TW200900417A - Method for stereoselective preparation and separation of tri-o-acetyl-5-deoxy-β]-D-ribofuranose - Google Patents

Abstract

The present invention discloses a method for preparing highly pure tri-O-acetyl-5-deoxy-β -D-ribofuranose which comprises a highly stereoselective acetylation step of 1-methylacetonide, and the pure β -anomer thus obtained can be advantageous used for preparing capecitabine.

Description

200900417 IX, invention description: L Ming belongs to the field of invention] ~0 'acetate-5-deoxy-tumor intermediate. The invention relates to a method for stereoselectively preparing and isolating tris/5-D-ribofuranose, which is used for preparing the background of the invention, (a nuclear bitter with a ribofuranose backbone), J, An antitumor agent, which is administered orally to treat metastatic breast cancer and rectal itching and has a 10-fluorocytosine moiety in which the 5-fluorocytosine moiety attached to position 1 of the glucopyranose has a orientation as shown below. Chemical structure:

As described in U.S. Patent No. 5,453,497, the nodulation can be achieved by saccharification of trioxo-5-deoxyjD-pyridose ribose with fluorocytosine followed by accepting the amine for mercaptolation of the product obtained by 15 The reaction is prepared by hydrolysis and is shown in the reaction scheme (A). Reaction flow 裎 Α,

(V) 5 (I) 200900417 The above-mentioned raw materials, the formula (1) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Preparation, as shown in the reaction scheme (9). Specifically, (1) hydrolyzing a compound of the formula (1) to obtain a triol compound of the formula (III); (ii) using acetic anhydride 5 in a bite (将) The triol compound is acetylated to obtain the ternary oxime of the formula (II) _ 〇 醯 · · 去 去 去 , , , , 关于 关于 关于 关于 关于 在 在 在 在 在a mixture of spinning isomers; (iii) subjecting the reaction mixture to vacuum distillation to purify the /3-/α-raceomer mixture; and (iv) the _ _ _ _ Separation from the mixture. 10 Reaction Scheme (B)

Furthermore, the acetylation reaction of tris-ol compounds in pyridine with acetic anhydride to obtain tris-oxime-5-deoxy-D-ribofuranose has also been described in other reports [J. Med·Chem ·, 2000, vol. 43, pp 2566-2574], 15 [Carbohydrate Research, 2003, vol. 338, pp 303-306], [Nuclear Medicine and Biology, 2004, vol. 31, pp 1033-1041] and [ J. Am. Chem. Soc., 1957, vol. 79, pp 5534-5540]. However, the above process for preparing tris-O-acetam-5-deoxy-D-ribofuranose is hampered by various problems due to the use of pyridine as a solvent: the amount of finishing after the reaction 20 is very large and requires complicated multi-steps. Finishing procedure; the selectivity of the formation of the racemic isomer is low, the ratio of the /5-/α-raceomer of the trioxo-5-deoxy-D-ribofuranose product does not exceed 3:1 To 3.5:1; and due to the relatively large amount of α-raceomers present in 200900417, the desired formulae of the formula (I) is changed from /3-/α- by recrystallization. Separation of the mixture of isomers is difficult and only yields from about 35 to 40% are obtained. Accordingly, the present invention seeks to develop an improved process for the preparation of tris-indole-5-deoxy-5/5-D-ribofuranose and finds that the ratio of /3-/[alpha]-helical isomers can be Significant improvement is achieved by the use of alkylamines or cyclic amine bases in place of pyridine during the oximation reaction. SUMMARY OF THE INVENTION According to the present invention, it is an object of the present invention to provide a bismuth-5-deoxy-A-Dn ribose ribose having a high ratio of /5-rotational isomers. Methods. Another object of the present invention is to provide a pure yS-raceomer of trioxo-5-deoxy-D-ribofuranose from its/5-/α-spinning isomer mixture A simple and easy way to separate. According to one aspect of the present invention, there is provided a process for the preparation of the trioxo-5-deoxy-lu-Da-flana ribose of the formula (1), which comprises the steps. (1) in the presence of an alkylamine or a cyclic amine The reaction of the compound of the formula (III) with acetic anhydride in an organic solvent to obtain the compound of the formula (II); and (ii) the separation of the compound (1) and the formula by recrystallization using a solvent and an antisolvent ( II) Compound: 200900417

