CN108329260A - A kind of preparation method of Rui Gefeini compounds - Google Patents
A kind of preparation method of Rui Gefeini compounds Download PDFInfo
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- CN108329260A CN108329260A CN201810277526.2A CN201810277526A CN108329260A CN 108329260 A CN108329260 A CN 108329260A CN 201810277526 A CN201810277526 A CN 201810277526A CN 108329260 A CN108329260 A CN 108329260A
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- 0 C[C@]1([C@@](CC2)*=C)N2C(C2)[C@]2CC(C)(*)C#C1 Chemical compound C[C@]1([C@@](CC2)*=C)N2C(C2)[C@]2CC(C)(*)C#C1 0.000 description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a kind of preparation methods of Rui Gefeini compounds.The present invention, which is reacted using 4 amino, 3 fluorophenol with compound III, is made compounds Ⅳ, and the compounds Ⅳ of gained reacts to obtain finished product Rui Gefeini (I) with compound V, methyl isobutyrylacetate again.The reaction process route is simple, and total recovery is high, and reaction condition is mild, environmental-friendly, is suitble to industrialized production.
Description
Technical field
The present invention relates to the synthesis fields of drug, and in particular to the preparation method of antitumor drug Rui Gefeini compounds.
Background technology
Rui Gefeini is a kind of novel hexichol ureas wide spectrum kinases suppression for the tool Orally active researched and developed by Bayer A.G
Preparation, by inhibition promote tumor tissue growth a variety of enzymes (including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- β,
FGFR1 and c-KIT etc.), and then play the role of inhibiting Tumor Angiongesis and tumor cell proliferation.
The chemical name of Rui Gefeini is 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorine
Phenoxy group]-N- picoline -2- formamides, concrete structure is as follows：
It is as follows about Rui Gefeini synthetic routes report situation at present：
1, " research (Su Peng, Yuan Chenhuan, Wang Decai etc.) of the improvement in synthesis of Rui Gefeini " is reported：
The reaction route complex steps, and that there are stability is poor for final step isocyanate compound, is easy to generate symmetrical
Urea by-product is not suitable for industrialized production.
2, patent WO2011128261 reports synthetic route:
This method is in order to solve the problems, such as the less nucleophilic of oxygen atom in 4- amino -3- fluorophenols in the prior art, by 4-
Amino -3- fluorophenols are prepared into corresponding imines intermediate, then the imines intermediate again with [4- chlorine (2- pyridyl groups)] -
N- methyl-formamide (7) reaction, enhances the nucleophilicity of oxygen atom in 4- amino -3- fluorophenols, Selective long-range DEPT so that main
It is ether compound 8b to want product, but operation and last handling process are all comparatively laborious.And final step still uses
Isocyanate compound participates in reaction, unfavorable to use industrialized production.
Invention content
It is an object of the invention to overcome the deficiencies of existing technologies, a kind of new Rui Gefeini compounds preparation side is provided
Method, the preparation method process route is simple, and reaction condition is mild, and total recovery is high, and by-product is few, environmental-friendly, is suitble to industrialization
Production.
Synthetic route of the present invention is as follows：
A kind of preparation method of Rui Gefeini compounds, it is characterised in that the preparation method includes the following steps：a、4-
Amino -3- fluorophenols, which are reacted with compound III under the conditions of potassium iodide, alkali, phase transfer catalyst, is made compounds Ⅳ；
B, compounds Ⅳ reacts to obtain finished product Rui Gefeini (I) with compound V, methyl isobutyrylacetate.
Wherein, the phase transfer catalyst used in step a be tetraethylammonium bromide, hexadecyltrimethylammonium chloride or
Triethyl benzyl ammonia chloride, further preferred triethyl benzyl ammonia chloride, phase transfer catalyst mole dosage are compound ii
1-2 times；The mol ratio of compound ii and compound III is 1:1-2；Used alkali is sodium hydroxide, 4- amino -3- fluorobenzene
The molar ratio of phenol and alkali is 1:1-2；The mole dosage of potassium iodide be 1-1.5 times of compound ii mole dosage, preferred mole with
Amount is 1.5 times.
Compounds Ⅳ, compound V, methyl isobutyrylacetate molar ratio described in step b are 1:1:1-2；Reaction temperature
It is 100-140 DEG C, preferably 100-120 DEG C；Reaction time is 3-4h.
Preparation method of the present invention about Rui Gefeini compounds, obtains following advantageous effect：
(1) step a is reacted using 4- amino -3- fluorophenols with compound III, improves etherification reaction yield, and utilize phase
Transfer catalysis technology makes reaction carry out in aqueous solution, has achieved the purpose that clean manufacturing.
(2) the technological reaction route is simple, and mild condition is easy to operate, and total yield of products is high, and by-product is few, and environment is dirty
Dye is few, is suitble to industrialized production.
Specific implementation mode
The invention content of the present invention is described in further detail below by specific embodiment, but is not therefore limited
Determine present disclosure.
Embodiment 1
The preparation of compound III
4- amino -3- fluorophenols 12.71g, sodium hydroxide 4.11g, potassium iodide 21.42g, tetraethyl are added in reaction bulb
Ammonium bromide 21.02g, 500ml water is heated to 30 DEG C of stirring and dissolvings, and when temperature reaches 70 DEG C, compound III is added dropwise step by step
21.61g being stirred to react 2h.After reaction, cooling, the washing of 2% sodium hydrate aqueous solution, liquid separation, organic layer ethyl alcohol is added
It is recrystallized, obtains compounds Ⅳ 23.44g, product yield 89.6%, purity 99.85%.
Embodiment 2
The preparation of compound III
Be added in reaction bulb 4- amino -3- fluorophenols 12.71g, sodium hydroxide 4.10g, tetraethylammonium bromide 21.01g,
500ml water is heated to 30 DEG C of stirring and dissolvings, when temperature reaches 70 DEG C, compound III 43.21g is added dropwise step by step, is stirred to react
2h.After reaction, cooling, the washing of 2% sodium hydrate aqueous solution is added, liquid separation, organic layer is recrystallized with ethyl alcohol, obtained
Compounds Ⅳ 13.31g, product yield 50.8%, purity 99.71%.
Embodiment 3
The preparation of compound III
4- amino -3- fluorophenols 12.71g, sodium hydroxide 8.12g, potassium iodide 42.82g, hexadecane are added in reaction bulb
Base trimethyl ammonium chloride 64.10g, 500ml water, is heated to 30 DEG C of stirring and dissolvings, and when temperature reaches 70 DEG C, chemical combination is added dropwise step by step
III 21.61g of object, is stirred to react 2h.After reaction, cooling, the washing of 2% sodium hydrate aqueous solution, liquid separation is added, organic layer is used
Ethyl alcohol is recrystallized, and compounds Ⅳ 24.90g, product yield 95.2%, purity 99.89% are obtained.
Embodiment 4
The preparation of compound III
4- amino -3- fluorophenols 12.71g, sodium hydroxide 4.13g, potassium iodide 32.11g, triethyl group are added in reaction bulb
Benzyl ammonium chloride 22.78g, 500ml water is heated to 30 DEG C of stirring and dissolvings, and when temperature reaches 70 DEG C, compound III is added dropwise step by step
21.61g being stirred to react 2h.After reaction, cooling, the washing of 2% sodium hydrate aqueous solution, liquid separation, organic layer ethyl alcohol is added
It is recrystallized, obtains compounds Ⅳ 25.48g, product yield 97.5%, purity 99.96%.
Embodiment 5
The preparation of Rui Gefeini (I)
Sequentially added into reaction bulb compounds Ⅳ 23.41g, V 17.52g of compound, methyl isobutyrylacetate 2.92g,
4- dimethylamino pyridines 16.42g, 800ml DMF, stirring and dissolving control temperature at 80 DEG C, react 4h, and TLC monitorings have been reacted
At.Stop reaction, cools the temperature to room temperature addition ethyl acetate and extracted, liquid separation obtains organic layer and be concentrated under reduced pressure
To 33.51g, product yield 71.8%, purity 99.68%.
Embodiment 6
The preparation of Rui Gefeini (I)
Sequentially added into reaction bulb compounds Ⅳ 24.87g, V 18.62g of compound, methyl isobutyrylacetate 27.45g,
4- dimethylamino pyridines 17.45g, 800ml DMF, stirring and dissolving control temperature at 100 DEG C, react 3h, TLC monitoring reactions
It completes.Stop reaction, cools the temperature to room temperature addition ethyl acetate and extracted, liquid separation obtains organic layer and be concentrated under reduced pressure
To 46.27g, product yield 93.5%, purity 99.89%.
Embodiment 7
The preparation of Rui Gefeini (I)
Sequentially added into reaction bulb compounds Ⅳ 25.47g, V 19.07g of compound, methyl isobutyrylacetate 14.06g,
4- dimethylamino pyridines 17.45g, 800ml DMF, stirring and dissolving control temperature at 120 DEG C, react 3h, TLC monitoring reactions
It completes.Stop reaction, cools the temperature to room temperature addition ethyl acetate and extracted, liquid separation obtains organic layer and be concentrated under reduced pressure
To 48.75g, product yield 96.2%, purity 99.91%.
Embodiment 8
The preparation of Rui Gefeini (I)
Compounds Ⅳ 13.27g, V 9.93g of compound, methyl isobutyrylacetate 7.32g, 4- are sequentially added into reaction bulb
Dimethylamino pyridine 6.21g, 800ml DMF, stirring and dissolving control temperature at 140 DEG C, react 4h, and TLC monitorings have been reacted
At.Stop reaction, cools the temperature to room temperature addition ethyl acetate and extracted, liquid separation obtains organic layer and is concentrated under reduced pressure to give
25.55g, product yield 96.8%, purity 99.93%.
Claims (10)
1. a kind of preparation method of Rui Gefeini compounds, it is characterised in that the preparation method includes the following steps：
A, 4- amino -3- fluorophenols, which are reacted with compound III under the conditions of potassium iodide, alkali, phase transfer catalyst, is made compound
Ⅳ；
B, compounds Ⅳ reacts to obtain finished product Rui Gefeini (I) with compound V, methyl isobutyrylacetate；
Its synthetic route is as follows：
。
2. according to the method described in claim 1, which is characterized in that the phase transfer catalyst described in step a is tetrem bromide
Change ammonium, hexadecyltrimethylammonium chloride or triethyl benzyl ammonia chloride, phase transfer catalyst mole dosage to rub for compound ii
1-2 times of that dosage.
3. according to the method described in claim 2, which is characterized in that the phase transfer catalyst described in step a is triethylbenzyl
Ammonium chloride.
4. according to the method described in claim 1, which is characterized in that compound ii and compound III mole matches in step a
Than being 1:1-2.
5. according to the method described in claim 1, which is characterized in that the alkali described in step a is sodium hydroxide, 4- amino-
The molar ratio of 3- fluorophenols and alkali is 1:1-2.
6. according to the method described in claim 1, which is characterized in that the mole dosage of potassium iodide described in step a is chemical combination
1-1.5 times of II mole dosage of object.
7. according to the method described in claim 6, which is characterized in that the mole dosage of potassium iodide described in step a is chemical combination
1.5 times of II mole dosage of object.
8. according to the method described in claim 1, which is characterized in that compounds Ⅳ, compound V described in step b, different
Butyryl methyl acetate molar ratio is 1:1:1-2.
9. according to the method described in claim 1, which is characterized in that step b reaction temperatures are 100-140 DEG C, the reaction time
For 3-4h.
10. according to the method described in claim 9, which is characterized in that step b reaction temperatures are 100-120 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851577A (en) * | 2019-11-26 | 2021-05-28 | 齐鲁制药有限公司 | Preparation method of regorafenib |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105218440A (en) * | 2015-09-07 | 2016-01-06 | 河南中医学院 | The preparation method of a kind of high-purity Rui Gefeini |
-
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- 2018-03-31 CN CN201810277526.2A patent/CN108329260A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105218440A (en) * | 2015-09-07 | 2016-01-06 | 河南中医学院 | The preparation method of a kind of high-purity Rui Gefeini |
Non-Patent Citations (3)
| Title |
|---|
| 武春江，等: "对甲苯磺酸索拉非尼的合成路线综述", 《精细化工中间体》 * |
| 苏鹏，等: "瑞戈非尼的合成工艺改进的研究", 《药学与临床研究》 * |
| 郑德强，等: "瑞戈非尼的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851577A (en) * | 2019-11-26 | 2021-05-28 | 齐鲁制药有限公司 | Preparation method of regorafenib |
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Application publication date: 20180727 |