CN108409724A - A kind of emtricitabine separation method - Google Patents
A kind of emtricitabine separation method Download PDFInfo
- Publication number
- CN108409724A CN108409724A CN201810565836.4A CN201810565836A CN108409724A CN 108409724 A CN108409724 A CN 108409724A CN 201810565836 A CN201810565836 A CN 201810565836A CN 108409724 A CN108409724 A CN 108409724A
- Authority
- CN
- China
- Prior art keywords
- emtricitabine
- potassium borohydride
- sodium hydroxide
- added
- absolute ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of emtricitabine separation methods, include the following steps：3 oxathiolane, 2 carboxylic acid l base esters (2.0g is added in stirring in 20 DEG C of aqueous dibasic potassium phosphate solution, 5.0mmol) and absolute ethyl alcohol (15ml), the potassium borohydride aqueous solution containing 25% sodium hydroxide solution is added dropwise, 15 30 DEG C of stirring 2h, it is adjusted to pH4 4.5 with 1mol/L hydrochloric acid, remaining potassium borohydride is decomposed, then pH6.8 7.2 is adjusted to 2mol/L sodium hydroxide solutions, 1 is removed with toluene extraction
Description
Technical field
The present invention relates to chemical industry processing technology field, specially a kind of emtricitabine separation method.
Background technology
Emtricitabine is inhibited by a kind of novel nucleoside reverse transcriptase of U.S.'s Gilead Siences Developeies
Agent belongs to antiviral class drug, has antiviral activity, antiviral activity to show it specifically HIV-1, HIV-2 and HBV
Anti-HIV-1, HIV-2 and HBV, and its medicine is dense rises to 100mnol/L, also have no it to HSV-1, HSV-2, HCMV, VZV,
Corona, flavivirus, respiratory syncytial virus (RSV), Rota, influenza virus or rhinovirus show activity.Even being less than
Micro-molar concentration, the medicine also show the potent suppression to the LAV and III B Strain and ROD2 the and ZY Strain of HIV-2 of HIV1
It makes and uses, IC50 value ratio AZT (Zidovudine) are 95 times low.
The patent of invention of Patent No. CN101671333A discloses a kind of separation method of emtricitabine, it includes as follows
Step：(1) Friedel-Crafts alkylation occurs under Aluminium Trichloride as Catalyst with polystyrene resin using chloromethylation salicylic acid to obtain
To the polystyrene resin of bigcatkin willow acid functional group；(2) utilize polystyrene resin and the synthesis grace of bigcatkin willow acid functional group bent
He heats the reaction mixture of shore together, and the throatroot acid complexing on the emtricitabine and resin in mixture is separated by filtration
It obtains the resin in conjunction with emtricitabine, then emtricitabine is parsed to obtain with triethylamine；Though the patent of invention makes certain improvements,
Yield is still low, and needs expensive reagent, causes production cost high, for this purpose, it is proposed that a kind of emtricitabine separation method.
Invention content
The purpose of the present invention is to provide a kind of emtricitabine separation methods, to solve mentioned above in the background art ask
Topic.
To achieve the above object, the present invention provides the following technical solutions：A kind of emtricitabine separation method, including walk as follows
Suddenly：In 20 DEG C of aqueous dibasic potassium phosphate solution stirring be added 3- oxathiolane -2- carboxylic acid l- base esters (2.0g,
5.0mmol) with absolute ethyl alcohol (15ml), the potassium borohydride aqueous solution containing 25% sodium hydroxide solution, 15-30 DEG C of stirring is added dropwise
2h is adjusted to pH4-4.5 with 1mol/L hydrochloric acid, decomposes remaining potassium borohydride, then be adjusted to 2mol/L sodium hydroxide solutions
PH6.8-7.2 is extracted with toluene and is removed l-Alcohol, water layer are concentrated to dryness, and absolute ethyl alcohol is added in residue, is heated to 60-
70 DEG C, it is filtered to remove inorganic salts while hot, filtrate decompression is concentrated into about surplus 15ml, adds ethyl acetate, and cooling crystallization filters,
Filtration cakes torrefaction obtains emtricitabine white solid.
Preferably, the aqueous dibasic potassium phosphate solution is made of the dipotassium hydrogen phosphate of 2.7g and the water of 3ml.
Preferably, the potassium borohydride aqueous solution is by 0.8g, the water composition of 14.8mmol potassium borohydrides and 4ml.
Preferably, the sodium hydroxide solution amount in the potassium borohydride aqueous solution is 0.04ml, the amount of the absolute ethyl alcohol
For 30ml.
Preferably, the addition of the ethyl acetate is 30ml.
Compared with prior art, the beneficial effects of the invention are as follows：Present invention optimizes process conditions, will directly remove l-
The solution decompression of alcohol is evaporated, and heating and filtering after absolute ethyl alcohol is added, and removes inorganic salts, then is obtained with re-crystallizing in ethyl acetate pure
Product, improved step reaction is easy to operate, total recovery 27%, solves that prior art yield is relatively low, and needs expensive examination
Agent leads to the problem that production cost is high.
Specific implementation mode
The following is a clear and complete description of the technical scheme in the embodiments of the invention, it is clear that described embodiment
Only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
The every other embodiment that art personnel are obtained without making creative work belongs to the model that the present invention protects
It encloses.
The present invention provides a kind of technical solution：A kind of emtricitabine separation method, includes the following steps：In 20 DEG C of phosphoric acid
3- oxathiolane -2- carboxylic acid l- base esters (2.0g, 5.0mmol) and absolute ethyl alcohol is added in stirring in two aqueous solutions of potassium of hydrogen
The potassium borohydride aqueous solution containing 25% sodium hydroxide solution, 15-30 DEG C of stirring 2h, with 1mol/L hydrochloric acid tune is added dropwise in (15ml)
To pH4-4.5, remaining potassium borohydride is decomposed, then pH6.8-7.2 is adjusted to 2mol/L sodium hydroxide solutions, is removed with toluene extraction
Remove l-Alcohol, water layer are concentrated to dryness, and absolute ethyl alcohol is added in residue, is heated to 60-70 DEG C, is filtered to remove while hot inorganic
Salt, filtrate decompression are concentrated into about surplus 15ml, add ethyl acetate, and cooling crystallization filters, and it is white to obtain emtricitabine for filtration cakes torrefaction
Color solid.
Embodiment one：
In 20 DEG C of aqueous dibasic potassium phosphate solution stirring be added 3- oxathiolane -2- carboxylic acid l- base esters (2.0g,
5.0mmol) with absolute ethyl alcohol (15ml), the potassium borohydride aqueous solution containing 25% sodium hydroxide solution, 15-30 DEG C of stirring is added dropwise
2h is adjusted to pH4-4.5 with 1mol/L hydrochloric acid, decomposes remaining potassium borohydride, then be adjusted to 2mol/L sodium hydroxide solutions
PH6.8-7.2 is extracted with toluene and is removed l-Alcohol, water layer are concentrated to dryness, and absolute ethyl alcohol is added in residue, is heated to 60-
70 DEG C, it is filtered to remove inorganic salts while hot, filtrate decompression is concentrated into about surplus 15ml, adds ethyl acetate, and cooling crystallization filters,
Filtration cakes torrefaction obtains emtricitabine white solid.
Embodiment two：
In embodiment one, following processes are added：
Aqueous dibasic potassium phosphate solution is made of the dipotassium hydrogen phosphate of 2.7g and the water of 3ml.
In 20 DEG C of aqueous dibasic potassium phosphate solution stirring be added 3- oxathiolane -2- carboxylic acid l- base esters (2.0g,
5.0mmol) it is made of the dipotassium hydrogen phosphate of 2.7g and the water of 3ml with absolute ethyl alcohol (15ml), wherein aqueous dibasic potassium phosphate solution,
The potassium borohydride aqueous solution containing 25% sodium hydroxide solution is added dropwise, 15-30 DEG C of stirring 2h is adjusted to pH4- with 1mol/L hydrochloric acid
4.5, remaining potassium borohydride is decomposed, then pH6.8-7.2 is adjusted to 2mol/L sodium hydroxide solutions, is extracted with toluene and remove l-
Alcohol, water layer are concentrated to dryness, and absolute ethyl alcohol is added in residue, is heated to 60-70 DEG C, is filtered to remove inorganic salts, filtrate while hot
It is concentrated under reduced pressure into about surplus 15ml, adds ethyl acetate, cooling crystallization filters, and filtration cakes torrefaction obtains emtricitabine white solid.
Embodiment three：
In embodiment two, following processes are added：
Potassium borohydride aqueous solution is by 0.8g, the water composition of 14.8mmol potassium borohydrides and 4ml.
In 20 DEG C of aqueous dibasic potassium phosphate solution stirring be added 3- oxathiolane -2- carboxylic acid l- base esters (2.0g,
5.0mmol) it is made of the dipotassium hydrogen phosphate of 2.7g and the water of 3ml with absolute ethyl alcohol (15ml), wherein aqueous dibasic potassium phosphate solution,
The potassium borohydride aqueous solution containing 25% sodium hydroxide solution is added dropwise, potassium borohydride aqueous solution is by 0.8g, 14.8mmol hydroborations
Potassium and the water of 4ml composition, 15-30 DEG C of stirring 2h, are adjusted to pH4-4.5 with 1mol/L hydrochloric acid, decompose remaining potassium borohydride, then use
2mol/L sodium hydroxide solutions are adjusted to pH6.8-7.2, are extracted with toluene and remove l-Alcohol, water layer are concentrated to dryness, residue
Absolute ethyl alcohol is added, is heated to 60-70 DEG C, is filtered to remove inorganic salts while hot, filtrate decompression is concentrated into about surplus 15ml, adds second
Acetoacetic ester, cooling crystallization, filtering, filtration cakes torrefaction obtain emtricitabine white solid.
Example IV：
In embodiment three, following processes are added：
Sodium hydroxide solution amount in potassium borohydride aqueous solution is 0.04ml, and the amount of the absolute ethyl alcohol is 30ml.
In 20 DEG C of aqueous dibasic potassium phosphate solution stirring be added 3- oxathiolane -2- carboxylic acid l- base esters (2.0g,
5.0mmol) it is made of the dipotassium hydrogen phosphate of 2.7g and the water of 3ml with absolute ethyl alcohol (15ml), wherein aqueous dibasic potassium phosphate solution,
The potassium borohydride aqueous solution containing 25% sodium hydroxide solution is added dropwise, potassium borohydride aqueous solution is by 0.8g, 14.8mmol hydroborations
Potassium and the water of 4ml composition, wherein the sodium hydroxide solution amount in potassium borohydride aqueous solution are 0.04ml, and 15-30 DEG C of stirring 2h is used
1mol/L hydrochloric acid is adjusted to pH4-4.5, decomposes remaining potassium borohydride, then be adjusted to pH6.8-7.2 with 2mol/L sodium hydroxide solutions,
It is extracted with toluene and removes l-Alcohol, water layer are concentrated to dryness, and absolute ethyl alcohol is added in residue, and the amount of absolute ethyl alcohol is 30ml,
It is heated to 60-70 DEG C, is filtered to remove inorganic salts while hot, filtrate decompression is concentrated into about surplus 15ml, adds ethyl acetate, cooling analysis
Crystalline substance, filtering, filtration cakes torrefaction obtain emtricitabine white solid.
Embodiment five：
In example IV, following processes are added：
The addition of ethyl acetate is 30ml.
In 20 DEG C of aqueous dibasic potassium phosphate solution stirring be added 3- oxathiolane -2- carboxylic acid l- base esters (2.0g,
5.0mmol) it is made of the dipotassium hydrogen phosphate of 2.7g and the water of 3ml with absolute ethyl alcohol (15ml), wherein aqueous dibasic potassium phosphate solution,
The potassium borohydride aqueous solution containing 25% sodium hydroxide solution is added dropwise, potassium borohydride aqueous solution is by 0.8g, 14.8mmol hydroborations
Potassium and the water of 4ml composition, wherein the sodium hydroxide solution amount in potassium borohydride aqueous solution are 0.04ml, and 15-30 DEG C of stirring 2h is used
1mol/L hydrochloric acid is adjusted to pH4-4.5, decomposes remaining potassium borohydride, then be adjusted to pH6.8-7.2 with 2mol/L sodium hydroxide solutions,
It is extracted with toluene and removes l-Alcohol, water layer are concentrated to dryness, and 30ml absolute ethyl alcohols are added in residue, are heated to 60-70 DEG C, take advantage of
Heat filtering removes inorganic salts, and filtrate decompression is concentrated into about surplus 15ml, adds 30ml ethyl acetate, cooling crystallization, filtering, filter cake
It is dry, obtain emtricitabine white solid.
Present invention optimizes process conditions, will directly remove l-The solution decompression of alcohol is evaporated, and is added after absolute ethyl alcohol is added
Heat filtering removes inorganic salts, then obtains sterling with re-crystallizing in ethyl acetate, and improved step reaction is easy to operate, total recovery
27%, it solves that prior art yield is relatively low, and need expensive reagent, leads to the problem that production cost is high.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
Understanding without departing from the principles and spirit of the present invention can carry out these embodiments a variety of variations, modification, replace
And modification, the scope of the present invention is defined by the appended.
Claims (5)
1. a kind of emtricitabine separation method, it is characterised in that：Include the following steps：In 20 DEG C of aqueous dibasic potassium phosphate solution
3- oxathiolane -2- carboxylic acid l- base esters (2.0g, 5.0mmol) and absolute ethyl alcohol (15ml) is added in stirring, and dropwise addition contains
The potassium borohydride aqueous solution of 25% sodium hydroxide solution, 15-30 DEG C of stirring 2h, pH4-4.5 is adjusted to 1mol/L hydrochloric acid, is decomposed surplus
Remaining potassium borohydride, then it is adjusted to pH6.8-7.2 with 2mol/L sodium hydroxide solutions, it is extracted with toluene and removes l-Alcohol, water layer subtract
Pressure is concentrated to dryness, and absolute ethyl alcohol is added in residue, is heated to 60-70 DEG C, is filtered to remove inorganic salts while hot, filtrate decompression is concentrated into
About surplus 15ml adds ethyl acetate, and cooling crystallization filters, and filtration cakes torrefaction obtains emtricitabine white solid.
2. a kind of emtricitabine separation method according to claim 1, it is characterised in that：The aqueous dibasic potassium phosphate solution
It is made of the dipotassium hydrogen phosphate of 2.7g and the water of 3ml.
3. a kind of emtricitabine separation method according to claim 1, it is characterised in that：The potassium borohydride aqueous solution by
The water of 0.8g, 14.8mmol potassium borohydride and 4ml form.
4. a kind of emtricitabine separation method according to claim 1, it is characterised in that：In the potassium borohydride aqueous solution
Sodium hydroxide solution amount be 0.04ml, the amount of the absolute ethyl alcohol is 30ml.
5. a kind of emtricitabine separation method according to claim 1, it is characterised in that：The addition of the ethyl acetate
For 30ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810565836.4A CN108409724A (en) | 2018-06-04 | 2018-06-04 | A kind of emtricitabine separation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810565836.4A CN108409724A (en) | 2018-06-04 | 2018-06-04 | A kind of emtricitabine separation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108409724A true CN108409724A (en) | 2018-08-17 |
Family
ID=63141155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810565836.4A Pending CN108409724A (en) | 2018-06-04 | 2018-06-04 | A kind of emtricitabine separation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108409724A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101407513A (en) * | 2008-11-14 | 2009-04-15 | 江苏科本医药化学有限公司 | Method for synthesizing nucleoside analogue |
| CN102234269A (en) * | 2010-04-29 | 2011-11-09 | 重庆医药工业研究院有限责任公司 | Industrial preparation method for lamivudine |
| WO2012131541A1 (en) * | 2011-03-25 | 2012-10-04 | Piramal Healthcare Limited | A process for the isolation of emtricitabine |
| CN102746284A (en) * | 2012-07-05 | 2012-10-24 | 湖南千金湘江药业股份有限公司 | Preparation method for lamivudine |
| CN103450166A (en) * | 2012-05-31 | 2013-12-18 | 上海迪赛诺药业有限公司 | Preparation method of nucleotide compound |
-
2018
- 2018-06-04 CN CN201810565836.4A patent/CN108409724A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101407513A (en) * | 2008-11-14 | 2009-04-15 | 江苏科本医药化学有限公司 | Method for synthesizing nucleoside analogue |
| CN102234269A (en) * | 2010-04-29 | 2011-11-09 | 重庆医药工业研究院有限责任公司 | Industrial preparation method for lamivudine |
| WO2012131541A1 (en) * | 2011-03-25 | 2012-10-04 | Piramal Healthcare Limited | A process for the isolation of emtricitabine |
| CN103450166A (en) * | 2012-05-31 | 2013-12-18 | 上海迪赛诺药业有限公司 | Preparation method of nucleotide compound |
| CN102746284A (en) * | 2012-07-05 | 2012-10-24 | 湖南千金湘江药业股份有限公司 | Preparation method for lamivudine |
Non-Patent Citations (1)
| Title |
|---|
| 孟静芳等: "恩曲他滨的合成", 《中国医药工业杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101870713A (en) | Industrial production process for tenofovir disoproxil fumarate | |
| CN104262393A (en) | Energy-saving clean production method and device of glyphosate | |
| CN102241582A (en) | Synthesis technology of sodium valproate | |
| CN106699814A (en) | Preparation method of adefovir dipivoxil crystals | |
| CN104262200A (en) | Production method for preparing N,N'-dicyclohexylcarbodiimide (DCC) by recycling wastewater | |
| CN103694271A (en) | Preparation method of calcium phosphorylcholine chloride | |
| CN104211727A (en) | Preparation method of tributyl phosphate | |
| CN106006589A (en) | Method for joint production of hypophosphite of calcium, magnesium and aluminum | |
| CN101250199B (en) | Method for preparing diisopropyl phosphite | |
| CN102311394B (en) | Preparation method for 5-ethyl-5-phenyl barbituric acid | |
| CN108409724A (en) | A kind of emtricitabine separation method | |
| CN104119243A (en) | Iminodiacetic acid energy saving cleaning production method | |
| CN102267897A (en) | Preparation method of malonate | |
| CN103214421B (en) | The industrialized preparing process of 2-sulfydryl-1-Methylimidazole | |
| CN103288801A (en) | Preparation method for high-purity esomeprazole sodium | |
| CN100549013C (en) | The synthetic method of 2-amino-6-chloropurine | |
| CN103408474B (en) | High purity N-acetyl-D, the high-efficiency method for producing of L-Methionine | |
| CN102603514B (en) | Process for preparing sodium gluconate from crop straws | |
| CN111961077B (en) | Preparation method of beta sodium glycerophosphate containing crystal water | |
| CN103754854A (en) | Preparation method for feed and calcium hydrogen phosphate by using hydrochloric acid process | |
| CN103420882B (en) | A kind of preparation method of L-Methionine | |
| CN103864847B (en) | A kind of technique of preparing tenofovir | |
| CN101481387A (en) | Preparation for synthesizing glyphosate by catalytic oxidation | |
| CN105130972A (en) | Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate | |
| CN105541712A (en) | Method for preparing solifenacin intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180817 |
|
| RJ01 | Rejection of invention patent application after publication |