L. Embodiment 3 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A method for stereoselective acetamylation reaction and separation of /5-dependent spiromers according to the present invention is shown in Scheme (C). Process (C)

(IV) (ill) (II) (I) In particular, the methylacetonide compound of the formula (IV) is protected by the conventional method described in U.S. Patent No. 4,340,729. A triol compound of formula (III) having a ratio of a-//3-isomer mixture of about 1:1 to 2:1 ratio of α-pair/5-. The racemic isomers can be separated by column chromatography as used in the next step, as desired. The fluorenyl acetonide compound of the formula (IV) can be easily prepared by the method described in U.S. Patent No. 4,340,729. In the step of acetylating the triol compound of the formula (III), an alkylamine or a cyclic amine 200900417 in an amount of 3 mole equivalents or more based on the compound of the formula (III) may be used instead of the prior art. The teaching uses a pure alpha ratio bite as a solvent to achieve a south stereoselective reaction of a triol compound with acetic acid. The product of formula (II) tris-0-acetam-5-deoxyribofuranose includes a significant high The ratio of the osmolality to the α-p-/5-stacked isomer is 1:10 or higher. The product of the cerium-rich vortexomer can be subjected to recrystallization using a solvent or an anti-solvent to obtain a /3 - vortex of the formula (I) having a high purity of 99.5% and higher in south purity. Isomer. As described above, unlike the conventional method using an excess of pure pyridine as a solvent, the method of the present invention obtains tris10-acetam-5-deoxy-D-ribofuranose having a high cold-rotational isomer content. The use of an equivalent amount of an alkylamine or a cyclic amine is carried out together with an organic solvent. Therefore, the finishing process after the reaction is greatly simplified. That is, pure tris-O-acetam-5-deoxy-stone-D-arabose can be recovered from the acetamidine reaction mixture, and can be easily obtained by simple recrystallization of solvent and antisolvent. High yields of % and higher without the high vacuum distillation used in the conventional 15 methods. The organic solvent used in the brewing reaction according to the present invention may be selected from the group consisting of tetrahydrofuran, acetonitrile, di-methane methane, dibromoethane, dichloroethane, acetic acid, toluene and mixtures thereof. Among the groups, it is preferred to use dichloromethane. 20 The alkylamine or cyclic amine used in the present invention may be selected from triethylamine, n-tributylamine, dicyclohexylamine, tetramethylethylenediamine, diisopropylethylamine, N-methylamine A group consisting of a mixture thereof and triethylamine is preferred. Depending on the alkylamine or cyclic amine species used, the selectivity of the racemic isomer beyond the α-helical isomer increases from at least 1 〇:丨 to 15:丨, of which three 200900417 ethylamine is preferred for use. And ° σ σ is invalid. In the present invention, the amount of the alkylamine or cyclic amine may be from 3 to 12 mol equivalents, preferably from 4 to 5 mol equivalents, based on the compound of the formula (III). The acetylation reaction according to the present invention can be carried out at 10 to 50 ° C, preferably 5 to 25 5 ° C, for 6 to 24 hours. After the B-stuffing reaction, the tri-O-acetyl-5-deoxy-D-ribofuranose of the formula (II) is obtained as a solid due to its high point-rotational isomer content, unlike the use of pyridine. The product obtained by the conventional method is oil or semi-solid. The trioxo-5-10-deoxy-D-ribofuranose of the formula (II) obtained by the acetylation method of the present invention is mainly composed of the desired yS-raceomer, α- The content of the spinning isomer is only 6 to 9%. In order to obtain a pure/5-rotational isomer therefrom, the α-rotation isomer can be removed by recrystallization according to any conventional method. For example, a pure /5-rotational isomer can be removed by adding an anti-solvent to a solution 15 obtained by dissolving the mixture of the rotatory isomers in a suitable solvent. The filtrate of the isomer is easily separated by collecting as a solid/5-. A suitable solvent for use in the recrystallization may be a polar organic solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, acetone, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, acetic acid. The group consisting of ethyl ester, diethyl 20 ether and mixtures thereof is preferably isopropanol. The anti-solvent used in the recrystallization may be a non-polar organic solvent selected from the group consisting of n-hexanol, heptane, cinnabar, teriyaki, petroleum ether, isopropyl ether, and mixtures thereof, or It may be water, preferably n-hexane or water. Recrystallization can be carried out at -60 to 30 ° C, preferably -10 to 5 ° C, 10 200900417 and the amount of solvent and anti-solvent, with the formula (II) _ _ _ _ _ 5 _ deoxygenation Based on the seven-ribose sugar, it can be 2 to 5 times (volume/weight) and 5 to 2 product/weight, respectively. σ (the body of the 5 - mutated isomer obtained after recrystallization has - to less than 99.5% purity, the α_ Cyclone isomer content is less than 〇 5%. As described above, with stereoselection The method of the present invention for preparing the triethyl _5_deoxy-/3-D· tranose ribose of the formula (1) exhibits significantly improved stereoselectivity compared to the conventional method, and in a conventional manner The obtained yield reduction of less than 35 to 40% yields a high yield of at least 75%. The following examples are intended to illustrate the invention without limiting its scope. In the following examples, in the formula (1) In the case of the compound, GC (gas chromatography) is a column of cyanopropyl stupid polyoxygen tube (inner diameter: 〇32 mm, length 60 m' thickness: 丨8 μm) (for example, db 624) Operation, and the test solution was prepared by dissolving (10) mg of the compound of the formula (1) in dimethyl sulphur wind 15 to prepare a 25 ml solution. Interest: Formula (II) 3 - 〇 B listen _ 5 ·Selective preparation of degassing such as vanillin

