CN114014863A - Preparation method of bone marrow protective agent traasiril - Google Patents
Preparation method of bone marrow protective agent traasiril Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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Abstract
The invention relates to a preparation method of traasiril. The method adopts the existing intermediate compound which is easy to obtain commercially, and synthesizes the target molecule through halogenation reaction, protective group removal, amide condensation, methylthio and amino substitution reaction, and the total steps are 4 steps of reaction synthesis of the target compound of the traasiril. The preparation method has the advantages of single site of each step of chemical reaction, higher yield, mild reaction conditions of the whole synthesis route, simple and cheap used reagents, and effectively improved total yield of the reaction and industrialized operability.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a preparation method of a marrow protective agent, namely traasiril.
Background
Trilaciclib is a 'First-in-Class' small molecule short-acting CDK 4/6 inhibitor discovered and developed by G1 Therapeutics, a comprehensive myeloprotectant that was approved by FDA for priority qualification and breakthrough therapy. On 12 d 2/2021, traasiril (trade name: COSELA), a bone marrow protective agent from G1 company, was approved by the U.S. FDA for preventing myelosuppression in adult patients with diffuse small cell lung cancer due to chemotherapy with a platinum/etoposide regimen or a topotecan regimen. The approval of traasiril on the market means that it is the first and only new drug worldwide that is administered prophylactically during chemotherapy to protect bone marrow and immune system function.
The chemical structure of traasiril is specifically shown as a compound in formula I:
however, the current process for the preparation of traasiril remains to be improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. To this end, an object of the present invention is to propose a novel process for the preparation of traasiril. Compared with the prior art, in the reaction, the site of each step of chemical reaction is single, and the yield is high; the post-treatment of the reaction is simple, the separation and purification cost is reduced, and the reaction yield is improved.
In one aspect of the invention, the invention provides a process for the preparation of the compound traasiril represented by formula I. According to an embodiment of the invention, the method comprises:
(1) contacting a compound represented by formula 1 with an inorganic base, a compound represented by formula 2, so as to obtain a compound represented by formula 3;
(2) contacting a compound represented by formula 3 with an inorganic base to obtain a compound represented by formula 4;
(3) contacting the compound shown in the formula 4 with HATU and triethylamine to obtain a compound shown in a formula 5;
(4) contacting a compound of formula 5 with a compound of formula 6 to obtain a compound of formula I, traasiril,
the inventor finds that by utilizing the preparation method of the invention, the existing intermediate compound which is easily obtained commercially is used as a raw material, the step 1 adopts a halogenation reaction, the step 2 adopts an inorganic base (such as KOH) aqueous solution to remove the protecting groups of amino and carboxyl, the step 3 carries out intramolecular amidation on the amino and carboxyl with the removed protecting groups, and the step 4 carries out substitution reaction with the amino after the methylthio is oxidized, so that the compound Trirasilide shown in the formula I can be effectively prepared.
The term "contacting" as used herein is to be understood broadly and can be any means that enables a chemical reaction of at least two reactants, such as mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed with stirring as necessary, and thus, the type of stirring is not particularly limited, and may be, for example, mechanical stirring, that is, stirring under the action of a mechanical force.
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
According to embodiments of the present invention, the above-described method for preparing the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 5, and the compound represented by formula I may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the starting materials for preparing the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 5, and the compound represented by formula I is not particularly limited, and it may be prepared by any known method or may be commercially available.
According to an embodiment of the present invention, in step (1), the manner of contacting the compound represented by formula 1 with the inorganic base, and the compound represented by formula 2 is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1, the inorganic base and the compound shown in the formula 2 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to an embodiment of the present invention, in the step (1), the following steps are included: at room temperature, adding the compound shown in the formula 1 and inorganic base into DMF (dimethyl formamide) under stirring, continuously stirring, slowly dropwise adding the compound shown in the formula 2, heating and stirring for reaction after the dropwise adding is finished, carrying out post-treatment and pulping purification after the reaction is finished, filtering to obtain a solid, and drying to obtain the compound shown in the formula 3. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1, the inorganic base and the compound shown in the formula 2 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to an embodiment of the present invention, in the step (1), the inorganic base is at least one selected from sodium carbonate, potassium carbonate, cesium carbonate; preferably, the inorganic base in step (2) is selected from potassium carbonate.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1, K2CO3The molar ratio of the compound represented by the formula 2 is 1 (1.0-1.3) to 1.0-1.15, preferably the compound represented by the formula 1 and K2CO3The molar ratio of the compound represented by formula 2 is 1:1.15: 1.05. Thus, the efficiency of preparing the compound represented by formula 3 using this method can be further improved.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1, K2CO3The reaction time of the contact stirring of the compound shown as the formula 2 is 1.5-2.5 h, and the compound shown as the formula 1 and K are preferably selected2CO3The reaction time for contacting and stirring the compound represented by the formula 2 was 2 hours. Thus, the compound represented by the formula 1, K, can be promoted2CO3And the efficiency of the contact reaction of the compound shown in the formula 2 further improves the efficiency of preparing the compound shown in the formula 3 by using the method.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1, K2CO3The reaction temperature for heating the compound represented by the formula 2 by contact stirring is 92 to 105 ℃, and preferably the compound represented by the formula 1 and K2CO3And heating the compound shown in the formula 2 to 100 ℃, and stirring for reaction. Thus, the compound represented by the formula 1, K, can be promoted2CO3The efficiency of the contact reaction of the compound represented by the formula 2The efficiency of preparing the compound shown in the formula 3 by using the method is improved in one step.
