CN104744472A - Preparation method of high-quality 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine - Google Patents
Preparation method of high-quality 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine Download PDFInfo
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- CN104744472A CN104744472A CN201510108607.6A CN201510108607A CN104744472A CN 104744472 A CN104744472 A CN 104744472A CN 201510108607 A CN201510108607 A CN 201510108607A CN 104744472 A CN104744472 A CN 104744472A
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- purine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- 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 invention relates to a preparation method of high-quality 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine. The preparation method comprises the following steps: preparing an alkaline water solution of the 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine; regulating the solution to be neutral by using hydrochloric acid; decompressing and concentrating to remove methanol and a part of water; adding sodium chloride; extracting by using n-butyl alcohol; drying the n-butyl alcohol extraction solution by using a drying agent; decompressing and concentrating; adding acetone into concentration residues; stirring and crystalizing; filtering and drying to obtain the 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine. The preparation method disclosed by the invention has the beneficial effects that the prepared 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine is good in quality, the purity of HPLV is above 99.5%, and the residue on ignition is smaller than 3.0%; the preparation method has the characteristics of being simple to operate and low in energy consumption and is suitable for large-scale industrial production; the 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine can be used as a midbody for producing famciclovir and penciclovir, and the product quality is enabled to satisfy the Europe and America pharmacopeia standard requirements.
Description
Technical field
The present invention relates to a kind of chemosynthesis technical field, particularly relate to the preparation method of the chloro-9-of a kind of high-quality 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine.
Background technology
Penciclovir and Famciclovir are the antiviral of widespread use in the market, mainly through suppressing viral dna replication to play antivirus action, are applicable to the treatment of the virus infectiones such as serious Patients with Herpes Zoster and primary genitalia herpes.Famciclovir is first and gets permission the oral drug for herpes labialis and genital herpes in the U.S., also be the only antiviral reducing postherpetic neuralgia, further research finds, Famciclovir has broad-spectrum disease resistance toxic action, all has activity to simplexvirus, hepatitis B virus, cytomegalovirus, Epstein-Barr virus etc.Because Penciclovir is the active metabolite of Famciclovir in human body, its indication is identical with Famciclovir.
In the Famciclovir extensively adopted at present and Penciclovir preparation method, all first to prepare the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) this key intermediate of purine, by the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl), purine prepares Famciclovir also needs two-step reaction, prepare Penciclovir and only need single step reaction, therefore the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) the product confrontation Famciclovir of purine and the quality of Penciclovir have larger impact.
The preparation method of the chloro-9-of current 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine: with the chloro-9-of 2-amino-6-(3-ethoxycarbonyl ethyl butyrate-4-base) purine or the chloro-9-of 2-amino-6-(3-methoxycarbonyl ethyl butyrate-4-base) purine or the chloro-9-of 2-amino-6-(3-methoxycarbonyl methyl-butyrate-4-base) purine or their mixture for starting raw material, through sodium borohydride reduction, then the shrend adding dosage is gone out reaction, divide water-yielding stratum, with hydrochloric acid, water layer is adjusted to neutrality, then concentrating under reduced pressure falls methyl alcohol and most water, then freezing and crystallizing separates out solid, obtain the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine after filtration.Chemical equation is as follows:
Because the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine solubleness in water is larger, need freezing and crystallizing, energy consumption is high in this approach, yield is low in institute, containing the inorganic salt of 15 ~ 25% in the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine prepared, HPLC purity is generally between 92 ~ 96%.The chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine applying such quality prepares Famciclovir and Penciclovir, all need through repeatedly refining quality product could be qualified, cause the finished product raw materials cost to rise, be also unfavorable for that GMP manages simultaneously.
Summary of the invention
The technical problem to be solved in the present invention is: based on the problems referred to above, the invention provides the preparation method of the chloro-9-of a kind of high-quality 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine.
The present invention solves the technical scheme that its technical problem adopts: the preparation method of the chloro-9-of a kind of high-quality 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine, comprises the following steps:
(1) by the chloro-9-of 2-amino-6-(3-ethoxycarbonyl ethyl butyrate-4-base) purine or the chloro-9-of 2-amino-6-(3-methoxycarbonyl ethyl butyrate-4-base) purine or the chloro-9-of 2-amino-6-(3-methoxycarbonyl methyl-butyrate-4-base) purine input reaction flask, add methylene dichloride and sodium borohydride, slowly methyl alcohol is added under room temperature, stirring reaction 4 ~ 6 hours, add water, stir 15 ~ 20 minutes, divide water-yielding stratum, obtain the alkaline aqueous solution of the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine;
(2) with hydrochloric acid, alkaline aqueous solution is adjusted to neutrality, concentrating under reduced pressure falls methyl alcohol and part water, adds sodium-chlor and makes concentrated solution saturated;
(3) with the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine in the aqueous solution in n-butanol extraction step (2);
(4) butanol extraction liquid desiccant dryness, concentrating under reduced pressure, obtains concentrating residues thing;
(5) in the concentrating residues thing of step (4), acetone is added, 0 ~ 10 DEG C of stirring and crystallizing 3 ~ 5 hours;
(6) filter, filter cake decompression drying, obtain the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine, its HPLC purity is greater than 99.5%, and residue on ignition is less than 1.0%.
Further, in step (4), siccative is anhydrous magnesium sulfate, anhydrous sodium sulphate, preferred anhydrous sodium sulphate.
Further, in step (5), the consumption of acetone is 2 ~ 4 times of concentrating residues thing weight, preferably 3 times; Recrystallization temperature is 5 ~ 10 DEG C, preferably 4 hours crystallization time.
The invention has the beneficial effects as follows: the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) the purine quality prepared is good, HPLC purity is more than 99.5%, residue on ignition is less than 3.0%, have the advantages that operation is comparatively simple, energy consumption is low, be suitable for large-scale industrial production, for intermediate produces Famciclovir and Penciclovir, can guarantee that quality product meets American-European standards of pharmacopoeia requirement.
Embodiment
The invention will be further described in conjunction with specific embodiments now, and following examples are intended to the present invention instead of limitation of the invention further are described.
Embodiment 1
In reaction flask, drop into the chloro-9-of 2-amino-6-(3-ethoxycarbonyl ethyl butyrate-4-base) purine 12g, methylene dichloride 120ml and sodium borohydride 4g, less than 30 DEG C drip methyl alcohol 30.4g, in about 30 DEG C insulation reaction 4 hours after dropwising.Insulation is finished, add water 30ml, stir about left standstill phase-splitting after 20 minutes, separated organic phase, extracted once with water 20ml, merge aqueous phase, with hydrochloric acid, filtrate is adjusted to neutrality, concentrating under reduced pressure falls methyl alcohol and part water, obtains concentrated solution and is about 50g, adding sodium-chlor makes concentrated solution saturated, then with in n-butanol extraction to water substantially without the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine.Merge propyl carbinol, do with concentrating under reduced pressure after anhydrous sodium sulfate drying, obtain concentrating residues thing and be about 12g, add acetone 36g, stirred crystallization 4 hours between 5 ~ 10 DEG C, filter, filter cake decompression drying, obtain the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine 7.8g, purity (HPLC) 99.65%, residue on ignition 0.71%.
Embodiment 2
In reaction flask, drop into the chloro-9-of 2-amino-6-(3-methoxycarbonyl ethyl butyrate-4-base) purine 12g, methylene dichloride 120ml and sodium borohydride 4g, less than 30 DEG C drip methyl alcohol 30.4g, in about 30 DEG C insulation reaction 4 hours after dropwising.Insulation is finished, add water 30ml, stir about left standstill phase-splitting after 20 minutes, separated organic phase, extracted once with water 20ml, merge aqueous phase, with hydrochloric acid, filtrate is adjusted to neutrality, concentrating under reduced pressure falls methyl alcohol and part water, obtains concentrated solution and is about 50g, adding sodium-chlor makes concentrated solution saturated, then with in n-butanol extraction to water substantially without the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine.Merge propyl carbinol, do with concentrating under reduced pressure after anhydrous sodium sulfate drying, obtain concentrating residues thing and be about 12g, add acetone 48g, stirred crystallization 4 hours between 5 ~ 10 DEG C, filter, filter cake decompression drying, obtain the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine 7.9g, purity (HPLC) 99.69%, residue on ignition 0.74%.
Embodiment 3
In reaction flask, drop into the chloro-9-of 2-amino-6-(3-methoxycarbonyl methyl-butyrate-4-base) purine 12g, methylene dichloride 120ml and sodium borohydride 4g, less than 30 DEG C drip methyl alcohol 30.4g, in about 30 DEG C insulation reaction 4 hours after dropwising.Insulation is finished, add water 30ml, stir about left standstill phase-splitting after 20 minutes, separated organic phase, extracted once with water 20ml, merge aqueous phase, with hydrochloric acid, filtrate is adjusted to neutrality, concentrating under reduced pressure falls methyl alcohol and part water, obtains concentrated solution and is about 50g, adding sodium-chlor makes concentrated solution saturated, then with in n-butanol extraction to water substantially without the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine.Merge propyl carbinol, do with concentrating under reduced pressure after anhydrous sodium sulfate drying, obtain concentrating residues thing and be about 12g, add acetone 24g, stirred crystallization 4 hours between 5 ~ 10 DEG C, filter, filter cake decompression drying, obtain the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine 7.5g, purity (HPLC) 99.56%, residue on ignition 0.68%.
Claims (3)
1. a preparation method for the chloro-9-of high-quality 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine, is characterized in that: comprise the following steps:
(1) by the chloro-9-of 2-amino-6-(3-ethoxycarbonyl ethyl butyrate-4-base) purine or the chloro-9-of 2-amino-6-(3-methoxycarbonyl ethyl butyrate-4-base) purine or the chloro-9-of 2-amino-6-(3-methoxycarbonyl methyl-butyrate-4-base) purine input reaction flask, add methylene dichloride and sodium borohydride, slowly methyl alcohol is added under room temperature, stirring reaction 4 ~ 6 hours, add water, stir 15 ~ 20 minutes, divide water-yielding stratum, obtain the alkaline aqueous solution of the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine;
(2) with hydrochloric acid, alkaline aqueous solution is adjusted to neutrality, concentrating under reduced pressure falls methyl alcohol and part water, adds sodium-chlor and makes concentrated solution saturated;
(3) with the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine in the aqueous solution in n-butanol extraction step (2);
(4) butanol extraction liquid desiccant dryness, concentrating under reduced pressure, obtains concentrating residues thing;
(5) in the concentrating residues thing of step (4), acetone is added, 0 ~ 10 DEG C of stirring and crystallizing 3 ~ 5 hours;
(6) filter, filter cake decompression drying, obtain the chloro-9-of 2-amino-6-(4-hydroxyl-3 – methylol-butyl) purine, its HPLC purity is greater than 99.5%, and residue on ignition is less than 1.0%.
2. the preparation method of the chloro-9-of high-quality 2-amino-6-according to claim 1 (4-hydroxyl-3 – methylol-butyl) purine, it is characterized in that: in described step (4), siccative is anhydrous magnesium sulfate, anhydrous sodium sulphate, preferred anhydrous sodium sulphate.
3. the preparation method of the chloro-9-of high-quality 2-amino-6-according to claim 1 (4-hydroxyl-3 – methylol-butyl) purine, it is characterized in that: in described step (5), the consumption of acetone is 2 ~ 4 times of concentrating residues thing weight, preferably 3 times; Recrystallization temperature is 5 ~ 10 DEG C, preferably 4 hours crystallization time.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713490A (en) * | 2018-07-12 | 2020-01-21 | 浙江医药股份有限公司新昌制药厂 | Preparation method of penciclovir |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150427A (en) * | 1994-04-19 | 1997-05-21 | 史密斯克莱·比奇曼公司 | Preparation of purines |
| CN101195622A (en) * | 2007-12-13 | 2008-06-11 | 吴江市方霞企业信息咨询有限公司 | Method of producing famciclovir |
| CN101233134A (en) * | 2005-05-20 | 2008-07-30 | 箭锋国际有限公司 | Preparation of famciclovir and other purine derivatives |
-
2015
- 2015-03-12 CN CN201510108607.6A patent/CN104744472A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150427A (en) * | 1994-04-19 | 1997-05-21 | 史密斯克莱·比奇曼公司 | Preparation of purines |
| CN101233134A (en) * | 2005-05-20 | 2008-07-30 | 箭锋国际有限公司 | Preparation of famciclovir and other purine derivatives |
| CN101195622A (en) * | 2007-12-13 | 2008-06-11 | 吴江市方霞企业信息咨询有限公司 | Method of producing famciclovir |
Non-Patent Citations (1)
| Title |
|---|
| 陈梅玲等: "喷昔洛韦合成工艺研究", 《药物研究》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713490A (en) * | 2018-07-12 | 2020-01-21 | 浙江医药股份有限公司新昌制药厂 | Preparation method of penciclovir |
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