WO2008092405A1

WO2008092405A1 - Method for synthesizing 1,2,3-tri-o-acetyl-5-deoxy-d-ribose

Info

Publication number: WO2008092405A1
Application number: PCT/CN2008/070190
Authority: WO
Inventors: Chengju Wang; Donglin Tang
Original assignee: Donglin Tang; Chengju Wang
Priority date: 2007-01-30
Filing date: 2008-01-25
Publication date: 2008-08-07
Also published as: CN100432088C; CN101012252A

Abstract

The invention discloses a method for synthesizing 1,2,3-tri-O-acetyl-5-deoxy-D -ribose, an intermediate of nucleotide compounds: using inosine as starting material and firstly reacting inosine with iodine in an organic solvent to obtain 5-iodo-5-deoxyinosine; then using Ni as a catalyst, introducing hydrogen in liquid phase to obtain 5-deoxyinosine; reacting the obtained 5-deoxyinosine with acetic anhydride in an organic solvent to obtain 2,3-di-O-acyl-5-deoxyinosine; and lastly treating the obtained 2,3-di-O-acyl-5-deoxyinosine with a strong-acid cation exchange resin in acetic anhydride-acetic acid mixed solvent to break bond and remove glycoside to obtain the target product 1,2,3-tri-O-acetyl-5-deoxy-D-ribose. The method has the advantages of raw material easy to get and cheap, operation and control simple, and yield of every unit reaction high; and total yield of the method is up to 61.5%.

Description

1, 2, 3-tri-O-acetyl-5-deoxy-D-ribose synthesis method

The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a method for synthesizing an antitumor nucleoside drug intermediate 5-deoxy-D-ribose, in particular to 1,2,3-tri-O-acetyl A method for the synthesis of keto-5-deoxy-D-ribose intermediates. Background technique

1, 2, 3-Tri-O-acetyl-5-deoxy-D-ribose is an intermediate for the synthesis of nucleoside drugs. At present, the synthesis method of the intermediate is mainly prepared by reacting five-carbon sugar or penta-deoxyribose as raw materials with acetic anhydride, and the raw materials thereof are difficult to obtain, and the intermediates prepared are high in cost. Summary of the invention

-D-ribose, especially 1,2,3-tri-O-acetyl-5-deoxy-D-ribose, the technical problem to be solved is to seek a new synthetic starting material for the intermediate and a novel synthesis method thereof .

The technical scheme of the present invention is as follows:

The present invention provides a method for synthesizing 5-deoxy-D-ribose represented by the formula I, characterized in that the inosine of the formula V is used as a raw material, and the compound of the formula I is obtained by the following steps:

(1) The hydroxymethylene group at the 5-position of the inosine is converted to a methyl group to prepare 5-deoxyinosine of the formula III.

III (2) ⁵ -deoxyinosine via hydroxyglycoside to produce 5-deoxy-D-ribose of formula I

III wherein Ri, R ₂ and R _{3 are the} same or different and each independently is a hydroxy protecting group. Among them, hydroxy protecting groups are well known to the skilled person in the field of organic chemistry, and examples thereof can be found in Greene & Wuts, "protective groups in organic synthesis", John Wiley & Sons, NY (1991). Preferably the present invention wherein R _2, R ₃ are the same, are an acetyl group.

In the above-mentioned method, wherein in the step (1), the inosine is halogenated to form a 5-substituted-5-deoxyinosine of the formula IV, and then hydrogenated to obtain a 5-deoxy muscle of the formula III. Glycosides

Wherein X is a halogen atom such as bromine, iodine or the like, and among them, iodine is preferred.

The method according to the above, wherein, in the step (2), the hydroxyl group on the 5-deoxyinosine saccharide is protected to form 5-deoxyinosine of the formula II, then the deglycosyl group and the hydroxy group are protected. I

5-deoxy-D-ribose

Wherein Ri, R ₂ and R _{3 are the} same or different and are each independently a hydroxy protecting group. Hydroxy protecting groups, which are well known to the skilled person in the field of organic chemistry, are described, for example, in Greene & Wuts, "protective groups in organic synthesis", John Wiley & Sons, NY (1991). In the present invention, it is preferred that R ₂ and R _{3 are the} same and both are acetyl groups.

