CN109810051A - A method of preparing targeting antineoplastic medicine object Sorafenib Tosylate salt - Google Patents
A method of preparing targeting antineoplastic medicine object Sorafenib Tosylate salt Download PDFInfo
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Abstract
The invention discloses a kind of methods for preparing targeting antineoplastic medicine object Sorafenib Tosylate salt, which is characterized in that synthetic route is as follows:Wherein, carbonate (M2CO3) it is sodium carbonate, potassium carbonate or cesium carbonate;Solvent (Solvent) is MDF or DMA.The present invention substitutes potassium tert-butoxide using carbonate, enormously simplifies operation, and reduce costs.Solve the problems, such as that the reaction time is too long finally by being heated to reflux by repetition test and conditional filtering.
Description
Technical field
The invention belongs to antitumor pharmaceutical compounds to synthesize field, and in particular to a kind of to prepare targeting antineoplastic medicine object rope
The new technology of La Feini.
Background technique
The main method of synthesis Sorafenib has at present:
Route 1
Source: WO2006/034796, Bayer Bitterfeld GmbH
Route 2
Source: " improvement of anti-tumor drug Sorafenib synthesis technology ", Journal of Yantai University: natural science and engineering,
2012,25 (2):147-149.
Route 3
Source: " improvement in synthesis of Sorafenib ", Shandong medicine thing, 2008,27 (3): 168-170.
Route 4:
Source: CN201510862797.0, Shandong Luo Xin
Route 5:
Source: CN201210389786.1, Shandong pharmacy
Route 6:
Source: CN201410777342.4, Harbin Pharmaceutical Group
Route 7:
Organic Process Research&Development 2002,6,777 781
By synthesizing the method for Sorafenib above it is found that all synthetic routes are all needed by intermediate compound I, N- methyl -4-
(4- amino-benzene oxygen) pyridine-2-carboxamide (seeing below formula)
Intermediate compound I is that with N- methyl -4- chloropyridine -2- formamide nucleophilic occurs for 4-aminophenol under potassium tert-butoxide effect
Substitution reaction preparation.When potassium tert-butoxide is added to DMF, meeting very exothermic, cannot be added at one time, need to be added in batches.
Since potassium tert-butoxide is highly basic, to moisture-sensitive, it is easy to bigger with the reaction of moisture in air, especially air humidity
When.It is inevitably directly contacted with air when potassium tert-butoxide because weigh and add into reaction kettle in batches, this just brings to operation
It is not convenient.On the other hand, 4-aminophenol can by the dioxygen oxidation in air, react need under inert gas protection into
Row.When potassium tert-butoxide is added portionwise, in order to avoid air enters in reaction system it is necessary to using a large amount of inert gases to maintain
Reaction system keeps positive pressure.
Summary of the invention
In order to solve the above-mentioned technical problem, the present invention substitutes potassium tert-butoxide using carbonate, not only can simplify operation,
Cost can be reduced.
The present invention uses carbonate (Na during preparing Sorafenib Tosylate salt intermediate compound I2CO3, K2CO3,
Cs2CO3) instead of potassium tert-butoxide, operation is not only simplified, preparation cost is also reduced.Since carbonate is not very to moisture
Sensitivity, using the problem of reacting with moisture is just not present when them, and carbonate is added in DMF not heat release, Ke Yi
All materials are placed in reaction kettle at room temperature, then by air displacement at inert gas.During heating and back flow reaction, instead
It answers system no longer to be contacted with outside air, enormously simplifies operation.The price of sodium carbonate and potassium carbonate is far below uncle
The price of butanol potassium, can effectively reduce cost of material.
When existing method prepares Sorafenib Tosylate salt intermediate compound I, 4- is sloughed using highly basic potassium tert-butoxide
Proton in amino-phenol forms phenol negative oxygen ion, participates in subsequent nucleophilic substitution.Inventor is based on to 4- aminobenzene
After the analysis of phenol physico-chemical property, it is believed that do not need the highly basic as potassium tert-butoxide, relatively weaker alkali metal carbonic acid theoretically
Salt can take off the Hydrogen Proton in 4-aminophenol on hydroxyl, form phenol negative oxygen ion, participate in nucleophilic substitution.With alkali gold
Belong to carbonate to substitute potassium tert-butoxide, operation can not only be simplified, production cost can also be reduced.But it is used in similarity condition
Carbonate substitutes in the reaction process of potassium tert-butoxide, has intermediate compound I generation really, but the reaction time is too long, still has after 24 hours
Many starting material lefts.The expection of this and inventor are consistent, because carbonate is indissoluble in solvent DMF, so that de- matter
Sub- rate is slack-off.Last inventor determines that reaction carries out under reflux conditions by repetition test and conditional filtering.
Scheme provided by the invention is as follows:
A method of targeting antineoplastic medicine object Sorafenib Tosylate salt being prepared, synthetic route is as follows:
Wherein,
Carbonate (M2CO3) it is sodium carbonate, potassium carbonate or cesium carbonate;
Solvent (Solvent) is MDF or DMA.
Specifically, the above-mentioned method for preparing targeting antineoplastic medicine object Sorafenib Tosylate salt, comprising the following steps:
(1) 4-aminophenol is added in DMF, carbonate and N- methyl -4- chloropyridine -2- is added after stirring and dissolving
Formamide is heated to reflux to raw material and disappears substantially, is cooled to room temperature;
(2) water and ethyl acetate is added, water phase is extracted with ethyl acetate twice, is merged organic phase, is successively used water and saturation
Brine It, anhydrous sodium sulfate is dry, filter, solvent is removed under reduced pressure, and purification obtains Light brown solid after crude product recrystallization
That is intermediate compound I;
(3) by intermediate compound I adding into dichloromethane, in 0 DEG C of chloro- 3- trifluoromethyl isocyanic acid of dropwise addition 4- under stirring
The dichloromethane solution of ester, drop finish, and are stirred at room temperature to raw material and are disappeared, solid is obtained by filtration and is washed with methylene chloride, vacuum
Intermediate II is obtained after drying;
(4) intermediate II is dissolved in THF, stirs the lower THF solution for instilling p-methyl benzenesulfonic acid, drop finishes, continues stirred
Night, filtering, solid are washed through THF, are drained, and vacuum drying obtains white solid, Sorafenib Tosylate salt.
Above-mentioned carbonate is sodium carbonate, potassium carbonate or cesium carbonate.
The molar ratio of reactant in above-mentioned steps (1): N- methyl -4- chloropyridine -2- formamide: 4-aminophenol: carbonic acid
Salt=1:1-1.5:1.5-6.
The molar ratio of reactant in above-mentioned steps (3): intermediate compound I: the chloro- 3- trifluoromethylbenzene based isocyanate=1:1- of 4-
1.5.The molar ratio of reactant in above-mentioned steps (4): intermediate II: p-methyl benzenesulfonic acid=1:1-1.5.
Beneficial effects of the present invention:
Highly basic potassium tert-butoxide is substituted using carbonate, operation is enormously simplified, reduces synthesis cost;By repeatedly
Test and conditional filtering solve the problems, such as that the reaction time is too long finally by being heated to reflux.
Specific embodiment
The present invention is further described combined with specific embodiments below, and the contents of the present invention are completely without being limited thereto.
A method of targeting antineoplastic medicine object Sorafenib Tosylate salt being prepared, synthetic route is as follows:
Wherein,
Carbonate (M2CO3) it is sodium carbonate, potassium carbonate or cesium carbonate;
Solvent (Solvent) is MDF or DMA.
Specifically, the method for preparing targeting antineoplastic medicine object Sorafenib Tosylate salt, comprising the following steps:
(1) 4-aminophenol is added in DMF or DMA, carbonate and N- methyl -4- chlorine pyrrole is added after stirring and dissolving
Pyridine -2- formamide, is heated to reflux to raw material and disappears substantially, be cooled to room temperature;
(2) water and ethyl acetate is added, water phase is extracted with ethyl acetate twice, is merged organic phase, is successively used water and saturation
Brine It, anhydrous sodium sulfate is dry, filtering, depressurizes away solvent, and purification obtains Light brown solid after crude product recrystallization,
Intermediate compound I;
(3) by intermediate compound I adding into dichloromethane, in 0 DEG C of chloro- 3- trifluoromethyl isocyanic acid of dropwise addition 4- under stirring
The dichloromethane solution of ester, drop finish, and are stirred at room temperature to raw material and are disappeared, and the solid being obtained by filtration is washed with methylene chloride, vacuum
Intermediate II is obtained after drying;
(4) intermediate II is dissolved in THF, stirs the lower THF solution for instilling p-methyl benzenesulfonic acid, drop finishes, continues stirred
Night, filtering, solid are washed through THF, are drained, and vacuum drying obtains white solid, Sorafenib Tosylate salt.
Above-mentioned carbonate is sodium carbonate, potassium carbonate or cesium carbonate.
The molar ratio of reactant in above-mentioned steps (1): N- methyl -4- chloropyridine -2- formamide: 4-aminophenol: carbonic acid
Salt=1:1-1.5:1.5-6.
The molar ratio of reactant in above-mentioned steps (3): intermediate compound I: the chloro- 3- trifluoromethylbenzene based isocyanate=1:1- of 4-
1.5。
The molar ratio of reactant in above-mentioned steps (4): intermediate II: p-methyl benzenesulfonic acid=1:1-1.5.
Embodiment 1
Prepare targeting antineoplastic medicine object Sorafenib Tosylate salt
(1) N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide, the synthesis of intermediate compound I
In reaction flask side not Jia Ru 4-aminophenol (7.65g) and 100ml DMF, add potassium carbonate after stirring and dissolving
(16.2g) and N- methyl -4- chloropyridine -2- formamide (10.0g).It is heated to reflux to raw material and disappears substantially, be cooled to room temperature,
Water and ethyl acetate is added.Water phase be extracted with ethyl acetate it is secondary, merge organic phase, respectively use water and saturated common salt water washing,
Anhydrous sodium sulfate dries, filters, and solvent is removed under reduced pressure.Crude product obtains Light brown solid after recrystallization purification, intermediate compound I,
9.27g。
1HNMR(400MHz,DMSO-d6):δ3.05(3H,s);3.75(2H,s,br);6.71(2H,m);6.88(2H,m);
6.92 (1H,dd);7.68(1H,d);8.00(1H,s,br);8.33(1H,d).
(2) Sorafenib free alkali, the synthesis of intermediate II
N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide (5.0g) and 10ml DCM are added into reaction flask, stirs
It mixes down and instills solution of the chloro- 3- trifluoromethylbenzene based isocyanate (4.78g) of 4- in 10ml DCM in 0 DEG C.Drop finishes, at room temperature
Stirring to raw material disappears.Filtering, solid are washed with DCM, and intermediate II, 8.60g are obtained after vacuum drying.
1HNMR(400MHz,DMSO-d6):δ2.79(3H,d);7.14(1H,d);7.16(2H,d);7.38(1H,d);
7.60(2H, d);7.65(2H,m);8.12(1H,d);8.50(1H,d);8.78(1H,q);9.03(1H,s);9.24(1H,
s).
(3) synthesis of Sorafenib Tosylate salt
Sorafenib free alkali (5.0g) and 15ml THF are added in reaction flask, stirs lower instillation p-methyl benzenesulfonic acid
The 5ml THF solution of (2.46g).Drop finishes, and continues to be stirred overnight.Filtering, solid are washed through THF, are drained, and vacuum drying obtains
White solid, Sorafenib Tosylate salt 6.40g.
1HNMR(400MHz,DMSO-d6):δ2.30(3H,s);2.83(3H,d);7.16(2H,d);7.21(2H,d);
7.28(1H, d);7.55(2H,d),7.66(2H,d);7.70(3H,m);8.14(1H,d);8.58(1H,d);9.05(1H,
q);9.26(1H,s);9.45(1H,s);12.44(1H,s,br).
Embodiment 2
Prepare targeting antineoplastic medicine object Sorafenib Tosylate salt
(1) N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide, the synthesis of intermediate compound I
In reaction flask side not Jia Ru 4-aminophenol (17.6g) and 150ml DMF, add potassium carbonate after stirring and dissolving
(40.5g) and N- methyl -4- chloropyridine -2- formamide (25.0g).It is heated to reflux to raw material and disappears substantially, be cooled to room temperature,
Water and ethyl acetate is added.Water phase be extracted with ethyl acetate it is secondary, merge organic phase, respectively use water and saturated common salt water washing,
Anhydrous sodium sulfate dries, filters, and solvent is removed under reduced pressure, and vacuum drying obtains 26.2g intermediate compound I.
(2) Sorafenib free alkali, the synthesis of intermediate II
N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide (5.0g) and 10ml DCM are added into reaction flask, stirs
It mixes down and instills solution of the chloro- 3- trifluoromethylbenzene based isocyanate (4.78g) of 4- in 10ml DCM in 0 DEG C.Drop finishes, at room temperature
Stirring to raw material disappears.Filtering, solid are washed with DCM, and intermediate II, 8.60g are obtained after vacuum drying.
(3) synthesis of Sorafenib Tosylate salt
Sorafenib free alkali (5.0g) and 15ml THF are added in reaction flask, stirs lower instillation p-methyl benzenesulfonic acid
The 5ml THF solution of (2.46g).Drop finishes, and continues to be stirred overnight.Filtering, solid are washed through THF, are drained, and vacuum drying obtains
White solid, Sorafenib Tosylate salt 6.40g.
Embodiment 3
Prepare targeting antineoplastic medicine object Sorafenib Tosylate salt
(1) N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide, the synthesis of intermediate compound I
In reaction flask side not Jia Ru 4-aminophenol (7.03g) and 100ml DMF, add potassium carbonate after stirring and dissolving
(32.8g) and N- methyl -4- chloropyridine -2- formamide (10.0g).It is heated to reflux to raw material and disappears substantially, be cooled to room temperature,
Water and ethyl acetate is added.Water phase be extracted with ethyl acetate it is secondary, merge organic phase, respectively use water and saturated common salt water washing,
Anhydrous sodium sulfate dries, filters, and solvent is removed under reduced pressure, and vacuum drying obtains 11.5g intermediate compound I.
(2) Sorafenib free alkali, the synthesis of intermediate II
N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide (5.0g) and 10ml DCM are added into reaction flask, stirs
It mixes down and instills solution of the chloro- 3- trifluoromethylbenzene based isocyanate (4.78g) of 4- in 10ml DCM in 0 DEG C.Drop finishes, at room temperature
Stirring to raw material disappears.Filtering, solid are washed with DCM, and intermediate II, 8.60g are obtained after vacuum drying.
(3) synthesis of Sorafenib Tosylate salt
Sorafenib free alkali (5.0g) and 15ml THF are added in reaction flask, stirs lower instillation p-methyl benzenesulfonic acid
The 5ml THF solution of (2.46g).Drop finishes, and continues to be stirred overnight.Filtering, solid are washed through THF, are drained, and vacuum drying obtains
White solid, Sorafenib Tosylate salt 6.40g.
Embodiment 4
(1) N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide, the synthesis of intermediate compound I
In reaction flask side not Jia Ru 4-aminophenol (6.72g) and 100ml DMF, add potassium carbonate after stirring and dissolving
(16.2g) and N- methyl -4- chloropyridine -2- formamide (10g).It is heated to reflux to raw material and disappears substantially, be cooled to room temperature, add
Enter water and ethyl acetate.Water phase is extracted with ethyl acetate secondary, merging organic phase, respectively with water and saturated common salt water washing, nothing
Aqueous sodium persulfate dries, filters, and solvent is removed under reduced pressure, and vacuum drying obtains 12.2g intermediate compound I.
(2) Sorafenib free alkali, the synthesis of intermediate II
N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide (5.0g) and 10ml DCM are added into reaction flask, stirs
It mixes down and instills solution of the chloro- 3- trifluoromethylbenzene based isocyanate (5.01g) of 4- in 10ml DCM in 0 DEG C.Drop finishes, at room temperature
Stirring to raw material disappears.Filtering, solid are washed with DCM, and intermediate II, 8.30g are obtained after vacuum drying.
(3) synthesis of Sorafenib Tosylate salt
Sorafenib free alkali (5.0g) and 15ml THF are added in reaction flask, stirs lower instillation p-methyl benzenesulfonic acid
The 5ml THF solution of (2.46g).Drop finishes, and continues to be stirred overnight.Filtering, solid are washed through THF, are drained, and vacuum drying obtains
White solid, Sorafenib Tosylate salt 6.40g.
Embodiment 5
(1) N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide, the synthesis of intermediate compound I
In reaction flask side not Jia Ru 4-aminophenol (7.03g) and 100ml DMF, add potassium carbonate after stirring and dissolving
(32.8g) and N- methyl -4- chloropyridine -2- formamide (10.0g).It is heated to reflux to raw material and disappears substantially, be cooled to room temperature,
Water and ethyl acetate is added.Water phase be extracted with ethyl acetate it is secondary, merge organic phase, respectively use water and saturated common salt water washing,
Anhydrous sodium sulfate dries, filters, and solvent is removed under reduced pressure, and vacuum drying obtains 11.5g intermediate compound I.
(2) Sorafenib free alkali, the synthesis of intermediate II
N- methyl -4- (4- amino-benzene oxygen) pyridine-2-carboxamide (5.0g) and 10ml DCM are added into reaction flask, stirs
It mixes down and instills solution of the chloro- 3- trifluoromethylbenzene based isocyanate (4.64g) of 4- in 10ml DCM in 0 DEG C.Drop finishes, at room temperature
Stirring to raw material disappears.Filtering, solid are washed with DCM, and intermediate II, 7.93g are obtained after vacuum drying.
(3) synthesis of Sorafenib Tosylate salt
Sorafenib free alkali (5.0g) and 15ml THF are added in reaction flask, stirs lower instillation p-methyl benzenesulfonic acid
The 5ml THF solution of (2.46g).Drop finishes, and continues to be stirred overnight.Filtering, solid are washed through THF, are drained, and vacuum drying obtains
White solid, Sorafenib Tosylate salt 6.40g.
The foregoing is only a preferred embodiment of the present invention, but the scope of protection of the invention be not limited thereto,
Any modification that anyone skilled in the art is made in the technical scope disclosed by the present invention, equivalent replacement and
Improve etc., it should be included within the protection scope of invention.
Claims (6)
1. a kind of method for preparing targeting antineoplastic medicine object Sorafenib Tosylate salt, which is characterized in that synthetic route is such as
Under:
Wherein,
Carbonate (M2CO3) it is sodium carbonate, potassium carbonate or cesium carbonate;
Solvent (Solvent) is MDF or DMA.
2. the method according to claim 1 for preparing targeting antineoplastic medicine object Sorafenib Tosylate salt, feature
It is, comprising the following steps:
(1) 4-aminophenol is added in solvent, carbonate and N- methyl -4- chloropyridine -2- formyl is added after stirring and dissolving
Amine is heated to reflux to raw material and disappears substantially, is cooled to room temperature;
(2) water and ethyl acetate is added, separates water phase and organic phase, water phase is merged into organic phase after being extracted with ethyl acetate, according to
It is secondary to use water and saturated common salt water washing, it is then dry with anhydrous sodium sulfate, crude product is obtained using filtering, solvent being removed under reduced pressure, is passed through
Light brown solid i.e. intermediate compound I is obtained after recrystallization purification;
(3) intermediate compound I is dissolved in methylene chloride, is added dropwise the two of the chloro- 3- trifluoromethylbenzene based isocyanate of 4- in 0 DEG C under stirring
Chloromethanes solution, drop finish, and are stirred at room temperature to raw material and are disappeared, solid is obtained by filtration and is washed with methylene chloride, after vacuum drying
Obtain intermediate II;
(4) intermediate II is dissolved in THF, stirs the lower THF solution for instilling p-methyl benzenesulfonic acid, drop finishes, continues to be stirred overnight, mistake
Filter, solid are washed through THF, are drained, and vacuum drying obtains white solid, Sorafenib Tosylate salt.
3. according to the method described in claim 2, it is characterized by: the carbonate is sodium carbonate, potassium carbonate or cesium carbonate.
4. according to the method described in claim 2, it is characterized in that, in the step (1) reactant molar ratio: N- methyl-
4- chloropyridine -2- formamide: 4-aminophenol: carbonate=1:1-1.5:1.5-6.
5. according to the method described in claim 2, it is characterized in that, in the step (3) reactant molar ratio: intermediate compound I:
The chloro- 3- trifluoromethylbenzene based isocyanate=1:1-1.5 of 4-.
6. according to the method described in claim 2, it is characterized in that, in the step (4) reactant molar ratio: intermediate
II: p-methyl benzenesulfonic acid=1:1-1.5.
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CN110216872A (en) * | 2019-06-17 | 2019-09-10 | 薛启煌 | A kind of liver three-dimensional rebuilding method and its 3D printing model based on CTA data |
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CN104177292A (en) * | 2014-08-08 | 2014-12-03 | 亿腾药业(泰州)有限公司 | Method for industrial production of sorafenib tosylate polymorphic form I |
CN106543077A (en) * | 2016-10-27 | 2017-03-29 | 西安交通大学 | N, N ' disubstituted arylthiourea derivative and its synthetic method and application |
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