CN113637001A - Synthesis method of droperidol intermediate - Google Patents
Synthesis method of droperidol intermediate Download PDFInfo
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- CN113637001A CN113637001A CN202110906288.9A CN202110906288A CN113637001A CN 113637001 A CN113637001 A CN 113637001A CN 202110906288 A CN202110906288 A CN 202110906288A CN 113637001 A CN113637001 A CN 113637001A
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Abstract
The disclosed embodiment relates to a synthesis method of a droperidol intermediate, wherein the intermediate is 1- [1- (1,2,3, 6-tetrahydro-4-pyridyl) ] -2-benzimidazolone hydrochloride, and the synthesis method comprises the following steps: step one, 1-N-Boc-4-oxo-3-piperidine carboxylic acid ethyl ester is used as a reactant and is subjected to condensation reaction with o-phenylenediamine to obtain 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylic acid tert-butyl ester; and step two, reacting the product obtained in the step one with an organic solution of HCl to obtain the intermediate. In the embodiment, a new process for preparing a target compound is developed by using an easily available compound 1-N-Boc-4-oxo-3-piperidinecarboxylic acid ethyl ester as a raw material, and the yield is high. The process does not need to refine and remove impurities for many times, avoids the use of reactants with strong pungent taste, is easy for industrial production, and solves the problem that the post-treatment purification and impurity removal in the prior art are difficult.
Description
Technical Field
The embodiment of the disclosure relates to the technical field of drug synthesis, in particular to a synthesis method of a droperidol intermediate.
Background
The droperidol is used for controlling agitation of acute psychosis, and has effects of neuroleptic and enhancing analgesic effect. The key intermediate 1- (1,2,3, 6-tetrahydro-4-pyridyl) -2-benzimidazolone for synthesizing the droperidol has the following chemical structural formula:
1- (1,2,3, 6-tetrahydro-4-pyridyl) -2-benzimidazolone is used as a reactant for synthesizing the droperidol, and the purity of the droperidol directly influences the quality and the yield of the droperidol medicament. The original production process for producing the droperidol (compound 6) by using the 1- (1,2,3, 6-tetrahydro-4-pyridyl) -2-benzimidazolone comprises the following steps:
in the original production process, the compound 6 is formed by debenzylating the compound 5 by Pd-C/hydrogen, and the defect is that the formation of the over-reduced impurity compound 6-1 cannot be effectively controlled, and the formula is as follows:
since the physicochemical properties of this impurity (compound 6-1) are similar to compound 6, it is difficult to remove by conventional purification methods, and it can generate the corresponding droperidol impurity in the step of preparing droperidol, as shown in the following formula:
it is therefore necessary to remove the impurity compound 6-1 in the intermediate 6 or to remove the impurity by multiple refinements in the post-treatment of droperidol preparation, which would increase the pressure for impurity removal and thus lower the yield.
Alternatively, compound 5 can be debenzylated and the hydrochloride salt of compound 6 is prepared, typically by the classical chloroformate method, as follows:
although this makes up for the deficiencies of the Pd-C/hydrogen debenzylation process and avoids the formation of the reduced impurity compound 6-1, there are significant disadvantages: chloromethyl chloroformate has strong harsh characteristics, which are contrary to green chemistry and environment-friendly concept in industrial production, and thus is not suitable for industrial mass production.
Accordingly, there is a need to ameliorate one or more of the problems with the related art solutions described above.
It is noted that this section is intended to provide a background or context to the disclosure as recited in the claims. The description herein is not admitted to be prior art by inclusion in this section.
Disclosure of Invention
An object of the embodiments of the present disclosure is to provide a method for synthesizing a droperidol intermediate, thereby overcoming, at least to some extent, one or more of the problems due to the limitations and disadvantages of the related art.
The disclosed embodiment provides a synthesis method of a droperidol intermediate, wherein the intermediate is 1- [1- (1,2,3, 6-tetrahydro-4-pyridyl) ] -2-benzimidazolone hydrochloride, and the synthesis method comprises the following steps:
step one, 1-N-Boc-4-oxo-3-piperidine carboxylic acid ethyl ester is used as a reactant and is subjected to condensation reaction with o-phenylenediamine to obtain 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylic acid tert-butyl ester;
reacting the 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylic acid tert-butyl ester with an organic solution of HCl to obtain 1- [1- (1,2,3, 6-tetrahydro-4-pyridyl) ] -2-benzimidazolone hydrochloride;
the reaction formula of the above reaction is as follows:
in an embodiment of the present disclosure, the reaction process of the first step is:
1-N-Boc-4-oxo-3-piperidinecarboxylic acid ethyl ester and o-phenylenediamine in a molar ratio of 1 (0.8-1.2) are reacted in a first organic solvent at the temperature of 130-150 ℃ for 3-7 h. Wherein, the molar ratio can be 1:0.9, 1:1, 1:1.1, etc.
In one embodiment of the present disclosure, the first organic solvent is xylene or N-methylpyrrolidone.
In one embodiment of the disclosure, the reaction molar ratio of the ethyl 1-N-Boc-4-oxo-3-piperidinecarboxylate to o-phenylenediamine is 1:1.
In one example of the present disclosure, ethyl 1-N-Boc-4-oxo-3-piperidinecarboxylate was added dropwise to a xylene solution of o-phenylenediamine for reaction.
In one embodiment of the present disclosure, the reaction is performed at 140 ℃ for 5 h.
In an embodiment of the present disclosure, the reaction process of the second step is:
dissolving the 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylic acid tert-butyl ester prepared in the step one in a second organic solvent, adding a 1N-3N organic solution of hydrogen chloride, and reacting for 2-4H at 5-25 ℃.
In an embodiment of the present disclosure, the second organic solvent is dichloromethane or ethyl acetate.
In one embodiment of the present disclosure, the organic solution of hydrogen chloride is HCl/EtOAc, HCl/MeOH, or HCl/Et2O solutionAnd (4) liquid.
In one embodiment of the disclosure, the molar ratio of the reaction of the tert-butyl 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylate and the organic solution of hydrogen chloride is 1 (1-1.5).
The technical scheme provided by the embodiment of the disclosure can have the following beneficial effects:
according to the synthesis method of the droperidol intermediate in the embodiment of the disclosure, a new process for preparing a target compound is developed by adopting an easily-obtained compound 1-N-Boc-4-oxo-3-piperidine carboxylic acid ethyl ester as a raw material, and the yield is high. The process does not need to refine and remove impurities for many times, avoids the use of reactants with strong pungent taste, is easy for industrial production, and solves the problem that the post-treatment purification and impurity removal in the prior art are difficult.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present disclosure and together with the description, serve to explain the principles of the disclosure. It is to be understood that the drawings in the following description are merely exemplary of the disclosure, and that other drawings may be derived from those drawings by one of ordinary skill in the art without the exercise of inventive faculty.
Figure 1 shows a nuclear magnetic spectrum of tert-butyl 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylate (compound 3) in an exemplary embodiment of the present disclosure;
FIG. 2 shows a nuclear magnetic spectrum of 1- [1- (1,2,3, 6-tetrahydro-4-pyridinyl) ] -2-benzimidazolone hydrochloride (compound 6 hydrochloride) in an exemplary embodiment of the present disclosure.
Detailed Description
Example embodiments will now be described more fully with reference to the accompanying drawings. Example embodiments may, however, be embodied in many different forms and should not be construed as limited to the examples set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of example embodiments to those skilled in the art. The described features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
In this exemplary embodiment, a method is provided for synthesizing a droperidol intermediate, which is 1- [1- (1,2,3, 6-tetrahydro-4-pyridinyl) ] -2-benzimidazolone hydrochloride, which can be prepared according to the following reaction scheme:
according to the synthesis method of the droperidol intermediate in the embodiment of the disclosure, a new process for preparing a target compound is developed by adopting an easily-obtained compound 1-N-Boc-4-oxo-3-piperidine carboxylic acid ethyl ester as a raw material, and the yield is high. The process does not need to refine and remove impurities for many times, avoids the use of reactants with strong pungent taste, is easy for industrial production, and solves the problem that the post-treatment purification and impurity removal in the prior art are difficult.
The reaction steps of the above reaction formula are specifically described below.
First, the preparation example of tert-butyl 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylate (Compound 3) is as follows.
Example 1:
o-phenylenediamine (27.0g) and xylene (300mL) were added to a 1L jacketed flask and heated to 135 ℃. Compound 2(67.8g) was dissolved in xylene (300mL) in advance, and then added dropwise to the above system, followed by reaction at this temperature for 6 hours after completion of the addition. After the reaction is finished, concentrating the volume of the system to about 150mL, cooling to room temperature, dropwise adding n-hexane (500mL) into the system, stirring for 1-2h at room temperature, filtering, and drying at 45-50 ℃ for 6h to obtain 35.2g of a product, namely a white solid with the yield of 44.7%.
Example 2:
o-phenylenediamine (27.0g) and xylene (300mL) were added to a 1L jacketed flask and heated to 140 ℃. Compound 2(67.8g) was dissolved in xylene (300mL) in advance, and then added dropwise to the above system, followed by reaction at this temperature for 5 hours after completion of the addition. After the reaction is finished, concentrating the volume of the system to about 150mL, cooling to room temperature, dropwise adding n-hexane (500mL) into the system, stirring for 1-2h at room temperature, filtering, and drying at 45-50 ℃ for 6h to obtain 37.6g of a product, namely a white solid with the yield of 47.8%.
Example 3:
o-phenylenediamine (27.1g) and xylene (300mL) were added to a 1L jacketed flask and heated to 145 ℃. Compound 2(67.8g) was dissolved in xylene (300mL) in advance, and then added dropwise to the above system, followed by reaction at this temperature for 4 hours after completion of the addition. After the reaction is finished, concentrating the volume of the system to about 150mL, cooling to room temperature, dropwise adding n-hexane (500mL) into the system, stirring for 1-2h at room temperature, filtering, and drying at 45-50 ℃ for 6h to obtain 34.8g of a product, namely a white solid with the yield of 44.2%.
Next, examples of the preparation of 1- (1,2,3, 6-tetrahydro-4-pyridyl) -2-benzimidazolone hydrochloride (compound 6 hydrochloride) are described below.
Example 4:
compound 3(50.0g) and dichloromethane (250mL) were added to a 500mL jacketed flask, and a 4N HCl/EtOAc solution (50mL) was added dropwise at 25 ℃ and stirred for 2 h. After the reaction, the mixture was filtered, and the filter cake was washed with dichloromethane (100mL) and dried at 45-50 ℃ for 6 hours to obtain 38.2g of a white-like solid with a yield of 95.7%.
Example 5:
compound 3(50.0g) and dichloromethane (250mL) were added to a 500mL jacketed flask, and a 4N HCl/EtOAc solution (50mL) was added dropwise at 15 deg.C, with stirring at room temperature for 4 h. After the reaction, the mixture was filtered, and the filter cake was washed with dichloromethane (100mL) and dried at 45-50 ℃ for 6 hours to obtain 38.6g of a white-like solid with a yield of 96.6%.
Example 6:
compound 3(50.0g) and dichloromethane (200mL) were added to a 500mL jacketed flask, 4N HCl/EtOAc solution (50mL) was added dropwise at 5 ℃ and stirred at 15 ℃ for 4 h. After the reaction, the mixture was filtered, and the filter cake was washed with dichloromethane (80mL) and dried at 45-50 ℃ for 6 hours to obtain 39.0g of a product as a white solid with a yield of 97.7%.
The hydrochloride solution of hydrogen chloride used in the preparation of the hydrochloride salt of compound 6 can be HCl/EtOAc (ethyl acetate), HCl/MeOH (methanol), orHCl/Et2O (diethyl ether) solution. The 4- (2-oxo-2, 3-dihydro-1H-benzo [ d)]The molar ratio of the reaction of imidazol-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylic acid tert-butyl ester with the organic solution of hydrogen chloride is 1 (1-1.5), and may be, for example, 1:1.2, 1:1.26, 1:1.3, etc., with 1:1.26 being most preferred.
The compound 3 and the compound 6 hydrochloride prepared in the above examples are subjected to nuclear magnetic testing and characterization, and nuclear magnetic spectra of fig. 1 and fig. 2 are obtained respectively. From fig. 1, it can be seen that:1H NMR(400MHz,d6-DMSO):10.960(1H,s,NH),7.068-6.989(4H,m,ArH),5.954-5.920(1H,m,C＝CH),4.068-4.063(2H,m,CH2),3.611-3.583(2H,m,CH2),2.498-2.494(2H,m CH2),1.286(9H,s,3CH3). From fig. 2, it can be derived:1h NMR (400MHz, d-MeOD) 7.194-7.170(1H, m, ArH),7.098-7.087(3H, m, ArH),6.059-6.051(1H, m, C ═ CH),3.973-3.965(2H, m, CH2),3.558-3.551(2H, m CH2),2.841-3.2.837(2H, m CH 2). The structural formulas of the hydrochloride of the compound 3 and the compound 6 are verified as follows:
the 1- [1- (1,2,3, 6-tetrahydro-4-pyridyl) ] -2-benzimidazolone hydrochloride prepared by the method can be directly used for producing the droperidol, and is favorable for improving the synthesis quality and the yield of the droperidol.
It is to be understood that the terms "first", "second" and "first" are used 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 embodiments of the present disclosure, "a plurality" means two or more unless specifically limited otherwise.
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 present disclosure. 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 described in this specification can be combined and combined by those skilled in the art.
Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. This application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure as come within known or customary practice within the art to which the disclosure pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.
Claims (10)
1. A method for synthesizing a droperidol intermediate, wherein the intermediate is 1- [1- (1,2,3, 6-tetrahydro-4-pyridyl) ] -2-benzimidazolone hydrochloride, and the method comprises the following steps:
step one, 1-N-Boc-4-oxo-3-piperidine carboxylic acid ethyl ester is used as a reactant and is subjected to condensation reaction with o-phenylenediamine to obtain 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylic acid tert-butyl ester;
reacting the 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylic acid tert-butyl ester with an organic solution of HCl to obtain 1- [1- (1,2,3, 6-tetrahydro-4-pyridyl) ] -2-benzimidazolone hydrochloride;
the reaction formula of the above reaction is as follows:
2. the synthesis method according to claim 1, wherein the reaction process of the first step is as follows:
1-N-Boc-4-oxo-3-piperidinecarboxylic acid ethyl ester and o-phenylenediamine in a molar ratio of 1 (0.8-1.2) are reacted in a first organic solvent at the temperature of 130-150 ℃ for 3-7 h.
3. The method of synthesis according to claim 2, wherein the first organic solvent is xylene or N-methylpyrrolidone.
4. The synthesis method according to claim 2, wherein the reaction molar ratio of the ethyl 1-N-Boc-4-oxo-3-piperidinecarboxylate to o-phenylenediamine is 1:1.
5. The synthesis method according to claim 2, wherein the reaction is carried out by dropping ethyl 1-N-Boc-4-oxo-3-piperidinecarboxylate into a xylene solution of o-phenylenediamine.
6. The synthesis method according to claim 2, characterized in that the reaction is carried out at 140 ℃ for 5 h.
7. The synthesis method according to any one of claims 1 to 6, wherein the reaction process of the second step is as follows:
dissolving the 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylic acid tert-butyl ester prepared in the step one in a second organic solvent, adding a 1N-3N organic solution of hydrogen chloride, and reacting for 2-4H at 5-25 ℃.
8. The method of synthesis of claim 7, wherein the second organic solvent is dichloromethane or ethyl acetate.
9. The method of claim 7, wherein the organic solution of hydrogen chloride is HCl/EtOAc, HCl/MeOH, or HCl/Et2And (4) O solution.
10. The synthesis method according to claim 7, wherein the molar ratio of the reaction of the tert-butyl 4- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) -3, 6-dihydro-2H-piperidine-1-carboxylate and the organic solution of hydrogen chloride is 1 (1-1.5).
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