V^〇h ——.Vr〇At HO 〇H ?

AeO OAc 0") (II) (ll) M using diethylamine as a procedure for the test 20 Add 100 grams of methyl-2,3-indole-5-deoxy ID-bisting ribose to 500 亳Rise in Μ2Μ sulfuric acid and stir for 2 hours at 8〇 to 85<^. Decrease the temperature to 45 to 耽 and remove the water in the loss of money until the total volume 11 200900417 is reduced from 2/3 to 1/2. 500 ml of 0 02 M sulfuric acid was added to the resulting solution at 80 to 85. (The mixture was stirred for 1 hour. The temperature was lowered to room temperature, the resulting solution was neutralized to pH 5.3 to 5.5 with 0. 2 Μ sodium carbonate, and concentrated under reduced pressure. The obtained residue was suspended in 1,000 ml of acetonitrile. 5 gram of anhydrous sodium sulfate was added thereto and stirred for 1 hour. The resulting mixture was filtered through a column of celite, and then washed with 100 ml of acetonitrile, and the filtrate and washings were combined and concentrated under reduced pressure. To remove the solvent, 1. 〇〇〇ml of dichloromethane and 370 ml of triethylamine were added to the residue while maintaining the temperature at 5. (:, 235_5 ml of acetic anhydride was added and stirred for 20 hours. After the reaction was completed, 1,000 ml of water was added to the obtained reaction mixture, and the organic layer was separated, and then the organic layer was successively washed with 1,000 ml portions of 丨N HCl, saturated sodium hydrogencarbonate and brine, and then Drying over anhydrous sodium sulfate. The obtained organic layer was concentrated under reduced pressure to give the title compound (140.8 g). The product thus obtained was analyzed by GC, which showed that the product included a ratio of 1:15 U.8. With stone-variation Isomers. 4 NMR (300MHz, CDC13): (泠-Zero isomers) δ 6-〇9(s,1H), 5.30 5.32(dd,lH), 5.06 5.10(dd,lH), 4.26( q,lH), 2-l〇(s,3H),2.07(s,3H),2.05(s,3H),1.35(d,3H). 4 NMR (300MHz, CDC13) : ( a - Structure) <5 2〇6-2l(d,lH), 5.11(dd,lH), 4.8(dd,lH), 4.15 4.20(m,lH), 1970,111),1.92(8,311), 1.89 (8, 311), 1.21 ((1, 311) ° d-2) The initial procedure for repeating (1-1) when using tri-n-butylamine as the base, except for the use of 5 gram methyl-2,3-0- In addition to propion-5-deoxy-/5-D-ribofuranose, a triol compound is obtained. In 12200900417, 50 ml of dichloromethane and 31.6 ml of tri-n-butylamine are added to the residue. 11.8 ml of acetic anhydride was slowly added thereto, and stirred at room temperature for 12 hours. After the reaction was completed, 50 ml of water was added to the reaction mixture, stirred and the organic layer was separated. Then the organic layer was added in 50 ml portions. 