CN103408548B - The method of synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4 - Google Patents
The method of synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4 Download PDFInfo
- Publication number
- CN103408548B CN103408548B CN201310384536.3A CN201310384536A CN103408548B CN 103408548 B CN103408548 B CN 103408548B CN 201310384536 A CN201310384536 A CN 201310384536A CN 103408548 B CN103408548 B CN 103408548B
- Authority
- CN
- China
- Prior art keywords
- vitamin
- hydroxypropyl
- add
- stirring
- reaction
- 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.)
- Active
Links
Abstract
The invention discloses a kind of method of synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4, comprise the following steps successively: (1) primary amino acetylize: VITAMIN B4 is dissolved in organic solvent, add alkali, catalyzer, stir, 0 ~ 10 DEG C drips diacetyl oxide; 80 ~ 85 DEG C of insulated and stirred reaction 6 ~ 10h obtain reaction solution; (2) N-is hydroxypropylated: regulate reaction solution pH=9 ~ 10, add propylene carbonate, 120 ~ 140 DEG C of stirring reactions, and cool to 70 ~ 80 DEG C and add toluene stirring 2 ~ 3h, separation, drying, obtain solid product; (3) deacetylation: joined by solid product in aqueous sodium hydroxide solution, 90 ~ 95 DEG C of stirring reaction 2 ~ 4h, are neutralized to pH=6 ~ 8 with concentrated hydrochloric acid after being down to room temperature, and separation, drying, obtain product.The present invention makes the selectivity of reaction greatly increase, avoid the generation of by product (R)-6-(2-hydroxypropyl) VITAMIN B4, (R)-9-(2-hydroxypropyl) VITAMIN B4 yield brought up to more than 90%, significantly reduces the production cost of tenofovir disoproxil.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to a kind of synthetic method of tenofovir disoproxil intermediate, relate to a kind of method of synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4 more specifically.
Background technology
In recent years, acquired immune deficiency syndrome (AIDS) constantly spreads, the trend of existing pandemic disease, tenofovir disoproxil (tenofovir), chemical name: (R)-9-(2-phosphate methoxy propyl group) VITAMIN B4 two (butyloxycarbonyl oxygen methyl) ester is the nucleoside analog that FDA first approval is used for the treatment of HIV (human immunodeficiency virus) infection, its importance obtains admitting of the World Health Organization, and is proposed as a line antiviral medication, and market demand is increasing.(R)-9-(2-hydroxypropyl) VITAMIN B4 produces the key intermediate of tenofovir disoproxil; producing tenofovir disoproxil is generally Material synthesis (R)-9-(2-(two ethyl phosphoryl) methoxy-propyl) VITAMIN B4 with (R)-9-(2-hydroxypropyl) VITAMIN B4, then carries out two ethyl sloughing process obtained.(R)-9-(2-hydroxypropyl) VITAMIN B4 is generally raw material with VITAMIN B4, reacts obtained in the basic conditions with propylene carbonate.But due to the existence of C-6 bit amino, make to create by product (R)-6-(2-hydroxypropyl) VITAMIN B4 while generation (R)-9-(2-hydroxypropyl) VITAMIN B4, have a strong impact on the yield of this step reaction, and by product and target product separation difficulty, cause industrial operation difficulty to increase, have impact on the overall yield of tenofovir disoproxil product, restrict the development of such medicine.
(R) structure of-9-(2-hydroxypropyl) VITAMIN B4 and (R)-6-(2-hydroxypropyl) VITAMIN B4 is as follows:
(R)-9-(2-hydroxypropyl) VITAMIN B4 (A) (R)-6-(2-hydroxypropyl) VITAMIN B4 (B)
Summary of the invention
The object of the invention is to provide a kind of method of easy-operating synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4, reduce the generation of by product (R)-6-(2-hydroxypropyl) VITAMIN B4, improve (R)-9-(2-hydroxypropyl) VITAMIN B4 yield.
The method of synthesis of the present invention (R)-9-(2-hydroxypropyl) VITAMIN B4, step is as follows:
(1) primary amino acetylize:
VITAMIN B4 be dissolved in organic solvent, add alkali, catalyzer, stir, 0 ~ 10 DEG C drips diacetyl oxide; 80 ~ 85 DEG C of insulated and stirred reaction 6 ~ 10h obtain reaction solution;
(2) N-is hydroxypropylated:
Regulate reaction solution pH=9 ~ 10; Add propylene carbonate, 120 ~ 140 DEG C of stirring reaction 3-5h; Cool to 70 ~ 80 DEG C and add toluene stirring 2 ~ 3h, separation, drying, obtain solid product;
(3) deacetylation:
Joined by solid product in aqueous sodium hydroxide solution, 90 ~ 95 DEG C of stirring reaction 2 ~ 4h, are neutralized to pH=6 ~ 8 with concentrated hydrochloric acid after being down to room temperature, and separation, drying, obtain product.
Wherein:
Described organic solvent is one or more the arbitrary proportion mixing in DMF, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO); Alkali is pyridine or triethylamine; Catalyzer is DMAP (DMAP); The mol ratio of VITAMIN B4, alkali, diacetyl oxide, propylene carbonate and catalyzer is: 1:(1 ~ 1.2): (1 ~ 1.2): (1 ~ 1.2): (0.1 ~ 0.11);
Described adjustment reacting liquid pH value sodium carbonate, sodium bicarbonate or sodium hydroxide one wherein;
Described aqueous sodium hydroxide solution concentration is 0.1 ~ 8mol/L.
The reaction formula of this invention is as follows:
The present invention compared with prior art, has following beneficial effect:
Described synthesis (R)-9-(2-hydroxypropyl) method of VITAMIN B4 makes the selectivity of reaction greatly increase, avoid the generation of by product (R)-6-(2-hydroxypropyl) VITAMIN B4, product yield has brought up to more than 90%, significantly reduces the production cost of tenofovir disoproxil.
Embodiment
Below in conjunction with embodiment, the present invention is described further, but scope of the present invention is not by any restriction of embodiment.
Embodiment 1
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 40mLN, dinethylformamide, add pyridine (9.5g, 0.12mol) and DMAP (1.2g, 0.01mol), stir borehole cooling to 5 DEG C, drip diacetyl oxide (11.2g, 0.11mol), drip finish be warming up to 85 DEG C of stirring reactions 6 hours.Be down to room temperature, sodium carbonate adjusts pH=10, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 130 DEG C of stirring reactions 4 hours.Be cooled to 70 DEG C; stir lower dropping 80mL toluene; then slowly room temperature is down under stirring; insulated and stirred 2 hours, suction filtration, 10mL toluene foam washing; dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 22.0g, yield 93.8%, high performance liquid chromatography (HPLC) purity 98.6%.
In 100mL there-necked flask, (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 90 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=6; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 18.4g; yield 95.7%, HPLC purity 98.7%.
Embodiment 2
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 30mLN, dinethylformamide, 10mLN-methyl-2-pyrrolidone, add triethylamine (12.1g, 0.12mol) and DMAP (1.2g, 0.01mol), stir borehole cooling to 0 DEG C, drip diacetyl oxide (11.2g, 0.11mol), drip finish be warming up to 80-85 DEG C of stirring reaction 6 hours.Be down to room temperature, sodium carbonate adjusts pH=10, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 135 DEG C of stirring reactions 3 hours.Be cooled to 75 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 22.0g, yield 93.8%, HPLC purity 98.9%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 90 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=7; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 18.7g; yield 96.8%, HPLC purity 99.0%.
Embodiment 3
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 20mLN, dinethylformamide, 20mLN-methyl-2-pyrrolidone, add triethylamine (12.1g, 0.12mol) and DMAP (1.2g, 0.01mol), stir borehole cooling to 0 DEG C, drip diacetyl oxide (12.2g, 0.12mol), drip finish be warming up to 80-85 DEG C of stirring reaction 6 hours.Be down to room temperature, sodium carbonate adjusts pH=9, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 130 DEG C of stirring reactions 4 hours.Be cooled to 80 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 21.2g, yield 90.3%, HPLC purity 98.2%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 90 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=8; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 17.9g; yield 93.1%, HPLC purity 98.6%.
Embodiment 4
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 10mLN, dinethylformamide, 30mLN-methyl-2-pyrrolidone, add pyridine (9.5g, 0.12mol) and DMAP (1.2g, 0.01mol), stir borehole cooling to 5 DEG C, drip diacetyl oxide (11.2g, 0.11mol), drip finish be warming up to 80-85 DEG C of stirring reaction 8 hours.Be down to room temperature, sodium carbonate adjusts pH=9, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 120 DEG C of stirring reactions 4 hours.Be cooled to 80 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 23.1g, yield 98.5%, HPLC purity more than 98%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 90 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=7; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 17.9g; yield 92.9%, HPLC purity 98.8%.
Embodiment 5
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 20mLN-methyl-2-pyrrolidone, 10mL dimethyl sulfoxide (DMSO), 10mLN, dinethylformamide, add triethylamine (12.1g, 0.12mol) and DMAP (1.2g, 0.01mol), stir borehole cooling to 5 DEG C, drip diacetyl oxide (11.2g, 0.11mol), drip finish be warming up to 80-85 DEG C of stirring reaction 9 hours.Be down to room temperature, sodium bicarbonate adjusts pH=10, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 140 DEG C of stirring reactions 4 hours.Be cooled to 75 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 21.5g, yield 91.6%, HPLC purity more than 98%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 93 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=7; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 18.2g; yield 94.8%, HPLC purity 98.9%.
Embodiment 6
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 40mLN-methyl-2-pyrrolidone, add pyridine (9.5g, 0.12mol) with DMAP (1.2g, 0.01mol), stir borehole cooling to 5 DEG C, drip diacetyl oxide (11.2g, 0.11mol), drip finish be warming up to 80-85 DEG C of stirring reaction 7 hours.Be down to room temperature, sodium bicarbonate adjusts pH=10, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 125 DEG C of stirring reactions 4 hours.Be cooled to 80 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 22.9g, yield 97.6%, HPLC purity more than 98%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 93 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=7; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 18.4g; yield 95.3%, HPLC purity 98.1%.
Embodiment 7
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 40mLN-methyl-2-pyrrolidone, add triethylamine (12.1g, 0.12mol) with DMAP (1.2g, 0.01mol), stir borehole cooling to 5 DEG C, drip diacetyl oxide (11.2g, 0.11mol), drip finish be warming up to 80-85 DEG C of stirring reaction 10 hours.Be down to room temperature, sodium bicarbonate adjusts pH=9, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 130 DEG C of stirring reactions 4 hours.Be cooled to 70 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 21.9g, yield 93.4%, HPLC purity more than 98%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 93 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=7; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 18.9g; yield 97.7%, HPLC purity 99.2%.
Embodiment 8
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 40mL dimethyl sulfoxide (DMSO), add pyridine (9.5g, 0.12mol) with DMAP (1.2g, 0.01mol), stir borehole cooling to 5 DEG C, drip diacetyl oxide (11.2g, 0.11mol), drip finish be warming up to 80-85 DEG C of stirring reaction 8 hours.Be down to room temperature, sodium hydroxide adjusts pH=9, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 125 DEG C of stirring reactions 4 hours.Be cooled to 80 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 21.7g, yield 92.5%, HPLC purity more than 98%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 95 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=7; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 18.7g; yield 97.1%, HPLC purity 99.5%.
Embodiment 9
Embodiment 3 is in 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 20mL dimethyl sulfoxide (DMSO), 20mLN-methyl-2-pyrrolidone, add triethylamine (12.1g, 0.12mol) with DMAP (1.2g, 0.01mol), stir borehole cooling to 5 DEG C, drip diacetyl oxide (11.2g, 0.11mol), drip finish be warming up to 80 DEG C of stirring reactions 6 hours.Be down to room temperature, sodium hydroxide adjusts pH=9, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 135 DEG C of stirring reactions 4 hours.Be cooled to 70 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 21.7g, yield 92.5%, HPLC purity 98.4%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 95 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=7; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 18.7g; yield 96.9%, HPLC purity 99.3%.
Embodiment 10
In 250mL there-necked flask, add VITAMIN B4 (13.5g, 0.10mol), then add 40mL dimethyl sulfoxide (DMSO), add pyridine (9.5g, 0.12mol) with DMAP (1.2g, 0.01mol), stir borehole cooling to 5 DEG C, drip diacetyl oxide (12.2g, 0.12mol), drip finish be warming up to 85 DEG C of stirring reactions 8 hours.Be down to room temperature, sodium hydroxide adjusts pH=10, then adds propylene carbonate (12.2g, 0.12mol), is warming up to 130 DEG C of stirring reactions 4 hours.Be cooled to 80 DEG C, under insulated and stirred, drip 80mL toluene, be slowly down to room temperature under then stirring, stir 2 hours; suction filtration, 10mL toluene foam washing, dry; obtain (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 21.6g, yield 92.1%, HPLC purity 99.1%.
In 100mL there-necked flask, add (R)-6-ethanoyl-9-(2-hydroxypropyl) VITAMIN B4 (23.5g, 0.10mol); add 60mL massfraction 10% aqueous sodium hydroxide solution; be warming up to 95 DEG C of insulated and stirred and react 2 hours, be down to room temperature, concentrated hydrochloric acid is neutralized to pH=7; suction filtration; 20mL bubble filter wash cake, dry, obtain (R)-9-(2-hydroxypropyl) VITAMIN B4 18.7g; yield 96.9%, HPLC purity 98.2%.
Claims (6)
1. synthesizing a method for (R)-9-(2-hydroxypropyl) VITAMIN B4, take VITAMIN B4 as raw material, and react obtained in the basic conditions with propylene carbonate, it is characterized in that, step is as follows:
(1) primary amino acetylize:
VITAMIN B4 be dissolved in organic solvent, add alkali, catalyzer, stir, 0 ~ 10 DEG C drips diacetyl oxide; 80 ~ 85 DEG C of stirring reaction 6 ~ 10h obtain reaction solution;
(2) N-is hydroxypropylated:
Regulate reaction solution pH=9 ~ 10; Add propylene carbonate, 120 ~ 140 DEG C of stirring reaction 3 ~ 5h; Cool to 70 ~ 80 DEG C and add toluene stirring 2 ~ 3h, separation, drying, obtain solid product;
(3) deacetylation:
Joined by solid product in aqueous sodium hydroxide solution, 90 ~ 95 DEG C of stirring reaction 2 ~ 4h, are neutralized to pH=6 ~ 8 with concentrated hydrochloric acid after being down to room temperature, and separation, drying, obtain product;
The mol ratio of described VITAMIN B4, alkali, diacetyl oxide, propylene carbonate and catalyzer is: 1:(1 ~ 1.2): (1 ~ 1.2): (1 ~ 1.2): (0.1 ~ 0.11).
2. the method for synthesis according to claim 1 (R)-9-(2-hydroxypropyl) VITAMIN B4, it is characterized in that, described organic solvent is one or more the arbitrary proportion mixing in DMF, N-Methyl pyrrolidone and dimethyl sulfoxide (DMSO).
3. the method for synthesis according to claim 2 (R)-9-(2-hydroxypropyl) VITAMIN B4, is characterized in that, described alkali is pyridine or triethylamine.
4. the method for synthesis according to claim 3 (R)-9-(2-hydroxypropyl) VITAMIN B4, is characterized in that, described catalyzer is DMAP.
5. the method for synthesis according to claim 4 (R)-9-(2-hydroxypropyl) VITAMIN B4, is characterized in that, regulates reaction solution pH value sodium carbonate, sodium bicarbonate or sodium hydroxide one wherein.
6. the method for synthesis according to claim 5 (R)-9-(2-hydroxypropyl) VITAMIN B4, is characterized in that, described aqueous sodium hydroxide solution concentration is 0.1 ~ 8mol/L.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310384536.3A CN103408548B (en) | 2013-08-30 | 2013-08-30 | The method of synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310384536.3A CN103408548B (en) | 2013-08-30 | 2013-08-30 | The method of synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103408548A CN103408548A (en) | 2013-11-27 |
| CN103408548B true CN103408548B (en) | 2016-03-02 |
Family
ID=49601604
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310384536.3A Active CN103408548B (en) | 2013-08-30 | 2013-08-30 | The method of synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103408548B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530050A (en) * | 2014-12-23 | 2015-04-22 | 江西富祥药业股份有限公司 | Synthesis method of tenofovir disoproxil fumarate intermediate impurity 1-amino adenine-2-propyl alcohol |
| CN104892613B (en) * | 2015-05-23 | 2016-06-29 | 洛阳德胜生物科技股份有限公司 | A kind of new R-9-(2-hydroxypropyl) the purification process technique of adenine |
| CN106632340B (en) * | 2016-12-20 | 2018-09-04 | 深圳市万物生医药研发有限公司 | A method of synthesis tenofovir intermediate |
| CN112645952B (en) * | 2020-12-24 | 2021-10-01 | 江苏阿尔法药业股份有限公司 | Synthetic method of (R) - (+) -9- (2-hydroxypropyl) adenine |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230065A (en) * | 2008-01-23 | 2008-07-30 | 台州市知青化工有限公司 | Method for producing 9-[2(hydroxyl)propyl] adenine |
| CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
| CN102060876A (en) * | 2010-12-29 | 2011-05-18 | 中山百灵生物技术有限公司 | Preparation method for tenofovir |
| CN102863445A (en) * | 2011-07-04 | 2013-01-09 | 北京六盛合医药科技有限公司 | Novel method for synthesizing 9-substituted adenine compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928302B (en) * | 2010-04-29 | 2012-09-12 | 浙江康多利药业有限公司 | N-benzyl-9-[2-(dialkyl phosphoryl methoxy) alkyl] adenine and preparation method and application thereof |
-
2013
- 2013-08-30 CN CN201310384536.3A patent/CN103408548B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230065A (en) * | 2008-01-23 | 2008-07-30 | 台州市知青化工有限公司 | Method for producing 9-[2(hydroxyl)propyl] adenine |
| CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
| CN102060876A (en) * | 2010-12-29 | 2011-05-18 | 中山百灵生物技术有限公司 | Preparation method for tenofovir |
| CN102863445A (en) * | 2011-07-04 | 2013-01-09 | 北京六盛合医药科技有限公司 | Novel method for synthesizing 9-substituted adenine compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103408548A (en) | 2013-11-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105330609B (en) | A kind of method for preparing LCZ696 | |
| CN106749194B (en) | A kind of preparation method for pyrimidine | |
| CN103408548B (en) | The method of synthesis (R)-9-(2-hydroxypropyl) VITAMIN B4 | |
| CN103980253B (en) | Synthetic method for 5-chloro-6-(2-iminopyrrolidinyl-1-yl)methyl-2,4-(1H,3H)pyrimidinedione hydrochloride | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN104059025B (en) | A kind of intermediate for preparing avanaphil and preparation method thereof | |
| CN102584795A (en) | Preparing method of crizotinib | |
| CN106349245A (en) | Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities | |
| CN105198821B (en) | Lip river former times replaces the preparation method of Buddhist nun | |
| CN104262397B (en) | A kind of preparation method of high-purity tenofovir | |
| CN103319462B (en) | Preparation method of halosulfuron methyl | |
| CN102633801B (en) | Method for preparing tebipenem ester | |
| CN104557877B (en) | A kind of avanaphil intermediate and its preparation method and application | |
| CN111646998A (en) | Synthesis method of ibrutinib | |
| CN103787924A (en) | New purification method of antitumor drug Belinostat | |
| CN103351386B (en) | A kind of synthetic method of Azasetron hydrochloride | |
| CN103130700B (en) | Preparation method of azelnidipine intermediate | |
| CN104710424B (en) | (R) (+) preparation method of 9 (2 hydroxypropyl) adenine | |
| CN102633779B (en) | Fasudil acetate as well as preparation method and application thereof | |
| CN104876911A (en) | Simple method for synthesizing delafloxacin | |
| CN104341452A (en) | Preparation method of tenofovir disoproxil fumarate impurities | |
| CN104016954A (en) | Method for preparing and purifying nebivolol intermediate | |
| KR20180105450A (en) | A Method of preparing Fimarsartan choline salt and hydrate thereof | |
| CN105503853A (en) | Synthetic method of cefdinir activated thioester | |
| CN105753870A (en) | Sildenafil impurity F and preparing method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL GROUP CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL & CHEMICAL Co.,Ltd. |