As a specific embodiment of the present invention, wherein 1,2,3-tri-O-acetyl-5-deoxy-D represented by formula la is obtained by the method comprising the following steps, using inosine of the formula V as a raw material -ribose: (1) 5-inodo-5-deoxyinosine of formula IVa is prepared by reacting inosine of formula V with iodine in an organic solvent.

V IVa

(2) 5-iodo-5- off of formula IVa

5-deoxyinosine of formula III

IVa III

Wherein Ac represents an acetyl group;

(4) In the mixed solvent of acetic anhydride and acetic acid, 2, 3-di-0-acetyl-5-deoxyinosine of the formula Ila is deactivated by a strong acidic cationic resin to obtain 1, 2, 3-Tri-0-acetyl-5-deoxy-D-ribose

Ila la wherein Ac represents an acetyl group.

Wherein the method described above, wherein in the step (1), the inosine of the formula V is in the fluorene, in the presence of an imidazole and a triphenylphosphine catalyst, at 80-120 ° C with iodine 5-Iodo-5-deoxyinosine of formula IVa is formed by reacting for 4-6 hours, wherein the mass ratio of inosine to imidazole, inosine and triphenylphosphine, and inosine and iodine are 1: 0.8-1.4, 1: 1 ~ 1.4 and 1: 0.9~1.4.

Wherein, in the above-mentioned method, in the step (2), 5-iodo-5-deoxyinosine of the formula IVa is reacted with hydrogen in the presence of triethylamine in methanol with nickel as a catalyst. 5-Deoxyinosine of formula III is produced wherein the amount of nickel is from 30 to 50% of 5-iodo-5-deoxyinosine of formula IVa.

Wherein, in the above-mentioned method, wherein in the step (3), the 5-deoxyinosine of the formula III is reacted with acetic anhydride at 40 to 50 ° C in the presence of triethylamine in dichloromethane. 2, 3-Di-0-acetyl-5-deoxyinosine of the formula Ila is formed in 1 to 3 hours.

Wherein, in the above-mentioned method, wherein in the step (4), 2,3-di-0-acetyl-5-deoxyinosine of the formula Ila is added to a mixed solvent of acetic anhydride and acetic acid, and then added The strongly acidic cationic resin is heated under reflux for 4-8 hours to form 1,2,3-tri-O-acetyl-5-deoxy-D-ribose of the formula la. More specifically, the synthesis process is as follows:

1. Preparation of intermediates by iodination 5-iodo-5-deoxyinosine

Using DMF as solvent, inosine is reacted with iodine added in batches at 80-120 ° C for 4-6 hours in the presence of the catalyst imidazole and triphenylphosphine, then methanol is neutralized, and finally 5-10% (quality) Percentage, the same as) sulfite saturated brine solution (that is, adding NaCl to saturation in 5 ~ 10% sulfurous acid solution), stirring for 20 to 30 minutes, standing, freezing and crystallization, filtering, and filtering the residue with toluene to obtain a white solid. The product 5-iodo-5-deoxyinosine, the mass ratio of inosine to imidazole, triphenylphosphine and iodine was 1: 0.8 - 1.4, 1: 1 ~ 1.4 and 1: 0.9 - 1.4, respectively.

2. Hydrogenation to prepare intermediates 5-deoxyinosine

Using methanol as solvent and nickel as catalyst, hydrogen and intermediate 5-iodo-5-deoxyinosine were reacted to the end point in the presence of room temperature and triethylamine, then filtered, and the filtrate was concentrated, cooled and crystallized, and separated. The white crystal is the intermediate product 5-deoxyinosine, and the amount of nickel is 30 to 50% of the intermediate 5-iodo-5-deoxyinosine.

3. Preparation of an intermediate by acylation 2, 3-di-O-acetyl-5-deoxyinosine

Using dichloroethane as a solvent, the intermediate product 5-deoxyinosine and acetic anhydride are reacted at 40-50 ° C for 1 to 3 hours in the presence of triethylamine, concentrated and crystallized, and separated to obtain a white powder, intermediate product 2, 3-Di-0-acetyl-5-deoxyinosine.

