Background technology
Famciclovir (Famciclovir) is mainly used in treatment zoster, primary genitalia herpes.DNA has restraining effect to duck hepatitis B virus.Synthetic route report about famciclovir mainly contains following 3 at present:
1,2-amino-6-chloropurine and 3-N-PROPYLE BROMIDE-1,1, the condensation of 1-tricarboxylic acid triethyl generates 2-amino-6-chloro-9-(2,2-diethoxy carbonyl ethyl butyrate-4-yl) purine is again through decarboxylation, reduction and esterification preparation method VCV, 3-N-PROPYLE BROMIDE 1,1 in this route, 1-tricarboxylic acid triethyl need self-control, reaction scheme is longer relatively, and cost is higher.
2, with 2,5-diamino 4,6-dihydroxy-pyrimidine and N-alkyl chlorimide are feedstock production, and it is that raw material is more expensive that there is shortcoming in this route, and yield is lower.
3, with 1,3-diacetoxy acetone and ethene magnesium bromide are that feedstock production goes out side chain, go out famciclovir with the amino 6-chloropurine prepared in reaction of 2-again, and this route reaction step is less relatively, but reaction needs to carry out unsuitable suitability for industrialized production under low temperature-78 ℃ condition.
Summary of the invention
The purpose of this invention is to provide a kind of can overcome above-mentioned technological deficiency that existing production technique exists, can improve convergency, take into account the method for the preparation method VCV of efficient and safety standards.
The technical scheme of adopt liking is so for achieving the above object, i.e. a kind of synthetic method of famciclovir, and it is characterized in that: method may further comprise the steps:
Step (1), in reaction flask, drop into ethanol and diethyl malonate, be warming up to 30-100 ℃, add the sodium ethylate with diethyl malonate mol ratio 2.5-1.2, in 40-85 ℃ of reaction, progressively be warming up to backflow, steam ethanol, the sodium salt of diethyl malonate;
Step (2), in reaction flask, add the ethyl acetate with diethyl malonate sodium salt mol ratio 5-30, suitable water, drop into the sodium salt of diethyl malonate, be cooled to below 10 ℃, the glycol dibromide of adding and diethyl malonate sodium salt mol ratio 0.8-5, controlled temperature is no more than 20 ℃, reaction finishes. and anhydrous magnesium sulfate drying gets the bromotrifluoromethane diethyl malonate;
Add in step (3) reaction flask bromotrifluoromethane diethyl malonate and with the DMF of bromotrifluoromethane diethyl malonate mol ratio 10-150, make homogeneous solution, be warming up to 30-80 ℃, drip sodium borohydride with bromotrifluoromethane diethyl malonate mol ratio 0.5-20, keep 40-85 ℃ of temperature, react 2-8 hour dichloromethane extraction, evaporated under reduced pressure gets the bromotrifluoromethane propylene glycol;
Step (4), backflow is housed, in the reaction flask of whipping appts, add the bromotrifluoromethane propylene glycol and with the diacetyl oxide of bromotrifluoromethane propylene glycol mol ratio 0.5-10, be heated to 80-100 ℃, continue to be warming up to back flow reaction, add washing, until pH value 5-8, get 2-acetoxy-methyl-4-brombutyl acetic ester;
Step (5), in reaction flask, drop into 2-amino-6-chloropurine, with 2-acetoxy-methyl-4-brombutyl acetic ester of 2-amino-6-chloropurine mol ratio 0.5-5, with the DMF salt of wormwood of 2-amino-6-chloropurine mol ratio 0.8-20, heat 40-95 ℃ of reaction, filter, use re-crystallizing in ethyl acetate again. obtain 2-(2-acetoxy-methyl-4-brombutyl acetic ester)-6-chloropurine;
Step (6) is in reaction flask, add 2-(2-acetoxy-methyl-4-brombutyl acetic ester)-6-chloropurine, with ethyl acetate, triethylamine and 2-(the palladium carbon of 2-acetoxy-methyl-4-brombutyl acetic ester weight 0.05-5% of 2-(2-acetoxy-methyl-4-brombutyl acetic ester)-6-chloropurine mol ratio 0.1-10, feed hydrogen reaction to finishing. the reduction vaporization ethyl acetate, use ethyl acetate-methyl alcohol (1: 0.1-1 again, / V) mixed solvent recrystallization, the famciclovir finished product.
The present invention is with respect to present existing synthetic technology, and have following characteristics: reactions steps is less, and starting material are cheap and easy to get, and are simple to operate, process stabilizing, and stable and reliable product quality, cost is low, has very strong
Competitive power, help suitability for industrialized production.
Embodiment
1, the making of the sodium salt of diethyl malonate
In reaction flask, drop into ethanol 400ml and 162 gram diethyl malonates, stir, be warming up to 45 degree, add 70 gram sodium ethylates in batches, in 50 ~ 55 degree reactions 3 hours, progressively be warming up to backflow, under the reflux state, reacted again 1 hour, steam about 200ml ethanol, be cooled to room temperature, begin to occur white crystals, placement is spent the night. suction filtration, with a small amount of ether washing leaching cake, drying, get the sodium salt of diethyl malonate, the white crystals thing.
2, the making of bromotrifluoromethane diethyl malonate
In the reaction flask, add ethyl acetate 350ml, water 200ml, under the vigorous stirring, drop into sodium salt 185 grams of diethyl malonate in batches, make suspension liquid, be cooled to below 10 degree, dropwise add 1,2-ethylene dibromide 188 grams, controlled temperature is no more than 20 degree, continues reaction 3 hours, limpid to solution, reaction finishes. and stop to stir, reaction solution is changed in the separating funnel over to static layering, get rid of water. use 750ml water, divide three washings, anhydrous magnesium sulfate drying, evaporate to dryness, get the bromotrifluoromethane diethyl malonate, light yellow oil.
3, the making of bromotrifluoromethane propylene glycol
In the reaction flask, add DMF250ml, bromotrifluoromethane diethyl malonate 270 grams stir, make homogeneous solution, be warming up to 50 degree, stop heating, drip the solution of making by 45 gram sodium borohydrides and 150mlDMF, the control rate of addition keeps temperature to be no more than 65 degree, reacts 5 hours, be cooled to below 30 degree, add methylene dichloride 300ml, stir, change in the separating funnel 250ml washing three times, anhydrous magnesium sulfate drying methylene dichloride phase over to, evaporated under reduced pressure gets the bromotrifluoromethane propylene glycol, light yellow liquid.
4, the making of 2-acetoxy-methyl-4-brombutyl acetic ester
Backflow is being housed, in the reaction flask of whipping appts, is adding bromotrifluoromethane propylene glycol 185 grams, 200 gram acetate
Acid anhydride, the 15ml vitriol oil is heated to 80 degree, constant temperature 2 hours continues to be warming up to backflow, reacts 8 hours, naturally cool to room temperature, be transferred in the separating funnel, add 500ml water, washing is told spent acid, repeated multiple times, until pH value greater than 6. anhydrous magnesium sulfate dryings, filter, get 2-acetoxy-methyl-4-brombutyl acetic ester, light yellow liquid.
5, the making of 2-(2-acetoxy-methyl-4-brombutyl acetic ester)-6-chloropurine
In reaction flask, drop into 170 gram 2-amino-6-chloropurines, 260 gram 2-acetoxy-methyl-4-brombutyl acetic ester, 550mlDMF, 25 gram salt of wormwood, heated and stirred was in 60 ~ 65 degree reactions 18 hours. and reaction finishes, be cooled to room temperature, filter, filter cake is again with a spot of DMF washing, merging filtrate. anhydrous sodium sulfate drying, to filter. underpressure distillation is to doing. use re-crystallizing in ethyl acetate again. obtain 2-(2-acetoxy-methyl-4-brombutyl acetic ester)-6-chloropurine, the white crystals body.
6, the making of famciclovir
In reaction flask, add 2-(2-acetoxy-methyl-4-brombutyl acetic ester)-6-chloropurine 200 grams, 500ml ethyl acetate, 10 gram triethylamines, 10% palladium carbon, 20 grams, stir, feed nitrogen replacement 3 times, be warming up to 60 degree again, fed hydrogen reaction 8 hours, reaction finishes. filtered and recycled palladium carbon, and with amount of ethyl acetate washing palladium carbon. merging filtrate, wash with 300ml, anhydrous magnesium sulfate drying, filter. the reduction vaporization ethyl acetate is to doing, use again ethyl acetate-methyl alcohol (85: 15, V/V) mixed solvent recrystallization, separate, drying under reduced pressure gets the famciclovir finished product, white crystals.
Technological process total recovery 61% of the present invention, used starting material are the conventional chemical raw material, production process easy handling, environmental friendliness.Product content 99.5%, other quality index reach the national drug quality standard.