CN109438336A - A kind of preparation method of Rui Gefeini hydrate - Google Patents
A kind of preparation method of Rui Gefeini hydrate Download PDFInfo
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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 method of Rui Gefeini hydrate.The Rui Gefeini hydrate is condensed get Rui Gefeini intermediate 1 by 4-methyl-2 pentanone, 4- amino -3- fluorophenol and N- methyl -4- Chloro-2-Pyridyle formamide, the condensation of 4- chloro- 3- (trifluoromethyl) phenylisocyanate, the obtained Rui Gefeini intermediate 2 of salt-forming reaction are added, finally dissociate in alkaline aqueous acetone solution hydration get Rui Gefeini hydrate.A kind of preparation method of Rui Gefeini hydrate 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；Prepared Rui Gefeini hydrate impurity content is low, substantially without dissolvent residual, significantly reduces purification time, and property is stablized, and keeps stablizing in accelerated stability test, highly-safe.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation method of Rui Gefeini hydrate.
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 hexichol
Ureas tyrosine kinase inhibitor can inhibit including the kinases such as VEGFRI-2, PDGFR- β, FGFR1, KIT, to play anti-swollen
Tumor 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 a kind of prepare
The method of Rui Gefeini, 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 wherein mesosome be even more need column chromatography could remove impurity, be unfavorable for industrializing
Production.
Technical solution 2: Wang Yabo (Chinese antibiotic impurity, in August, 2015 the 8th phase of volume 40,590-592) discloses
A method of Rui Gefeini is prepared, specifically:
This method is condensed using p-aminobenzene sulfonic acid as initial feed through diazotising, coupling, reduction, nucleophilic displacement of fluorine and CDI
It reacts and Rui Gefeini is made, but this method yield is general, entire technique time-consuming is very long, and it is cumbersome, and N, N '-carbonyl
Diimidazole price is higher, unstable under the high environment of humidity, meets water and is hydrolyzed and releases carbon dioxide in a few seconds,
Charging inaccuracy is caused, is easy to generate more difficult isolated dimer, while its synthesis is also required to be unfavorable for industry using phosgene
Metaplasia produces.
Technical solution 3: Chinese patent CN106083711A discloses the synthetic method of Rui Gefeini a kind of, specifically:
After with the chloro- 3- of 4- (trifluoromethyl) aniline and phenyl chloroformate amidation process occurs for this method, then with 4- ammonia
Amidation process occurs for base -3- fluorophenol, and it is anti-that alkylation then occurs with starting material 4- chloro-n-methyl -2- pyridine carboxamides
It answers, finally recrystallizes get Rui Gefeini.But the method overall yield is lower, and the N for being difficult to recycle, N- bis- are used in reacting at ether
Methylformamide, synthesis cost is higher, and pollution is larger, and the synthetic yield of phenyl chloroformate is lower, while the purifying of product
Column chromatography separation method is also needed, economy is too poor；Although the synthesis process is avoided using triphosgene, but raw material chloro-carbonic acid -2-
Nitro phenyl ester and phenyl chloroformate are unstable and have corrosivity, have certain damage to equipment, industrial production danger is huge
Greatly, and it is unfriendly to environment.In addition, its products therefrom Rui Gefeini monohydrate stability is poor, in organic solvent easily
It loses the crystallization water and becomes the worse Rui Gefeini free alkali of dissolubility, along with the hygroscopicity of Rui Gefeini monohydrate is larger,
Stability is poor.
Therefore, there is an urgent need to a kind of Rui Gefeini hydrates easy to operate, high income, impurity content is low, property is stable
Preparation method.
Summary of the invention
The present invention is intended to provide a kind of Rui Gefeini hydration easy to operate, high income, impurity content is low, property is stable
The preparation method of object.
In order to achieve the above object, the invention adopts the following technical scheme:
A kind of preparation method of Rui Gefeini hydrate, the Rui Gefeini hydrate is by 4-methyl-2 pentanone, 4- ammonia
Base -3- fluorophenol and N- methyl -4- Chloro-2-Pyridyle formamide are condensed get Rui Gefeini intermediate 1, add the chloro- 3- (three of 4-
Methyl fluoride) phenylisocyanate condensation, the obtained Rui Gefeini intermediate 2 of salt-forming reaction, finally dissociate in alkaline aqueous acetone solution
It is hydrated get Rui Gefeini hydrate.
Further, the reactive chemistry equation of the preparation method are as follows:
Further, the preparation method comprises the following steps:
The preparation of S1, Rui Gefeini intermediate 1: 4-methyl-2 pentanone, 4- amino -3- fluorophenol and toluene are added anti-
It answers in kettle, under the conditions of 109~114 DEG C, reflux water-dividing, after TLC monitors fully reacting, in rotary evaporation after reaction solution is cooled down
Instrument is concentrated under reduced pressure, and adds N-Methyl pyrrolidone, N- methyl -4- Chloro-2-Pyridyle formamide and potassium tert-butoxide, and 10~25 DEG C
10~15min is stirred, heating is opened, 45~65min rises to 97~103 DEG C, and after HPLC monitors fully reacting, toluene, pure is added
Change water, glacial acetic acid, setting temperature is 70~80 DEG C, keeps the temperature 1~1.5h, and purified water is added and adds controlled at 35~45 DEG C
Enter 1 crystal seed of Rui Gefeini intermediate, reduce temperature to 3~8 DEG C, 10~12h of crystallization, by gained crystallizing and washing, drying, purifying,
Recrystallization, dry, get Rui Gefeini intermediate 1；
The preparation of S2, Rui Gefeini intermediate 2: Rui Gefeini intermediate 1 obtained by step S1 is dissolved in tetrahydrofuran
In reaction kettle, under nitrogen protection, controlled at 20~30 DEG C, it is molten that the chloro- 3- of 4- (trifluoromethyl) phenylisocyanate is added
Liquid, 25~30 DEG C of 2.5~3h of reaction are added methanol, hydrochloric acid are added after 25~30 DEG C of 0.5~1h of reaction, react in 20~30 DEG C
3~4h is filtered, washing, dry, get Rui Gefeini intermediate 2；
The preparation of S3, Rui Gefeini hydrate: take Rui Gefeini intermediate 2 obtained by step S2 that acetone and purified water is added
It is placed in reaction kettle, sodium hydroxide solution is added dropwise, 35~45 DEG C of stirrings to reaction solution dissolved clarification add Rui Gefeini crystal seed, drip
3~8 DEG C are cooled to after adding purified water, 2~3h of stirring and crystallizing is then centrifuged for, washs, dries, dissolves, recrystallizes, dries, i.e.,
?.
Further, the weight ratio of 4-methyl-2 pentanone and 4- amino -3- fluorophenol is (2~3) in the step S1:
1；Reflux water-dividing divides water that need to be more than or equal to 305g in the step S1.
Further, TLC is monitored with petroleum ether in the step S1: ethyl acetate=2:1 is as solvent, 254nm
Ultraviolet lamp colour developing, fully reacting when product spot is more than or equal to raw material spot；HPLC monitoring is to take in the step S1
0.1ml reaction solution adds 1 drop 2M hydrochloric acid to be detected with methanol dilution to 1ml with HPLC, when peak areas and 4- amino -3- fluorine
When the ratio of phenol peak area is greater than 24, fully reacting.
Further, the amount that 1 crystal seed of step S1 China and Sweden Ge Feini intermediate is added is 6~8g.
Further, 4- chloro- 3- (trifluoromethyl) phenylisocyanate solution is to contain 30~35% in the step S2
The tetrahydrofuran solution of 4- chloro- 3- (trifluoromethyl) phenylisocyanate.
Further, the weight percent of sodium hydroxide solution is 18~25% in the step S3.
In addition, the present invention also provides a kind of preparation method application in preparations of anti-tumor drugs.
Further, the tumour includes intestinal cancer, breast cancer, pancreas cancer and non-small cell lung cancer.
Further, the anti-tumor drug 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 Rui Gefeini intermediate 1, and the chloro- 3- of 4- (trifluoromethyl) phenylisocyanate is then added and synthesizes Rui Gefeini intermediate
2, finally dissociating to be hydrated is made Rui Gefeini hydrate.The preparation method is easy to operate, is easy to monitor, products therefrom high income,
Impurity content is low, property is stable.By test example 1 as it can be seen that Rui Gefeini hydrate yield prepared by preparation method of the present invention is high
Up to 90% or more, high production efficiency；By test example 2 as it can be seen that outside Rui Gefeini hydrate finished product prepared by preparation method of the present invention
The indexs such as sight, dissolubility, moisture content comply with standard regulation, and impurity content is extremely low, substantially without dissolvent residual, peace
Quan Xinggao；By test example 3 as it can be seen that Rui Gefeini hydrate prepared by preparation method of the present invention was tried in 6 months accelerated stabilities
It tests rear moisture, content and total impurities content to be held essentially constant, stability is high.And comparative example 1~5 (changes raw materials for production base
Group) prepared by Rui Gefeini hydrate yield reduce by 10% or so, related impurities are more, active constituent content significantly reduce,
Prescribed limit is had exceeded, stability is significantly reduced.
The invention has the following advantages that
(1) a kind of preparation method of Rui Gefeini hydrate 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.
(2) Rui Gefeini of the preparation method preparation of a kind of Rui Gefeini hydrate of the present invention, impurity content is low, substantially
There is no dissolvent residual, significantly reduce purification time, property is stablized, and keeps stablizing in accelerated stability test, safety
It is high.
Detailed description of the invention
Fig. 1 is the related substance reference substance HPLC map of Rui Gefeini.
Fig. 2 is that the related substance of Rui Gefeini hydrate prepared by the embodiment of the present invention 1 detects HPLC map.
Fig. 3 is that the related substance of Rui Gefeini hydrate prepared by the embodiment of the present invention 2 detects HPLC map.
Fig. 4 is that the related substance of Rui Gefeini hydrate prepared by the embodiment of the present invention 3 detects HPLC map.
Fig. 5 is Rui Gefeini reference substance HPLC map.
Fig. 6 is that Rui Gefeini hemihydrate content prepared by the embodiment of the present invention 1 detects HPLC map.
Fig. 7 is that Rui Gefeini hemihydrate content prepared by the embodiment of the present invention 2 detects HPLC map.
Fig. 8 is that Rui Gefeini hemihydrate content prepared by the embodiment of the present invention 3 detects HPLC map.
Fig. 9 is the reactive chemistry equation of the preparation method of Rui Gefeini hydrate 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 Rui Gefeini hydrate of embodiment
1. the preparation of Rui Gefeini intermediate 1
Chemical equation are as follows:
Preparation method:
While stirring by toluene 26.140kg, 4-methyl-2 pentanone 10.320kg, 4- amino -3- fluorophenol 4.300kg
It is added in reaction kettle, is warming up to 112 DEG C, reaction solution is cooled to 85 DEG C, be placed in by reflux water-dividing after TLC monitors fully reacting
In rotary evaporator, control water temperature is 70 DEG C, and vacuum degree is -0.10MPa, is concentrated under reduced pressure into solvent-free ooze；To rotary evaporation
It is filled with nitrogen in device, N-Methyl pyrrolidone 12.900kg is added, stirring and dissolving is transferred in reaction kettle, opens stirring, nitrogen
Gas shielded cools to 15 DEG C, takes N- methyl -4- Chloro-2-Pyridyle formamide 5.830kg that reaction kettle is added, and controls interior 15 DEG C of temperature,
Potassium tert-butoxide 3.980kg is added in five times, adds stirring 15min, opens heating, 55min rises to 101 DEG C, HPLC monitoring reaction
After completely, adds toluene 18.750kg, purified water 5.000kg, glacial acetic acid 1.370kg and be added in reaction kettle, temperature is set
It is 75 DEG C, keeps the temperature 1.5h；Reaction solution is transferred in another reaction kettle, purified water 53.710kg is added, controlled at 40
DEG C, be added 1 crystal seed 8g of Rui Gefeini intermediate, reduce temperature to 4 DEG C, crystallization 12h, by gained crystallizing and washing, drying, 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
Fully reacting when spot is more than or equal to raw material spot；HPLC monitoring is to take 0.1ml reaction solution, adds 1 drop 2M hydrochloric acid, dilute with methanol
1ml is released, is detected with HPLC, when the ratio of peak areas and 4- amino -3- fluorophenol peak area is greater than 24, has been reacted
Entirely.
2. the preparation of Rui Gefeini intermediate 2
Chemical equation are as follows:
Preparation method (weight of charging is in terms of the weight multiple of Rui Gefeini intermediate 1):
Rui Gefeini intermediate 1 and 8.300 times of its weight tetrahydrofurans measured are added while stirring in reaction kettle, sets
Nitrogen is changed, controlled at 25 DEG C, 25min is interior to be added dropwise 2.948 times of 1 weight of the Rui Gefeini intermediate chloro- 3- of 32% 4- measured
0.906 times of 1 weight of Rui Gefeini intermediate is added in (trifluoromethyl) phenylisocyanate-tetrahydrofuran solution, 25 DEG C of reaction 3h
The methanol of amount, 25 DEG C of reaction 1h；The hydrochloric acid of 0.457 times of 1 weight of Rui Gefeini intermediate amount is added dropwise, in 25 DEG C of reaction 4h, takes out
Filter, washing, it is dry to get.
3. the preparation of Rui Gefeini finished product
Chemical equation:
Preparation method (weight of raw material is in terms of the weight multiple of Rui Gefeini intermediate 2):
Take Rui Gefeini intermediate 2,6.550 times of 2 weight of Rui Gefeini intermediate acetone, the Rui Gefeini intermediates 2 measured
The purified water of 1.070 times of weight amounts is added in reaction kettle, and controlled at 40 DEG C, 2 weight of Rui Gefeini intermediate is added dropwise
The sodium hydroxide solution of 0.3886 times of amount 20%, drop finish, 40 DEG C of stirrings to reaction solution dissolved clarification；Add Rui Gefeini intermediate 2
The Rui Gefeini crystal seed of 0.001 times of weight amount, is cooled to 15 DEG C, 20min drips off 0.930 times of 2 weight of Rui Gefeini intermediate amount
Purified water, continue to be cooled to 4 DEG C, stirring and crystallizing 3h；Centrifugation, washing, dry, dissolution, recrystallization, it is dry to get.
The preparation of 2~3 Rui Gefeini hydrate of embodiment
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 Rui Gefeini hydrate supplementary material inventory
Preparation method reference implementation example 1.
The preparation of 1 Rui Gefeini hydrate of comparative example
Difference from Example 1 is that the comparative example 1 prepares the chemical equation of Rui Gefeini intermediate 1
Are as follows:
Remaining parameter and operation reference implementation example 1.
The preparation of 2 Rui Gefeini hydrate of comparative example
Difference from Example 1 is that the comparative example 2 prepares the chemical equation of Rui Gefeini intermediate 1
Are as follows:
Remaining parameter and operation reference implementation example 1.
The preparation of 3 Rui Gefeini hydrate of comparative example
Difference from Example 1 is that the comparative example 3 prepares the chemical equation of Rui Gefeini intermediate 1
Are as follows:
Remaining parameter and operation reference implementation example 1.
The preparation of 4 Rui Gefeini hydrate of comparative example
Difference from Example 1 is that the comparative example 4 prepares the chemical equation of Rui Gefeini intermediate 1
Are as follows:
Remaining parameter and operation reference implementation example 1.
The preparation of 5 Rui Gefeini hydrate of comparative example
Difference from Example 1 is that the comparative example 5 prepares the chemical equation of Rui Gefeini intermediate 1
Are as follows:
Remaining parameter and operation reference implementation example 1.
The yield of 1 Rui Gefeini hydrate of test example
The yield of the Rui Gefeini hydrate of Examples 1 to 3 and the preparation of 1~5 preparation method of comparative example is measured and calculates,
Calculation formula is as follows:
1. 1 yield of Rui Gefeini intermediate:
4- amino -3- fluorophenol: Rui Gefeini intermediate 1=127.12: 261.25
2. 2 yield of Rui Gefeini intermediate:
1: Rui Gefeini intermediate 2=261.25: 519.28 of Rui Gefeini intermediate
3. Rui Gefeini yield:
Rui Gefeini intermediate 2: Rui Gefeini=519.28: 500.83
4. test result
2 Rui Gefeini product yield calculated result of table
| Group | Yield (%) |
| Embodiment 1 | 95.6 |
| Embodiment 2 | 93.1 |
| Embodiment 3 | 90.5 |
| Comparative example 1 | 80.4 |
| Comparative example 2 | 81.7 |
| Comparative example 3 | 83.9 |
| Comparative example 4 | 82.3 |
| Comparative example 5 | 79.6 |
As can be seen from Table 2, Rui Gefeini hydrate yield prepared by the embodiment of the present invention 1~3 is up to 90% or more, life
Produce high-efficient, and the Rui Gefeini hydrate yield of comparative example 1~5 (change raw materials for production group) preparation then significantly reduces
10% or so.
The quality testing of 2 Rui Gefeini hydrate of test example
Detect the Rui Gefeini hydrate appearance, dissolubility, moisture, related substance, dissolvent residual of Examples 1 to 3 preparation
Etc. parameters, related map is referring to Fig. 1~8, and specific data are referring to table 3.
3 Examples 1 to 3 Rui Gefeini hydrate quality measurements of table
Wherein, the essential information in relation to substance is shown in Table 4.
Table 4 is in relation to substance essential information
Detect the appearance of Rui Gefeini hydrate, dissolubility, identification, moisture, related substance prepared by comparative example 1~5,
The parameters such as dissolvent residual.Wherein, appearance, dissolubility, identification, moisture, residue on ignition, heavy metal, dissolvent residual and microorganism limit
Degree meets regulation, and related substance and assay examination criteria reference table 3, specific data are referring to 5.
5 comparative example 1~5 of table is in relation to substance, impurity and content detection result
By table 3 and table 5 as it can be seen that Rui Gefeini hydrate indices prepared by the embodiment of the present invention 1~3 meet rule
Fixed, impurity content is few, almost without dissolvent residual, purity is high；And comparative example 1~5 (changing raw materials for production group) preparation is auspicious
Ge Feini hydrate related impurities are more, and active constituent content significantly reduces, and have exceeded prescribed limit.
The stability test of 3 Rui Gefeini hydrate of test example
With reference to " Chinese Pharmacopoeia ", (the 4th 9001 material medicine of general rule of version in 2015 and preparation stability test direction are former
Then) Rui Gefeini hydrate prepared by embodiment 1 and comparative example 1~5 carries out accelerated stability test, and the during test
0,1,2,3,6 the end of month separately sampled measurement its appearance, moisture and content.Test result is referring to table 6.
The stability test result of 6 Rui Gefeini hydrate of table
By table 6 as it can be seen that the Rui Gefeini hydrate for preparing of the embodiment of the present invention 1 is in 6 months of accelerated test, moisture,
Total impurities and content are held in regulation content range without significant change, are had good stability；And comparative example 1~5
The Rui Gefeini hydrate moisture content of (changing raw materials for production group) preparation exceeds prescribed limit since the 1st, 2 month respectively,
Total impurities are gradually increased also with the time, and active constituent content then gradually decreases, and stability is poor.
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, those of ordinary skill in the art institute without departing from the spirit and technical ideas disclosed in the present invention such as
All equivalent modifications or change completed, should be covered by the claims of the present invention.
Claims (10)
1. a kind of preparation method of Rui Gefeini hydrate, which is characterized in that the Rui Gefeini hydrate is by 4- methyl -2- penta
Ketone, 4- amino -3- fluorophenol and N- methyl -4- Chloro-2-Pyridyle formamide are condensed get Rui Gefeini intermediate 1, and it is chloro- to add 4-
Rui Gefeini intermediate 2 is made in the condensation of 3- (trifluoromethyl) phenylisocyanate, salt-forming reaction, finally in alkaline aqueous acetone solution
Free hydration get Rui Gefeini hydrate.
2. preparation method according to claim 1, which is characterized in that the preparation method comprises the following steps:
The preparation of S1, Rui Gefeini intermediate 1: reaction kettle is added in 4-methyl-2 pentanone, 4- amino -3- fluorophenol and toluene
In, under the conditions of 109~114 DEG C, reflux water-dividing after TLC monitors fully reacting, is depressurized after reaction solution is cooled down in Rotary Evaporators
Concentration, adds N-Methyl pyrrolidone, N- methyl -4- Chloro-2-Pyridyle formamide and potassium tert-butoxide, and 10~25 DEG C of stirrings 10~
15min, opens heating, and 45~65min rises to 97~103 DEG C, after HPLC monitors fully reacting, toluene, purified water, ice second is added
Acid, setting temperature are 70~80 DEG C, keep the temperature 1~1.5h, purified water is added, and controlled at 35~45 DEG C, Rui Gefeini is added
1 crystal seed of intermediate reduces temperature to 3~8 DEG C, 10~12h of crystallization, by gained crystallizing and washing, drying, purifying, recrystallization, does
It is dry, get Rui Gefeini intermediate 1；
The preparation of S2, Rui Gefeini intermediate 2: Rui Gefeini intermediate 1 obtained by step S1 is dissolved in reaction with tetrahydrofuran
In kettle, under nitrogen protection, controlled at 20~30 DEG C, the addition chloro- 3- of 4- (trifluoromethyl) phenylisocyanate solution, 25~
30 DEG C of 2.5~3h of reaction are added methanol, hydrochloric acid are added after 25~30 DEG C of 0.5~1h of reaction, in 20~30 DEG C of 3~4h of reaction, take out
Filter, washing, dry, get Rui Gefeini intermediate 2；
The preparation of S3, Rui Gefeini hydrate: 2 addition acetone of Rui Gefeini intermediate and purified water obtained by step S2 is taken to be placed in instead
It answers in kettle, sodium hydroxide solution is added dropwise, 35~45 DEG C of stirrings to reaction solution dissolved clarification add Rui Gefeini crystal seed, purifying is added dropwise
3~8 DEG C, 2~3h of stirring and crystallizing are cooled to after water, be then centrifuged for, wash, drying, dissolving, recrystallizing, dry to get.
3. preparation method according to claim 2, which is characterized in that 4-methyl-2 pentanone and 4- amino-in the step S1
The weight ratio of 3- fluorophenol is (2~3): 1；Reflux water-dividing divides water that need to be more than or equal to 305g in the step S1.
4. preparation method according to claim 2, 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；The step
HPLC monitoring adds 1 drop 2M hydrochloric acid to be detected with methanol dilution to 1ml with HPLC, when product peak in rapid S1 to take 0.1ml reaction solution
When the ratio of area and 4- amino -3- fluorophenol peak area is greater than 24, fully reacting.
5. preparation method according to claim 2, which is characterized in that 1 crystal seed of step S1 China and Sweden Ge Feini intermediate adds
The amount entered is 6~8g.
6. preparation method according to claim 1, which is characterized in that the chloro- 3- of 4- (trifluoromethyl) benzene is different in the step S2
Cyanic acid ester solution is the tetrahydrofuran solution containing 30~35%4- chloro- 3- (trifluoromethyl) phenylisocyanate.
7. preparation method according to claim 1, which is characterized in that the weight percent of sodium hydroxide solution in the step S3
Number is 18~25%.
8. any preparation method application in preparation of anti-tumor drugs according to claim 1~7.
9. applying according to claim 8, which is characterized in that the tumour includes intestinal cancer, breast cancer, pancreas cancer and non-small cell lung
Cancer.
10. applying according to claim 8 or claim 9, which is characterized in that the anti-tumor drug can be made into oral agents or injection
Agent.
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| CN201811428079.2A CN109438336B (en) | 2018-11-27 | 2018-11-27 | A kind of preparation method of Rui Gefeini hydrate |
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| CN109796401A (en) * | 2019-04-04 | 2019-05-24 | 新乡双鹭药业有限公司 | A kind of preparation method of Rui Gefeini bulk pharmaceutical chemicals |
| CN112842998A (en) * | 2021-01-19 | 2021-05-28 | 深圳市简一生物科技有限公司 | Regorafenib dispersant and preparation method thereof |
| CN114315710A (en) * | 2022-01-07 | 2022-04-12 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
| CN115108977A (en) * | 2021-03-19 | 2022-09-27 | 南京正大天晴制药有限公司 | Preparation method of regorafenib |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109796401A (en) * | 2019-04-04 | 2019-05-24 | 新乡双鹭药业有限公司 | A kind of preparation method of Rui Gefeini bulk pharmaceutical chemicals |
| CN109796401B (en) * | 2019-04-04 | 2023-10-17 | 新乡双鹭药业有限公司 | Preparation method of regorafenib bulk drug |
| CN112842998A (en) * | 2021-01-19 | 2021-05-28 | 深圳市简一生物科技有限公司 | Regorafenib dispersant and preparation method thereof |
| CN115108977A (en) * | 2021-03-19 | 2022-09-27 | 南京正大天晴制药有限公司 | Preparation method of regorafenib |
| CN114315710A (en) * | 2022-01-07 | 2022-04-12 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
| CN114315710B (en) * | 2022-01-07 | 2024-04-26 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
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