CN107098936A - A kind of preparation method of TAF nucleoside derivates - Google Patents
A kind of preparation method of TAF nucleoside derivates Download PDFInfo
- Publication number
- CN107098936A CN107098936A CN201710292902.0A CN201710292902A CN107098936A CN 107098936 A CN107098936 A CN 107098936A CN 201710292902 A CN201710292902 A CN 201710292902A CN 107098936 A CN107098936 A CN 107098936A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- crown
- alkali
- mol ratio
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention discloses a kind of preparation method of TAF nucleoside derivates, methods described includes, compound II adds alkali and catalyst in a solvent, it is stirred to reaction complete, compound I is obtained, compared with prior art, preparation method raw material of the invention is cheap and easy to get, reaction condition is gentle, side reaction is few, high income, environmental pollution are small, suitable for industrialized production, ended for fumaric acid tenofovir and draw the preparation of phenol amine key intermediate to provide a new approach.
Description
Technical field
The Preparation Method And Their Intermediate of the important intermediate of phenol amine is drawn the present invention relates to fumaric acid tenofovir Chinese mugwort.
Background technology
Fumaric acid tenofovir Chinese mugwort draws phenol amine (tenofovir alafenamide fumarate), chemical entitled 9-
[(R) -2- [[(S)-[[(S) -1- (isopropoxy carbonyl) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl group] adenine
Fumarate, is a kind of novel nucleoside acids RTI.
The compound is researched and developed by Gilead Sciences companies of the U.S., in U.S.'s listing, is grown up for treating within 2015
HIV.The medicine also be used to treat hepatitis B, be currently in the III phases clinical.It is changed into rapidly for promise good fortune after this product is oral
Wei, is phosphorylated to tenofovir diphosphate in the presence of cell kinase, by competitively with natural deoxyribose bottom
Thing, which is combined suppression varial polymerases and is inserted into after viral DNA, causes DNA extension termination, is lived so as to suppress HIV and HBV
Property.
(R) -9- (2- phenoxy group phosphate methoxies propyl group) adenine (I) is that synthesis fumaric acid tenofovir Chinese mugwort draws phenol amine
Important intermediate, structure is as follows：
Compound I ends as tenofovir draws the key intermediate of phenol amine synthesis, and its primary synthetic methods has two kinds, specifically
Reaction is as follows：
One kind be with (R)-tenofovir (II) be raw material, and phenol in nmp solvent under heating condition add DCC and three
Ethamine reaction obtains required I:
(NUCLEOSIDES,NUCLEOTIDES&NUCLEIC ACIDS 2001,20,621；US2014/288025 A1；
US2015/315221 A1；WO2014/68265 A1；US2016/115186 A1；WO2015/40640 A2).This method
Problem is that the coupling reagent DCC used in reaction generates substantial amounts of byproduct, it is difficult to removed, product is difficult purification.It is even final
Purification, a large amount of solid wastes of generation also cause the technique to be difficult to industrialized production.
Another method is that with acetonitrile or NMP II and triphenyl phosphite are made into solvent, under DMAP, triethylamine effect
Heating response obtains I,
(US 2013/0090473 A1；WO 2013/052094 A2；WO2015/107451 A2).The master of this method
It is that equivalent uses the triphenyl phosphite of raw material containing phosphine to want problem, ultimately produces a large amount of phosphorus-containing wastewaters, causes this method to be difficult to apply
In industrialized production.
Another method is that compound IIa and alkaline reagent are hydrolyzed into reaction to obtain monophenyl Ia
(WO2015161785 A1),
The subject matter of this method is that substrate needs additional step plus blocking group Boc, is removed again in subsequent technique,
Production stage is longer；Monophenyl preparation process is heated, it is necessary to press device using ammoniacal liquor as alkali, it is difficult to applied to industrial metaplasia
Production.
The content of the invention
The technical problems to be solved by the invention are to overcome 9- [(R) -2- [[(phenoxy group phosphinyl) first in the prior art
Epoxide] propyl group]] defect that synthetic method reaction yield is not high, environmental pollution is larger of adenine, and there is provided a kind of new
Preparation method, this method reaction condition is gentle, side reaction is few, high income, environmental pollution are small, suitable for industrialized production.
Therefore, the present invention provides a kind of compound I preparation method, it the described method comprises the following steps：To dissolved with chemical combination
Alkali and catalyst are added in thing II solution, reaction is stirred to completely, obtains required compound I,
Wherein, the solution dissolved with compound II, its solvent is selected from：Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, water
In one or more combination solvents；Solvent and compound II volume mass ratio are 1~10000ml：1g；The alkali is selected from
Lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali and compound II mol ratio are 1~1000：1；The catalyst is crown ether,
Itself and compound II mol ratio are 0.001~10：1, wherein the reaction, temperature is 0~80 DEG C.
It is preferred that, described reaction dissolvent is the combination of the one or both in tetrahydrofuran, methanol.
It is preferred that, solvent and compound II volume mass ratio are 10~1000ml：1g.
It is furthermore preferred that solvent and compound II volume mass ratio are 30~50ml：1g.
It is preferred that, alkali and compound II mol ratio are 1~100：1.
It is furthermore preferred that alkali and compound II mol ratio are 1.5~3：1.
It is preferred that, the crown ether is selected from 12-crown-4,15- crown-s 5 or 18- crown-s 6, and itself and compound II mol ratio are
0.01~1：1.
It is preferred that, alkali used is lithium hydroxide；Catalyst used is 12-crown-4, its mol ratio with compound II
For 0.05~0.5：1.
It is preferred that, alkali used is sodium hydroxide；Catalyst used is 15- crown-s 5, its mol ratio with compound II
For 0.05~0.5：1.
It is preferred that, alkali used is potassium hydroxide；Catalyst used is 18- crown-s 6, its mol ratio with compound II
For 0.05~0.5：1.
It is preferred that, reaction temperature is 20~60 DEG C.
It is furthermore preferred that the temperature of reaction is 35~65 DEG C.
In the present invention, the compound II is prior art, can commercially be obtained, can also be by with lower section
Method is made：
Phenol is added in compound III organic solvent, esterification obtains required compound II,
Wherein, described organic solvent includes one or more combinations in dichloromethane, acetonitrile and tetrahydrofuran, institute
The organic solvent stated and compound III volume mass ratio are 1~10000ml/g, preferably 10~1000ml/g；Phenol used
With compound III mol ratio 1~1000：1, preferably 1~100：1；Reaction temperature is 0~80 DEG C, preferably 20~60 DEG C.
Wherein, compound III is prior art, can commercially obtain, can also be made using the following method：
Chlorinating agent and catalysis are added in compound VI (being prior art, can make by oneself or commercially obtain) organic solvent
Agent, back flow reaction obtains required compound III.
Wherein, described organic solvent includes dichloromethane, tetrahydrofuran or solvent-free reaction, described organic solvent
Volume mass ratio with compound IV is 1~10000ml：1g, preferably 10~1000ml：1g；Chlorinating agent used is dichloro
One kind in sulfoxide, oxalyl chloride or sulfonic acid chloride, the mol ratio 1~1000 of chlorinating agent and compound IV：1, preferably 1~100：1；
Described catalyst is DMF, its mol ratio 1 with compound IV:1~1000, preferably 1:1~100；
Reaction temperature is 0~80 DEG C, preferably 20~60 DEG C.
The present invention method, compared to the prior art its advantage as shown in Table 1, wherein, prior art 1 with reference to text
Offer for：NUCLEOSIDES,NUCLEOTIDES&NUCLEIC ACIDS 2001,20,621；WO2015/40640 A2；
WO2015/107451 A2
The document of prior art 2 is：US 2013/0090473 A1；
The document of prior art 3 is：WO2015161785 A1
Table one：
Embodiment
Following Examples further illustrate the present invention, it is not intended that embodiment limitation of the present invention.
The III of embodiment 1 preparation
IV (100g, 0.348mol) is placed in 2L three-necked bottles, nitrogen protection is lower to add thionyl chloride (1L), is heated to outer
Warm 70 degree of back flow reactions are stayed overnight, and TLC shows that reaction is finished, and solvent is directly evaporated to the crude pale yellow solid 110g for obtaining III
(0.341mol, yield 97.9%).
The II of embodiment 2 preparation
III crude product 100g (0.310mol) is placed in 2L three-necked bottles, nitrogen protection is lower to add anhydrous acetonitrile (1L), stirs
Mix and dissolve and be cooled to 0 degree, add phenol (116g, 1.23mol), be slowly increased to 25 degrees Celsius and react 16 hours, TLC display reactions
Completely, reaction is quenched in saturated sodium bicarbonate solution, and dichloromethane extracting and demixing, organic phase is washed with saturated sodium-chloride, anhydrous slufuric acid
Magnesium is dried, and is filtered and after solvent evaporated, is recrystallized with ethyl acetate-hexane, obtain II 125g (0.285mol, yield
91.9%).
Characterize data NMR (400MHz, d6-DMSO):8.12(s,1H),8.03(s,1H),7.38(m,4H),7.24(m,
4H),7.16(m,2H),7.08(m,2H),4.22(m,2H),4.18(br,2H),4.06(dd,1H),1.08(d,3H)。
ESI-MS[M+H]+:440.15
The I of embodiment 3 preparation
II 135g (0.308mol) is placed in 2L three-necked bottles, Isosorbide-5-Nitrae-dioxane 1.35L, 1M potassium hydroxide is added
The aqueous solution (350mL, 0.35mol), 18- crown-s 6 (4g, 15.1mmol), 25 degrees Celsius are stirred 12 hours, and TLC displays have been reacted
Entirely, added water (350mL), and ethyl acetate (350mL) is extracted twice, and aqueous phase is adjusted to pH=2-3 with concentrated hydrochloric acid, and solid I is separated out, mistake
Filter, filter cake 2N salt pickling obtains I (100g, 0.275mol, yield 89.4%) after 60 degrees Celsius of drying of hot-air oven.
Characterize data NMR (400MHz, d6-DMSO):8.13(s,1H),8.11(s,1H),7.55(br,2H),7.25(m,
2H),7.08(m,1H),7.03(m,2H),4.22(m,2H),3.95(br,1H),3.75(m,3H),1.02(br,3H)。
ESI-MS[M+H]+:364.14
Embodiment 4I preparation
II crude product 135g (0.308mol) is placed in 2L three-necked bottles, tetrahydrofuran 1.35L, 1M sodium hydroxide is added
The aqueous solution (350mL, 0.35mol), 15- crown-s 5 (6g, 27.3mmol), is stirred overnight at room temperature, and TLC display reactions are complete, add water
(350mL), ethyl acetate (350mL) is extracted twice, and aqueous phase is adjusted to pH=2-3 with concentrated hydrochloric acid, and solid I is separated out, and filtering, filter cake is used
2N salt pickling, I (102g, 0.281mol, yield 91.2%) is obtained after 60 degrees Celsius of drying of baking oven.
Characterize data be the same as Example 3
Embodiment 5I preparation
II crude product 135g (0.308mol) is placed in 2L three-necked bottles, methanol 1.35L, 1 M lithium hydroxide water is added
Solution (350mL, 0.35mol), 12-crown-4 (2.5g, 14.4mmol), is stirred overnight at room temperature, and HPLC display reactions are complete, add water
(350mL), ethyl acetate (350mL) is extracted twice, and aqueous phase is adjusted to pH=2-3 with concentrated hydrochloric acid, and solid I is separated out, and filtering, filter cake is used
2N salt pickling, I (96g, 0.264mol, yield 85.9%) is obtained after 60 degrees Celsius of drying of baking oven.
Characterize data be the same as Example 3.
Claims (14)
1. a kind of compound I preparation method, it is characterised in that the described method comprises the following steps：To dissolved with compound II's
Alkali and catalyst are added in solution, reaction is stirred to completely, obtains required compound I,
2. preparation method according to claim 1, it is characterised in that wherein, the solution dissolved with compound II, its is molten
Agent is Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, one or more combinations in water；The volume matter of solvent and compound II
Amount is than being 1~10000ml：1g；The alkali is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide；Mole of alkali and compound II
Than for 1~1000：1；The catalyst is crown ether, and itself and compound II mol ratio are 0.001~10：1, wherein described anti-
Should, temperature is 0~80 DEG C.
3. preparation method according to claim 2, it is characterised in that wherein, the volume matter of the solvent and compound II
Amount is than being 10~1000ml：1g.
4. preparation method according to claim 2, the solvent and compound II volume mass ratio are 30~50ml：
1g。
5. preparation method according to claim 2, it is characterised in that wherein, alkali and compound II mol ratio for 1~
100：1.
6. preparation method according to claim 2, it is characterised in that wherein, alkali and compound II mol ratio for 1.5~
3：1.
7. preparation method according to claim 2, it is characterised in that wherein, the crown ether is selected from 12-crown-4,15- crown-s 5
Or 18- crown-s 6, itself and compound II mol ratio are 0.01~1：1.
8. preparation method according to claim 2, it is characterised in that wherein, reaction temperature is 20~60 DEG C.
9. preparation method according to claim 2, it is characterised in that wherein, the temperature of reaction is 35~65 DEG C.
10. method according to claim 2, it is characterised in that described organic solvent is one in tetrahydrofuran, methanol
Plant or combination.
11. method according to claim 2, it is characterised in that alkali used is lithium hydroxide；Catalyst used is
12-crown-4, itself and compound II mol ratio are 0.05~0.5：1.
12. method according to claim 2, it is characterised in that alkali used is sodium hydroxide；Catalyst used is
15- crown-s 5, itself and compound II mol ratio are 0.05~0.5：1.
13. method according to claim 2, it is characterised in that alkali used is potassium hydroxide；Catalyst used is
18- crown-s 6, itself and compound II mol ratio are 0.05~0.5：1.
14. method according to claim 2, it is characterised in that step is as follows：
II crude product 135g (0.308mol) is placed in 2L three-necked bottles, the sodium hydroxide for adding tetrahydrofuran 1.35L, 1M is water-soluble
Liquid (350mL, 0.35mol), 15- crown-s 5 (6g, 27.3mmol), is stirred overnight at room temperature, and TLC display reactions are complete, add water
(350mL), ethyl acetate (350mL) is extracted twice, and aqueous phase is adjusted to pH=2-3 with concentrated hydrochloric acid, and solid I is separated out, and filtering, filter cake is used
2N salt pickling, I (102g, 0.281mol, yield 91.2%) is obtained after 60 DEG C of drying of baking oven.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710292902.0A CN107098936B (en) | 2017-04-28 | 2017-04-28 | Preparation method of TAF nucleoside derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710292902.0A CN107098936B (en) | 2017-04-28 | 2017-04-28 | Preparation method of TAF nucleoside derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107098936A true CN107098936A (en) | 2017-08-29 |
| CN107098936B CN107098936B (en) | 2020-09-08 |
Family
ID=59656371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710292902.0A Active CN107098936B (en) | 2017-04-28 | 2017-04-28 | Preparation method of TAF nucleoside derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107098936B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107936059A (en) * | 2017-11-14 | 2018-04-20 | 中国药科大学 | A kind of improved method of hexadecane oxygen propyl group tenofovir disoproxil synthesis technique |
| CN110272455A (en) * | 2019-04-15 | 2019-09-24 | 浙江车头制药股份有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws the preparation method of phenol amine key intermediate |
| CN112390824A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Preparation method of tenofovir alafenamide intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817593A (en) * | 2015-04-27 | 2015-08-05 | 广州同隽医药科技有限公司 | Synthetic process of key intermediate of hemifumarate tenofovir alafenamide |
| WO2015127848A1 (en) * | 2014-02-27 | 2015-09-03 | 四川海思科制药有限公司 | Substituted phosphoramidate derivative, preparation method therefor, and uses thereof |
| WO2015161781A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing nucleoside analogue and intermediate thereof |
-
2017
- 2017-04-28 CN CN201710292902.0A patent/CN107098936B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127848A1 (en) * | 2014-02-27 | 2015-09-03 | 四川海思科制药有限公司 | Substituted phosphoramidate derivative, preparation method therefor, and uses thereof |
| WO2015161781A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing nucleoside analogue and intermediate thereof |
| WO2015161785A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing phosphoramidate derivative and intermediates thereof, and method for preparing intermediates |
| CN104817593A (en) * | 2015-04-27 | 2015-08-05 | 广州同隽医药科技有限公司 | Synthetic process of key intermediate of hemifumarate tenofovir alafenamide |
Non-Patent Citations (2)
| Title |
|---|
| MICHAŁ GÓRNY VEL GÓRNIAK等: "Synthesis of fluorescent (benzyloxycarbonylamino)(aryl)methylphosphonates", 《BEILSTEIN J. ORG. CHEM.》 * |
| 尹志刚 主编: "《有机磷化合物》", 31 March 2011, 北京：化学工业出版社 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107936059A (en) * | 2017-11-14 | 2018-04-20 | 中国药科大学 | A kind of improved method of hexadecane oxygen propyl group tenofovir disoproxil synthesis technique |
| CN110272455A (en) * | 2019-04-15 | 2019-09-24 | 浙江车头制药股份有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws the preparation method of phenol amine key intermediate |
| CN112390824A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Preparation method of tenofovir alafenamide intermediate |
| CN112390824B (en) * | 2019-08-19 | 2022-07-05 | 鲁南制药集团股份有限公司 | Preparation method of tenofovir alafenamide intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107098936B (en) | 2020-09-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107021984B (en) | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates | |
| CN112533892B (en) | Alkoxyphenyl derivative, nucleoside protector, nucleotide protector, method for producing oligonucleotide, and method for removing substituent | |
| CN104876995B (en) | The preparation method of chenodeoxycholic acid derivatives | |
| CN102584795B (en) | Preparing method of crizotinib | |
| CN112279877B (en) | Nucleoside phosphate and synthesis method thereof | |
| CN107098936A (en) | A kind of preparation method of TAF nucleoside derivates | |
| CN105330700A (en) | Tenofovir alafenamide fumarate impurity preparing method | |
| CN106478528A (en) | The synthesis technique of Favipiravir | |
| CN110105392A (en) | What a kind of tenofovir Chinese mugwort drew phenol amine efficiently synthesizes technique | |
| CN104628773A (en) | Preparation method of (R)-9-[2-(phosphoryl phenol methoxy)propyl]adenine | |
| CN106632484B (en) | Preparation method of tenofovir alafenamide | |
| KR20120037932A (en) | Process for producing flurocytidine derivatives | |
| CN110372749A (en) | A kind of preparation method of third phenol tenofovir key intermediate, one phenyl PMPA | |
| CN105622671A (en) | Preparing method for realizing industrial mass production of tenofovir disoproxil fumarate | |
| WO2020158687A1 (en) | Method of producing photoreactive nucleotide analog | |
| CN109970832B (en) | Alkynyl-modified deoxyadenosine phosphoramidite monomer and preparation method thereof | |
| CN105440012A (en) | Lenalidomide and lenalidomide intermediate preparation method | |
| CN113480539B (en) | Synthetic method of nitric acid catalyzed hypoxanthine derivative | |
| CN100526321C (en) | Method of Synthesizing adefovir dipivoxil | |
| CN106946935A (en) | A kind of preparation method of diastereoisomer nucleoside derivates | |
| CN113549054B (en) | Vonoprazan fumarate intermediate and preparation method thereof | |
| CN104447548B (en) | The method for synthesizing the isoquinolin of substitution | |
| CN101531680B (en) | Method for synthesizing (R)-9(2-(diethyl phosphonyl methoxyl) propyl)-adenine | |
| CN109134569B (en) | A kind of production technology of Vidarabine Monophosphate | |
| CN107245043B (en) | A kind of preparation method preparing 3 methylthiol propyl alcohol from 3- methylthiopropionaldehydes |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |