CN111116560A - Preparation method of succinamide derivative - Google Patents
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- CN111116560A CN111116560A CN201911200725.4A CN201911200725A CN111116560A CN 111116560 A CN111116560 A CN 111116560A CN 201911200725 A CN201911200725 A CN 201911200725A CN 111116560 A CN111116560 A CN 111116560A
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a succinamide derivative, which comprises the following steps: under the condition of ice-water bath, dissolving trelagliptin in a solvent, and adding succinic acid and a first reactant; adding a second reactant into the solvent in batches at low temperature, and reacting until no raw material exists; after the second reactant completely reacts, concentrating and recovering the solvent; and after the solvent is concentrated, crystallizing by using ethanol to obtain the target compound. The preparation method of the succinamide derivative provided by the invention has the advantages of simple purification method, high yield and high product purity.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a succinamide derivative.
Background
Trelagliptin succinate impurity N1, N4-bis ((R) -1- (3- (2-cyano-5-fluorophenyl) -1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) succinamide is one of the succinamide derivatives. Trelagliptin succinate (Trelagliptin succinate) is a dipeptidyl peptidase IV (DPP-4) inhibitor; DPP-4 is an enzyme that triggers the inactivation of incretin and glucose-dependent insulinotropic polypeptides, both of which play important roles in blood glucose regulation. Inhibiting DPP-4 can increase the secretion of insulin dependent on blood glucose level, thereby controlling blood glucose level. Therefore, the succinic acid trelagliptin can control the blood sugar level by selectively and continuously inhibiting DPP-4. In the existing preparation technology, a large amount of solvents are used, the reaction time is long, column chromatography purification is carried out, the purification method is complicated, and the yield is extremely low.
Disclosure of Invention
The present invention aims to overcome the above-mentioned disadvantages of the prior art and to provide a process for the preparation of succinamide derivatives with the aim of increasing the yield and purity of the succinamide derivatives obtained.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a method for preparing a succinamide derivative, comprising:
under the condition of ice-water bath, dissolving trelagliptin in a solvent, and adding succinic acid and a first reactant;
adding a second reactant into the solvent in batches at low temperature, and reacting until no raw material exists;
after the second reactant completely reacts, concentrating and recovering the solvent;
after the solvent is concentrated, crystallizing by ethanol to obtain a target compound, wherein the target compound is N1, N4-bis ((R) -1- (3- (2-cyano-5-fluorophenyl) -1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) succinamide, and the target compound has the structure:
in one embodiment, the first reactant comprises triethylamine or N, N-diisopropylethylamine.
In one embodiment, when the first reactant is triethylamine, the second reactant is 2- (7-oxo)Benzotriazole)-N,N,N',N'-TetramethylureaA hexafluorophosphate salt.
In one embodiment, when the first reactant is N, N-diisopropylethylamine, the second reactant is O-benzotriazol-N, N' -tetramethyluronium tetrafluoroborate.
In one embodiment, in the step of dissolving the trelagliptin in the solvent under the condition of the ice-water bath, adding the succinic acid and the first reactant, the mass ratio of the volume of the solvent to the trelagliptin is 4-40 ml/g.
In one embodiment, the second reactant is added in batches at a low temperature, and the reaction is carried out until no raw material exists, wherein the low temperature is 5-10 ℃.
In one embodiment, the step of concentrating and recovering the solvent after the second reactant is completely reacted comprises:
after the second reactant completely reacts, adding purified water to carry out quenching reaction;
after quenching the reaction, the reaction solution was transferred, and the solvent was recovered by concentration under reduced pressure.
In one embodiment, after the solvent is concentrated, the step of obtaining the target compound by ethanol crystallization comprises:
after the solvent is concentrated, adding ethanol, and stirring for crystallization to obtain a solid, wherein the mass ratio of the volume of the ethanol to the trelagliptin is 5-20ml/g, and the crystallization temperature is 0-30 ℃;
and washing the solid by using ethanol to obtain the target compound.
In a second aspect, the present invention provides a method for preparing a succinamide derivative, comprising:
placing succinic acid in a solvent solution at low temperature;
adding a third reactant into the solvent solution, and reacting until no raw material exists to obtain a reaction solution;
adding a solvent solution prepared with trelagliptin into the reaction solution;
after the reaction is finished, concentrating and recovering the solvent;
after the solvent is concentrated, crystallizing by ethanol to obtain a target compound, wherein the target compound is N1, N4-bis ((R) -1- (3- (2-cyano-5-fluorophenyl) -1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) succinamide, and the target compound has the structure:
in one embodiment, the solvent comprises at least one of dichloromethane, chloroform, tetrahydrofuran, acetonitrile.
In one embodiment, the third reactant comprises oxalyl chloride or thionyl chloride.
In one embodiment, in the step of adding the third reactant into the solvent solution to react until no raw material is available to obtain the reaction solution, after the reaction until no raw material is available, the excess third reactant is removed by concentration.
In one embodiment, the step of adding the solvent solution prepared with the trelagliptin into the reaction solution is carried out at the reaction temperature of 5-10 ℃.
In one embodiment, the step of obtaining the target compound by ethanol crystallization after the solvent concentration is finished comprises:
after the solvent is concentrated, adding ethanol, and stirring for crystallization to obtain a solid, wherein the mass ratio of the volume of the ethanol to the trelagliptin is 5-20ml/g, and the crystallization temperature is 0-30 ℃;
and washing the solid by using ethanol to obtain the target compound.
The preparation method of the succinamide derivative provided by the invention has the advantages of simple solvent system, recyclable solvent, high reaction rate, simple purification method and high yield. The preparation method has the characteristics of simple process, convenience in operation and high product purity, and has important significance in improving the production efficiency.
Drawings
FIG. 1 is a liquid mass spectrum of the final product obtained in example 1 of the present invention;
FIG. 2 is a high performance liquid chromatography spectrum of the final product obtained in example 1 of the present invention;
FIG. 3 is a NMR spectrum obtained in example 1 of the present invention.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In one aspect, an embodiment of the present invention provides a preparation method of a succinamide derivative, including:
step S11, dissolving trelagliptin in a solvent under the condition of ice-water bath, and adding succinic acid and a first reactant;
step S12, adding a second reactant into the solvent in batches at low temperature, and reacting until no raw material exists;
step S13, after the second reactant completely reacts, concentrating and recovering the solvent;
step S14, after the solvent is concentrated, performing ethanol crystallization to obtain a target compound, wherein the target compound is N1, N4-bis ((R) -1- (3- (2-cyano-5-fluorophenyl) -1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) succinamide, and the target compound has the structure:
further, in step S11, the first reactant includes triethylamine or N, N-diisopropylethylamine; the solvent comprises at least one of dichloromethane, chloroform, tetrahydrofuran and acetonitrile, and is preferably dichloromethane; the mass ratio of the volume of the solvent to the trelagliptin is 4-40ml/g, for example, 4ml/g, 6ml/g, 8ml/g, 12ml/g, 16ml/g, 20ml/g, 28ml/g, 32ml/g, 40ml/g, etc., preferably 10-30 ml/g.
Further, in step S12, the low temperature is 5 to 10 ℃, for example, 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃, 10 ℃ and the like, and this temperature range can avoid the problem that adding reactants at high temperature increases the occurrence probability of side reactions, which reduces the purity of the product.
When the first reactant is triethylamine, the second reactant is 2- (7-oxybenzotriazazole) -N, N' -tetramethyluronium hexafluorophosphate; when the first reactant is N, N-diisopropylethylamine, the second reactant is O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate.
Further, step S13 includes: after the second reactant completely reacts, adding purified water to carry out quenching reaction;
after quenching the reaction, the reaction solution was transferred, and the solvent was recovered by concentration under reduced pressure.
Further, step S14 includes: after the solvent is concentrated, adding ethanol, and stirring for crystallization to obtain a solid, wherein the mass ratio of the volume of the ethanol to the trelagliptin is 5-20ml/g, for example, 5ml/g, 6ml/g, 7ml/g, 8ml/g, 9ml/g, 10ml/g, 15ml/g, 20ml/g, and the like, preferably 5-10ml/g, and the crystallization temperature is 0-30 ℃, for example, 0 ℃, 1 ℃, 2 ℃, 3 ℃, 4 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, and the like, preferably 25-30 ℃, and the problems of high-temperature crystallization and product yield reduction can be avoided in this temperature range;
and washing the solid by using ethanol to obtain the target compound.
In another aspect, the present invention provides a method for preparing a succinamide derivative, comprising:
step S21, placing succinic acid in a solvent solution at low temperature;
step S22, adding a third reactant into the solvent solution, and reacting until no raw material exists to obtain a reaction solution;
step S23, adding a solvent solution prepared with trelagliptin into the reaction solution;
step S24, concentrating and recovering the solvent after the reaction is finished;
step S25, after the solvent is concentrated, performing ethanol crystallization to obtain a target compound, wherein the target compound is N1, N4-bis ((R) -1- (3- (2-cyano-5-fluorophenyl) -1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) succinamide, and the target compound has the structure:
further, in step S21, the solvent includes at least one of dichloromethane, chloroform, tetrahydrofuran and acetonitrile, preferably dichloromethane; the third reactant comprises oxalyl chloride or thionyl chloride.
Further, in step S22, after the reaction is completed until no raw material is present, the excess third reactant is removed by concentration.
Further, in step S23, the reaction temperature is 5-10 deg.C, such as 5 deg.C, 6 deg.C, 7 deg.C, 8 deg.C, 9 deg.C, 10 deg.C, etc., and in this temperature range, the problem of low product purity due to the increased side reaction probability caused by adding reactants at high temperature can be avoided.
Further, step S24 includes: after the second reactant completely reacts, adding purified water to carry out quenching reaction; after quenching the reaction, the reaction solution was transferred, and the solvent was recovered by concentration under reduced pressure.
Further, step S25 includes: after the solvent is concentrated, adding ethanol, and stirring for crystallization to obtain a solid, wherein the mass ratio of the volume of the ethanol to the trelagliptin is 5-20ml/g, for example, 5ml/g, 6ml/g, 7ml/g, 8ml/g, 9ml/g, 10ml/g, 15ml/g, 20ml/g, and the like, preferably 5-10ml/g, and the crystallization temperature is 0-30 ℃, for example, 0 ℃, 1 ℃, 2 ℃, 3 ℃, 4 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, and the like, preferably 25-30 ℃, and the problems of high-temperature crystallization and product yield reduction can be avoided in this temperature range;
and washing the solid by using ethanol to obtain the target compound.
The preparation method of the succinamide derivative provided by the invention has the advantages of simple solvent system, recyclable solvent, high reaction rate, simple purification method and high yield. The preparation method has the characteristics of simple process, convenience in operation and high product purity, and has important significance in improving the production efficiency.
It is to be understood that the succinamide derivative may include trelagliptin succinate impurity, and may also include other types of compounds, without limitation herein.
The invention is described in further detail with reference to a number of tests performed in sequence, and a part of the test results are used as reference, and the following detailed description is given with reference to specific examples.
Example 1
Step S301, adding 100ml of dichloromethane into a 250ml three-neck bottle, starting stirring, then sequentially adding trelagliptin (10.00g, 27.98mmol), triethylamine (7.13g, 70.50mmol) and succinic acid (1.65g, 13.99mmol), and stirring to dissolve the solution;
step S302, cooling the mixture to 0-5 ℃ in an ice water bath, adding O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate (10.64g, 27.98mmol) in three batches, and heating the mixture to room temperature for reaction;
step S303, after the reaction is finished, adding 1ml of purified water to carry out quenching reaction, transferring the reaction liquid to a single-port flat, and concentrating dichloromethane under reduced pressure at the temperature of 30 ℃;
and step S304, adding 70ml of ethanol into the concentrate, starting stirring at the temperature of 20 ℃, performing suction filtration on the solid, washing the solid with 10ml of ethanol, and drying to obtain the target product, wherein the yield is 83.7%.
The roadmap is as follows:
the purity of the target compound is detected in the following way: the mass spectrometer model is LCMS-IT-TOF, 210nm is detection wavelength, the column temperature is 30 ℃, the eluent composition is acetonitrile/water, and high performance liquid chromatography is carried out under 80/20 isocratic elution and the flow rate of 1.0ml/min, so as to obtain the high performance liquid chromatogram shown in figure 1.
Electrospray mass spectrometry, as shown in figure 2: ESI-MS M/z 797.34[ M + H ]]Theoretical formula N1, N4-bis ((R) -1- (3- (2-cyano-5-fluorophenyl) -1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) succinamide: c40H42F2N10O6Molecular weight: 796.84.
the NMR spectrum is shown in FIG. 3, and the specific chemical shifts are shown below:
1H-NMR(400MHz，DMSO)δ7.947ppm-7.919ppm(m,2H),7.815-7.800(d, 2H),7.342-7.305(m,2H),7.192-7.173(m,2H),5.338(s,2H),5.192-5.102(t,4H), 3.687(s,2H),3.086-3.047(s,8H),2.941-2.918(m,2H),2.69(m,2H),2.256-2.155(m, 4H),1.747-1.729(m,4H),1.324(m,2H)。
example 2
Step S401, adding 10ml of dichloromethane into a 50ml three-neck bottle, starting stirring, sequentially adding trelagliptin (1.00g, 2.8mmol), triethylamine (0.71g, 7.1mmol) and succinic acid (0.17g, 1.4mmol), and stirring to dissolve the solution;
step S402, cooling the mixture to 0-5 ℃ in an ice-water bath, adding 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.91g, 2.81mmol) in two batches, and heating the mixture to room temperature for reaction;
step S403, after the reaction is finished, adding 0.5ml of purified water to carry out quenching reaction, transferring the reaction solution to a single-port flat, and concentrating dichloromethane under reduced pressure at 30 ℃;
and S404, adding 5ml of ethanol into the concentrate, starting stirring at the temperature of 20 ℃, performing suction filtration on the solid, washing the solid with 5ml of ethanol, and drying to obtain a target product, wherein the yield is 92.1%.
The roadmap is as follows:
example 3
Step S501, in a 50ml three-mouth bottle, succinic acid (0.5g, 4.23mmol) is placed in 10ml dichloromethane, and the temperature is reduced to 0-5 ℃ in an ice water bath;
step S502, dropwise adding thionyl chloride (0.76g, 6.35mmol) at the temperature of 0-5 ℃, reacting until no raw material exists, concentrating under reduced pressure to remove excessive thionyl chloride, adding 10ml of dichloromethane after concentration is finished, starting stirring, and cooling to 0-5 ℃ to obtain a reaction solution;
step S503, dissolving trelagliptin (1.5g, 8.46mmol) in 10ml dichloromethane, and dripping into the reaction solution at 0-5 ℃, wherein the reaction temperature is controlled at 0-10 ℃;
and step S504, after the reaction is finished, adding 0.5ml of purified water to carry out quenching reaction, transferring the reaction liquid to a single-port plate, and concentrating dichloromethane under reduced pressure at the temperature of 30 ℃.
And step S505, adding 5ml of ethanol into the concentrate, starting stirring at the temperature of 25 ℃, performing suction filtration on the solid, washing the solid with 5ml of ethanol, and drying to obtain a target product, wherein the yield is 89.3%.
The roadmap is as follows:
the proportion of the ingredients is as follows:
under the alkaline condition, succinic acid reacts with a condensing agent to generate an active intermediate, and then the active intermediate reacts with trelagliptin succinate to prepare the succinamide derivative, wherein the molecular structural formula of the succinamide derivative is as follows:
according to the preparation method provided by the reference, a large amount of N, N-dimethylformamide is used as a solvent, the reaction is carried out at 35 ℃, the reaction is carried out overnight under the condition of stirring at room temperature, the reaction time is long, the column chromatography purification is carried out, the purification method is complicated, the yield is extremely low and is only 17.85%. The preparation method has the characteristics of simple process, convenience in operation and high product purity, and has important significance in improving the production efficiency.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (14)
1. A process for the preparation of a succinamide derivative, which comprises:
under the condition of ice-water bath, dissolving trelagliptin in a solvent, and adding succinic acid and a first reactant;
adding a second reactant in batches into the solvent at a low temperature, and reacting until no raw material exists;
after the second reactant completely reacts, concentrating and recovering the solvent;
after the solvent is concentrated, crystallizing by ethanol to obtain a target compound, wherein the target compound is N1, N4-bis ((R) -1- (3- (2-cyano-5-fluorophenyl) -1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) succinamide, and the target compound has the structure:
2. the method of preparing a succinamide derivative according to claim 1, wherein the first reactant comprises triethylamine or N, N-diisopropylethylamine.
3. The method of preparing a succinamide derivative according to claim 2, wherein when the first reactant is triethylamine, the second reactant is 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate.
4. The method of claim 2, wherein when the first reactant is N, N-diisopropylethylamine, the second reactant is O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate.
5. The method for preparing the succinamide derivative according to claim 1, wherein in the step of dissolving trelagliptin in a solvent under the condition of an ice-water bath, adding succinic acid and the first reactant, the mass ratio of the volume of the solvent to the trelagliptin is 4-40 ml/g.
6. The method for preparing succinamide derivative according to claim 1, wherein the second reactant is added in portions at a low temperature of 5 to 10 ℃ until no raw material is present.
7. The method of claim 1, wherein the step of recovering the solvent by concentration after the second reactant is completely reacted comprises:
after the second reactant completely reacts, adding purified water to carry out quenching reaction;
after quenching the reaction, the reaction solution was transferred, and the solvent was recovered by concentration under reduced pressure.
8. The method for preparing succinamide derivative according to claim 1, wherein the step of obtaining the target compound by ethanol crystallization after the solvent concentration is completed comprises:
after the solvent is concentrated, adding ethanol, and stirring for crystallization to obtain a solid, wherein the mass ratio of the volume of the ethanol to the trelagliptin is 5-20ml/g, and the crystallization temperature is 0-30 ℃;
and washing the solid by using ethanol to obtain the target compound.
9. A process for the preparation of a succinamide derivative, which comprises:
placing succinic acid in a solvent solution at low temperature;
adding a third reactant into the solvent solution, and reacting until no raw material exists to obtain a reaction solution;
adding a solvent solution prepared with trelagliptin into the reaction solution;
after the reaction is finished, concentrating and recovering the solvent;
after the solvent is concentrated, crystallizing by ethanol to obtain a target compound, wherein the target compound is N1, N4-bis ((R) -1- (3- (2-cyano-5-fluorophenyl) -1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) succinamide, and the target compound has the structure:
10. the method for preparing a succinamide derivative according to any one of claims 1 or 9, wherein the solvent comprises at least one of dichloromethane, chloroform, tetrahydrofuran, acetonitrile.
11. The method of claim 9, wherein the third reactant comprises oxalyl chloride or thionyl chloride.
12. The method of preparing a succinamide derivative according to claim 9, wherein the step of adding the third reactant to the solvent solution to react until no raw material is present to obtain a reaction solution comprises concentrating to remove an excess of the third reactant after the reaction until no raw material is present.
13. The method for preparing a succinamide derivative according to claim 9, wherein the step of adding the solvent solution in which trelagliptin is formulated to the reaction solution has a reaction temperature of 5 to 10 ℃.
14. The method for preparing succinamide derivative according to claim 9, wherein the step of obtaining the target compound by ethanol crystallization after the completion of the concentration of the solvent comprises:
after the solvent is concentrated, adding ethanol, and stirring for crystallization to obtain a solid, wherein the mass ratio of the volume of the ethanol to the trelagliptin is 5-20ml/g, and the crystallization temperature is 0-30 ℃;
and washing the solid by using ethanol to obtain the target compound.
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| CN103788070A (en) * | 2012-10-26 | 2014-05-14 | 南京华威医药科技开发有限公司 | DPP-4 inhibitor polymer |
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| CN103788070A (en) * | 2012-10-26 | 2014-05-14 | 南京华威医药科技开发有限公司 | DPP-4 inhibitor polymer |
| CN105524044A (en) * | 2014-10-22 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Trelagliptin impurity and its composition |
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| CN106896166A (en) * | 2017-01-22 | 2017-06-27 | 合肥拓锐生物科技有限公司 | About the analysis method of material in a kind of amber love song Ge Lieting raw materials and its preparation |
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