1N 5 HCl, saturated sodium hydrogencarbonate and brine were washed successively, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound. The product thus obtained was analyzed by GC, which showed that the product included α- and /5-raceomers of a ratio of j: 11.2. (1-3) When tetramethylethylenediamine was used as a base Procedure 10 The initial procedure of (1-1) was repeated except that 5 g of fluorenyl-2,3-indole-5-deoxy-/SD-ribofuranose was used to obtain a triol compound. Next, 50 ml of dichloromethane and 20 ml of tetramethylethylenediamine were added to the residue, and 11.8 ml of acetic anhydride was slowly added thereto, and stirred at room temperature for 12 hours. After the reaction was completed, 50 ml of water was added to the reaction mixture, 15 was stirred and the organic layer was separated. The organic layer was successively washed with 50 ml portions of 1N HCl, saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure to give the title compound (7 g). The product thus obtained was analyzed by Gc, which showed that the product included the α-and-dot-spin isomer of the ratio: 10.3. 20 raw carpets ^: When using pyridine as an organic test procedure, add 5 grams of methyl-2,3-0-isopropylene _5_deoxy_stone_D_pyranose to 25 ml of 〇.〇2M sulfuric acid Medium, and in the ribs to "It is stirred for 2 hours. Let the temperature drop to 45 to 5 〇t, and remove the water under reduced pressure until the total volume is reduced from milk to 1/2. 25 ml 〇.〇 2M sulfuric acid was added to the resulting solution, and 13 200900417 • Stir at 80 to 85 ° C for 1 hour. The temperature was lowered to room temperature, and the resulting solution was neutralized with 0.2 M sodium carbonate to pH 5.3 to 5.5, and decompressed. The residue was suspended in 50 ml of acetonitrile, and 5 g of anhydrous sodium sulfate was added thereto and stirred for 1 hour. The resulting mixture was filtered through a celite column, and then washed with 5 ml of acetonitrile. The filtrate and the washings were combined and concentrated under reduced pressure. 11.8 ml of acetic anhydride and 25 ml of pyridine were added to the residue and stirred for 12 hours. After the reaction was completed, '1 ml of water was added thereto' Spoiled for 1 hour' and extracted the resulting solution with 1 〇〇 ml of methylene chloride. The organic layer was 100 mM. Several portions of IN HC1 were washed three times, and then washed successively with 100 ml of a portion of saturated sodium hydrogencarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The title compound (6.8 g). The oily product wGc thus obtained

Selective crystallization of the I-spinning isomer (formula (1) _ _ _ _ _ _ 5 _ deoxy j_D gnash 15 ribose)

The fractions were subjected to recrystallization as described below. 20 (2-1) In the alcohol, 28 g of the α/rock-raceomer mixture was dissolved in lion isopropyl alcohol, and 168 ml of hexane was added dropwise thereto. The resulting solution was at 14 200900417. (: The title compound was obtained (31.9 g, total yield: 79.5%).

