CN102584922B - Method for preparing stavudine - Google Patents
Method for preparing stavudine Download PDFInfo
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- CN102584922B CN102584922B CN201110455907.3A CN201110455907A CN102584922B CN 102584922 B CN102584922 B CN 102584922B CN 201110455907 A CN201110455907 A CN 201110455907A CN 102584922 B CN102584922 B CN 102584922B
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- stavudine
- propionyl
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Abstract
The invention discloses a method for preparing stavudine shown as a formula (V). The method comprises the following steps of: (a) performing reductive elimination reaction on 3',5'-O-dipropionyl-2'-bromo-5-methyluridine shown as a formula (III) under the action of a Zn/ CuSO4 catalysis system to obtain 5'-O-propionyl-2',3'-didehydro-3'-deoxythymidine shown as a formula (IV), wherein the molar ratio of Zn to CuSO4 in the Zn/ CuSO4 catalysis system is (5-16): 1; and (b) removing propionyl from the 5'-O-propionyl-2',3'-didehydro-3'-deoxythymidine, and thus obtaining the stavudine. The method is high in yield, good in quality, convenient to operate, low in cost and suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of stavudine.
Background technology
Stavudine, chemistry is by name 2 ', 3 '-bis-dehydrogenation-3 '-deoxythymidine (being compound V), is a kind of reverse transcriptase inhibitors of the treatment for immune deficiency syndrome (acquired immune deficiency syndrome (AIDS)).Use clinically in a large number because it has the inexpensive advantage of high-efficiency low-toxicity, the existing method of preparing stavudine has a lot, but still has some technological deficiencies, as: cost is high, prepares on a large scale yield low, manufacturing conditions harshness.These all need further research with improve, therefore develop that a kind of yield is high, cost is low, easy preparation and to be suitable for the method for stavudine of suitability for industrialized production necessary.
The synthetic route of (the compound V) of the stavudine of reporting on document is at present mainly that specifically route is as follows taking beta-thymidine (Compound I) and methyl uracil (Compound I I) as starting raw material:
1, the synthetic stavudine taking beta-thymidine as raw material:
Route one: through 2, the synthetic stavudine of 3 '-dehydration thymidine intermediate (1. fine-chemical intermediate, 14-17,
02 (36), 2006)
Route two: through 3 ', the synthetic stavudine (2.US5539099A (1996)) of 5 '-dehydration thymidine intermediate
2, the synthetic stavudine taking methyl uracil as raw material:
Route three: through 2 ', 3 '-ring thiocarbonic ester-5-methyl-uridin intermediate prepare stavudine (3.J Org Chem, 2217-2225,
54, 1989)
Route four: through 2 ', 3 '-ring ortho-formiate-5-methyl-uridin intermediate is prepared stavudine (4.EP0519464A1 (1992); 5.Drugs Fut, 925-932,19 (10), 1994)
Route five: through 2 ', 2 '-dehydration-5-methyl-uridin intermediate prepare stavudine (6.JOrg Chem, 4780-4785,
54 (20), 1989; 7.CN1324800A (2001); 8. Chinese Journal of Pharmaceuticals, 403-404,
38 (6), 2007)
In above-mentioned route, route one has been used high boiling solvent DMF and DMSO, the pyridine of foul odour, aftertreatment difficulty.
Route two and route three raw and auxiliary materials are more expensive, and cost is high.
Glycosidic bond easy fracture in route four reaction process, the chest pyrimidine of generation is removed with other by products are more difficult.
Contrast above route and find, the two respectively has superiority, taking beta-thymidine as starting raw material, easy and simple to handle, and beta-thymidine is produced in a large number at present, is convenient to suitability for industrialized production.And using methyl uracil as raw material, cost is low.
But the industrial beta-thymidine of preparing is mainly taking methyl uracil as raw material, through acidylate, the bromo of propionyl bromide, shortening, alcoholysis and obtain, technique is as follows: (9.CN1216766A (1999))
Therefore from considering economically, the route taking methyl uracil as raw material is reasonable just before dawn.Route five has the following advantages compared with other routes, as: 1, raw and auxiliary material is cheap and easy to get; 2, reactions steps is few, easy and simple to handle; 3, reactant is stablized single; 4, owing to first methyl uracil being converted into 2, the methyl uracil of 2 '-dehydration, this compound is not easy fracture of glycosidic bond in acidic medium, has reduced the generation of by product, thereby has improved yield and the purity of reaction.In route five, react and make 3 ' with propionyl bromide with methyl uracil simultaneously; this step process of 5 '-O-, bis-propionyl-2 '-bromo-5-methyl-uridins (compound III) is also the current domestic main technological route for the preparation of beta-thymidine; therefore route five combines the advantage of the two; both reached and reduced costs; simplifying again the object of technological operation, is the current industrial the most frequently used synthetic method of preparing stavudine.But this operational path overall yield is on the low side, so if can improve the yield of this technique, the industrial production of will going a long way greatly.
In route five, prepare IV by III, owing to adopting the easy inactivation of Zn-Cu title complex, necessary immediate system is standby.Zn-Cu title complex, can be through Zn/ (CH
3cOO)
2cu.H
2o now-making-now-using (6.J Org Chem, 4780-4785,
54 (20), 1989), industrial operation has certain inconvenience, and neutralized verdigris cost is relatively high.This step is the route five industrial bottleneck of restriction at present.
For this reason, the present invention has carried out process modification to the catalyst system of route five, adopts the Zn/CuSO that optimizes consumption
4catalyst system, yield reaches 65%, and prior art yield is 46.2%, sees patent CN1324800A (2001), and therefore to have cost low, easy to operate in the present invention, product yield high.
Summary of the invention
The technical problem to be solved in the present invention is to provide that a kind of yield is high, quality good, easy to operate, cost is low, is applicable to the synthetic method of the stavudine of suitability for industrialized production.
For solving the problems of the technologies described above, adopt following technical scheme:
The preparation method of the stavudine shown in a kind of formula (V), comprises the following steps:
(a) taking the mixed solvent of ethyl acetate and acetic acid as reaction solvent, 3 ', 5 '-O-, the bis-propionyl-2 '-bromo-5-methyl-uridins shown in formula (III) are at Zn/CuSO
4under catalyst system effect, eliminate reaction through reduction and obtain the 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione shown in formula (IV); Described Zn/CuSO
4in catalyst system, Zn and CuSO
4mol ratio be 5～16: 1;
(b) 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione removes propionyl and obtains stavudine;
In described step (a), described Zn/CuSO
4catalyst system adopts the mixture of zinc powder and cupric sulfate pentahydrate, preferably Zn and CuSO
4mol ratio be 8～10: 1.
In described step (a), temperature of reaction is preferably-5 DEG C to 0 DEG C.
In described step (a), 3 ', 5 '-O-, bis-propionyl-2 '-bromo-5-methyl-uridins and the GuSO shown in formula (III)
4mole proportioning be 1.0: 0.25～0.40.
In described step (a), described reduction is eliminated reaction using the mixed solvent of ethyl acetate and acetic acid as reaction solvent; In the mixed solvent of described ethyl acetate and acetic acid, the volume ratio of ethyl acetate and acetic acid is 1: 0.5～1.0.
After the reduction of described step (a) is eliminated and reacted completely, gained reaction mixture obtains 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione through aftertreatment.Described post-treating method is: reaction mixture first filters zinc powder, and the extremely surplus a small amount of ethyl acetate (not needing evaporate to dryness) of filtrate steaming, gets methylene dichloride and water adds, and fully stirs rear stratification; Get organic layer and steam methylene dichloride to oily matter, add water to stir and spend the night, filter, 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione is dried and obtained to filter cake.
In described step (b), 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione can adopt the disclosed method of prior art to remove propionyl and obtain stavudine.
The concrete 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione of recommending of the present invention, using methyl alcohol as reaction solvent, removes propionyl under sodium methylate effect.
Further, sodium methylate and 3 ', the molar ratio of 5 '-O-, bis-propionyl-2 '-bromo-5-methyl-uridins is 0.8～1.2: 10.0.
Further, the temperature of reaction of described step (b) is 25～30 DEG C, and the reaction times is 5-6 hour.
Further, described step (b), after reacting completely, is used acetic acid to regulate reaction system pH=6, then obtains stavudine by ordinary method separation and purification.
The present invention has following useful result:
1. reduced production cost.2. improved the yield of product.3. constant product quality, industrial operation is simpler.
Embodiment
Below in conjunction with embodiment, the invention will be further described:
Embodiment 1: the preparation of stavudine
Get cupric sulfate pentahydrate (4g), bromo-derivative (compound III) (21.8g, 50mmol) is sneaked in reaction flask with 60ml ethyl acetate and 40ml acetic acid, stirs.Be incubated-5 DEG C to 0 DEG C, slowly add 9.8g zinc powder in batches, and put plate and follow the tracks of reaction.When after the basic disappearance of raw material point, filtration zinc powder, the extremely surplus a small amount of ethyl acetate (not needing evaporate to dryness) of filtrate steaming, gets 120g methylene dichloride and 100ml water adds, the rear stratification of abundant stirring.Water layer is used 80ml dichloromethane extraction again, after combined dichloromethane, steams methylene dichloride to oily matter, adds the stirring of 100ml water and spends the night.Next day, filter washing, filter cake washing is dried, and obtains 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione.
5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione is mixed with methyl alcohol and the 0.27g sodium methylate (5mmol) of 100ml, at 25 DEG C, stir 5-6 hour; react, adjusted pH=6, evaporated under reduced pressure methyl alcohol with acetic acid; add 0.3 gram of activated carbon; 100mL acetone, temperature rising reflux, filtration of active charcoal; crystallisation by cooling; obtain 7.3 grams of stavudines, purity: 99.35%, yield: 65%.Fusing point: 165.4～166.8 DEG C.Specific rotation value: [α]
20 d=-44.8 ° (c=0.6, water).
Structural characterization is as follows:
Hydrogen spectrum (
1h-NMR) (DMSO-d
6) δ: 1.71 (s, 3H), 3.61 (m, 2H), 4.77 (m, 1H), 4.95 (s, 1H), 5.90 (d, J=5.6Hz, 1H), 6.39 (d, J=5.6Hz, 1H), 6.82 (s, 1H), 7.62 (s, 1H), 11.21 (s, 1H).Mass spectrum (ESI-MS): 223 (M-1).Infrared IR (KBr, cm
-1): 852,1091,1252,1468,1689,3034,3454.Ultimate analysis (C
10h
12n
2o
4, %) and (measured value/calculated value): C 53.52/53.57, H 5.42/5.39, N12.41/12.49.
Embodiment 2-10
Change raw material consumption and the condition shown in embodiment 1, thereby the product result obtaining is as shown in table 1.
Table 1
Within invention simple replacement or the improvement etc. done all being belonged to those skilled in that art the technical scheme that the present invention protects.
Claims (8)
1. a preparation method for the stavudine shown in formula (V), comprises the following steps:
(a) taking the mixed solvent of ethyl acetate and acetic acid as reaction solvent, 3 ', 5 '-O-, the bis-propionyl-2 '-bromo-5-methyl-uridins shown in formula (III) are at Zn/CuSO
4under catalyst system effect, eliminate reaction through reduction and obtain the 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione shown in formula (IV); Described Zn/CuSO
4catalyst system adopts the mixture of zinc powder and cupric sulfate pentahydrate, described Zn/CuSO
4in catalyst system, Zn and CuSO
4mol ratio be 5～16:1;
(b) 5 '-O-propionyl-1-(5-Hydroxymethyl-2,5-dihydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-dione removes propionyl and obtains stavudine;
2. the preparation method of stavudine according to claim 1, is characterized in that: in described step (a), it is-5 DEG C to 0 DEG C that temperature of reaction is eliminated in reduction.
3. the preparation method of stavudine according to claim 1, is characterized in that: in described step (a), and 3 ', 5 '-O-, bis-propionyl-2 '-bromo-5-methyl-uridins and the CuSO shown in formula (III)
4mole proportioning be 1.0:0.25～0.40.
4. the preparation method of stavudine according to claim 1, is characterized in that: in the mixed solvent of described ethyl acetate and acetic acid, the volume ratio of ethyl acetate and acetic acid is 1:0.5～1.0.
5. the preparation method of stavudine according to claim 4, is characterized in that: in described step (a), it is-5 DEG C to 0 DEG C that temperature of reaction is eliminated in reduction; 3 ', 5 '-O-, bis-propionyl-2 '-bromo-5-methyl-uridins and CuSO shown in formula (III)
4mole proportioning be 1.0:0.25～0.40.
6. the preparation method of stavudine according to claim 5, is characterized in that: described Zn/CuSO
4in catalyst system, Zn and CuSO
4mol ratio be 8～10:1.
7. according to the preparation method of the stavudine one of claim 1～6 Suo Shu, it is characterized in that: the molar ratio of described sodium methylate and 3 ', 5 '-O-, bis-propionyl-2 '-bromo-5-methyl-uridins is 0.8～1.2:10.0.
8. according to the preparation method of the stavudine one of claim 1～6 Suo Shu, it is characterized in that: in described step (b), temperature of reaction is 25～30 DEG C, and the reaction times is 5-6 hour.
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Inventor after: You Jinzong Inventor after: Jiang Shanhui Inventor after: Wang Xuejie Inventor after: Shao Shuang Inventor after: Ren Haihua Inventor after: He Jianshi Inventor after: Cai Jinyuan Inventor before: You Jinzong Inventor before: Jiang Shanhui Inventor before: Zhao Kun Inventor before: Xu Huigang Inventor before: Cai Jinyuan Inventor before: He Jianshi Inventor before: Ren Haihua Inventor before: Ye Rui |
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