According to the embodiment of the invention, in the step (1), the mixed solvent of petroleum ether/ethyl acetate with the volume ratio of (2-10): 1 is adopted for pulping purification, and preferably, the mixed solvent of petroleum ether/ethyl acetate with the volume ratio of 5:1 is adopted for pulping purification.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: at room temperature, the compound represented by the formula 1 (5.0g,22.40mmol) and K2CO3(3.56g,25.76mmol) is added into DMF (50mL) which is stirred for mixing, stirring is continued, the compound shown in the formula 2 (4.45g,23.52mmol) is slowly and dropwise added, after the dropwise addition, the temperature is raised to 100 ℃, stirring is carried out for 2h, after the reaction is finished, the reaction liquid is poured into water (100mL), the precipitated solid is filtered and collected, then the mixed solvent (50mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 5:1 is used for stirring, pulping and purifying for 30min, the solid is obtained by filtration, and the compound shown in the formula 3 is obtained after drying, the yield is 7.97g, and the yield is 90.7%.
According to an embodiment of the present invention, in the step (2), the contacting manner of the compound represented by formula 3 with the inorganic base is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 3 and the inorganic base can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the following steps are included: adding the compound shown in the formula 3 into EtOH at room temperature, stirring and mixing, keeping the room temperature, slowly dropwise adding the prepared aqueous solution of inorganic base, heating and stirring for reaction after dropwise adding, completely dissolving all solids, concentrating the organic solvent at low temperature under reduced pressure, extracting the water layer by DCM, adding a proper amount of dilute hydrochloric acid into the water layer under stirring at room temperature to adjust the pH value to about 7, allowing a large amount of solids to appear, filtering, and drying to obtain the compound shown in the formula 4. Therefore, the efficiency of the contact reaction of the compound shown in the formula 3 and the inorganic base can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the inorganic base is at least one selected from KOH, NaOH, LiOH, CsOH; preferably, the inorganic base in step (2) is selected from KOH.
According to the embodiment of the invention, in the step (2), the molar ratio of the compound shown in the formula 3 to KOH is 1 (2.1-4.2), and the molar ratio of the compound shown in the formula 3 to KOH is preferably 1: 2.5. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (2), the reaction time of the compound represented by formula 3 in contact with KOH under stirring is 0.8 hour to 1.5 hours, and preferably the reaction time of the compound represented by formula 3 in contact with KOH under stirring is 1 hour. Therefore, the efficiency of the contact reaction of the compound shown in the formula 3 and KOH can be improved, and the efficiency of preparing the compound shown in the formula 4 by using the method can be further improved.
According to an embodiment of the present invention, in the step (2), the reaction temperature for increasing the temperature of the compound represented by formula 3 by contacting with KOH under stirring is 40 ℃ to 50 ℃, and preferably the reaction temperature for increasing the temperature of the compound represented by formula 3 by contacting with KOH under stirring is 45 ℃. Therefore, the efficiency of the contact reaction of the compound shown in the formula 3 and KOH can be improved, and the efficiency of preparing the compound shown in the formula 4 by using the method can be further improved.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: adding a compound shown as a formula 3 (5.0g,12.74mmol) into EtOH (40mL) at room temperature, stirring and mixing, slowly dropwise adding 18g of 10% KOH aqueous solution (containing 1.8g of KOH (32.09mmol)) while keeping the temperature at room temperature, heating to 45 ℃ after dropwise adding, stirring for 1 hour, completely dissolving all solids, concentrating an organic solvent at low temperature under reduced pressure, extracting an aqueous layer with DCM (10mL), adding a proper amount of 20% diluted hydrochloric acid into the aqueous layer while stirring at room temperature to adjust the pH value to about 7, allowing a large amount of solids to appear, filtering, and drying to obtain 3.61g of solids, namely the compound shown as the formula 4, wherein the yield is 88.2%.
According to an embodiment of the present invention, in the step (3), the contacting manner of the compound represented by formula 4 with 2- (7-azabenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), triethylamine is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 with HATU and triethylamine can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 5 by using the method is further improved.
According to an embodiment of the present invention, in the step (3), the following steps are included: at room temperature, in N2Adding the compound shown in the formula 4 into DMF under protection, adding HATU and triethylamine, stirring, heating the solution to 45-55 ℃, keeping the temperature, stirring, reacting, concentrating the reaction solution in vacuum to about half of the original volume, stopping concentrating, gradually adding water dropwise, stirring to separate out solids, filtering and collecting the separated solids, pulping, purifying, filtering, and drying to obtain the compound shown in the formula 5. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 with HATU and triethylamine can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 5 by using the method is further improved.
According to the embodiment of the invention, in the step (3), the molar ratio of the compound shown in the formula 4 to HATU and triethylamine is 1 (1.0-1.3) to (2.0-4.5), and the molar ratio of the compound shown in the formula 4 to HATU and triethylamine is preferably 1:1.1: 3.0. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to the embodiment of the present invention, in the step (3), the reaction time of the compound represented by the formula 4 with HATU and triethylamine through contact stirring is 0.8 to 1.5 hours, and preferably the reaction time of the compound represented by the formula 4 with HATU and triethylamine through contact stirring is 1 hour. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 with HATU and triethylamine can be improved, and the efficiency of preparing the compound shown in the formula 5 by using the method can be further improved.
According to the embodiment of the invention, in the step (3), the mixed solvent of petroleum ether and ethyl acetate with the volume ratio of (2-10): 1 is adopted for pulping purification, and preferably, the mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 5:1 is adopted for pulping purification.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: at room temperature, in N2Adding a compound (3.2g,10mmol) shown in the formula 4 into DMF (40mL) under protection, adding HATU (4.18g,11mmol) and triethylamine (3.04g,30mmol) into the mixture, stirring the mixture, heating the solution to 50 ℃, keeping the temperature, stirring the mixture for reaction for 1 hour, and vacuumizing the reaction solutionConcentrating to about half of the original volume, stopping concentrating, gradually dripping water (20mL), stirring to precipitate solid, filtering and collecting the precipitated solid, stirring and pulping for 30min by using a mixed solvent (20mL) composed of petroleum ether/ethyl acetate with the volume ratio of 5:1, filtering, and drying to obtain 2.80g of solid which is the compound shown in the formula 5, wherein the yield is 92.6%.
According to an embodiment of the present invention, in the step (4), the contacting manner of the compound represented by formula 5, m-chloroperoxybenzoic acid (mCPBA), N-Diisopropylethylamine (DIPEA), and the compound represented by formula 6 is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown as the formula 5, mCPBA, DIPEA and the compound shown as the formula 6 can be improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown as the formula I, namely the traasiril by using the method is further improved.
According to an embodiment of the present invention, in the step (4), the following steps are included: adding a compound shown in formula 5 and mCPBA into toluene at room temperature, keeping the mixture at room temperature, stirring and reacting for 1h to obtain a reaction liquid a, then adding DIPEA and a compound shown in formula 6 into the reaction liquid a, keeping the reaction mixture at room temperature, stirring and reacting, carrying out post-treatment after the reaction is finished, concentrating the obtained filtrate, purifying by silica gel column chromatography, and concentrating to obtain a solid compound shown in formula I, namely traasiril. Therefore, the efficiency of preparing the compound of formula I, namely the traasimide by using the method can be further improved.
According to an embodiment of the invention, in the step (4), the molar ratio of the compound represented by the formula 5, mCPBA, DIPEA and the compound represented by the formula 6 is 1 (1.0-1.5) to (4-7) to (1.0-1.3), and preferably the molar ratio of the compound represented by the formula 5, mCPBA, DIPEA and the compound represented by the formula 6 is 1:1.15:5.2: 1.05. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (4), the contact stirring reaction time of the compound represented by formula 5, mCPBA, DIPEA, or the compound represented by formula 6 is 14 hours to 22 hours, and preferably the contact stirring reaction time of the compound represented by formula 5, mCPBA, DIPEA, or the compound represented by formula 6 is 17 hours. Therefore, the efficiency of the contact reaction of the compound shown as the formula 5, mCPBA, DIPEA and the compound shown as the formula 6 can be improved, and the efficiency of preparing the compound shown as the formula I, namely traasiril by using the method can be further improved.
According to the embodiment of the invention, in the step (4), the mixed solvent of dichloromethane/methanol with a volume ratio of (10-30): 1 is adopted for the silica gel column chromatography, and the mixed solvent of dichloromethane/methanol with a volume ratio of 20:1 is preferably adopted for the column chromatography.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: adding a compound shown in formula 5 (3.02g,0.01mol) and mCPBA (1.98g,0.0115mol) into toluene (30mL) at room temperature, keeping the mixture at room temperature, stirring and reacting for 1h to obtain a reaction liquid a, then adding DIPEA (6.72g,0.052mol) and a compound shown in formula 6 (2.02g,0.0105mol) into the reaction liquid a, keeping the reaction mixture at room temperature, stirring and reacting for 17h, and after the reaction is finished, adding saturated NaHCO3The solution (30ml) was extracted with ethyl acetate (2 × 15ml), the organic layer was washed with saturated brine (30ml), dried over sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography using a mixed solvent of dichloromethane/methanol at a volume ratio of 20:1 to obtain a solid (3.70 g) which was the compound of formula I, traasiril, yield 82.9% and HPLC purity 99.5%.
According to an embodiment of the present invention, the synthetic route of the compound traasimide of formula I can be as follows:
compared with the prior art, the preparation method of the traasiril has at least the following beneficial effects: the method adopts the intermediate compound which is easy to obtain commercially, and synthesizes the target molecule through halogenation reaction, protective group removal, amide condensation and methylthio and amino substitution reaction, and the total steps are 4 steps of reaction. More specifically, the method is characterized in that each reaction operation: (1) the step 1 adopts halogenation reaction, the yield is high (amino is protected), and the post-treatment pulping purification step is simple; (2) step 2, removing amino and carboxyl protecting groups by using KOH aqueous solution; (3) step 3, performing intramolecular amidation on the amino and carboxyl groups subjected to protecting group removal, wherein the two reactions of step (2) and step () have the advantages of mild reaction conditions, simple post-treatment and high yield; (4) and 4, the methylthio group is subjected to substitution reaction with the amino group after being subjected to peroxidation, so that the halogenation reaction after the methyl group is halogenated is avoided, the experimental steps are simplified, the reaction conditions are milder, and the yield is high. In addition, the preparation method has single site of each step of chemical reaction and higher yield; the post-reaction treatment is simple, and the purification mostly adopts a pulping purification method, so that the use of column chromatography is reduced, the purification cost is reduced, and the reaction yield is improved. The preparation method has the advantages of mild reaction conditions of the whole synthesis route, simple and cheap used reagents, and effectively improved total yield of the reaction and industrialized operability.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound represented by formula 3
At room temperature, the compound represented by the formula 1 (5.0g,22.40mmol) and K2CO3(3.56g,25.76mmol) is added into DMF (50mL) which is stirred for mixing, stirring is continued, the compound shown in the formula 2 (4.45g,23.52mmol) is slowly and dropwise added, after the dropwise addition, the temperature is raised to 100 ℃, stirring is carried out for 2h, after the reaction is finished, the reaction liquid is poured into water (100mL), the precipitated solid is filtered and collected, then the mixed solvent (50mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 5:1 is used for stirring, pulping and purifying for 30min, the solid is obtained by filtration, and the compound shown in the formula 3 is obtained after drying, the yield is 7.97g, and the yield is 90.7%.
LC-MS(APCI):m/z＝393.2(M+1)+。
EXAMPLE 2 Synthesis of Compound represented by formula 3
At room temperature, the compound of formula 1The compound shown (5.0g,22.40mmol) and K2CO3(3.10g,22.43mmol) is added into DMF (50mL) which is stirred for mixing, stirring is continued, the compound shown in formula 2 (4.24g,22.40mmol) is slowly and dropwise added, the temperature is raised to 92 ℃, stirring is carried out for reaction for 2.5h, after the reaction is finished, the reaction liquid is poured into water (100mL), the precipitated solid is filtered and collected, then the mixed solvent (50mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 2:1 is used for stirring, pulping and purifying for 30min, the solid is obtained by filtration, and the compound shown in formula 3 is obtained after drying, the yield is 7.75g, and the yield is 88.1%.
EXAMPLE 3 Synthesis of Compound represented by formula 3
At room temperature, the compound represented by the formula 1 (5.0g,22.40mmol) and K2CO3(4.02g,29.10mmol) is added into DMF (60mL) which is stirred for mixing, the stirring is continued, the compound shown in the formula 2 (4.87g,25.74mmol) is slowly and dropwise added, the temperature is raised to 105 ℃, the stirring reaction is carried out for 1.5h, after the reaction is finished, the reaction liquid is poured into water (120mL), the precipitated solid is filtered and collected, the mixed solvent (50mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 10:1 is used for stirring, pulping and purifying for 30min, the solid is obtained by filtration, and the compound shown in the formula 3 is obtained after drying, the yield is 7.50g, and the yield is 85.3%.
Example 4 Synthesis of Compound represented by formula 4
Adding a compound shown as a formula 3 (5.0g,12.74mmol) into EtOH (40mL) at room temperature, stirring and mixing, slowly dropwise adding 18g of 10% KOH aqueous solution (containing 1.8g of KOH (32.09mmol)) while keeping the temperature at room temperature, heating to 45 ℃ after dropwise adding, stirring for 1 hour, completely dissolving all solids, concentrating an organic solvent at low temperature under reduced pressure, extracting an aqueous layer with DCM (10mL), adding a proper amount of 20% diluted hydrochloric acid into the aqueous layer while stirring at room temperature to adjust the pH value to about 7, allowing a large amount of solids to appear, filtering, and drying to obtain 3.61g of solids, namely the compound shown as the formula 4, wherein the yield is 88.2%.
LC-MS(APCI):m/z＝321.1(M+1)+。
EXAMPLE 5 Synthesis of Compound represented by formula 4
At room temperature, the compound shown in the formula 3 (5.0g,12.74mmol) is added into EtOH (40mL) and stirred for mixing, 15g of 10% KOH aqueous solution (containing 1.5g of KOH (26.74mmol)) is slowly added dropwise at room temperature, after the dropwise addition, the temperature is raised to 40 ℃ and stirred for 1.5 hours, all solids are dissolved completely, after the organic solvent is concentrated at low temperature under reduced pressure, the water layer is extracted by DCM (10mL), under the stirring at room temperature, a proper amount of 20% diluted hydrochloric acid is added into the water layer to adjust the pH value to about 7, a large amount of solids appear, and the solid is filtered and dried to obtain 3.45g of solids which are the compound shown in the formula 4, and the yield is 84.5%.
EXAMPLE 6 Synthesis of Compound represented by formula 4
Adding a compound shown as a formula 3 (5.0g,12.74mmol) into EtOH (40mL) at room temperature, stirring and mixing, slowly dropwise adding 30g of 10% KOH aqueous solution (containing 3.0g of KOH (53.48mmol)) while keeping the room temperature, heating to 50 ℃ after dropwise adding, stirring for 0.8 hour, dissolving all solids, concentrating an organic solvent at low temperature under reduced pressure, extracting an aqueous layer with DCM (10mL), adding a proper amount of 20% dilute hydrochloric acid into the aqueous layer while stirring at room temperature to adjust the pH value to about 7, allowing a large amount of solids to appear, filtering, and drying to obtain 3.55g of solids which are compounds shown as a formula 4, wherein the yield is 87.0%.
Example 7 Synthesis of Compound represented by formula 5
At room temperature, in N2Under protection, adding a compound (3.2g and 10mmol) shown in the formula 4 into DMF (40mL), adding HATU (4.18g and 11mmol) and triethylamine (3.04g and 30mmol) into the mixture, stirring the mixture, heating the solution to 50 ℃, keeping the temperature, stirring the mixture for reaction for 1h, concentrating the reaction solution in vacuum to about half of the original volume, stopping concentrating the reaction solution, gradually dropwise adding water (20mL) into the reaction solution, stirring the solution to separate out a solid, filtering and collecting the separated solid, stirring and pulping the solid for 30min by using a mixed solvent (20mL) composed of petroleum ether and ethyl acetate in a volume ratio of 5:1, filtering the solid, drying the solid to obtain 2.80g of the compound shown in the formula 5, wherein the yield is 92.6%.
LC-MS(APCI):m/z＝303.2(M+1)+。
EXAMPLE 8 Synthesis of Compound represented by formula 5
At room temperature, in N2Under protection, adding a compound (3.2g,10mmol) shown in the formula 4 into DMF (40mL), adding HATU (3.80g,10mmol) and triethylamine (2.02g,20mmol) into the mixture, stirring the mixture, heating the solution to 45 ℃, keeping the temperature, stirring the mixture to react for 0.8h, concentrating the reaction solution in vacuum to about half of the original volume, stopping concentration, and gradually dropwise adding waterStirring to precipitate a solid (20mL), filtering and collecting the precipitated solid, stirring and pulping for 30min by using a mixed solvent (20mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 10:1, filtering, and drying to obtain 2.61g of a solid which is the compound shown in the formula 5, wherein the yield is 86.3%.
Example 9 Synthesis of Compound represented by formula 5
At room temperature, in N2Under protection, adding a compound (3.2g and 10mmol) shown in the formula 4 into DMF (50mL), adding HATU (4.94g and 13mmol) and triethylamine (4.55g and 45mmol) into the mixture, stirring the mixture, heating the solution to 55 ℃, keeping the temperature, stirring the mixture to react for 1.5h, concentrating the reaction solution in vacuum to about half of the original volume, stopping concentrating the reaction solution, gradually adding water (20mL) dropwise into the reaction solution, stirring the mixture to separate out a solid, filtering and collecting the separated solid, stirring and pulping the solid by using a mixed solvent (20mL) composed of petroleum ether and ethyl acetate in a volume ratio of 2:1 for 30min, filtering the solid, drying the solid to obtain 2.69g of the compound shown in the formula 5, wherein the yield is 89.0%.
EXAMPLE 10 preparation of the Compound Triazapride of formula I
Adding a compound shown in formula 5 (3.02g,0.01mol) and mCPBA (1.98g,0.0115mol) into toluene (30mL) at room temperature, keeping the mixture at room temperature, stirring and reacting for 1h to obtain a reaction liquid a, then adding DIPEA (6.72g,0.052mol) and a compound shown in formula 6 (2.02g,0.0105mol) into the reaction liquid a, keeping the reaction mixture at room temperature, stirring and reacting for 17h, and after the reaction is finished, adding saturated NaHCO3The solution (30ml) was extracted with ethyl acetate (2 × 15ml), the organic layer was washed with saturated brine (30ml), dried over sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography using a mixed solvent of dichloromethane/methanol at a volume ratio of 20:1 to obtain a solid (3.70 g) which was the compound of formula I, traasiril, yield 82.9% and HPLC purity 99.5%.
LC-MS(APCI):m/z＝447.4(M+1)+。
EXAMPLE 11 preparation of the Compound Triazapride of formula I
A compound represented by formula 5 (30.2g,0.1mol) and mCPBA (17.3g,0.1mol) were added to toluene (300mL) at room temperature, and the mixture was stirred at room temperature for 1 hour to obtain a reaction solution a, which was then added to the reaction solution aDIPEA (51.7g,0.4mol) and the compound of formula 6 (19.2g,0.1mol) were added, the reaction mixture was kept stirred at room temperature for 14h, and after completion of the reaction, saturated NaHCO was added3The solution (300ml) was extracted with ethyl acetate (2X 150ml), the organic layer was washed with saturated brine (300ml), dried over sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography on silica gel using a mixed solvent of dichloromethane/methanol at a volume ratio of 10:1 to give 35.9g of a solid, which was the compound of formula I, Triaxetil in 80.4% yield and 99.4% HPLC purity.
EXAMPLE 12 preparation of the Compound Triazapride of formula I
Adding a compound shown in formula 5 (35.7g,0.1mol) and mCPBA (25.9g,0.15mol) into toluene (300mL) at room temperature, keeping the mixture at room temperature, stirring for 1h to obtain a reaction solution a, adding DIPEA (90.5g,0.7mol) and a compound shown in formula 6 (25.0g,0.13mol) into the reaction solution a, keeping the reaction mixture at room temperature, stirring for 22h to react, and adding saturated NaHCO into the reaction solution after the reaction is finished3The solution (300ml) was extracted with ethyl acetate (2X 150ml), the organic layer was washed with saturated brine (300ml), dried over sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography using a mixed solvent of dichloromethane/methanol at a volume ratio of 30:1 to give 34.9g of a solid, which was the compound of formula I, Triazalide, yield 78.2%, and HPLC purity 99.2%.
Example 13 Synthesis of Compound represented by formula 3
Example 13 is a comparative example in which the inventors have adjusted the compound shown in formula 1, K2CO3The reaction molar ratio of the compound represented by the formula 2 to the compound represented by the formula 2 is 1:1.6:1.3, and the yield of the product obtained in the example is lower than that of the compound represented by the formula 1 and K2CO3The yield of the product is 1 (1.0-1.3) to 1.0-1.15.
At room temperature, the compound represented by the formula 1 (5.0g,22.40mmol) and K2CO3(4.95g,35.84mmol) was added to DMF (80mL) while stirring, stirring was continued, the compound represented by formula 2 (5.51g,29.12mmol) was slowly added dropwise, after dropping, the temperature was raised to 100 ℃ and the reaction was stirred for 2.5 hours, and then the reaction was carried outAfter reaction, the reaction solution was poured into water (120mL), the precipitated solid was collected by filtration, and then the mixture was slurried with a 5:1 by volume petroleum ether/ethyl acetate mixture (60mL) for 30min, filtered to obtain a solid, and dried to obtain the compound represented by formula 3 in an amount of 6.92g with a yield of 78.7%.
EXAMPLE 14 Synthesis of Compound represented by formula 5
Example 14 is a comparative example, in this example, the inventors adjusted the reaction molar ratio of the compound represented by formula 4 to HATU and triethylamine to 1:1.8:5.0, and extended the reaction time from 1.5 hours to 2.5 hours. In the technical effect of the embodiment, the yield of the obtained product is lower than that of the compound shown in the formula 4 when the molar ratio of the compound to HATU and triethylamine is 1 (1.0-1.3) to 2.0-4.5.
At room temperature, in N2Under protection, adding a compound (3.2g and 10mmol) shown in the formula 4 into DMF (50mL), adding HATU (6.84g and 18mmol) and triethylamine (5.06g and 50mmol) into the mixture, stirring the mixture, heating the solution to 50 ℃, keeping the temperature, stirring the mixture for reaction for 2.5 hours, concentrating the reaction solution in vacuum to about half of the original volume, stopping concentrating the reaction solution, gradually adding water (20mL) dropwise into the reaction solution, stirring the solution to separate out a solid, filtering and collecting the separated solid, stirring and pulping the solid for 30 minutes by using a mixed solvent (25mL) composed of petroleum ether and ethyl acetate with a volume ratio of 5:1, filtering the solid, drying the solid to obtain 2.48g of the compound shown in the formula 5, wherein the yield is 82.0%.
EXAMPLE 15 preparation of the Compound Triazapride of formula I
Example 15 is a comparative example, in this example, the inventors adjusted the molar ratio of the compound represented by formula 5, mCPBA, DIPEA, and the compound represented by formula 6 to 1:2.0:3.0:1.6, and obtained a product yield lower than that when the molar ratio of the compound represented by formula 6, mCPBA, DIPEA, and the compound represented by formula 7 is 1 (1.0 to 1.5) to (4 to 7) to (1.0 to 1.3), and the HPLC purity of the obtained traasiril product was significantly reduced and impurities in the product increased.
A compound represented by formula 5 (3.02g,0.01mol) and mCPBA (3.45g,0.02mol) were added to toluene (30mL) at room temperature, and the mixture was stirred at room temperature for 1 hour to obtain a reaction solution a, and then DIP was added to the reaction solution aEA (3.88g,0.03mol) and the compound of formula 6 (3.08g,0.016mol) were added to the reaction mixture, the mixture was stirred at room temperature for 22 hours, and after completion of the reaction, saturated NaHCO was added3The solution (30ml) was extracted with ethyl acetate (2 × 15ml), the organic layer was washed with saturated brine (30ml), dried over sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography using a mixed solvent of dichloromethane/methanol at a volume ratio of 20:1 to obtain a solid (3.28 g) which was the compound of formula I, traasiril, yield 73.4% and HPLC purity 97.6%.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A preparation method of the traasiril is characterized by comprising the following steps:
(1) contacting a compound represented by formula 1 with an inorganic base, and a compound represented by formula 2, so as to obtain a compound represented by formula 3;
(2) contacting a compound represented by formula 3 with an inorganic base to obtain a compound represented by formula 4;
(3) contacting the compound shown in the formula 4 with HATU and triethylamine to obtain a compound shown in a formula 5;
(4) contacting a compound of formula 5 with a compound of formula 6 to obtain a compound of formula I, traasiril,
2. the method according to claim 1, wherein in step (1), the following steps are included: adding the compound shown in the formula 1 and inorganic base into DMF (dimethyl formamide) under stirring at room temperature, continuously stirring, slowly dropwise adding the compound shown in the formula 2, heating, stirring for reaction, performing post-treatment and pulping purification after the reaction is finished, filtering to obtain solid, drying to obtain the compound shown in the formula 3,
optionally, the inorganic base is at least one selected from sodium carbonate, potassium carbonate, cesium carbonate;
preferably the inorganic base is selected from potassium carbonate.
3. The method according to claim 2, wherein in step (1), the compound represented by formula 1, K2CO3The molar ratio of the compound represented by the formula 2 is 1 (1.0-1.3) to 1.0-1.15, preferably the compound represented by the formula 1 and K2CO3The molar ratio of the compound shown in the formula 2 is 1:1.15:1.05,
optionally, in step (1), a compound represented by formula 1, K2CO3The reaction time of the contact stirring of the compound shown as the formula 2 is 1.5-2.5 h, preferably in the step (1), the compound shown as the formula 1 and K2CO3The reaction time of the contact stirring of the compound shown in the formula 2 is 2 hours,
optionally, in step (1), a compound represented by formula 1, K2CO3The reaction temperature for increasing the temperature of the compound represented by the formula 2 by contact stirring is 92 to 105 ℃, and preferably the compound represented by the formula 1 in the step (1) and K2CO3Heating the compound shown in the formula 2 to 100 ℃, stirring and reacting,
optionally, in the step (1), a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (2-10): 1 is adopted for pulping purification, and preferably, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1 is adopted for pulping purification.
4. The method of claim 1, wherein in step (2), the following steps are included: adding the compound shown in the formula 3 into EtOH at room temperature, stirring and mixing, keeping the room temperature, slowly dropwise adding the prepared aqueous solution of inorganic base, heating and stirring for reaction after dropwise adding, completely dissolving all solids, concentrating the organic solvent at low temperature under reduced pressure, extracting the water layer by DCM, adding a proper amount of dilute hydrochloric acid into the water layer under stirring at room temperature to adjust the pH value to about 7, generating a large amount of solids, filtering, drying to obtain the compound shown in the formula 4,
optionally, the inorganic base is at least one selected from KOH, NaOH, LiOH, CsOH;
preferably the inorganic base is selected from KOH.
5. The method of claim 4, wherein in step (2), the molar ratio of the compound represented by formula 3 to KOH is 1 (2.1-4.2), preferably the molar ratio of the compound represented by formula 3 to KOH is 1:2.5,
optionally, in the step (2), the reaction time of the compound shown in the formula 3 contacted with KOH under stirring is 0.8 hour to 1.5 hours, and preferably the reaction time of the compound shown in the formula 3 contacted with KOH under stirring in the step (2) is 1 hour;
optionally, in the step (2), the reaction temperature for increasing the temperature of the compound shown in the formula 3 by contacting with KOH through stirring is 40-50 ℃, and preferably, in the step (2), the reaction temperature for increasing the temperature of the compound shown in the formula 3 by contacting with KOH through stirring is 45 ℃.
6. The method of claim 1, wherein in step (3), the following steps are included: at room temperature, in N2Adding the compound shown in the formula 4 into DMF under protection, adding HATU and triethylamine, stirring, heating the solution to 45-55 ℃, keeping the temperature, stirring, reacting, and reactingConcentrating the reaction solution in vacuum to about half of the original volume, stopping concentrating, gradually dropwise adding water, stirring to separate out solids, filtering and collecting the separated solids, pulping, purifying, filtering, and drying to obtain the compound shown in the formula 5.
7. The method of claim 6, wherein in step (3), the molar ratio of the compound represented by formula 4 to HATU and triethylamine is 1 (1.0-1.3) to (2.0-4.5), preferably the molar ratio of the compound represented by formula 4 to HATU and triethylamine is 1:1.1:3.0,
optionally, in the step (3), the contact stirring reaction time of the compound shown in the formula 4 with HATU and triethylamine is 0.8-1.5 hours, and preferably the contact stirring reaction time of the compound shown in the formula 4 with HATU and triethylamine in the step (3) is 1 hour;
optionally, in the step (3), the temperature of the heat-preservation reaction of the compound shown in the formula 4, HATU and triethylamine in contact stirring is 50 ℃,
optionally, in the step (3), a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (2-10): 1 is adopted for pulping purification, and preferably, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1 is adopted for pulping purification.
8. The method according to claim 1, wherein in step (4), the following steps are included: adding a compound shown in formula 5 and mCPBA into toluene at room temperature, keeping the mixture at room temperature, stirring and reacting for 1h to obtain a reaction liquid a, then adding DIPEA and a compound shown in formula 6 into the reaction liquid a, keeping the reaction mixture at room temperature, stirring and reacting, carrying out post-treatment after the reaction is finished, concentrating the obtained filtrate, purifying by silica gel column chromatography, and concentrating to obtain a solid compound shown in formula I, namely traasiril.
9. The method of claim 8, wherein in step (4), the molar ratio of the compound represented by formula 5, mCPBA, DIPEA and the compound represented by formula 6 is 1 (1.0-1.5) to (4-7) to (1.0-1.3), preferably the molar ratio of the compound represented by formula 5, mCPBA, DIPEA and the compound represented by formula 6 is 1:1.15:5.2:1.05,
optionally, in the step (4), the contact stirring reaction time of the compound shown in the formula 5, mCPBA, DIPEA and the compound shown in the formula 6 is 14 hours to 22 hours, preferably the contact stirring reaction time of the compound shown in the formula 5, mCPBA, DIPEA and the compound shown in the formula 6 in the step (4) is 17 hours,
optionally, in the step (4), the silica gel column chromatography adopts a mixed solvent of dichloromethane and methanol in a volume ratio of (10-30): 1, and preferably, the column chromatography adopts a mixed solvent of dichloromethane and methanol in a volume ratio of 20: 1.
10. The method according to claims 1-9, characterized in that the synthetic route can be as follows:
optionally, in step (1), the following steps are included: mixing 5.0g of the compound represented by the formula 1 and 3.56g K at room temperature2CO3Adding the mixture into stirred 50mL of mixed solution of DMDMF, continuously stirring, slowly dropwise adding 4.45g of the compound shown in the formula 2, heating to 100 ℃, stirring and reacting for 2 hours, pouring the reaction solution into 100mL of water after the reaction is finished, filtering and collecting the precipitated solid, stirring and pulping for 30 minutes by using 50mL of mixed solvent consisting of petroleum ether and ethyl acetate with the volume ratio of 5:1, filtering to obtain the solid, and drying to obtain the compound shown in the formula 3, wherein the yield is 7.97g and 90.7%;
in the step (2), the method comprises the following steps: at room temperature, adding 5.0g of the compound shown in the formula 3 into 40mL of EtOH, stirring and mixing, slowly dropwise adding 18g of 10% KOH aqueous solution at room temperature, heating to 45 ℃ after dropwise adding, stirring for 1 hour, completely dissolving all solids, concentrating the organic solvent at low temperature under reduced pressure, extracting the water layer with 10mL of DCM, adding a proper amount of 20% dilute hydrochloric acid into the water layer under stirring at room temperature to adjust the pH value to about 7, generating a large amount of solids, filtering, drying to obtain 3.61g of solids, namely the compound shown in the formula 4, wherein the yield is 88.2%;
in step (3), comprisesThe method comprises the following steps: at room temperature, in N2Under protection, adding 3.2g of the compound shown as the formula 4 into 40mL DMF, adding 4.18g of HATU and 3.04g of triethylamine, stirring, heating the solution to 50 ℃, keeping the temperature, stirring and reacting for 1h, concentrating the reaction solution in vacuum to about half of the original volume, stopping concentrating, gradually dripping water (20mL), stirring to separate out a solid, filtering and collecting the separated solid, stirring and pulping for 30min by using a mixed solvent (20mL) consisting of petroleum ether and ethyl acetate in a volume ratio of 5:1, filtering, drying to obtain 2.80g of the solid, wherein the yield is 92.6 percent of the compound shown as the formula 5;
in the step (4), the method comprises the following steps: adding 3.02g of the compound shown in the formula 5 and 1.98g of mCPBA into 30mL of toluene at room temperature, stirring and reacting for 1h while keeping the room temperature to obtain a reaction liquid a, then adding 6.72g of DIPEA and 2.02g of the compound shown in the formula 6 into the reaction liquid a, stirring and reacting the reaction mixture for 17h while keeping the room temperature, and adding 30mL of saturated NaHCO after the reaction is finished3The solution was extracted with 2X 15ml of ethyl acetate, the organic layer was washed with 30ml of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography using a mixed solvent of dichloromethane/methanol at a volume ratio of 20:1, and the concentrated solution was concentrated to give 3.70g of a solid, which was the compound of formula I, Triplex in 82.9% yield and 99.5% HPLC purity.
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