Melting point: 65-66 ° C /3 Spinal isomer content: 99.6% (α-rotational isomer content: 0.1%) 5 4 NMR (300MHz, CDC13) : ( /3 - torsion isomer) 5 6.09(s,lH), 5.30 5.32(dd,lH), 5.06 5.10(dd,lH), 4.26(q,lH), 2.10(s,3H), 2.07(s,3H), 2.05(s,3H ), 1.35 (d, 3H). (2-2) A 28 g α/cold-rotation isomer mixture was dissolved in 56 ml of isopropyl alcohol, and 168 ml of hexane was added dropwise thereto. The resulting solution was aged at 0 to 5 °C for 3 hours, and filtered to give the title compound (21.0 g,yield: 76_4%) as white solid. /3-Zero isomer content: 99.7% (α-rotational isomer content: 0.05%) The melting point and 1H-NMR data were the same as those obtained in Example 2-1. 15 (2-3) A mixture of 28 g of the α//3-isomer mixture was dissolved in 56 ml of isopropyl alcohol, and 168 ml of distilled water was added dropwise thereto. The resulting solution was aged at 5 °C for 7 hours, and filtered to give the title compound (21.3 g,j. 20 Stone-rotational isomer content: 99.5% (α-rotational isomer content: 0.1%) The melting point and 1H-NMR data were the same as those obtained in Example 2-1. (2-4) A 28 g 〇:/call-raceomer mixture was dissolved in 56 ml of isopropyl alcohol, and 112 ml of distilled water was added dropwise thereto. The resulting solution was aged at 5 15 200900417 °C for 7 hours, and filtered to give the title compound (20.7 g, <RTIgt; /5-Zero isomer content: 99.6% (α-rotational isomer content: 0.1%) Melting point and 1 Η - N M R data are the same as those obtained in Example 2-1. 5 (2-5) 28 g of the α//3-isomer mixture was dissolved in 56 ml of methylene chloride, and 168 ml of hexane was added dropwise thereto. The resulting solution was aged at 10 °C for 3 hours, and filtered to give the title compound (21.1 g,j. 10 Call-spin isomer content: 99.5% (α-rotation isomer content: 0.1%) The melting point and 1H-NMR data were the same as those obtained in Example 2-1. Comparative Example 2 A 6.8 g of a spinning isomer mixture (spin isomer:/5-rotational isomer = 1: 15 3.4) of Comparative Example 1 obtained by using pyridine as an organic base was dissolved. In 13.6 ml of isopropanol, 40.8 ml of hexane was added dropwise thereto. The resulting solution was aged at 0 to 5 °C for 3 hours, and filtered to give the title compound (2.5 g, m.

Melting point: 63-65 ° C /3 - Variable isomer content: 99.0% (α - Cyclone content: 0.6%) 20 [Simple description of the diagram] (None) [Key component symbol description] (None ) 16

Claims (1)

200900417 X. Patent application scope: 1. A method for preparing trioxo-5-deoxy-/3-D-ribofuranose of formula (I), comprising the steps of: (1) in an alkylamine or a cyclic amine The reaction of the compound of the formula (III) with acetic anhydride in an organic solvent to obtain the compound of the formula (II); and (ii) the separation of the compound of the formula (I) and the formula by recrystallization using a solvent and an antisolvent II) Compound: 2. The method of claim 1, wherein the alkylamine or cyclic amine used in the step (i) is selected from the group consisting of triethylamine, n-tributylamine, dicyclohexylamine, and tetramethyl Ethylenediamine, diisopropylethylamine, N-methylmorpholine and 3. The method of claim 2, wherein the amount of the alkylamine or cyclic amine ranges from 3 to 12 mole equivalents based on the compound of formula (III). 4. The method of claim 1, wherein the solvent used in the step (ii) is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, acetone, acetonitrile, tetrahydrofuran, A group consisting of chloroform, dichlorodecane, ethyl acetate, diethyl ether, and mixtures thereof. The method of claim 1, wherein the anti-solvent used in the step (ii) is selected from the group consisting of n-hexane, heptane, octane, decane, petroleum ether, and isopropyl ether. , a group of water and its mixture. 6. The method of claim 4, wherein the solvent is isopropyl alcohol and the anti-solvent is hexamethylene or water. 18 200900417 VII. Designated representative map: (1) The representative representative of the case is: ( ). (None) ' (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: