (en) * | 2015-09-02 | 2017-03-08 | 正大天晴药业集团股份有限公司 | The preparation method of 2 ', 3 '-two-O- acetyl -5 '-fluoro- N4- of deoxidation -5- [(amoxy) carbonyl] cytidines |
| CN106478751B (en) * | 2015-09-02 | 2020-06-26 | 正大天晴药业集团股份有限公司 | Preparation method of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytosine nucleoside |
| CN108558960A (en) * | 2018-05-16 | 2018-09-21 | 新乡拓新药业股份有限公司 | A kind of preparation method of tri--O- acetyl group -5- deoxidations-β of 1,2,3--D-ribose |
| CN110483593A (en) * | 2019-08-14 | 2019-11-22 | 贵州永诺菲特生物制药有限公司 | A kind of preparation method of capecitabine intermediate |
| CN118812465A (en) * | 2024-09-18 | 2024-10-22 | 天津兴博润生物制药有限公司 | A method for preparing tetrahydrofuran derivatives |
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Effective date of registration: 20161206 Address after: 222062 Lianyungang, Jiangsu Province, Yu Road, Haizhou District No. 369 Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Patentee after: Lianyungang Runzhong Pharmaceutical Co.,Ltd. Patentee after: Shanghai Institute of pharmaceutical industry Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry |