CN108484605A - A kind of chloro- 9- of 2- amino -6-（4- acetoxy-3s-acetyl-o-methyl butyl）The preparation method of purine - Google Patents
A kind of chloro- 9- of 2- amino -6-（4- acetoxy-3s-acetyl-o-methyl butyl）The preparation method of purine Download PDFInfo
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- CN108484605A CN108484605A CN201810219345.4A CN201810219345A CN108484605A CN 108484605 A CN108484605 A CN 108484605A CN 201810219345 A CN201810219345 A CN 201810219345A CN 108484605 A CN108484605 A CN 108484605A
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- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
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Abstract
The present invention relates to a kind of preparation methods of 6 chlorine 9 (4 3-acetyl-o-methyl of acetoxyl group butyl) purine of 2 amino, including step：1, 3 dichloro, 2 propyl alcohol is obtained by the reaction 1 with acetate, 3 diacetoxy, 2 propyl alcohol, 1 is obtained by bromo-reaction, 3 diacetoxy, 2 N-Propyl Bromide, then it is reacted with zinc powder and is prepared 1, 3 diacetoxy, 2 bromination zinc-base propane, then coupling and deprotection reaction are carried out with 2 bromoethanols by hydroxyl protection, obtain 1, 3 diacetoxy 2 (2 ethoxy) propane, 2 amino 6 chlorine 9 (4 3-acetyl-o-methyl of acetoxyl group butyl) purine is obtained by the reaction by Mitsunobu with 2 amino, 6 chloropurine again, HPLC purity is 99.5% or more, it can be used for preparing famciclovir and Penciclovir.
Description
Technical field
The invention belongs to chemosynthesis technical fields, are related to a kind of 2- amino -6- chloro- 9- (4- acetoxy-3s-acetyl oxygen
Methyl butyl) purine preparation method.
Background technology
Penciclovir and famciclovir are Britain SmithKline Beecham in the antiviral of the 20 practical exploitations nineties
Drug is suitable for serious Patients with Herpes Zoster and primary sexual reproduction mainly by inhibiting viral dna replication to play antivirus action
The treatment of the virus infection such as device bleb.Famciclovir is first and is approved for the oral of herpes labialis and genital herpes in the U.S.
Drug, and the only antiviral drugs of postherpetic neuralgia is reduced, further study show that, famciclovir has wide spectrum
Antivirus action, it is active to herpesviral, hepatitis B, cytomegalovirus, Epstein-Barr virus etc..Penciclovir is famciclovir
Active metabolite in human body, famciclovir oral administration biaavailability are more preferable.
In widely used at present famciclovir and Penciclovir preparation method, 2- amino -6- will first be prepared
This key intermediate of chloro- 9- (4- acetoxy-3s-acetyl-o-methyl butyl) purine, by 2- amino -6- chloro- 9- (4- acetyl
Oxygroup-3-acetyl-o-methyl butyl) purine prepare famciclovir also need a step hydrogenation, preparing Penciclovir also needs two steps anti-
It answers, therefore the quality of the chloro- 9- of 2- amino -6- (4- acetoxy-3s-acetyl-o-methyl butyl) purine and cost are to famciclovir
There is bigger influence with the quality and cost of Penciclovir.
The preparation side of the current widely used chloro- 9- of 2- amino -6- (4- acetoxy-3s-acetyl-o-methyl butyl) purine
There are three types of methods：
Method one, 2- amido-6-chloropurines and 3- N-Propyl Bromides -1,1,1- tricarboxylic acids triethyls carry out condensation reaction, obtain
The chloro- 9- of 2- amino -6- (2,2- diethyl oxygen carbonyl ethyl butyrate -4- bases) purine；Then sodium alkoxide decarboxylation is used, 2- amino -6- is obtained
Chloro- 9- (2- carbethoxyl group butyrate -4- bases) purine；Then 2- amino -6- chloro- 9- (4- hydroxyls-are obtained with sodium borohydride reduction
3-methylol-butyls) purine；2- amino -6- chloro- 9- (4- acetoxy-3s-acetyl-o-methyl fourth are obtained by the reaction with aceticanhydride again
Base) purine.
Reaction route：
The advantages of this method is to prepare the chloro- 9- of 2- amino -6- (2,2- diethyl oxygen carbonyl ethyl butyrate -4- bases) purine
When the chloro- 7- of 2- amino -6- (2,2- diethyl oxygen carbonyl ethyl butyrate -4- bases) purine isomers for generating it is considerably less, be current work
Widely used method in industry.But the shortcomings that route is that critical component 2- amino -6- chloropurines participate in instead in the first step
It answers, then also to pass through decarboxylation, reduction and esterification, 2- amino -6- chloropurine utilization rates are not high, cause final products whole
Body high expensive.
