CN1310936C

CN1310936C - Industrial process for preparing beta-thymidine

Info

Publication number: CN1310936C
Application number: CNB2004100902505A
Authority: CN
Inventors: 吴发明; 宁向阳
Original assignee: Zhejiang Shaxing Pharma & Chemical Co Ltd
Current assignee: Zhejiang Pharmaceutical Co., Ltd.
Priority date: 2004-10-28
Filing date: 2004-10-28
Publication date: 2007-04-18
Anticipated expiration: 2024-10-28
Also published as: CN1634959A

Abstract

The present invention relates to a four-step synthetic method of the industrial preparation of beta-thymidine, which belongs to the medical midbody field. The four-step synthetic method is characterized in that D-ribose is used as starting raw materials which are firstly directly condensed with thymine, the D-ribose carries out halogenation-acylation reaction with propionyl chloride and is reduced by catalytic hydrogenation, and finally, the D-ribose is converted to the beta-thymidine by catalytic alcoholysis, and a total yield is larger than 65%.

Description

The industrial production process of beta-thymidine

Technical field

The invention belongs to the medicine intermediate field, relate to a kind of industrial production process of beta-thymidine.

Background technology

(β-Thymidine), claim deoxythymidine (Deoxythymidine) again is the key intermediate of treatment acquired immune deficiency syndrome (AIDS) (AIDS) the neat many furans pyridine of medicine (Zidovodine) to beta-thymidine.At present, the preparation method of beta-thymidine mainly contains chemical synthesis, DNA enzymolysis process, fermentation method and 4 kinds of methods of enzyme process.At present, use having of chemical synthesis: the US4914233 (applying date: on March 1st, 1988) disclose a kind of method that changes into beta-thymidine with α, β four-O-acyl ribose, this method starting raw material is difficult for obtaining, and a, beta comfiguration proportioning raw materials be difficult for grasping, and stereoselectivity is poor; CN1055293 (the applying date: on October 6th, 1998) narrated and a kind ofly go on foot synthesis method with thymus pyrimidine and α, β-tetrem acyl-D-ribose condensation under the Louis acid catalysis effect, alcoholysis, halo one acylations, catalytic hydrogenation and alcoholysis five through protection, this method starting raw material adopts α, β-tetrem acyl-D-ribose, through condensation, alcoholysis prepares the 5-methyluridine, complex process, and the condensation catalyst employing is expensive and acid is torn in Louis that be difficult for reclaiming, and route is long, yield is low, the cost height; (applying date: on May 30th, 1994) relating to a kind of is the method for feedstock production beta-thymidine with the wooden thymidine without protection, adopts propionyl bromide in halo one acylations process, and yield is low, and equipment corrosion is serious at US5596087.

Summary of the invention

The objective of the invention is to overcome the defective of prior art, adopt novel starting raw material, a kind of economy, simple, the preparation method that cleans, be applicable to suitability for industrialized production are provided.The present invention adopts four step chemical synthesiss, is starting raw material with D-ribose, through condensation, halo one acylations, and the catalytic hydrogenation reduction, catalyzed alcoholysis prepares beta-thymidine, and its synthetic route is as follows:

5-methyluridine (IV), condensation generation 5-methyl-2 under existing document (CN1055293) employing tetrem acyl ribose and the katalysis of thymus pyrimidine at anhydrous stannic chloride through protecting ', 3 ', 5 '-O-triacetyl-β-D-ribose, make through alcoholysis, route is long again, and yield is low, the cost height, and the tin tetrachloride contaminated wastewater is serious; We adopt with D-ribose is raw material, under the katalysis of acid, makes with the direct condensation of thymus pyrimidine.The consumption of D-ribose (II) is 0.8-1.3 times (mol ratio) of thymus pyrimidine (III), and preferably 0.9-1.1 doubly; Catalyzer is the vitriol oil, oleum, and consumption is 3-1O times (mol ratio) of thymus pyrimidine (III), and preferably 4-6 doubly; Dropping temperature is-10--40 ℃, and preferably 0--30 ℃; Reaction solvent is methylene dichloride, chloroform, ethyl acetate, toluene, dimethylbenzene, hexane, acetonitrile, DMF; Reaction times is 2-20 hour, preferably 8-12 hour.This reaction stereoselectivity is strong, and the content of beta isomer is more than 99%.