4. Preparation of the target product from the intermediate product 2, 3-di-O-acetyl-5-deoxyinosine

The intermediate 2, 3-di-O-acetyl-5-deoxyinosine is added to a mixed solution of acetic anhydride and acetic acid, heated and heated under the action of a strong acidic cationic resin for 4-8 hours, cooled and filtered and separated. The filtrate was concentrated to dryness, and an aqueous methanol solution (methanol to water volume ratio of 3:1) was added. After dissolution, the crystals were allowed to stand for crystallization and separation to obtain white crystals, i.e., the target product 1, 2, 3-tri-O-acetyl-5-deoxy- D-ribose.

The synthetic route is as follows:

Inosine

2, 3-di-O-acetyl-5-deoxyinosine

Acetic anhydride / resin

1, 2, 3-Tri-O-acetyl-5-deoxy-D-ribose The synthesis method of the present invention is to first convert a hydroxymethylene group at the 5-position of the glycosidic group to a methyl group to obtain a 5-deoxygen muscle. Glycosides. The hydroxy group on the two sides of the glycosidic group 2, 3 is then acetylated to give 2,3-di-0-acetyl-5-deoxyinosine. Finally, the deglycosyl group is simultaneously acetylated at the 1-position to give the target product. 5%。 Compared with the prior art, the main difference is that the inosine as a starting material, the raw material is easy to obtain and the price is low, the operation and control are simple, the reaction yield of each unit is high, the total yield is 61.5%. The product has a melting point of 66 to 67 °C. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be further described by way of examples. The described embodiments are not to be construed as limiting the scope or spirit of the invention.

Example 1: Preparation of intermediate 5-iodo-5-deoxyinosine (IVa)

50g (0.187mol) of inosine and catalyst imidazole and triphenylphosphine were added to DMF and stirred, wherein the amount of imidazole should be 45g ~ 65g, the amount of triphenylphosphine added is 55g ~ 65g, the amount of DMF added is 75ml ~ 150ml, oil bath Heating, the reaction temperature is controlled between 80 ° C ~ 120 ° C, the iodine is added in three batches, the amount of iodine is 50g ~ 65g, the reaction time is 4 ~ 6 hours, TCL detection reaction is finished with 75ml methanol neutralization, stirring half Hour, add 100ml ~ 400ml 8% sulfuric acid saturated brine solution, stir for half an hour, put it in the refrigerator for freezing overnight, crystallize, filter, filter residue with toluene wash 3~6 times, get white solid (IVa) 64g, yield 90% . The HPLC detection content is greater than 98%. Example 2: Preparation of intermediate 5-deoxyinosine (III)

50g 5 -殃_5_deoxyinosine is added to 250ml ~ 500ml methanol, 30ml ~ 55ml triethylamine, 20g nickel catalyst is added, hydrogen reaction is carried out at room temperature for 12-24 hours, the raw material point disappears by TCL, and the reaction is terminated. The reaction solution was filtered, the catalyst was removed, and the filtrate was concentrated to a minimum amount. The crystals were cooled and filtered to yield white crystals (30 g). The HPLC detection content is greater than 98.5%. Example 3: Preparation of 2, 3-di-O-acetyl-5-deoxy-inosine (Ila)

50g (0.198) 5_deoxyinosine is added to 100ml of dichloromethane, 20ml ~ 55ml of triethylamine and 40~80ml of acetic anhydride are added to react at 40 °C ~ 50 °C for 1-3 hours, TCL detection, reaction is concentrated The amount was crystallized at least, and 63.3 g of a white powder was obtained by filtration, yield 95%. The HPLC detection content is greater than 98%. Example 4: Preparation of 1,2,3-tri-O-acetyl-5-deoxy-D-ribose

20g 2, 3 - 2-0-acetyl-5-deoxy-inosine is added to 50 ml ~ 120 ml of acetic anhydride. Add 5ml ~ 10ml acetic acid. Add 3-5g 732 resin after heating and dissolve, heat and reflux for 4~8 hours, TCL detection reaction is finished, filter, rinse the filter residue with acetic anhydride for 2 times, collect the filtrate to dryness, add The aqueous methanol solution was dissolved, crystallized, and separated to obtain a white crystal of 12.5 g in a yield of 80%. Melting point: 66~ 67 °C; MS- EI m/z: 261 [M+H]+. Elemental analysis: C11H1607, calculated (%): C 50.77, H 6.15; Found (%): C 50.68, H 6.03. 'H-NMR (300MHz, CDC1 ₃ ) δ 1.36-1.38 (3H, -CH ₃ ) , 2.06-2.12 (9H, C0CH ₃ ) , 4.25-4.29 (1H, 5-position hydrogen on sugar), 5.08-5.33 (2H , 3 and 4 on the sugar are hydrogen), 6.11 (1H, 2 hydrogen on the sugar). The invention has been described in terms of a preferred embodiment. It is to be understood that the foregoing description and embodiments are merely illustrative of the invention. Numerous alternatives and modifications of the invention may be devised by those skilled in the art without departing from the spirit and scope of the invention.

Claims

Claim

A method for synthesizing 5-deoxy-D-ribose represented by Formula I, characterized in that the inosine of the formula V is used as a raw material, and the compound of the formula I is obtained by the following steps:

V III

(2) 5-deoxygen

III wherein, Ri, R _2, R ₃ the same or different, _2, R is independently the same as a hydroxy protecting group, preferably Ri, R _3, are an acetyl group.

2. The method according to claim 1, wherein in the step (1), the inosine is halogenated to form a 5-halo-5-deoxyinosine of the formula IV, and then hydrogenated to obtain a formula. 5-deoxyinosine III

V IV III Wherein X is a halogen atom, preferably iodine.

The method according to claim 1 or 2, wherein in the step (2), the hydroxyl group on the 5-deoxyinosine saccharide is protected to form 5-deoxyinosine of the formula II, and then a deglycosyl group. And protecting the hydroxyl group to produce 5-deoxy-D-ribose of formula I

II I wherein Ri, R ₂ and R _{3 are the} same or different, and each independently is a hydroxy protecting group, and preferably Ri, R ₂ and R _{3 are the} same, and all are acetyl groups.

The method according to claim 3, wherein the inosine of the formula V is used as a raw material, and the 1, 2, 3-tri-O-acetyl group represented by the formula la is obtained by a method comprising the following steps: 5-deoxy-D-ribose:

(1) 5-inodo-5-deoxyinosine of formula IVa is prepared by reacting inosine of formula V with iodine in an organic solvent.

Preparation of 5-deoxyinosine of formula III

(3) The 5-deoxyinosine of the formula III is reacted with acetic anhydride in an organic solvent to prepare 2,3-di-O-acetyl-5-deoxyinosine of the formula Ila.

III Ila wherein, Ac represents an acetyl group;

(4) In a mixed solvent of acetic anhydride and acetic acid, 2, 3-di-0-acetyl-5-deoxyinosine of the formula Ila is deactivated by a strong acidic cationic resin to obtain a formula 1 of 2, 3-Tri-0-acetyl-5-deoxy-D-ribose

Ila la wherein AC represents an acetyl group.

The method according to claim 4, wherein in the step (1), the inosine of the formula V is in DMF, in the presence of an imidazole and a triphenylphosphine catalyst, at 80-120 ° C. 5-iodo-5-deoxyinosine of formula IVa is formed by iodine reaction for 4-6 hours, wherein the mass ratio of inosine to imidazole, inosine and triphenylphosphine and inosine and iodine are 1: 0.8~1.4 1, 1: ~ 1.4 and 1: 0.9 ~ 1.4.

The method according to claim 4, wherein in the step (2), 5-iodine of the formula IVa Dehydro-5-deoxyinosine is reacted with hydrogen in methanol in the presence of triethylamine to form 5-deoxyinosine of formula III, wherein the amount of nickel is 5-iodo-5 of formula IVa. - 30 to 50% of deoxyinosine.

The method according to claim 4, wherein in the step (3), the 5-deoxyinosine of the formula III is in methylene chloride in the presence of triethylamine at 40 to 50 ° with acetic anhydride. C reaction

2, 3-di-O-acetyl-5-deoxyinosine of formula Ila is formed in 1 to 3 hours.

The method according to claim 4, wherein in the step (4), 2,3-di-0-acetyl-5-deoxyinosine of the formula Ila is added to a mixed solvent of acetic anhydride and acetic acid, Further, a strong acid cation resin is added and heated under reflux for 4 to 8 hours to form 1,2,3-tris--0-acetyl-5-deoxy-D-ribose of the formula la.