CN109810031A - The preparation method of Fei Luokao former times intermediate - Google Patents
The preparation method of Fei Luokao former times intermediate Download PDFInfo
- Publication number
- CN109810031A CN109810031A CN201711162230.8A CN201711162230A CN109810031A CN 109810031 A CN109810031 A CN 109810031A CN 201711162230 A CN201711162230 A CN 201711162230A CN 109810031 A CN109810031 A CN 109810031A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- mixture
- gained
- tert
- 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
Abstract
The present invention relates to the preparation methods of Fei Luokao former times intermediate, belong to pharmaceutical technology field.Preparation method provided by the invention includes: after a kind of raw material is first reacted with acyl chlorides reagent, then reacts under alkali existence condition with another raw material, after post treatment, obtained target product.Method strong operability provided by the invention is conducive to the operation and cost control of industrialized production.
Description
Technical field
The present invention relates to the preparation methods of Fei Luokao former times intermediate, belong to pharmaceutical technology field.
Background technique
Fei Luokao former times is a kind of non-steroidal anti-inflammatory drugs for animals, the forefront for inhibiting to the property of can choose cyclooxygenase-2 to mediate
The synthesis of parathyrine generates the anti-inflammatory effect of antipyretic-antalgic, and Fei Luokao former times can be used for treating a variety of Acute or chronic pains and inflammation.
The preparation of Fei Luokao former times needs that a kind of intermediate is first prepared, and in the prior art, generallys use sodium chloroacetate
Acid is obtained under sodium hydride effect with cyclopropyl-carbinol, then reacts to obtain among target under condensing agent effect with sulphur compound
Obtained acid is reacted with the sulphur compound after bromination to obtain title intermediate by body, in both methods, using sodium hydride,
It is dangerous in mass production, easily occur kindling etc., and use condensing agent or bromination, complicated for operation, yield is low, be unfavorable for production and
Cost control.Therefore, safer, the simple method of one kind is studied to be necessary.
Summary of the invention
The present invention provides a kind of method of intermediate i.e. compound (I) for preparing and preparing for Fei Luokao former times.
A kind of method of prepare compound (I), comprising: step b: after compound (01) is reacted with acyl chlorides reagent, gains
It contacts with compound (02), under alkali existence condition, after fully reacting after post treatment, is made compound (I), reaction equation is as follows
Shown in formula:
In some embodiments, a kind of method of prepare compound (I), comprising:
Step a: cyclopropyl-carbinol is contacted with potassium tert-butoxide, and then gained mixture is contacted with halide, after fully reacting
After post treatment, compound (01) is obtained,
Step b: after compound (01) is reacted with acyl chlorides reagent, gains are contacted with compound (02), in alkali existence condition
Under, after fully reacting after post treatment, it is made compound (I), reaction equation is shown below:
In the above method, the acyl chlorides reagent is thionyl chloride, oxalyl chloride, spy's acyl chlorides or combinations thereof.In some implementations
In mode, the acyl chlorides reagent is thionyl chloride, is more advantageous to reaction and carries out, controls or handle.The halide is monoxone
Sodium, bromoacetic acid sodium, monoxone, bromoacetic acid or combinations thereof.In some embodiments, the halide is sodium chloroacetate, is more had
It carries out and handles conducive to reaction.
In some embodiments, a kind of method of prepare compound (I), comprising: step b: compound (01) and dichloro
After sulfoxide reaction, gains are contacted with compound (02), under alkali existence condition, after fully reacting after post treatment, obtainedization
It closes object (I), reaction equation is shown below:
In some embodiments, a kind of method of prepare compound (I), comprising:
Step a: cyclopropyl-carbinol is contacted with potassium tert-butoxide, and then gained mixture is contacted with sodium chloroacetate, fully reacting
Afterwards after post treatment, compound (01) is obtained,
Step b: after compound (01) is reacted with thionyl chloride, gains are contacted with compound (02), in alkali existence condition
Under, after fully reacting after post treatment, it is made compound (I), reaction equation is shown below:
On the other hand, present aspect provides a kind of method for preparing Fei Luokao former times comprising: it will be prepared by the above method
The compound (I) arrived is in the presence of 1,8- diazabicylo, 11 carbon -7- alkene (DBU) and trifluoroacetic acid isopropyl ester, in toluene
Cyclization reaction is carried out, Fei Luokao former times is obtained.
Inventors discovered through research that using potassium tert-butoxide rather than sodium hydride is alkali in step a, can be greatly reduced
The security risk of amplification production reacts safely controllable, easily operated；But meanwhile a kind of tert-butyl impurity A can be generated, make institute
Contain tert-butyl impurity A in the compound (01) obtained, subsequent reactions step is adversely affected.And inventor is by further
The study found that the tert-butyl impurity A generated in step a on a small quantity can be in step b compound (02) and compound (01) reaction process
In the reaction was continued with compound (02), generate corresponding tert-butyl impurity B, most of impurity A can pass through the post-processing in step b
It removes；In step b, by using acyl chlorides reagent such as thionyl chloride etc., by compound (01) and acyl chlorides reagent such as thionyl chloride etc.
It is reacted again with compound (02) after reaction, operation can be made to simplify, readily available compound (I), while can control keeps impurity B a small amount of
It generates, then part tert-butyl impurity B can be removed by post-processing, compound (I) simply is made, makes the compound being prepared
(I) the tert-butyl impurity B in is less.It is preparing during final product Fei Luokao former times reacts, tert-butyl impurity B can react generation impurity
C.In the present invention, by the control of the reaction condition to step a and step b, the compound (I) containing a small amount of impurity B can be obtained
Product prepares Fei Luokao in former days using this compound (I) for containing a small amount of impurity B, tert-butyl impurity C in Fei Luokao former times obtained
Content can achieve requirement (i.e. impurity content is lower than 0.1%).Although tert-butyl impurity is produced in first step, to final
Product Fei Luokao former times improves entire process safety without influence, and operation simplifies, and can guarantee yield and preferably control
Cost.Tert-butyl impurity A, impurity B, impurity C-structure are as follows:
In the present invention, the corresponding impurity C of remaining a small amount of tert-butyl impurity B and its generation can be in the mistake for preparing Fei Luokao former times
It controls and/or removes in journey, the impurity in final product Fei Luokao former times is made to meet the quality requirement lower than 0.1%.
In some embodiments, the cyclopropyl-carbinol contacted with potassium tert-butoxide include: optionally under inert gas atmosphere,
Potassium tert-butoxide, organic solvent and cyclopropyl-carbinol mixing, then mixture is controlled in certain temperature, maintains certain time, appoint
Mixture is cooled to certain temperature by choosing, obtains mixture.The organic solvent is tetrahydrofuran, 2- methyltetrahydrofuran, first
Base tertbutyl ether, or combinations thereof.Each gram of cyclopropyl-carbinol, the dosage of the organic solvent are 5mL-50mL.
The inert gas is the gas not reacted with reaction mass.
In some embodiments, in step a, gained mixture is contacted with sodium chloroacetate, small in 0 DEG C of -60 DEG C of reaction 5
When -50 hours, fully reacting.In some embodiments, in step a, gained mixture is contacted with sodium chloroacetate, 20 DEG C-
60 DEG C are reacted -50 hours 10 hours, fully reacting.In some embodiments, in step a, gained mixture and sodium chloroacetate
Contact is reacted -30 hours 10 hours, fully reacting at 30 DEG C -60 DEG C.In some embodiments, in step a, gained mixing
Object is contacted with sodium chloroacetate, is reacted -30 hours 15 hours at 30 DEG C -60 DEG C, fully reacting.
In step a, the molar ratio of cyclopropyl-carbinol and halide is 1:1-1:3.In some embodiments, cyclopropyl first
The molar ratio of alcohol and halide is 1:1-1:2.2, is more advantageous to reaction and carries out and control.
In step a, the molar ratio of cyclopropyl-carbinol and potassium tert-butoxide is 1:1-1:5.In some embodiments, cyclopropyl
The molar ratio of methanol and potassium tert-butoxide is 1:1-1:3.In some embodiments, the molar ratio of cyclopropyl-carbinol and potassium tert-butoxide
For 1:1.2-1:3, it is more advantageous to reaction and carries out and control.
In some embodiments, in step a, the molar ratio of cyclopropyl-carbinol and sodium chloroacetate is 1:1-1:3.Some
In embodiment, the molar ratio of cyclopropyl-carbinol and sodium chloroacetate is 1:1-1:2.2, is more advantageous to reaction and carries out and control
System.
In some embodiments, in step a, it is 0 DEG C -5 DEG C that the post-processing, which includes: by reaction solution temperature control, and salt is added
Then acid for adjusting pH adjusts pH to 9-10 with sodium hydroxide, water is added, stands after stirring, liquid separation to 1-2；By water phase dichloro
Methane wash, gained water phase salt acid for adjusting pH to 1-3, is then extracted with dichloromethane, and obtains two containing compound (01)
Chloromethanes solution can use the dry resulting dichloromethane solution containing compound (01) of anhydrous sodium sulfate when necessary.It will contain
Compound (01) can be obtained after removing solvent in the dichloromethane solution of compound (01).
In step b, the dichloromethane solution for containing compound (01) obtained in step a can be used, step also can be used
Dichloromethane solution containing compound (01) obtained in rapid a removes the substance obtained after solvent.
In some embodiments, in step b, the mixed liquor of compound (01) and reaction dissolvent is optionally added catalytic amount
N,N-Dimethylformamide (DMF), reacted with acyl chlorides reagent, react -10 hours 0.1 hour, obtain mixture；Then gained
Mixture is contacted with compound (02) and alkali, is optionally added catalyst, in 0 DEG C of -40 DEG C of reaction, is located later after fully reacting
Reason, obtains compound (I).In some embodiments, compound (02) and alkali, optional catalyst are dissolved in reaction dissolvent,
Then it is mixed with reaction system.In step b, the reaction dissolvent can be methylene chloride, DMF, DMSO equal solvent.In some implementations
In mode, in step b, reaction dissolvent is methylene chloride, is conducive to reaction and carries out and handle.
In some embodiments, in step b, the mixed liquor of compound (01) and methylene chloride is optionally added catalytic amount
N,N-Dimethylformamide (DMF), reacted with thionyl chloride, react -10 hours 0.1 hour, obtain mixture；Then gained
Mixture is contacted with compound (02) and alkali, is optionally added catalyst, in 0 DEG C of -40 DEG C of reaction, is located later after fully reacting
Reason, obtains compound (I).In some embodiments, compound (02) and alkali, optional catalyst are dissolved in methylene chloride,
Then it is mixed with reaction system.
In step b, the alkali be can with the alkali of hydrogen chloride, reaction of hydrogen bromide, such as triethylamine, N, N- diisopropyl ethyl
Amine etc..The molar ratio of the alkali and compound (02) is 1:1-1:5.In some embodiments, the alkali is triethylamine.
In step b, the catalyst can be 4-dimethylaminopyridine (DMAP).
In the above method, the molar ratio of the acyl chlorides reagent and compound (02) is 1:1-5:1.
The molar ratio of compound (01) and compound (02) is 1:1-5:1.In some embodiments, compound (01) with
The molar ratio of compound (02) is 1.2:1-3.6:1, is more advantageous to reaction and carries out and control.
In some embodiments, the molar ratio of the thionyl chloride and compound (02) is 1:1-5:1.
In step b, each g of compound (01) can be dissolved in 3mL-15mL methylene chloride.
In step b, the post-processing includes: that reaction solution is optionally added methylene chloride, and water washing, gained organic phase is added
Solvent is removed, compound (I) crude product is obtained.After gained crude product alcohol crystal, compound (I) product is obtained；Each gram of chemical combination
Object (02), ethanol consumption 3mL-30mL.In some embodiments, crude product is mixed with ethyl alcohol, is then heated to reflux, makes
Solid is completely dissolved, and may filter that removing insoluble matter when necessary, is then stopped heating, is cooled to room temperature, and stirring is 0.5 hour -10 small
When, solid is separated, with ethanol washing obtained solid, the solvent in obtained solid is then removed, obtains compound (I) product.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, disclose further below some non-
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention is available on the market or can described method system through the invention
It is standby and obtain.
In the present invention, g: gram；ML: milliliter；DEG C: degree Celsius；H: hour；Min: minute.
In the present invention, fully reacting or stopping reaction referring to that the surplus of reaction raw materials is no more than inventory or theoretical yield
2% or 1% no more than inventory or theoretical yield or 0.5% no more than inventory or theoretical yield.
In the present invention, room temperature refers to environment temperature, temperature range be 15 DEG C -35 DEG C or the temperature I 20 DEG C -30 DEG C or
22℃-28℃。
Embodiment 1
Potassium tert-butoxide (t-BuOK, 11.6g) is mixed in tetrahydrofuran (150mL), nitrogen protection is slowly added into cyclopropyl
Base methanol (5.0g) is heated to 50 DEG C of stirring 1h, is slowly cooled to room temperature after adding；Sodium chloroacetate (9.7g) is added at room temperature,
30min is stirred at room temperature after adding, after be heated to 40 DEG C and be stirred to react 40 hours.
Gained reaction solution is cooled to 0 DEG C -5 DEG C, is slowly added dropwise concentrated hydrochloric acid, adjusts pH to 1, then with 10% sodium hydroxide water
Solution (mass fraction) adjusts pH to 9-10, adds water (100mL), stands after being sufficiently stirred, liquid separation, and water phase has white insoluble solid
Body is added water and stirred to dissolution, is washed with methylene chloride (80mL × 2), and water phase is cooled to 0 DEG C again, water-soluble with the hydrochloric acid of 3mol/L
Liquid adjusts pH to 1~3, and control temperature is lower than 10 DEG C during adjusting pH value, is extracted, is merged with methylene chloride (100mL × 3) afterwards
Organic phase, anhydrous sodium sulfate are dry；Evaporated under reduced pressure organic phase obtains compound (01): light yellow oil 8.08g, tert-butyl
Impurity A content is 16.72%.
Embodiment 2
Potassium tert-butoxide (t-BuOK, 24.12g) is mixed in tetrahydrofuran (150mL), nitrogen protection is slowly added into ring
Propyl carbinol (5.0g) is heated to 50 DEG C of stirring 1h, is slowly cooled to room temperature after adding；Sodium chloroacetate is added at room temperature
(12.10g) is stirred at room temperature 30 minutes after adding, after be heated to 40 DEG C and be stirred to react 40 hours.
Gained reaction solution is cooled to 0 DEG C -5 DEG C, is slowly added dropwise concentrated hydrochloric acid, adjusts pH to 1, then with 10% sodium hydroxide water
Solution (mass fraction) adjusts pH to 9-10, adds water (100mL), stands after being sufficiently stirred, liquid separation, and water phase has white insoluble solid
Body is added water and stirred to dissolution, is washed with methylene chloride (80mL × 2), and water phase is cooled to 0 DEG C again, water-soluble with the hydrochloric acid of 3mol/L
Liquid adjusts pH to 1~3, and control temperature is lower than 10 DEG C during adjusting pH value, is extracted, is merged with methylene chloride (100mL × 3) afterwards
Organic phase, anhydrous sodium sulfate are dry；Evaporated under reduced pressure organic phase obtains compound (01): light yellow oil 8.11g, tert-butyl
Impurity A content is 15.48%.
Embodiment 3
By compound (01), (3.75g, tert-butyl Impurity A content are 16.72%) to be dissolved in methylene chloride (25mL), are added
Enter n,N-Dimethylformamide (227mg), be slowly added into thionyl chloride (1.7mL) at room temperature, adds rear room temperature and be stirred to react 6h,
Obtain mixture；Then at room temperature by gained mixture and compound (02) (4.84g), DMAP (733mg) and triethylamine
Methylene chloride (25mL) solution of (4.05g) mixes, and reaction 8 hours is stirred at room temperature.Gained reaction solution is washed with water (25mL × 2)
It washs, liquid separation, organic phase obtains brownish black solid crude product in 45 DEG C of evaporated under reduced pressure.Dehydrated alcohol is added in obtained solid crude product
(40mL), is heated to reflux and makes it completely dissolved, and is then naturally cooling to room temperature, stirs 12 hours, filters, solid dehydrated alcohol
(3mL × 3) washing, 50 DEG C of dry 8h are obtained compound (I): pale solid 6.03g, and tert-butyl impurity B content is
0.51%, tert-butyl impurity A is not detected.
Embodiment 4
By compound (01) (10.01g, tert-butyl Impurity A content be 16.41%) be dissolved in methylene chloride (25mL),
It is added n,N-Dimethylformamide (227mg), is slowly added into thionyl chloride (4.5mL) at room temperature, adds rear room temperature and be stirred to react
6h obtains mixture；Then at room temperature by gained mixture and compound (02) (4.84g), DMAP (733mg) and triethylamine
Methylene chloride (35mL) solution of (10.81g) mixes, and reaction 8 hours is stirred at room temperature.Gained reaction solution is washed with water (30mL × 2)
It washs, liquid separation, organic phase obtains brownish black solid crude product in 45 DEG C of evaporated under reduced pressure.Dehydrated alcohol is added in obtained solid crude product
(40mL), is heated to reflux and makes it completely dissolved, and is then naturally cooling to room temperature, stirs 12 hours, filters, solid dehydrated alcohol
(3mL × 3) washing, 50 DEG C of dry 8h are obtained compound (I): pale solid 6.10g, and tert-butyl impurity B content is
0.40%, tert-butyl impurity A is not detected.
Embodiment 5
The compound (01) (5.20g, tert-butyl Impurity A content 44%) for being enriched with tert-butyl impurity A is dissolved in dichloromethane
In alkane (25mL), DMF (10 drop) is added, is cooled to 0 DEG C, is added thionyl chloride (2.9mL), adds rear room temperature and be stirred to react 6h；
Gained mixture and compound (02) (4.84g), DMAP (733mg), triethylamine (6.07g) and methylene chloride (25mL) is mixed
It closes, reaction 12 hours is stirred at room temperature, and (to reaction solution sample detection, discovery has a large amount of compounds (02) remaining, and impurity B content is
1.80%).Methylene chloride (100mL) is added into reaction solution, is extracted with water (75mL × 2), liquid separation, organic phase anhydrous slufuric acid
Sodium is dry, is spin-dried for obtaining brown oil.
Dehydrated alcohol (40mL) is added in above-mentioned brown oil, is heated to reflux and makes it completely dissolved, then stops heating,
It being naturally cooling to be stirred at room temperature 12 hours, filter, solid is washed with dehydrated alcohol (3mL × 3), and it is dry at 50 DEG C of obtained solid,
It obtains compound (I): white solid 2.34g, tert-butyl impurity A is not detected in tert-butyl impurity B content 0.35%.Post-processing
There are raw material, tert-butyl impurity A and tert-butyl impurity B in mother liquor afterwards.
Embodiment 6
Compound (I) (6.26g, tert-butyl impurity B enrichment, content 11.75%) is dissolved in toluene (31mL), is added
Enter DBU (8.06g) and trifluoroacetic acid isopropyl ester (4.41g), is heated to 95 DEG C and is stirred to react 12 hours (by reaction solution sampling inspection
It surveys, tert-butyl impurity C content 6.75%).Stopping heating, reaction solution is down to room temperature naturally, vacuum distillation to no fraction is flowed out,
Then water (31mL) is slowly added dropwise, solid is slowly precipitated, 2h is stirred at room temperature after dripping off, filters, filter cake is washed with water (10mL × 2)
It washs, obtains solid wet product, detect, wherein tert-butyl impurity C content is 2.63%.
Above-mentioned solid wet product is added in dehydrated alcohol (18mL), is heated to being completely dissolved, then stops heating, is dropped naturally
Stirring 12 hours is warmed to room temperature, is filtered, solid is washed with ethyl alcohol (3mL × 2).50 DEG C of dryings of obtained solid, obtain Fei Luokao former times,
White solid 4.78g, tert-butyl impurity C content are 0.06%.
Embodiment 7
By compound (I), (4.40g, tert-butyl impurity B content are 0.42%) to be dissolved in toluene (22mL), and DBU is added
(5.66g) and trifluoroacetic acid isopropyl ester (3.10g) is heated to 95 DEG C and is stirred to react 12 hours (by reaction solution sample detection, tertiary fourth
Base impurity C, content 0.11%).Stop heating, reaction solution is down to room temperature naturally, and vacuum distillation to no fraction is flowed out, then slowly
It is added dropwise water (22mL), solid is slowly precipitated, 2h is stirred at room temperature after dripping off, filter, filter cake is washed with water (20mL), drains and consolidated
Body wet product, detection, wherein tert-butyl impurity C content is 0.09%.
Above-mentioned solid wet product is added in dehydrated alcohol (12mL), is heated to being completely dissolved, then stops heating, is dropped naturally
Warm to room temperature stirring 10 hours, after be transferred to -5-0 DEG C of stirring 1h, suction filtration, solid washs with ethyl alcohol (3mL).Obtained solid is 60
It is dried in vacuo 12h at DEG C, obtains Fei Luokao former times, tert-butyl impurity A, B and C is not detected in white solid 3.72g.
Method of the invention is described by preferred embodiment, related personnel obviously can the content of present invention,
To method described herein and application is modified or appropriate changes and combinations in spirit and scope, carry out the implementation and application present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that institute
There are similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (10)
1. a kind of method of prepare compound (I), comprising: step b: after compound (01) is answered with acyl chlorides reagent, gains and change
Object (02) contact is closed, under alkali existence condition, after fully reacting after post treatment, is made compound (I)；Reaction equation such as following formula institute
Show:
Wherein, the acyl chlorides reagent is thionyl chloride, oxalyl chloride, spy's acyl chlorides or combinations thereof.
2. method described in claim 1, further includes: step a: cyclopropyl-carbinol is contacted with potassium tert-butoxide, then gained mixing
Object is contacted with halide, after fully reacting after post treatment, obtains compound (01)；Reaction equation is shown below:
Wherein, the halide is sodium chloroacetate, bromoacetic acid sodium, monoxone, bromoacetic acid or combinations thereof.
3. method described in claim 1, wherein the mixed liquor of compound (01) and reaction dissolvent is optionally added catalytic amount
N,N-Dimethylformamide is reacted with thionyl chloride, is reacted -10 hours 0.1 hour, is obtained mixture；Then gained mixture
It is contacted with compound (02) and alkali, is optionally added catalyst, in 0 DEG C of -40 DEG C of reaction, after fully reacting after post treatment, obtained
Compound (I).
4. method described in claim 1, wherein the post-processing includes: that reaction solution is washed with water, and gained organic phase removes
Solvent obtains compound (I) crude product；After gained crude product alcohol crystal, compound (I) product is obtained；Each g of compound
(02), ethanol consumption 3mL-30mL.
5. method described in claim 1, the molar ratio of compound (01) and compound (02) is 1:1-5:1.
6. method described in claim 1, the molar ratio of the thionyl chloride and compound (02) is 1:1-5:1.
7. method as claimed in claim 2, in step a, optionally under inert gas atmosphere, potassium tert-butoxide, organic solvent and cyclopropyl
Then mixture is controlled in certain temperature, maintains certain time, mixture is optionally cooled to certain temperature by the mixing of base methanol
Degree, obtains mixture.
8. method as claimed in claim 2, in step a, gained mixture and halide are touched, and are reacted 5 hours -50 at 0 DEG C -60 DEG C
Hour.
9. method as claimed in claim 2, in step a, the molar ratio of cyclopropyl-carbinol and potassium tert-butoxide is 1:1-1:5.
10. a kind of method for preparing Fei Luokao former times, comprising: according to claim 1-10 any methods are prepared
It is anti-to carry out cyclization in the presence of 1,8- diazabicylo, 11 carbon -7- alkene and trifluoroacetic acid isopropyl ester in toluene for compound (I)
It answers, obtains Fei Luokao former times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711162230.8A CN109810031B (en) | 2017-11-21 | 2017-11-21 | Preparation method of tilobaxib intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711162230.8A CN109810031B (en) | 2017-11-21 | 2017-11-21 | Preparation method of tilobaxib intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109810031A true CN109810031A (en) | 2019-05-28 |
| CN109810031B CN109810031B (en) | 2023-10-17 |
Family
ID=66599460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711162230.8A Active CN109810031B (en) | 2017-11-21 | 2017-11-21 | Preparation method of tilobaxib intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109810031B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452198A (en) * | 2019-09-03 | 2019-11-15 | 山东鲁抗舍里乐药业有限公司 | A kind of preparation method of Fei Luokao former times |
| CN110452199A (en) * | 2019-09-03 | 2019-11-15 | 山东鲁抗舍里乐药业有限公司 | A kind of preparation method of Fei Luokao former times |
| CN112624943A (en) * | 2020-12-28 | 2021-04-09 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981576A (en) * | 1995-10-13 | 1999-11-09 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
| US6020343A (en) * | 1995-10-13 | 2000-02-01 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
| US20040157891A1 (en) * | 2003-01-17 | 2004-08-12 | Fujisawa Pharmaceutical Co., Ltd. | Inhibitor of cox |
| US20080153843A1 (en) * | 2006-09-29 | 2008-06-26 | Gruenenthal Gmbh | Substituted sulfonamide compounds |
| US20100210842A1 (en) * | 2009-02-13 | 2010-08-19 | Boehringer Ingelheim International Gmbh | Process for preparing |
| CN105859664A (en) * | 2016-05-03 | 2016-08-17 | 中国药科大学 | Firocoxib preparation method |
| WO2018109781A1 (en) * | 2016-12-13 | 2018-06-21 | Sequent Scientific Limited | A process for the preparation of firocoxib |
| CN110105314A (en) * | 2019-06-02 | 2019-08-09 | 江苏君若医药有限公司 | One method for preparing Fei Luokao former times |
-
2017
- 2017-11-21 CN CN201711162230.8A patent/CN109810031B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981576A (en) * | 1995-10-13 | 1999-11-09 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
| US6020343A (en) * | 1995-10-13 | 2000-02-01 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
| US20040157891A1 (en) * | 2003-01-17 | 2004-08-12 | Fujisawa Pharmaceutical Co., Ltd. | Inhibitor of cox |
| US20080153843A1 (en) * | 2006-09-29 | 2008-06-26 | Gruenenthal Gmbh | Substituted sulfonamide compounds |
| US20100210842A1 (en) * | 2009-02-13 | 2010-08-19 | Boehringer Ingelheim International Gmbh | Process for preparing |
| CN105859664A (en) * | 2016-05-03 | 2016-08-17 | 中国药科大学 | Firocoxib preparation method |
| WO2018109781A1 (en) * | 2016-12-13 | 2018-06-21 | Sequent Scientific Limited | A process for the preparation of firocoxib |
| CN110105314A (en) * | 2019-06-02 | 2019-08-09 | 江苏君若医药有限公司 | One method for preparing Fei Luokao former times |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452198A (en) * | 2019-09-03 | 2019-11-15 | 山东鲁抗舍里乐药业有限公司 | A kind of preparation method of Fei Luokao former times |
| CN110452199A (en) * | 2019-09-03 | 2019-11-15 | 山东鲁抗舍里乐药业有限公司 | A kind of preparation method of Fei Luokao former times |
| CN112624943A (en) * | 2020-12-28 | 2021-04-09 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
| CN112624943B (en) * | 2020-12-28 | 2022-07-01 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109810031B (en) | 2023-10-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104610250B (en) | 1,2,3-thiadiazole-5-formamidine compound containing three N-heterocycles and synthesis | |
| CN109810031A (en) | The preparation method of Fei Luokao former times intermediate | |
| CN105658629A (en) | Process for preparation of pde4 inhibitor | |
| CN112321602A (en) | Preparation method of Ruogeli drug intermediate | |
| CN103739500B (en) | A kind of synthesis of cinacalcet hydrochloride and process for purification | |
| CN106749259B (en) | A kind of synthetic method of cyclopenta pyrimido azoles | |
| CN107434786A (en) | Benzimidazole compound and preparation method thereof | |
| CN102351778A (en) | Preparation method of arbidol hydrochloride | |
| CN105622538B (en) | One kettle way prepares Cetilistat in high yield | |
| CN113336764B (en) | Bipyridine ligand with axial chirality and synthetic method thereof | |
| CN103922925B (en) | A kind of production technique of Fenofibric Acid | |
| CN103288708B (en) | The preparation method of 1- aryl -2- indolinone derivative | |
| CN105175317A (en) | Method for preparing sodium picosulfate | |
| CN105985316A (en) | Preparation method for trelagliptin and salt thereof | |
| CN104402813B (en) | Novel method for synthesizing sorafenib | |
| WO2021259051A1 (en) | Method for improving synthesis process of hypidone free base | |
| CN105753733A (en) | AHU377 crystal form and preparation method and uses thereof | |
| CN105175316A (en) | Method for preparing laxative sodium picosulfate | |
| CN105712920B (en) | A kind of preparation method of vildagliptin | |
| CN104817482A (en) | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin | |
| CN109384701A (en) | It is a kind of to be used to prepare compound and the preparation method and application thereof of the Sha Ku than song | |
| CN109970673B (en) | Preparation method of parecoxib sodium impurity | |
| CN101092394A (en) | Method for preparing Meixianduoxin | |
| CN105418497B (en) | The synthesis technique of 3 chlorine octahydro 2 (1H) quinolinones | |
| CN110759922B (en) | Preparation method of 6-benzyl-2, 6, 9-triazaspiro [4.5] decane-2-carboxylic acid tert-butyl ester |
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 |