CN105753806B - A kind of heterogeneous synthetic method of Ritonavir intermediate and its application - Google Patents
A kind of heterogeneous synthetic method of Ritonavir intermediate and its application Download PDFInfo
- Publication number
- CN105753806B CN105753806B CN201610072894.4A CN201610072894A CN105753806B CN 105753806 B CN105753806 B CN 105753806B CN 201610072894 A CN201610072894 A CN 201610072894A CN 105753806 B CN105753806 B CN 105753806B
- Authority
- CN
- China
- Prior art keywords
- methyl
- synthetic method
- ritonavir
- valine
- methyl esters
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
Abstract
Heterogeneous synthetic method and its application the invention discloses a kind of Ritonavir intermediate, L valine methyl ester hydrochlorides and triphosgene are dissolved in dichloromethane using multi-phases process, inorganic lye is added dropwise under low temperature, generate isocyanate ester compound, it need not separate, 2 isopropyl 4 (Methylaminomethyl) thiazoles are added in one pot, you can obtain N ((N methyl Ns ((2 isopropyl, 4 thiazolyl) methyl) amino) formyl) L valine methyl esters.The present invention realizes the one pot process of Ritonavir intermediate MTV methyl esters, and all products can be purified by mashing and crystallization, and product purity is more than 98%.Production process pollution is small, is conducive to environment, small to the harm of operating personnel, easy to operate, is particularly suitable for large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of heterogeneous synthetic method of Ritonavir intermediate and its
Using.
Background technology
Important intermediate N- ((N- methyl-the N- ((2- isopropyls -4- of anti-AIDS drug Ritonavir (Ritonavir)
Thiazolyl) methyl) amino) formyl)-Valine methyl esters, a large amount of reports be in anhydrous conditions, it is anti-with primary amine with excess phosgene
Should, it is (pyridine (Py), triethylamine, two different using organic base in the environment of dichloromethane (DCM) or toluene (Toluene) exist
Propylethylamine etc.) prepare generation isocyanate ester compound (S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；Thereafter should
The isocyanate ester compound of purifying reacts generation N- ((N- methyl-N- with 2- isopropyls -4- (Methylaminomethyl) thiazole again
((2- isopropyl -4- thiazolyls) methyl) amino) formyl)-Valine methyl esters, reaction equation is shown below：
In this synthetic method, phosgene is highly corrosive, hypertoxic gas, dangerous big in industrial processes, safety wind
Danger is high, and usage amount is difficult to control.In addition pyridine excessive used in production process has intense irritation, pollutes environment.In addition the life
Production process needs anhydrous condition, and the isocyanate ester compound generated needs purifies and separates to come out, then with 2- isopropyls -4-
(Methylaminomethyl) thiazole reaction generation N- ((N- methyl-N- ((2- isopropyl -4- thiazolyls) methyl) amino) formyl)-L-
Valine methyl ester.All of these factors taken together all considerably increases production cost and technology difficulty.
The content of the invention
It is an object of the invention in place of overcome the deficiencies in the prior art, provide a kind of the non-equal of Ritonavir intermediate
Method and its application are combined to, it being capable of one pot process N- ((N- methyl-N- ((2- isopropyl -4- thiazolyls) methyl) amino)
Formyl)-Valine methyl esters, and all products can be purified by mashing and crystallization, product purity is shown more than 98%, HPLC
Single impurity peaks are less than 0.1%.Involved production technology pollution is small simultaneously, is conducive to environment, small to the harm of operating personnel, easily
Operation, is particularly suitable for large-scale industrial production.
One of the technical solution adopted by the present invention to solve the technical problems is：
A kind of heterogeneous synthetic method of Ritonavir intermediate, including：
Valine methyl ester hydrochloride and triphosgene are dissolved in dichloromethane, at nitrogen protection, 5~28 DEG C thereto by
It is added dropwise to the aqueous solution of inorganic base；Then in 20~40 DEG C of 0.8~1.2h of insulated and stirred reaction generation isocyanate ester compounds
(S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；Then 2- isopropyls -4- is added portionwise thereto at 20~40 DEG C
(Methylaminomethyl) thiazole, 0.8~1.2h of insulation reaction；Liquid separation, water merge after mutually being extracted with dichloromethane with organic phase, then
It is washed with 14~16% sodium chloride solutions；Liquid separation, organic phase drying is to get N- [N- methyl-N- [(2- isopropyl -4- thiazolyls)
Methyl] amino carbonyl]-Valine methyl esters.
In one embodiment：The Valine methyl ester hydrochloride, triphosgene, dichloromethane, inorganic base, 2- isopropyls -4-
The formula rate of (Methylaminomethyl) thiazole is 29~31g：18~22g：260~280ml：0.56~0.58mol：31~
33g。
In one embodiment：It further includes：By obtained N- [N- methyl-N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyls
Base]-Valine methyl esters progress piptonychia ester, obtain N- [N- methyl-N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyls
Base]-Valine.
In one embodiment：To two dissolved with Valine methyl ester hydrochloride and triphosgene at nitrogen protection, 5~10 DEG C
The aqueous solution of inorganic base is added dropwise in chloromethanes.
In one embodiment：The inorganic base is sodium hydroxide, sodium carbonate, potassium carbonate or sodium acid carbonate.
In one embodiment：It is different in 35~40 DEG C of 0.8~1.2h of insulated and stirred reaction generations after the aqueous solution of inorganic base is added dropwise
Cyanate compound (S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters.
In one embodiment：After generating isocyanate ester compound, 2- isopropyl -4- (first is added portionwise at 35~40 DEG C
Base amino methyl) thiazole.
In one embodiment：After generating isocyanate ester compound, divide under conditions of 20~40 DEG C, pH value is 5.8~6.2
It criticizes and adds in 2- isopropyls -4- (Methylaminomethyl) thiazole.
Said synthesis route is shown below：
The technical solution adopted by the present invention to solve the technical problems second is that：
Application of the heterogeneous synthetic method of above-mentioned Ritonavir intermediate in Ritonavir synthesis.
The three of the technical solution adopted by the present invention to solve the technical problems are：
A kind of heterogeneous synthetic method of isocyanates, including：Primary amine and triphosgene are dissolved in dichloromethane, protected in nitrogen
Shield, the aqueous solution that inorganic base is added dropwise at 5~28 DEG C thereto；Then reacted in 20~40 DEG C of 0.8~1.2h of insulated and stirred
Generate isocyanate ester compound (S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；The primary amine, triphosgene, dichloromethane
Alkane, the formula rate of inorganic base are 0.18mol：18~22g：260~280ml：0.56~0.58mol.
Compared with background technology, it has the following advantages that the technical program：
1. primary amine and Solid triphosgene are dissolved in dichloromethane by the present invention using multi-phases process, lye life is added dropwise under low temperature
Into isocyanate ester compound, without separation, 2- isopropyls -4- (Methylaminomethyl) thiazole is added in one pot, you can anti-
N- ((N- methyl-N- ((2- isopropyl -4- thiazolyls) methyl) amino) formyl)-Valine methyl esters should be generated, one kettle way is
It can obtain product；Compared with the prior art, using present invention reduces the requirement to production equipment and reaction reagent water content, nothings
Anhydrous reagent need to be used, standard reagent thereby reduces production cost.
2. the Solid triphosgene that the present invention uses, toxicity is low compared with phosgene, safer, and pollution is small, is conducive to environment, to operation
The harm of personnel is small, improves production security, and usage amount is easy to control.
3. the post processing of the entire production technology of the present invention has pertained only to liquid separation, evaporated under reduced pressure, organic phase is evaporated, and water is beaten
Slurry, crystallization etc., you can purifying obtains product, is more conducive to isolating and purifying for product, and obtained product purity is single up to 99.42%
Item impurity is particularly suitable for large-scale industrial production less than 0.1%.
Specific embodiment
Present disclosure is illustrated below by embodiment：
Embodiment 1
It is in 1000ml four-hole bottles, Valine methyl ester hydrochloride 30g (0.18mol) and 18~21.2g of triphosgene is molten
In 270ml dichloromethane, the sodium bicarbonate water that 480ml concentration is 1.2M is added dropwise thereto at nitrogen protection, 5~10 DEG C
Solution (0.57mol), about 1h 10min are added；35~40 DEG C are then heated to, insulated and stirred 1h reaction generation isocyanates
Compound (S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；Then the 2- of 32g is added portionwise thereto at 35~40 DEG C
Isopropyl -4- (Methylaminomethyl) thiazole hydrochloride adjusts pH value with 10% sodium hydroxide solution of 50g during the addition process
Stablize 6；35~40 DEG C of insulation reaction 1h after being added dropwise；After the completion of HPLC monitoring reactions, liquid separation, water mutually uses 100g dichloromethanes
Alkane extracts, and extract liquor merges with organic phase, then washed once with 15% sodium chloride solution of 200g；Liquid separation, organic phase decompression are steamed
It is dry, light yellow or off-white powder is obtained, as N- [N- methyl-N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyl] -
Valine methyl esters (MTV methyl esters), yield 89.5%, HPLC detection purity is 98.85%.
As needed, can by obtained N- [N- methyl-N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyl] -
Valine methyl esters carries out piptonychia ester, obtains N- [N- methyl-N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyl]-L-
Valine (MTV)：
The MTV methyl esters 30g that the present embodiment obtains is taken to carry out piptonychia ester, crystallization obtains MTV 24.1g, yield 80.3%,
HPLC detects purity 98.8%.
The MTV 20g obtained again add in 60g water, are beaten 3h, filter, and drying obtains 18.5g, yield 92.5%,
HPLC detects purity 99.42%.
Embodiment 2
It is in 1000ml four-hole bottles, Valine methyl ester hydrochloride 30g (0.18mol) and 18~21.2g of triphosgene is molten
In 270ml dichloromethane, the sodium acid carbonate that 480ml concentration is 1.2M is added dropwise thereto at nitrogen protection, 10~20 DEG C
Aqueous solution (0.57mol), about 1h is added；30 DEG C are then heated to, insulated and stirred 1h reaction generation isocyanate ester compounds
(S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；Then the 2- isopropyls -4- of 32g is added portionwise thereto at 30 DEG C
(Methylaminomethyl) thiazole hydrochloride adjusts pH stable 6 with 10% sodium hydroxide solution of 50g during the addition process；
30 DEG C of insulation reaction 1h after being added dropwise；After the completion of HPLC monitoring reactions, liquid separation, water is mutually extracted with 100g dichloromethane, extraction
Liquid merges with organic phase, then washed once with 15% sodium chloride solution of 200g；Liquid separation, organic phase evaporated under reduced pressure obtain pale yellow
Color or off-white powder are MTV methyl esters, and yield 88.4%, HPLC detection purity is 99.15%.
Embodiment 3
In 1000ml four-hole bottles, Valine methyl ester hydrochloride 30g (0.18mol) and triphosgene 21g are dissolved in 270ml
The sodium bicarbonate aqueous solution that 480ml concentration is 1.2M is added dropwise in dichloromethane thereto at nitrogen protection, 20~28 DEG C
(0.57mol), about 1h is added；Then insulated and stirred 1h reactions generation isocyanate ester compound (S)-(-) -2- isocyanatos -
3 Methylbutanoic acid methyl esters；Then 2- isopropyls -4- (Methylaminomethyl) thiophene of 32g is added portionwise thereto at 20~28 DEG C
Triazole hydrochloride adjusts pH stable 6 with 10% sodium hydroxide solution of 50g during the addition process；20~28 after being added dropwise
DEG C insulation reaction 1h；After the completion of HPLC monitoring reactions, liquid separation, water is mutually extracted with 100g dichloromethane, and extract liquor is harmonious with organic
And it then washed once with 15% sodium chloride solution of 200g；Liquid separation, organic phase evaporated under reduced pressure obtain light yellow or off-white color and consolidate
Body is MTV methyl esters, and yield 88.5%, HPLC detection purity is 98.76%.
Embodiment 4
In 1000ml four-hole bottles, Valine methyl ester hydrochloride 30g (0.18mol) and triphosgene 18g are dissolved in 270ml
The sodium bicarbonate aqueous solution that 480ml concentration is 1.2M is added dropwise in dichloromethane thereto at nitrogen protection, 5~10 DEG C
(0.57mol), about 1h 10min are added；35~40 DEG C are then heated to, insulated and stirred 1h reaction generation isocyanates chemical combination
Object (S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；Then the 2- isopropyls of 32g are added portionwise thereto at 35~40 DEG C
Base -4- (Methylaminomethyl) thiazole hydrochloride adjusts solution to alkali with 10% sodium hydroxide solution of 50g during the addition process
Property；35~40 DEG C of insulation reaction 1h after being added dropwise；After the completion of HPLC monitoring reactions, liquid separation, water is mutually extracted with 100g dichloromethane
It takes, extract liquor merges with organic phase, then washed once with 15% sodium chloride solution of 200g；Liquid separation, organic phase evaporated under reduced pressure, obtains
It is N- [N- methyl-N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyl]-L- figured silk fabrics to light yellow or off-white powder
Propylhomoserin methyl esters (MTV methyl esters), yield 89.3%, HPLC detection purity is 98.44%.
Embodiment 5
In 1000ml four-hole bottles, Valine methyl ester hydrochloride 30g (0.18mol) and triphosgene 19g are dissolved in 270ml
The sodium hydrate aqueous solution that 480ml concentration is 1.2M is added dropwise in dichloromethane thereto at nitrogen protection, 10~20 DEG C
(0.57mol), about 1h is added；Then heat to 30 DEG C, insulated and stirred 1h reaction generation isocyanate ester compounds (S)-(-)-
2- isocyanatos -3 Methylbutanoic acid methyl esters；Then the 2- isopropyl -4- (methylaminos of 32g are added portionwise thereto at 30 DEG C
Methyl) thiazole hydrochloride, pH stable is adjusted 6 with 10% sodium hydroxide solution of 50g during the addition process；After being added dropwise
30 DEG C of insulation reaction 1h；After the completion of HPLC monitoring reactions, liquid separation, water is mutually extracted with 100g dichloromethane, extract liquor and organic phase
Merge, then washed once with 15% sodium chloride solution of 200g；Liquid separation, organic phase evaporated under reduced pressure obtain light yellow or off-white color
Solid is MTV methyl esters, and yield 88.4%, HPLC detection purity is 99.15%.
Embodiment 6
In 1000ml four-hole bottles, Valine methyl ester hydrochloride 30g (0.18mol) and triphosgene 20.5g is dissolved in
It is water-soluble that the potassium carbonate that 480ml concentration is 1.2M is added dropwise in 270ml dichloromethane thereto at nitrogen protection, 20~28 DEG C
Liquid (0.57mol), about 1h is added；Then insulated and stirred 1h reactions generation isocyanate ester compound (S)-(-) -2- isocyanide acyls
Base -3 Methylbutanoic acid methyl esters；Then 2- isopropyls -4- (the methylamino first of 32g is added portionwise thereto at 20~28 DEG C
Base) thiazole hydrochloride, pH stable is adjusted 6 with 10% sodium hydroxide solution of 50g during the addition process；20 after being added dropwise
~28 DEG C of insulation reaction 1h；HPLC monitoring reaction after the completion of, liquid separation, water mutually with 100g dichloromethane extract, extract liquor with it is organic
Mutually merge, then washed once with 15% sodium chloride solution of 200g；It is white to obtain light yellow or class for liquid separation, organic phase evaporated under reduced pressure
Color solid is MTV methyl esters, and yield 88.7%, HPLC detection purity is 98.32%.
Embodiment 7
The present invention also provides a kind of heterogeneous synthetic method of isocyanates, including：Primary amine and triphosgene are dissolved in two
The aqueous solution of inorganic base is added dropwise in chloromethanes thereto at nitrogen protection, 5~28 DEG C；Then stirred in 20~40 DEG C of heat preservations
Mix 0.8~1.2h reaction generation isocyanate ester compound (S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；Described primary
Amine, triphosgene, dichloromethane, the formula rate of inorganic base are 0.18mol：18~22g：260~280ml：0.56~
0.58mol。
The inorganic base is sodium hydroxide, sodium carbonate, potassium carbonate or sodium acid carbonate.
Skilled person will appreciate that when the technical parameter of the present invention changes in following scope, it is contemplated that obtain
Same as the previously described embodiments or similar technique effect：
A kind of heterogeneous synthetic method of Ritonavir intermediate, including：
Valine methyl ester hydrochloride and triphosgene are dissolved in dichloromethane, at nitrogen protection, 5~28 DEG C thereto by
It is added dropwise to the aqueous solution of inorganic base；Then in 20~40 DEG C of 0.8~1.2h of insulated and stirred reaction generation isocyanate ester compounds
(S)-(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；Then 2- isopropyls -4- is added portionwise thereto at 20~40 DEG C
(Methylaminomethyl) thiazole, 0.8~1.2h of insulation reaction；Liquid separation, water merge after mutually being extracted with dichloromethane with organic phase, then
It is washed with 14~16% sodium chloride solutions；Liquid separation, organic phase drying is to get N- [N- methyl-N- [(2- isopropyl -4- thiazolyls)
Methyl] amino carbonyl]-Valine methyl esters.
The Valine methyl ester hydrochloride, triphosgene, dichloromethane, inorganic base, 2- isopropyls -4- (methylamino first
Base) thiazole formula rate be 29~31g：18~22g：260~280ml：0.56~0.58mol：31~33g.
The inorganic base is sodium hydroxide, sodium carbonate, potassium carbonate or sodium acid carbonate.
The above is only present pre-ferred embodiments, therefore cannot limit the scope implemented of the present invention according to this, i.e., according to
The equivalent changes and modifications that the scope of the claims of the present invention and description are made all should still belong in the range of the present invention covers.
Claims (8)
1. a kind of heterogeneous synthetic method of Ritonavir intermediate, it is characterised in that：
Valine methyl ester hydrochloride and triphosgene are dissolved in dichloromethane, added dropwise thereto at nitrogen protection, 5~28 DEG C
Enter the aqueous solution of inorganic base；Then 20~40 DEG C of 0.8~1.2h of insulated and stirred reaction generation isocyanate ester compounds (S)-
(-) -2- isocyanatos -3 Methylbutanoic acid methyl esters；Then under conditions of being 5.8~6.2 in 20~40 DEG C, pH value thereto in batches
Add in 2- isopropyls -4- (Methylaminomethyl) thiazole hydrochloride, 0.8~1.2h of insulation reaction；Liquid separation, water mutually use dichloromethane
Merge after extraction with organic phase, then washed with 14~16% sodium chloride solutions；Liquid separation, organic phase drying to get N- [N- methyl-
N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyl]-Valine methyl esters.
2. a kind of heterogeneous synthetic method of Ritonavir intermediate according to claim 1, it is characterised in that：The L-
Valine methyl ester hydrochloride, triphosgene, dichloromethane, inorganic base, 2- isopropyls -4- (Methylaminomethyl) thiazole hydrochloride
Formula rate is 29~31g：18~22g：260~280ml：0.56~0.58mol：31~33g.
3. a kind of heterogeneous synthetic method of Ritonavir intermediate according to claim 1, it is characterised in that：Also wrap
It includes：Obtained N- [N- methyl-N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyl]-Valine methyl esters is taken off
Methyl esters obtains N- [N- methyl-N- [(2- isopropyl -4- thiazolyls) methyl] amino carbonyl]-Valine.
4. a kind of heterogeneous synthetic method of Ritonavir intermediate according to claim 1, it is characterised in that：In nitrogen
It protects, inorganic base is added dropwise into the dichloromethane dissolved with Valine methyl ester hydrochloride and triphosgene at 5~10 DEG C
Aqueous solution.
5. a kind of heterogeneous synthetic method of Ritonavir intermediate according to claim 1, it is characterised in that：The nothing
Machine alkali is sodium hydroxide, sodium carbonate, potassium carbonate or sodium acid carbonate.
6. a kind of heterogeneous synthetic method of Ritonavir intermediate according to claim 1, it is characterised in that：Nothing is added dropwise
After the aqueous solution of machine alkali, in 35~40 DEG C of 0.8~1.2h of insulated and stirred reaction generations isocyanate ester compound (S)-(-) -2-
Isocyanato -3 Methylbutanoic acid methyl esters.
7. a kind of heterogeneous synthetic method of Ritonavir intermediate according to claim 1, it is characterised in that：It generates different
After cyanate compound, 2- isopropyls -4- (Methylaminomethyl) thiazole hydrochloride is added portionwise at 35~40 DEG C.
8. the heterogeneous synthetic method of Ritonavir intermediate according to any one of claim 1 to 7 is in Ritonavir
Application in synthesis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610072894.4A CN105753806B (en) | 2016-02-02 | 2016-02-02 | A kind of heterogeneous synthetic method of Ritonavir intermediate and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610072894.4A CN105753806B (en) | 2016-02-02 | 2016-02-02 | A kind of heterogeneous synthetic method of Ritonavir intermediate and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105753806A CN105753806A (en) | 2016-07-13 |
| CN105753806B true CN105753806B (en) | 2018-06-05 |
Family
ID=56343042
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610072894.4A Active CN105753806B (en) | 2016-02-02 | 2016-02-02 | A kind of heterogeneous synthetic method of Ritonavir intermediate and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105753806B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101796040A (en) * | 2007-07-06 | 2010-08-04 | 吉里德科学公司 | The modulators of pharmacokinetic properties of therapeutical agent |
| CN102159285A (en) * | 2008-07-22 | 2011-08-17 | 默沙东公司 | Macrocyclic quinoxaline compounds as hcv ns3 protease inhibitors |
| CN102659632A (en) * | 2012-04-24 | 2012-09-12 | 江西科技师范学院 | Preparation method of aminonorbornane isocyanate |
| CN104447412A (en) * | 2014-11-12 | 2015-03-25 | 上海朗亿新材料科技有限公司 | Preparation method of isocyanate |
-
2016
- 2016-02-02 CN CN201610072894.4A patent/CN105753806B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101796040A (en) * | 2007-07-06 | 2010-08-04 | 吉里德科学公司 | The modulators of pharmacokinetic properties of therapeutical agent |
| CN102159285A (en) * | 2008-07-22 | 2011-08-17 | 默沙东公司 | Macrocyclic quinoxaline compounds as hcv ns3 protease inhibitors |
| CN102659632A (en) * | 2012-04-24 | 2012-09-12 | 江西科技师范学院 | Preparation method of aminonorbornane isocyanate |
| CN104447412A (en) * | 2014-11-12 | 2015-03-25 | 上海朗亿新材料科技有限公司 | Preparation method of isocyanate |
Non-Patent Citations (1)
| Title |
|---|
| A Safe and and Efficient Method for Preparation of N,N’-Unsymmetrically Disubstituted Ureas Utilizing Triphosgene;Pave1 Majer et al.;《J. Org. Chem.》;19941231;第59卷;1937-1938 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105753806A (en) | 2016-07-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108084033B (en) | Preparation method of N, N-diethyl ethylenediamine | |
| CN108947855A (en) | A kind of synthetic method of efavirenz key intermediate | |
| CN103724258B (en) | Preparation method of sorafenib | |
| CN105330600B (en) | A kind of preparation method of Rui Gefeini | |
| CN106083722A (en) | A kind of Six Steps prepares the synthesis technique of pyrazoles Fluoxastrobin | |
| CN105753806B (en) | A kind of heterogeneous synthetic method of Ritonavir intermediate and its application | |
| CN103833724A (en) | Preparation method of 5-penphene-2-formyl chloride | |
| CN104744266B (en) | The preparation method of ticagrelor intermediate | |
| CN111393319A (en) | Preparation method of oxytetracycline chloride | |
| CN108395440A (en) | A method of synthesizing ellagic acid using gallic acid-derivate | |
| CN111777590A (en) | New synthesis method of 2-thiophenecarboxaldehyde | |
| CN106380426B (en) | A kind of method that Aqueous phase prepares tetrabutyl urea | |
| CN102532010B (en) | Preparation method of 2-chloro-3-aminopyridine | |
| CN104788353B (en) | A kind of method for synthesizing 4 oxo L proline derivatives | |
| CN107721850A (en) | A kind of preparation method of cyclopropylamine intermediate γ chloro methyl butyrates | |
| CN105130949B (en) | The preparation method of 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropanecarbonitrile | |
| CN106588925A (en) | Method for preparing 1,4,7,10-tetraaza-2,6-pyridinophane | |
| CN108203368A (en) | A kind of production technology of high-quality trimethyl orthoacetate | |
| CN108084001A (en) | A kind of synthetic method of improved 1- acetyl-1-chlorcyclopropanes | |
| CN101717324A (en) | Green synthesizing method of triphenylchloromethane | |
| CN107033102B (en) | The synthetic method of mefenacet | |
| CN111269144A (en) | Preparation method of aminobenzonitrile | |
| CN111004184A (en) | Synthesis process of 4, 6-dichloropyrimidine | |
| CN108017531A (en) | The preparation method of formic acid | |
| CN103172500B (en) | Novel 2-chlororesorcinol preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200722 Address after: Unit 03, 9 / F, building B1, Xiamen biomedical industrial park, 2050 wengjiao West Road, Haicang District, Xiamen City, Fujian Province Patentee after: Xiamen Weijia Pharmaceutical Co.,Ltd. Address before: Haicang District of Xiamen City, Fujian province 361000 Xinyang Street Weng Kok Road section 289 building 523 unit Patentee before: XIAMEN CITY WEI JIA CHEMICAL TECHNOLOGY Co.,Ltd. |