2 '-halo-2 '-deoxidation-5-methyl-3 ', 5 '-O-alkyloyl-β-D-ribose uridine (V), existing document (US5596087) adopts 5-methyluridine (IV) and propionyl bromide generation halo one acylation reaction to make, and propionyl bromide price height, equipment corrosion is serious; We adopt propionyl chloride to make halo one acylting agent, the yield height, and cost is low.The consumption of propionyl chloride is 2-8 times (mol ratio) of 5-methyluridine (IV), and preferably 3-6 doubly; Reaction solvent is selected from acetonitrile, ethyl acetate, and methyl propionate, toluene, dimethylbenzene, hexane, methylene dichloride, DMF can be single solvents, also can be mixed solvents; Temperature of reaction is 30--90 ℃, is preferably 50--70 ℃; Reaction times is 1-10 hour, preferably 2-6 hour.

2 '-deoxidation-5-methyl-3 '; 5 '-O-alkyloyl-β-D ribose uridine (VI), make in following condition: under the A. normal pressure, 2 '-halo-2 '-deoxidation-5-methyl-3 '; 5 '-the logical hydrogen blistering reaction under catalyst action of O-alkyloyl-β-D-ribose uridine (V), the logical hydrogen of B. is to 2-5 * 10 ⁵Pa, 2 '-halo-2 '-deoxidation-5-methyl-3 ', 5 '-O-alkyloyl-β-D-ribose uridine (V) reacts under catalyst action.Catalyzer comprises Ru/c, Pd/c, Pd/CaCO ₃, Pd/BaSO ₄, PdCl ₂, Raney-Ni and nickel alloy catalyst, catalyst consumption is the 1-6 doubly (mol ratio) of compound (V), preferably 3-5 doubly; Reaction solvent comprises methyl alcohol, ethanol, benzene, toluene, chloroform, methylene dichloride, methanol, ethanol/water, benzene/water, toluene, chloroform/water, methylene dichloride/water; In order to keep the potential of hydrogen of reaction system, must add a certain amount of sodium-acetate, sodium bicarbonate, yellow soda ash; Temperature of reaction 10--50 ℃, preferably 20--30 ℃; Reaction times is 2-20 hour, preferably 3-6 hour.

Beta-thymidine (I), by 2 '-deoxidation-5-methyl-3 ', 5 '-O-alkyloyl-β-D ribose uridine (VI) makes through catalyzed alcoholysis.Alcoholysis reagent comprises methyl alcohol, ethanol, propyl alcohol, Virahol, butanols; Catalyzer comprises ammonia, sodium methylate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate; Temperature of reaction is 0--60 ℃, preferably 20--30 ℃; Reaction times is 5-30 hour, preferably 10-15 hour.

The present invention has overcome the defective that prior art exists, and is starting raw material with D-ribose, directly is condensed into the 5-methyluridine under the katalysis of the vitriol oil, shortens synthetic route; Make halo one acylting agent with propionyl chloride, production technique is simple, mild condition, and product yield is higher, and production cost is reduced greatly, is adapted to suitability for industrialized production.

Embodiment

Example 1:

Having agitator, thermometer, add D-ribose 15g (0.1mol) in the 250ml there-necked flask of dropping funnel, methylene dichloride 150ml, be stirred to dissolving, add thymus pyrimidine 12.5g again, (0.1mol), be cooled to below 10 ℃, the vitriol oil 12ml of dropping 98.5%, finish, be warming up to 20-25 ℃ naturally, stirring reaction 10 hours, add water, stir layering, the water layer dichloromethane extraction merges organic layer, steaming vibrating dichloromethane, ethyl alcohol recrystallization gets off-white color 5-methyluridine 23g, content (HPLC): 99.2%, and fusing point: 181-185 ℃: yield: 89.14%.

Example 2:

In the there-necked flask of the 500ml that has agitator, thermometer, add acetonitrile 150ml; propionyl chloride 30g (0.42mol); be warming up to 50 ℃; add 5-methyluridine 20g (0.077mol), 60 ℃ of insulated and stirred were reacted 3 hours, steamed acetonitrile in batches; cooling; add water 200ml, be cooled to below 5 ℃, insulated and stirred 2 hours; suction filtration; the washing, drying, faint yellow solid 2 '-chloro-2 '-deoxidation-5-methyl-3 '; 5 '-O-alkyloyl-β-D-ribose uridine 28g; fusing point: 132-134 ℃, content (HPLC): 97.3%, yield: 93%.

Example 3:

In autoclave, add 2 '-chloro-2 '-deoxidation-5-methyl 4-3 ', 5 '-O-alkyloyl-β-D-ribose uridine 39g (0.1mol), add methanol (1: 0.3) 400ml; sodium-acetate 12.5g (0.15mol); stirring and dissolving adds Pd/C40g, logical hydrogen to 3 * 10 ⁵Pa, 25--30 ℃ of reaction 4 hours, elimination catalyzer, concentrating under reduced pressure got thick thing, are directly used in the next step.

Example 4:

Charging capacity such as example 3, logical hydrogen blistering under the normal pressure, 25--30 ℃ of reaction 5 hours, concentrating under reduced pressure got thick thing, is directly used in the next step.

Example 5:

In having the 500ml there-necked flask of agitator, thermometer, add the whole products of embodiment 3 gained, add ammonia/methyl alcohol (7%) 250ml, 20-30 ℃ of stirring reaction 10 hours concentrates, ethyl alcohol recrystallization, filter, vacuum-drying gets beta-thymidine 19g, fusing point: 185--190 ℃, [α]=+ 17.5--+19.1 ° (c=3, H ₂O), content (HPLC): 98.5%, yield: 87%.

Example 6:

Have in the 500ml there-necked flask of agitator, thermometer, add total overall reaction product in the example 4, add methyl alcohol 250ml, add sodium methylate methanol solution (28%) 4ml, stirring reaction 8 hours, concentrate, ethyl alcohol recrystallization filters, vacuum-drying gets thymidine 20g, fusing point: 185--190 ℃, [α]=+ 17.5--+19.1 ° (c=3, H ₂O), content (HPLC): 98.5%, yield: 92%.

Claims

1, a kind of industrial production process of beta-thymidine is characterized in that with D-ribose be starting raw material, earlier with the direct condensation of thymus pyrimidine; carry out halo-acylation reaction with propionyl chloride again; through the catalytic hydrogenation reduction, after catalyzed alcoholysis is converted into beta-thymidine, its synthetic route is as follows then:

RCO in the above synthetic route represents alkyloyl,

Concrete steps are:

(1) directly reacts by D-ribose (II) and be converted into 5-methyluridine (IV) with thymus pyrimidine (III) catalyzing and condensing;

(2) compound (IV) by halo-acylation reaction be converted into 2 '-halo-2 '-deoxidation-5-methyl-3 ', 5 '-O-alkyloyl-β-D-ribose uridine (V);

(3) compound (V) by the catalytic hydrogenation reduction reaction be converted into 2 '-deoxidation-5-methyl-3 ', 5 '-O-alkyloyl-β-D-ribose uridine (VI);

(4) compound (VI) obtains beta-thymidine (I) by alcoholysis reaction in the presence of catalyzer.

2, beta-thymidine industrial production process as claimed in claim 1 is characterized in that in halo-acylation reaction, halo-acylting agent is selected propionyl chloride for use; Reaction solvent is a kind of in following these solvents: acetonitrile, ethyl acetate, methyl propionate, toluene, dimethylbenzene, hexane, methylene dichloride, DMF.

3, beta-thymidine industrial production process as claimed in claim 1 is characterized in that the catalytic hydrogenation reduction reaction carries out under one of following condition: under the A. normal pressure, and logical hydrogen blistering reaction under catalyst action; B. logical hydrogen to 2 * 1O ⁵Pa-5 * 10 ⁵Pa reacts under catalyst action, and the catalyzer in " A ", " B " condition is selected from Ru/c, Pd/c, Pd/CaCO ₃, Pd/BaSO ₄, PdCl ₂, Raney-Ni and nickel alloy catalyst.

4, beta-thymidine industrial production process according to claim 1 is characterized in that in the alcoholysis reaction, and alcoholysis reagent is a kind of in the following reagent: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols.

5, the beta-thymidine industrial production process described in claim 1 is characterized in that in the alcoholysis reaction with a kind of catalyzer of doing in the following reagent: ammonia, sodium methylate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash.