CN109438337B - A kind of preparation process of Rui Gefeini intermediate - Google Patents
A kind of preparation process of Rui Gefeini intermediate Download PDFInfo
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- CN109438337B CN109438337B CN201811428080.5A CN201811428080A CN109438337B CN 109438337 B CN109438337 B CN 109438337B CN 201811428080 A CN201811428080 A CN 201811428080A CN 109438337 B CN109438337 B CN 109438337B
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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Abstract
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation process of Rui Gefeini intermediate.Shown in the Rui Gefeini intermediate structure such as formula (I), formula (II) compound is condensed to obtain by 4-methyl-2 pentanone and 4- amino -3- fluorophenol, N- methyl -4- Chloro-2-Pyridyle formamide and formula (II) compound condensation is added and obtains.A kind of preparation process of Rui Gefeini intermediate of the present invention, it is easy to operate, it is easy monitoring, yield is up to 90% or more, is high-efficient, is suitable for large-scale industrial production Rui Gefeini；Prepared Rui Gefeini intermediate, impurity content is low, significantly reduces the time of edulcoration purification, highly-safe, has established solid foundation for subsequent synthesis Rui Gefeini.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation process of Rui Gefeini intermediate.
Background technique
Rui Gefeini (regorafenib), the entitled 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } of chemistry
Amino) -3- fluorophenoxy]-N- picoline -2- formamide, it is developed by German Bayer Healthcare Pharma company,
In U.S. FDA ratify list, trade name Stivarga, be it is a kind of with Orally active, multiple target point, wide spectrum novel acardite
Class tyrosine kinase inhibitor can inhibit including the kinases such as VEGFRI-2, PDGFR- β, FGFR1, KIT, to play antitumor
Effect, clinically for treating metastatic colorectal cancer.
Currently, the synthesis about Rui Gefeini mainly includes following several schemes:
Technical solution 1: side Liu Ya etc. (fine-chemical intermediate, 2012,42 (6), 31-34 pages) disclose it is a kind of prepare it is auspicious
The method of Ge Feini, specifically:
In the synthetic route, the reaction solution purity of step 1 is low (50% or less), and impurity is more, leads to final Rui Gefeini
Impurity in finished product is more, be easy it is exceeded, and its formula (I) intermediate be even more need column chromatography could remove impurity, it is cumbersome,
It is unfavorable for industrialized production.
Technical solution 2: Wang Yabo (Chinese antibiotic impurity, in August, 2015 the 8th phase of volume 40,590-592) discloses one
The method that kind prepares Rui Gefeini, specifically:
This method is condensed anti-using p-aminobenzene sulfonic acid as initial feed through diazotising, coupling, reduction, nucleophilic displacement of fluorine and CDI
Rui Gefeini should be made, but this method yield is general, entire technique time-consuming is very long, and it is cumbersome, and two miaow of N, N '-carbonyl
Azoles price is higher, unstable under the high environment of humidity, meets water and is hydrolyzed in a few seconds and releases carbon dioxide, causes to add
Material inaccuracy is easy to generate more difficult isolated dimer, while its synthesis is also required to be unfavorable for industrialized production using phosgene.
In the technical solution of above-mentioned 2 kinds of synthesis Rui Gefeini, it is required to first to prepare formula (I) Rui Gefeini intermediate and is further continued for
Rui Gefeini is synthesized, but all exists and prepares the technical problem that formula (I) Rui Gefeini intermediate faces in the prior art: first is that synthesis
There are more impurity during formula (I) Rui Gefeini intermediate, increase clarification difficulty；Second is that synthesis step is more, operation
Complexity, yield are low.
Therefore, there is an urgent need to a kind of preparation works of the low Rui Gefeini intermediate of easy to operate, high income, impurity content
Skill.
Summary of the invention
The present invention is intended to provide a kind of preparation work of the low Rui Gefeini intermediate of easy to operate, high income, impurity content
Skill.
In order to achieve the above object, the invention adopts the following technical scheme:
A kind of preparation process of Rui Gefeini intermediate, shown in the Rui Gefeini intermediate structure such as formula (I), by 4- first
Base -2 pentanone and 4- amino -3- fluorophenol are condensed to obtain formula (II) compound, add N- methyl -4- Chloro-2-Pyridyle formamide with
Formula (II) compound condensation and obtain；
Further, the preparation process reactive chemistry equation of formula (I) the Rui Gefeini intermediate are as follows:
Further, the preparation process the following steps are included:
The preparation of S1, formula (II) compound: reaction kettle is added in 4-methyl-2 pentanone, 4- amino -3- fluorophenol and toluene
In, under the conditions of 109~114 DEG C, reaction solution is cooled to 80~90 DEG C, is placed in rotation by reflux water-dividing after TLC monitors fully reacting
Turn in evaporimeter, 60~75 DEG C, -0.08~-0.10MPa is concentrated under reduced pressure, and obtains formula (II) compound；
The preparation of S2, formula (I) Rui Gefeini intermediate: N- methylpyrrole is added in formula (II) compound obtained by step S1
Alkanone, N- methyl -4- Chloro-2-Pyridyle formamide and potassium tert-butoxide, under nitrogen protection, 10~25 DEG C of 10~15min of stirring are opened
Heating is opened, 45~65min rises to 97~103 DEG C, after HPLC monitors fully reacting, adds toluene, purified water, glacial acetic acid, if
Setting temperature is 70~80 DEG C, keeps the temperature 1~1.5h, is eventually adding purified water, and controlled at 35~45 DEG C, formula (I) Rui Ge is added
Non- Buddhist nun's intermediate crystal seed reduces temperature to 3~8 DEG C, 10~12h of crystallization, gained crystal is washed, dry, purifying, recrystallize,
It is dry to get.
Further, the weight ratio of 4-methyl-2 pentanone and 4- amino -3- fluorophenol is (2~3) in the step S1:
1。
Further, in the step S1 reflux water-dividing divide water be more than or equal to 305g.
Further, TLC is monitored with petroleum ether in the step S1: for ethyl acetate=2:1 as solvent, 254nm is purple
Outer lamp colour developing, fully reacting when product spot is more than or equal to raw material spot.
Further, the amount that formula (I) Rui Gefeini intermediate crystal seed is added in the step S1 is 6~8g.
Further, HPLC monitoring adds 1 drop 2M hydrochloric acid, is arrived with methanol dilution in the step S2 to take 0.1ml reaction solution
1ml is detected with HPLC, when the ratio of peak areas and 4- amino -3- fluorophenol peak area is greater than 24, fully reacting.
In addition, the present invention also provides a kind of preparation processes to prepare answering in anti-tumor drug Rui Gefeini
With.
Further, the tumour includes intestinal cancer, breast cancer, pancreas cancer and non-small cell lung cancer.
Further, the anti-tumor drug Rui Gefeini can be made into oral agents or injection.
The present invention adds N- methyl -4- Chloro-2-Pyridyle formyl using 4-methyl-2 pentanone and 4- amino -3- fluorophenol
Amine synthesizes formula (I) Rui Gefeini intermediate.The preparation method is easy to operate, is easy monitoring, gained formula (I) Rui Gefeini intermediate
High income, impurity content are low.By test example 1 as it can be seen that formula prepared by preparation method of the present invention (I) Rui Gefeini intermediate yield is equal
Up to 90% or more, high production efficiency；By test example 2 as it can be seen that formula prepared by preparation method of the present invention (I) Rui Gefeini intermediate
Appearance and moisture content comply with standard regulation, and impurity content is low, reduce the miscellaneous of subsequent synthesis Rui Gefeini hydrate
Matter content, highly-safe, the step of decreasing edulcoration purification, by test example 3 as it can be seen that by invention preparation formula (I) Rui Gefei
The indexs such as Rui Gefeini hydrate appearance, dissolubility, moisture content prepared by Buddhist nun's intermediate comply with standard regulation, and impurity
Content is extremely low, highly-safe substantially without dissolvent residual.
The invention has the following advantages that
(1) a kind of preparation process of Rui Gefeini intermediate of the present invention, it is easy to operate, it is easy monitoring, yield is up to 90%
Above, high-efficient, it is suitable for large-scale industrial production Rui Gefeini.
(2) the Rui Gefeini intermediate of the preparation process preparation of a kind of Rui Gefeini intermediate of the present invention, impurity content is low,
Significantly reduce the time of edulcoration purification, it is highly-safe, solid foundation has been established for subsequent synthesis Rui Gefeini.
Detailed description of the invention
Fig. 1 is the related substance reference substance HPLC map of Rui Gefeini intermediate.
Fig. 2 is the related substance HPLC map of Rui Gefeini intermediate prepared by the embodiment of the present invention 1.
Fig. 3 is the related substance HPLC map of Rui Gefeini intermediate prepared by the embodiment of the present invention 2.
Fig. 4 is the related substance HPLC map of Rui Gefeini intermediate prepared by the embodiment of the present invention 3.
Fig. 5 is the related substance reference substance HPLC map of Rui Gefeini.
Fig. 6 is that the related substance of Rui Gefeini hydrate prepared by the embodiment of the present invention 4 detects HPLC map.
Fig. 7 is that the related substance of Rui Gefeini hydrate prepared by the embodiment of the present invention 5 detects HPLC map.
Fig. 8 is that the related substance of Rui Gefeini hydrate prepared by the embodiment of the present invention 6 detects HPLC map.
Fig. 9 is Rui Gefeini reference substance HPLC map.
Figure 10 is that Rui Gefeini hemihydrate content prepared by the embodiment of the present invention 4 detects HPLC map.
Figure 11 is that Rui Gefeini hemihydrate content prepared by the embodiment of the present invention 5 detects HPLC map.
Figure 12 is that Rui Gefeini hemihydrate content prepared by the embodiment of the present invention 6 detects HPLC map.
Figure 13 is the chemical equation of the preparation process of Rui Gefeini intermediate of the present invention.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
Wherein, agents useful for same is common agents, can be purchased from conventional reagent production and sales company.
The preparation of 1 formula of embodiment (I) Rui Gefeini intermediate
Chemical equation are as follows:
Preparation method:
The preparation of S1, formula (II) compound: while stirring by 4-methyl-2 pentanone 10.320kg, 4- amino -3- fluorophenol
4.300kg and toluene 26.140kg is added in reaction kettle, and under the conditions of 112 DEG C, reflux water-dividing will be anti-after TLC monitors fully reacting
It answers liquid to be cooled to 85 DEG C, is placed in Rotary Evaporators, 70 DEG C, -0.10MPa is concentrated under reduced pressure, and obtains formula (II) compound；
The preparation of S2, formula (I) Rui Gefeini intermediate: N- methylpyrrole is added in formula (II) compound obtained by step S1
Alkanone 12.900kg, N- methyl -4- Chloro-2-Pyridyle formamide 5.830kg and potassium tert-butoxide 3.980kg, under nitrogen protection, 15
DEG C stirring 15min, opens heating, and 55min rises to 101 DEG C, after HPLC monitors fully reacting, adds toluene 18.750kg, pure
Change water 5.000kg, glacial acetic acid 1.370kg, setting temperature is 75 DEG C, keeps the temperature 1.5h, purified water 53.710kg is added, control temperature
It is 40 DEG C, formula (I) Rui Gefeini intermediate crystal seed 8g is added, reduces temperature to 4 DEG C, crystallization 12h, gained crystal is washed, dry
Dry, purifying, recrystallization, it is dry to get；
Wherein, TLC monitoring is with petroleum ether: ethyl acetate=2:1 is as solvent, the colour developing of 254nm ultraviolet lamp, product spot
Fully reacting when point is more than or equal to raw material spot；HPLC monitoring adds 1 drop 2M hydrochloric acid, is arrived with methanol dilution to take 0.1ml reaction solution
1ml is detected with HPLC, when the ratio of peak areas and 4- amino -3- fluorophenol peak area is greater than 24, fully reacting.
The preparation of 2~3 formula of embodiment (I) Rui Gefeini intermediate
Difference from Example 1 is that the raw material inventory of the embodiment 2~3 is different, referring specifically to table 1.
1 embodiment of table 2~3 formula (I) Rui Gefeini intermediate supplementary material inventory
Preparation method reference implementation example 1.
The preparation of 4 Rui Gefeini hydrate of embodiment
Chemical equation are as follows:
Preparation method:
The tetrahydro furan of formula (I) Rui Gefeini intermediate prepared by embodiment 1 and 8.300 times of its weight amounts is added while stirring
It mutters in reaction kettle, replaces nitrogen, controlled at 25 DEG C, body weight 2.948 among dropwise addition formula (I) Rui Gefeini in 25min
Formula (I) Rui Ge is added in 32% 4- chloro- 3- (trifluoromethyl) phenylisocyanate-tetrahydrofuran solution of amount again, 25 DEG C of reaction 3h
The methanol of 0.906 times of body weight amount, 25 DEG C of reaction 1h among non-Buddhist nun；0.457 times of body weight amount among dropwise addition formula (I) Rui Gefeini
Hydrochloric acid filter, be washing, dry, obtaining formula (III) compound in 25 DEG C of reaction 4h；
Take acetone, formula (III) compound by weight of formula (III) compound, formula (III) 6.550 times of compound by weight amounts
The purified water of 1.070 times of amounts is added in reaction kettle, and controlled at 40 DEG C, formula (III) 0.3886 times of compound by weight amount is added dropwise
20% sodium hydroxide solution, drop finish, 40 DEG C of stirrings to reaction solution dissolved clarification；Add formula (III) 0.001 times of compound by weight amount
Rui Gefeini crystal seed, be cooled to 15 DEG C, 20min drips off purified water of formula (III) 0.930 times of compound by weight amount, continues to drop
Temperature is to 4 DEG C, stirring and crystallizing 3h；Centrifugation, washing, dry, dissolution, recrystallization, it is dry to get.
The preparation of 5 Rui Gefeini hydrate of embodiment
Formula (I) Rui Gefeini intermediate prepared by Example 2 prepares Rui Gefeini, preparation method reference implementation example 4.
The preparation of 6 Rui Gefeini hydrate of embodiment
Formula (I) Rui Gefeini intermediate prepared by Example 3 prepares Rui Gefeini, preparation method reference implementation example 4.
The preparation of 1 formula of comparative example (I) Rui Gefeini intermediate
Difference from Example 1 is that the comparative example 1 prepares the chemical reaction side of formula (I) Rui Gefeini intermediate
Formula are as follows:
Remaining parameter and operation reference implementation example 1.
The preparation of 2 formula of comparative example (I) Rui Gefeini intermediate
Difference from Example 1 is that the comparative example 2 prepares the chemical reaction side of formula (I) Rui Gefeini intermediate
Formula are as follows:
Remaining parameter and operation reference implementation example 1.
The preparation of 3 formula of comparative example (I) Rui Gefeini intermediate
Difference from Example 1 is that the comparative example 3 prepares the chemical reaction side of formula (I) Rui Gefeini intermediate
Formula are as follows:
Remaining parameter and operation reference implementation example 1.
The preparation of 4 formula of comparative example (I) Rui Gefeini intermediate
Difference from Example 1 is that the comparative example 4 prepares the chemical reaction side of formula (I) Rui Gefeini intermediate
Formula are as follows:
Remaining parameter and operation reference implementation example 1.
The preparation of 5 formula of comparative example (I) Rui Gefeini intermediate
Difference from Example 1 is that the comparative example 5 prepares the chemical reaction side of formula (I) Rui Gefeini intermediate
Formula are as follows:
Remaining parameter and operation reference implementation example 1.
The yield of 1 formula of test example (I) Rui Gefeini intermediate
The yield for measuring and calculating formula (I) Rui Gefeini intermediate prepared by Examples 1 to 3 and comparative example 1~5, calculates
Formula is as follows:
4- amino -3- fluorophenol: formula (I) Rui Gefeini intermediate=127.12:261.25
2. test result
2 formula of table (I) Rui Gefeini intermediate yield calculated result
| Group | Yield (%) |
| Embodiment 1 | 93.1 |
| Embodiment 2 | 91.6 |
| Embodiment 3 | 90.7 |
| Comparative example 1 | 79.2 |
| Comparative example 2 | 76.4 |
| Comparative example 3 | 72.0 |
| Comparative example 4 | 71.6 |
| Comparative example 5 | 75.9 |
As can be seen from Table 2, the embodiment of the present invention 1~3 prepare formula (I) Rui Gefeini intermediate yield be up to 90% with
On, high production efficiency, and comparative example 1~5 (changing raw materials for production group) yield then significantly reduces 10~20% or so.
The quality testing of 2 formula of test example (I) Rui Gefeini intermediate
Detect formula (I) Rui Gefeini intermediate appearance, moisture and the related material parameters of Examples 1 to 3 preparation, correlation figure
Spectrum is referring to Fig. 1~4, and specific data are referring to table 3.
Formula (I) Rui Gefeini intermediate testing result of 3 Examples 1 to 3 of table preparation
Wherein, the essential information in relation to substance is shown in Table 4.
The related substance essential information of 4 formula of table (I) Rui Gefeini intermediate
Detect the appearance, moisture and related substance of formula (I) Rui Gefeini intermediate prepared by comparative example 1~5.Measurement detection
Canonical reference table 3, specific data are referring to 5.
Formula (I) Rui Gefeini intermediate testing result of 5 comparative example 1~5 of table preparation
| Detection project | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 |
| Appearance | Meet regulation | Meet regulation | Meet regulation | Meet regulation | Meet regulation |
| Moisture (%) | 0.06 | 0.07 | 0.05 | 0.06 | 0.04 |
| GN-SM1 (%) | It is not detected | It is not detected | It is not detected | It is not detected | It is not detected |
| GN-SM2 (%) | It is not detected | 0.005 | 0.006 | 0.007 | It is not detected |
| GN-II-IP-B (%) | 0.53 | 0.61 | 0.70 | 0.55 | 0.48 |
| GN-II-IP-C (%) | 0.31 | 0.53 | 0.61 | 0.42 | 0.37 |
| GN-II-IP-D (%) | 0.53 | 0.67 | 0.69 | 0.70 | 0.52 |
| GN-II-IP-E (%) | 0.27 | 0.42 | 0.39 | 0.28 | 0.43 |
| Other single impurity (%) | 0.21 | 0.10 | 0.09 | 0.17 | 0.11 |
| Total impurities (%) | 1.85 | 2.33 | 2.48 | 2.12 | 1.91 |
By table 3 and table 5 as it can be seen that formula (I) Rui Gefeini intermediate indices prepared by the embodiment of the present invention 1~3 accord with
Regulation is closed, impurity content is few, purity is high；And in formula (I) Rui Gefeini of comparative example 1~5 (changing raw materials for production group) preparation
Mesosome related impurities are more, have exceeded prescribed limit.
The quality testing of 3 Rui Gefeini hydrate of test example
Detect Rui Gefeini hydrate appearance, dissolubility, moisture, related substance, dissolvent residual prepared by embodiment 4~6
Etc. parameters, related map is referring to Fig. 5~12, and specific data are referring to table 6.
6 embodiment of table, 4~6 Rui Gefeini hydrate quality measurements
The related substance essential information of 7 Rui Gefeini hydrate of table
By table 6 as it can be seen that Rui Gefeini hydrate indices prepared by the embodiment of the present invention 4~6 meet regulation, impurity
Content is few, almost without dissolvent residual, purity is high.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (8)
1. a kind of preparation process of Rui Gefeini intermediate, which is characterized in that the Rui Gefeini intermediate structure such as formula (I) institute
Show, formula (II) compound is condensed to obtain by 4-methyl-2 pentanone and 4- amino -3- fluorophenol, adds the chloro- 2- pyrrole of N- methyl -4-
Pyridine formamide and formula (II) compound condensation and obtain；
Wherein, the preparation process the following steps are included:
The preparation of S1, formula (II) compound: 4-methyl-2 pentanone, 4- amino -3- fluorophenol and toluene are added in reaction kettle,
Under the conditions of 109~114 DEG C, reaction solution is cooled to 80~90 DEG C after TLC monitors fully reacting by reflux water-dividing, is placed in rotation and is steamed
It sends out in instrument, 60~75 DEG C, -0.08~-0.10MPa is concentrated under reduced pressure, and obtains formula (II) compound；
The preparation of S2, formula (I) Rui Gefeini intermediate: N- crassitude is added in formula (II) compound obtained by step S1
Ketone, N- methyl -4- Chloro-2-Pyridyle formamide and potassium tert-butoxide, under nitrogen protection, 10~25 DEG C of 10~15min of stirring are opened
Heating, 45~65min rise to 97~103 DEG C, after HPLC monitors fully reacting, add toluene, purified water, glacial acetic acid, be arranged
Temperature is 70~80 DEG C, keeps the temperature 1~1.5h, is eventually adding purified water, and controlled at 35~45 DEG C, formula (I) Rui Gefei is added
Buddhist nun's intermediate crystal seed reduces temperature to 3~8 DEG C, 10~12h of crystallization, and gained crystal is washed, dry, purifying, recrystallization, does
It is dry to get；
Wherein, the weight ratio of 4-methyl-2 pentanone and 4- amino -3- fluorophenol is (2~3) in the step S1: 1.
2. preparation process according to claim 1, which is characterized in that in the step S1 reflux water-dividing divide water be greater than etc.
In 305g.
3. preparation process according to claim 1, which is characterized in that TLC monitoring is in the step S1 with petroleum ether: acetic acid second
Ester=2:1 is as solvent, the colour developing of 254nm ultraviolet lamp, fully reacting when product spot is more than or equal to raw material spot.
4. preparation process according to claim 1, which is characterized in that formula (I) Rui Gefeini intermediate is brilliant in the step S2
The amount that kind is added is 6~8g.
5. preparation process according to claim 1, which is characterized in that HPLC monitoring is that 0.1ml is taken to react in the step S2
Liquid adds 1 drop 2M hydrochloric acid to be detected with methanol dilution to 1ml with HPLC, when peak areas and 4- amino -3- fluorophenol peak area
Ratio be greater than 24 when, fully reacting.
6. any preparation process is preparing the application in anti-tumor drug Rui Gefeini according to claim 1~5.
7. applying according to claim 6, which is characterized in that the tumour is intestinal cancer, breast cancer, pancreas cancer or non-small cell lung
Cancer.
8. being applied described according to claim 6 or 7, which is characterized in that the anti-tumor drug Rui Gefeini be made oral agents or
Injection.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102947271A (en) * | 2010-04-15 | 2013-02-27 | 拜耳制药股份公司 | Process for the preparation of 4- {4-[({[4 -chloro-3 -(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monohydrate |
| CN104592105A (en) * | 2015-02-10 | 2015-05-06 | 杭州朱养心药业有限公司 | Regorafenib and manufacture method thereof |
-
2018
- 2018-11-27 CN CN201811428080.5A patent/CN109438337B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102947271A (en) * | 2010-04-15 | 2013-02-27 | 拜耳制药股份公司 | Process for the preparation of 4- {4-[({[4 -chloro-3 -(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monohydrate |
| CN104592105A (en) * | 2015-02-10 | 2015-05-06 | 杭州朱养心药业有限公司 | Regorafenib and manufacture method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 瑞戈非尼的合成;郑德强等;《中国医药工业杂志》;20161231;第47卷(第5期);528-530 * |
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