The chloro- 9- bromines of 2- amino -6- are obtained by the reaction in method two, 2- amido-6-chloropurines and bromoethanol or 1,2- Bromofumes
Then it is fast to be condensed to yield the chloro- 9- of 2- amino -6- (2- carbethoxyl group ethyl butyrate -4- bases) with diethyl malonate for ethyl purine
Purine is esterified to obtain 2- amino -6- chloro- 9- (4- acetoxy-3s-acetyl-o-methyl fourth using sodium borohydride reduction and aceticanhydride
Base) purine.
Reaction route：
Compared with method one, decarboxylic reaction step, but the chloro- 9- bromoethyls purine of 2- amino -6- and malonic acid two are eliminated
The more difficult progress of condensation reaction of ethyl ester, yield be not high.
Three 2- amido-6-chloropurines of method carry out condensation reaction with 3- N-Propyl Bromide -1,1- diethyl dicarboxylates, through recrystallization
The chloro- 9- of 2- amino -6- are obtained after separation N-7 isomers 2- amino -6- chloro- 7- (2- carbethoxyl group ethyl butyrate -4- bases) purine
(2- carbethoxyl group ethyl butyrate -4- bases) purine, is esterified to obtain the chloro- 9- of 2- amino -6- using sodium borohydride reduction and aceticanhydride
(4- acetoxy-3s-acetyl-o-methyl butyl) purine.
Reaction route：
Compared with method one, decarboxylic reaction step is eliminated, but has very more N-7 isomeries in condensation reaction
The chloro- 7- of body 2- amino -6- (2- carbethoxyl group ethyl butyrate -4- bases) purine generates, and needs to be detached by recrystallization, overall
Yield is not high.
The common feature of above-mentioned preparation method is to be both needed to first prepare 2- amino -6- chloro- 9- (2- carbethoxyl groups ethyl butyrates -
4- yls) purine, it is esterified to obtain 2- amino -6- chloro- 9- (4- acetoxy-3s-acetyl oxygen using sodium borohydride reduction and aceticanhydride
Methyl butyl) purine.
Invention content
The technical problem to be solved by the present invention is to：Based on the above issues, the present invention provides a kind of 2- amino -6- chloro- 9-
The preparation method of (4- acetoxy-3s-acetyl-o-methyl butyl) purine.
The present invention solves a technical solution used by its technical problem：1,3- dichloro 2- propyl alcohol and acetic acid reactant salt
Obtain 1,3- diacetoxy -2- propyl alcohol, 1,3- diacetoxy -2- N-Propyl Bromides obtained by bromo-reaction, then with zinc powder
1,3- diacetoxy -2- bromination zinc-base propane is prepared in reaction, is then carried out with the ethylene bromohyrin by hydroxyl protection even
Connection and deprotection reaction obtain 1,3- diacetoxies -2- (2- ethoxys) propane, then pass through with 2- amido-6-chloropurines
The chloro- 9- of 2- amino -6- (4- acetoxy-3s-acetyl-o-methyl butyl) purine is obtained by the reaction in Mitsunobu, and reaction route is such as
Shown in following formula：
This method specifically includes following steps：
With acetic acid reactant salt under the conditions of bis- chloro- 2- propyl alcohol of (1) 1,3- is existing for strong acid weak base salt, 1,3- diethyls are obtained
Acyloxy -2- propyl alcohol；
(2) 1,3- diacetoxy -2- propyl alcohol are reacted with brominated reagent, obtain 1,3- diacetoxy -2- N-Propyl Bromides；
(3) 1,3- diacetoxy -2- N-Propyl Bromides react under activator and initiator effect with zinc powder, obtain 1,3- bis-
Acetoxyl group -2- bromination zinc-base propane；
(4) 1,3- diacetoxy -2- bromination zinc-base propane are with the ethylene bromohyrin by hydroxyl protection in catalyzing by metal palladium
Negishi coupling reactions and deprotection reaction are carried out under agent catalytic action, obtain 1,3- diacetoxies -2- (2- ethoxys) third
Alkane；
(5) 1,3- diacetoxy -2- (2- ethoxys) propane are anti-by Mitsunobu with 2- amido-6-chloropurines
It answers, obtains the chloro- 9- of 2- amino -6- (4- acetoxy-3s-acetyl-o-methyl butyl) purine.
Further, strong base-weak acid salt is ammonium sulfate or ammonium chloride, strong base-weak acid salt and 1, bis- chloro- 2- of 3- in step (1)
The molar ratio of propyl alcohol is 0.8~1.2：1.
Further, acetate is sodium acetate or potassium acetate in step (1), and acetate and 1, bis- chloro- 2- propyl alcohol of 3- rubs
You are than being 2.5~3.5：1.
Further, in step (2) brominated reagent be triethylamine hydrobromide or pyridine hydrobromide salt, brominated reagent and 1,
The molar ratio of bis- chloro- 2- propyl alcohol of 3- is 1.3~1.8：1.
Further, activator is anhydrous lithium bromide or anhydrous lithium chloride in step (3), and initiator is trimethylchloro-silicane
Alkane, the amount of activator are the 5~15% of 1,3- diacetoxy -2- N-Propyl Bromide quality, and the amount of initiator is 1,3- diethyl acyl-oxygens
The 1~5% of base -2- N-Propyl Bromide quality, the amount of zinc powder are the 25~35% of 1,3- diacetoxy -2- N-Propyl Bromide quality.
Further, metal palladium catalyst is with S-Phos (2- dicyclohexyl phosphine -2', 6'- dimethoxys in step (4)
Biphenyl) be ligand palladium acetate catalyst, by the ethylene bromohyrin of hydroxyl protection and 1,3- diacetoxy -2- brominations zinc-base third
Alkane and molar ratio be 1.05~2：1.
Further, 1,3- diacetoxies -2- (2- ethoxys) propane and 2- amido-6-chloropurines in step (5)
Molar ratio is 1.1~2：1.
The beneficial effects of the invention are as follows：2- amino -6- chloro- 9- (the 4- acetoxy-3s-acetyl-o-methyl fourth of the present invention
Base) purine preparation method, final step use 2- amido-6-chloropurines the step of than later, can effectively reduce raw material at
This；The chloro- 9- of 2- amino-6- (- 3-methylol-butyl of 4- hydroxyls) purine this intermediate need not be prepared, it is anti-to avoid reduction
Should and esterification reaction process, process safety is more preferable, while also drastically reducing the amount of high-concentration salt-containing wastewater, is more suitable for
In large-scale industrial production.With 2- amino -6- chloro- 9- (the 4- acetoxy-3s-acetyl being prepared in the present inventive method
Oxygen methyl butyl) purine produces famciclovir and Penciclovir, product quality meet American-European standards of pharmacopoeia requirement.
Specific implementation mode
Presently in connection with specific embodiment, the invention will be further described, following embodiment be intended to illustrate invention rather than
Limitation of the invention further.
Embodiment 1
1,3-, bis- chloro- 2- propyl alcohol 129g, DMF 1000ml, potassium acetate 300g, ammonium chloride 53.5g are put into reaction bulb,
Insulation reaction is stirred between 100~110 DEG C 10 hours.Heat preservation is finished, and is cooled to room temperature, is filtered out the solid in system, filtrate
It is concentrated under reduced pressure DMF, ethyl acetate is added and dissolves concentrate, is washed with water 2 times, after being dried over anhydrous sodium sulfate processing, is added
Triethylamine hydrobromide 270g, stirs insulation reaction 5~6 hours between being warming up to 70~80 DEG C, be cooled to room temperature, filter out body
Then solid in system is washed 2 times with saturated nacl aqueous solution, carry out rectifying after being concentrated under reduced pressure ethyl acetate, obtain 1,3-
Diacetoxy -2- N-Propyl Bromide 110g, G/C content 90.4%.
THF100ml, anhydrous lithium bromide 9g and zinc powder 33g are added in reaction bulb, nitrogen is replaced 3 times, and 1,3- bis- is added
Acetoxyl group -2- N-Propyl Bromide 100g, are eventually adding 2.3g trim,ethylchlorosilanes, are heated to 50 DEG C, reacted between 50~55 DEG C
2h, between being then heated to 60~65 DEG C react 15~for 24 hours.GC tracing detections, until GC peak areas 1,3- diacetoxy -2- bromines
Propane/1,3- diacetoxy -2- bromination zinc-base propane<Reaction was completed when 3%, obtains zincon (1,3- diacetoxy -2- bromines
Change zinc-base propane), for use.
THF 5ml are added in reaction bulb, nitrogen is replaced 3 times, and palladium 0.15g and ligand 2- dicyclohexyls are added at room temperature
Phosphine -2', 6'- dimethoxy-biphenyl 1.1g, stirred under nitrogen atmosphere 20~30 minutes obtain catalyst, for use.
THF300ml, bromoethanol tetrahydropyranyl ethers 55g are added in reaction bulb, freshly prepd catalysis is added under nitrogen protection
Agent, is heated to 50~60 DEG C, and freshly prepd zincon is slowly added dropwise, and drop finishes the reaction 10h at 50~60 DEG C.Cool to 15~20
DEG C, ethyl alcohol 10ml is added dropwise, stirs 2h.It is concentrated to dryness, 300ml ethyl acetate, the ammonium chloride solution of 200ml 25% is added
Liquid stirs 0.5h, stands, and layering, organic layer is washed with water 2 times, adds water 100ml, cools to 5~10 DEG C, controls 5~10 DEG C of drops
Add the hydrochloric acid tune pH 4.0~5.0 of 6mol/L, stir 1h, layering, organic layer is washed with 100ml water and 100ml saturated brines, had
Machine layer is concentrated under reduced pressure, and obtains 1,3- diacetoxies -2- (2- ethoxys) propane 50g, 90% or more G/C content.
Tetrahydrofuran (moisture is less than 0.05%) 300ml, triphenylphosphine 58g and 2- amino -6- chlorine are put into reaction bulb
Purine 25g cools to 5 DEG C hereinafter, DIAD (diisopropyl azodiformate) 45g is slowly added dropwise, after dripping off under nitrogen protection
It is stirred 30 minutes at 0~5 DEG C, 1,3- diacetoxies -2- (2- ethoxys) propane 50g is then added dropwise, drop finishes, and 0~5 DEG C is stirred
It mixes 90 minutes, is then warming up between 20~30 DEG C, is stirred to react, TLC tracking reactions, until 2- amido-6-chloropurines have reacted
Entirely.It is concentrated under reduced pressure about 50% tetrahydrofuran, dichloromethane 250ml and diatomite 15g is added, stir 1 hour, filter, filter
Water 200ml and concentrated hydrochloric acid 50ml is added in liquid, stirs 20~30 minutes, layering, and organic layer is mixed with 150ml's and concentrated hydrochloric acid 30ml
It closes liquid washed once, then respectively washed once with water, sodium bicarbonate solution and water successively, concentration is dry, and concentrate is tied again with ethyl alcohol
2~3 times brilliant, it is pure to obtain the chloro- 9- of 2- amino -6- (4- acetoxy-3s-acetyl-o-methyl butyl) purine 42g, HPLC for decompression drying
99.5% or more degree.
Embodiment 2
Zincon (1,3- diacetoxy -2- bromination zinc-bases propane) and catalyst are prepared as described in Example 1,
For use.
THF 300ml are added in reaction bulb, bromoethanol benzyl oxide 50g is added, freshly prepd catalyst is added under nitrogen protection,
50~60 DEG C are heated to, freshly prepd zincon is slowly added dropwise, drop finishes the reaction 10h at 50~60 DEG C.15~20 DEG C are cooled to, drop
Add ethyl alcohol 10ml, stirs 2h.It is concentrated to dryness, the aqueous ammonium chloride solution of 300ml ethyl acetate, 200ml 25% is added, stirs
0.5h to be mixed, is stood, layering, organic layer is washed with water 2 times, is transferred in autoclave, addition palladium charcoal (5%, aqueous 50%) 2g, Yu Wen
It is reacted 10 hours under the conditions of 30~40 DEG C of degree, 0.1~0.2MPa of pressure, is filtered to remove palladium charcoal, filtrate water washs 2 times, decompression
Concentration is dry, obtains 1,3- diacetoxies -2- (2- ethoxys) propane 45g, 92% or more G/C content.
It is prepared into the chloro- 9- of 2- amino -6- (4- acetoxy-3s-acetyl-o-methyl butyl) purine as described in Example 1,
99.5% or more HPLC purity.
It is enlightenment with above-mentioned desirable embodiment according to the present invention, through the above description, relevant staff is complete
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property range is not limited to the contents of the specification, it is necessary to determine its technical scope according to right.
Claims (7)
- The preparation method of a kind of chloro- 9- of 2- amino -6- 1. (4- acetoxy-3s-acetyl-o-methyl butyl) purine, it is characterized in that： Include the following steps：With acetic acid reactant salt under the conditions of bis- chloro- 2- propyl alcohol of (1) 1,3- is existing for strong acid weak base salt, 1,3- diethyl acyl-oxygens are obtained Base -2- propyl alcohol；(2) 1,3- diacetoxy -2- propyl alcohol are reacted with brominated reagent, obtain 1,3- diacetoxy -2- N-Propyl Bromides；(3) 1,3- diacetoxy -2- N-Propyl Bromides react under activator and initiator effect with zinc powder, obtain 1,3- diacetyl Oxygroup -2- bromination zinc-base propane；(4) 1,3- diacetoxy -2- bromination zinc-base propane are urged with by the ethylene bromohyrin of hydroxyl protection in metal palladium catalyst Change effect is lower to carry out Negishi coupling reactions and deprotection reaction, obtains 1,3- diacetoxies -2- (2- ethoxys) propane；(5) 1,3- diacetoxy -2- (2- ethoxys) propane are reacted with 2- amido-6-chloropurines by Mitsunobu, are obtained The chloro- 9- of 2- amino -6- (4- acetoxy-3s-acetyl-o-methyl butyl) purine.
- A kind of chloro- 9- of 2- amino -6- according to claim 1 2. (4- acetoxy-3s-acetyl-o-methyl butyl) purine Preparation method, it is characterized in that：In the step (1) strong base-weak acid salt be ammonium sulfate or ammonium chloride, strong base-weak acid salt and 1, The molar ratio of bis- chloro- 2- propyl alcohol of 3- is 0.8~1.2：1.
- A kind of chloro- 9- of 2- amino -6- according to claim 1 3. (4- acetoxy-3s-acetyl-o-methyl butyl) purine Preparation method, it is characterized in that：Acetate is sodium acetate or potassium acetate, acetate and 1, bis- chloro- 2- of 3- in the step (1) The molar ratio of propyl alcohol is 2.5~3.5：1.
- A kind of chloro- 9- of 2- amino -6- according to claim 1 4. (4- acetoxy-3s-acetyl-o-methyl butyl) purine Preparation method, it is characterized in that：Brominated reagent is triethylamine hydrobromide or pyridine hydrobromide salt, bromine in the step (2) It is 1.3~1.8 for the molar ratio of reagent and bis- chloro- 2- propyl alcohol of 1,3-：1.
- A kind of chloro- 9- of 2- amino -6- according to claim 1 5. (4- acetoxy-3s-acetyl-o-methyl butyl) purine Preparation method, it is characterized in that：Activator is anhydrous lithium bromide or anhydrous lithium chloride, initiator three in the step (3) Methylchlorosilane, the amount of activator are the 5~15% of 1,3- diacetoxy -2- N-Propyl Bromide quality, and the amount of initiator is 1,3- The 1~5% of diacetoxy -2- N-Propyl Bromide quality, the amount of zinc powder be 1,3- diacetoxy -2- N-Propyl Bromide quality 25~ 35%.
- A kind of chloro- 9- of 2- amino -6- according to claim 1 6. (4- acetoxy-3s-acetyl-o-methyl butyl) purine Preparation method, it is characterized in that：Metal palladium catalyst is with S-Phos (2- dicyclohexyl phosphines -2', 6'- in the step (4) Dimethoxy-biphenyl) be ligand palladium acetate catalyst, by the ethylene bromohyrin of hydroxyl protection and 1,3- diacetoxy -2- bromines Change zinc-base propane and molar ratio be 1.05~2：1.
- A kind of chloro- 9- of 2- amino -6- according to claim 1 7. (4- acetoxy-3s-acetyl-o-methyl butyl) purine Preparation method, it is characterized in that：1,3- diacetoxies -2- (2- ethoxys) propane and 2- amino -6- in the step (5) The molar ratio of chloropurine is 1.1~2：1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5684153A (en) * | 1984-08-16 | 1997-11-04 | Beecham Group Plc | Process for the preparation of purine derivatives |
| WO2004007418A1 (en) * | 2002-07-12 | 2004-01-22 | Recordati S.A. | A process for the preparation of 2-acetoxymethyl-4 halo-but-1-yl acetates |
| CN101550137A (en) * | 2009-05-11 | 2009-10-07 | 彭洋 | Method for synthesizing famciclovir |
-
2018
- 2018-03-16 CN CN201810219345.4A patent/CN108484605B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5684153A (en) * | 1984-08-16 | 1997-11-04 | Beecham Group Plc | Process for the preparation of purine derivatives |
| WO2004007418A1 (en) * | 2002-07-12 | 2004-01-22 | Recordati S.A. | A process for the preparation of 2-acetoxymethyl-4 halo-but-1-yl acetates |
| CN101550137A (en) * | 2009-05-11 | 2009-10-07 | 彭洋 | Method for synthesizing famciclovir |
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