CN106674144B - Synthesis method of intermediate compound of temazepam serving as neurosurgical drug - Google Patents
Synthesis method of intermediate compound of temazepam serving as neurosurgical drug Download PDFInfo
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- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
Abstract
The invention provides a synthesis method of a compound of a neural surgery medicament temazepam intermediate compound shown in a formula (III), which comprises the following steps: reacting a compound shown in the following formula (I) and a compound shown in the formula (II) in an organic solvent in the presence of a catalyst, a ligand, alkali and a promoter, and performing post-treatment after the reaction is finished to obtain the compound shown in the formula (III),
Description
Technical Field
The invention relates to a synthesis method of a drug intermediate compound, in particular to a synthesis method of a neurosurgical drug temazepam intermediate compound, belonging to the field of organic chemical synthesis and pharmaceutical chemical intermediates.
Background
Temazepam, a benzodiazepine developed by roche in 1963
The chemical name of the medicine is 1-methyl-5-phenyl-7-chloro-1, 3-dihydro-2H-1, 4-benzodiazepine
-2-ketones, the structural formula of which is as follows:
temazepam is a neurosurgical drug, has the pharmaceutical activities of antianxiety, sedation, hypnosis, anticonvulsant, antiepileptic and the like, and has important position and effect in the field of neurosurgical drugs.
Since the time of the market for temazepam, numerous researchers have conducted extensive studies on its synthesis and developed several synthetic routes, such as:
CN10435608a1 discloses an intermediate for synthesizing temazepam, which is obtained by synthesizing 3-phenyl-5-chlorobenzoisoxazole and dimethyl carbonate, and then obtaining temazepam through subsequent reaction, wherein the structural formula of the intermediate and the reaction formula for obtaining the intermediate are as follows:
the 3-phenyl-5-chlorobenzoisoxazole described above is an important intermediate for the synthesis of temazepam, which can be obtained by subsequent reactions, for example, Shenyi et al ("pharmaceutical industry", 1982, 5 th) disclose that 3-phenyl-5-chloro-2, 1-benzisoxazole can be obtained by reacting p-chloronitrobenzene with phenylacetonitrile, and then the ring-opening and ring-expanding reactions are continued to obtain temazepam.
Due to such important roles of the compound, a great deal of intensive research into its synthesis has been carried out and different synthetic routes and process conditions have been developed, for example:
yaohai et al ("chemical synthesis of alprazolam", proceedings of zheng zhou university (medical edition), 2008, vol 43, phase 4) discloses a process for the synthesis of 3-phenyl-5-chlorobenzoisoxazole by the reaction of p-chloronitrobenzene with phenylacetonitrile in the presence of ethanol and NaOH to give the compound, the reaction formula:
benjamin J.Stokes et al ("Intramolecular Fe (II) -Catalyzed N-O or N-N Bond Formation from Aryl Azides", ORGANIC LETTERS, 2010, Vol.12, No.12) disclose the following synthetic methods:
as mentioned above, various processes for the preparation of this intermediate of temazepam are disclosed in the prior art, using different starting materials as starting materials in these synthetic processes. There is a continuing need for research and improvement in the synthesis of this intermediate compound for the synthesis of temazepam, which is also currently a focus and focus of research in this field, and more on which the present invention has been motivated and upon which it has been based.
Disclosure of Invention
The present inventors have conducted intensive studies in order to study a novel synthesis method of the above-mentioned intermediate for the synthesis of temazepam, and after having paid a lot of creative efforts, have completed the present invention.
The present invention relates to the following two aspects.
In a first aspect, the invention relates to a synthesis method of a neural surgery drug temazepam intermediate compound.
Specifically, the invention provides a synthesis method of a neurosurgical drug temazepam intermediate compound, namely a compound shown in a formula (III) (namely 3-phenyl-5-chlorobenzoisoxazole), which comprises the following steps: reacting a compound shown in the following formula (I) and a compound shown in the formula (II) in an organic solvent in the presence of a catalyst, a ligand, alkali and a promoter, and performing post-treatment after the reaction is finished to obtain the compound shown in the formula (III),
wherein t-Bu is tert-butyl.
In the synthesis method of the present invention, the catalyst is an organic iron compound.
Wherein the organic iron compound is selected from iron acetylacetonate (Fe (acac)3) Any one of cyclooctatetraene tricarbonyl iron, tris (2,2,6, 6-tetramethyl-3, 5-heptanedionate) iron, tris (dibenzoylmethyl) iron or 1,2,3,4, 5-pentaphenyl-1 '- (di-tert-butylphosphino) ferrocene, and 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphino) ferrocene is most preferable.
In the synthesis method of the present invention, the ligand is any one of the following formulas L1-L3,
most preferably, the ligand is L1.
In the synthesis method of the present invention, the base is any one of potassium tert-butoxide, NaOH, Tetramethylethylenediamine (TMEDA), triisopropanolamine, diethanolamine, or triethylamine, and most preferably triisopropanolamine.
In the synthesis method of the present invention, the promoter is 2- (tributylstannyl) furan.
In the synthesis method of the present invention, the organic solvent is any one of N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), benzene, ethanol, acetonitrile, 1, 4-dioxane, 1, 2-Dichloroethane (DCE), or N-methylpyrrolidone (NMP), and most preferably 1, 4-dioxane.
The amount of the organic solvent is not strictly limited, and can be appropriately selected and determined by those skilled in the art according to actual conditions, for example, the amount is determined to facilitate the reaction and the post-treatment, and will not be described in detail herein.
In the synthesis method of the present invention, the molar ratio of the compound of formula (I) to the compound of formula (II) is 1:1.5-2, and may be, for example, 1:1.5, 1:1.7, 1:1.9 or 1: 2.
In the synthesis method of the present invention, the molar ratio of the compound of formula (I) to the catalyst is 1:0.05-0.1, and may be, for example, 1:0.05, 1:0.07, 1:0.09, or 1: 0.1.
In the synthesis method of the present invention, the molar ratio of the compound of formula (I) to the ligand is 1:0.1-0.2, and may be, for example, 1:0.1, 1:0.15, or 1: 0.2.
In the synthesis method of the present invention, the molar ratio of the compound of formula (I) to the base is 1:1.2-1.8, and may be, for example, 1:1.2, 1:1.4, 1:1.6 or 1: 1.8.
In the synthesis method of the present invention, the molar ratio of the compound of formula (I) to the promoter is 1:0.03-0.06, and may be, for example, 1:0.03, 1:0.04, 1:0.05 or 1: 0.06.
In the synthesis method of the present invention, the reaction temperature is 70 to 100 ℃, and for example, may be 70 ℃, 80 ℃, 90 ℃ or 100 ℃.
In the synthesis method of the present invention, the reaction time is 6 to 10 hours, for example, 6 hours, 8 hours, or 10 hours.
In the synthesis method of the present invention, the post-treatment after the reaction is completed is specifically as follows: after the reaction is finished, filtering a reaction system obtained after the reaction is finished, pouring a filtrate into distilled water, adjusting the pH value of the obtained mixed solution to be 7-8 under stirring, standing until no solid is precipitated, filtering to obtain a solid, fully washing for 2-3 times by using deionized water, and completely drying in vacuum to obtain the compound of the formula (III).
As described above, the invention provides a synthesis method of a neurosurgical drug temazepam intermediate compound, and the synthesis method can obtain a target product at a high yield through selection of a specific reaction substrate and comprehensive selection and cooperation of a catalyst, a ligand, an alkali, an accelerator and an organic solvent, provides an intermediate with high purity and high yield for the synthesis of the temazepam, and has good application prospect and industrial production potential in the field of medicines.
In a second aspect, the present invention relates to a recrystallization purification method of the compound of the above formula (III), said recrystallization purification method comprising the steps of:
s1: obtaining the compound of formula (III) according to the synthesis method;
s2: at room temperature, adding the compound of the formula (III) obtained in the step S1 into a mixed solvent of chloroform and petroleum ether with a boiling range of 90-120 ℃ in a volume ratio of 1:4-5, heating to 60-70 ℃ at a heating rate of 5 ℃/min, fully stirring until the compound is completely dissolved, stopping stirring, and keeping the temperature for 25-35 min;
s3: and after the heat preservation is finished, cooling to 8-12 ℃ at a cooling rate of 1-5 ℃/min, standing for 60-70 min at the temperature, filtering, fully washing the obtained needle crystal with deionized water for 2-3 times, and fully drying in a vacuum oven completely to obtain the purified compound of the formula (III).
In the recrystallization purification method of the compound (III) according to the present invention, in the step S2, the ratio of the compound of the formula (III) of the step S1 in grams (g) to the mixed solvent in milliliters (ml) is 1:5 to 7, that is, 5 to 7ml of the mixed solvent is used for 1 gram of the compound of the formula (III).
In the method for purifying compound (III) by recrystallization according to the present invention, in step S3, the temperature decrease rate is 1 to 5 ℃/min, and most preferably 3 ℃/min.
The inventor finds that the purity of the target product can be further improved by the recrystallization purification method, so that a brand new purification method of the compound is provided, a higher-purity raw material is provided for subsequent reactions, subsequent flow post-treatment is simplified, the treatment difficulty of the subsequent reactions is reduced, and the method has important significance and effect in the full-flow production of temazepam.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
Example 1
Adding 100mmol of the compound of the formula (I), 150mmol of the compound of the formula (II), 10mmol of catalyst 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene, 10mmol of ligand L1, 180mmol of alkali triisopropanolamine and 3mmol of promoter 2- (tributylstannyl) furan into a proper amount of organic solvent 1, 4-dioxane at room temperature, stirring, heating to 70 ℃, and keeping the temperature for reaction for 10 hours;
after the reaction is finished, filtering a reaction system obtained after the reaction is finished, pouring a filtrate into distilled water, adjusting the pH value of the obtained mixed solution to be 7-8 under stirring, standing until no solid is precipitated, filtering to obtain a solid, fully washing for 2-3 times by using deionized water, and completely drying in vacuum to obtain the compound shown as the formula (III), wherein the yield is 97.9%, the purity is 91.9% by HPLC (high performance liquid chromatography), and the characterization data are as follows:
melting point: 113.2-114.5 ℃.
1H-NMR(400MHz,DMSO-d6)δ:7.36(d,1H),7.54-7.64(m,3H),7.72(d,1H),8.07(d,1H)，8.10(d，2H)。
Example 2
The reaction formula is the same as that of example 1, and the specific reaction process is as follows:
adding 100mmol of the compound of the formula (I), 200mmol of the compound of the formula (II), 5mmol of catalyst 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene, 20mmol of ligand L1, 120mmol of alkali triisopropanolamine and 6mmol of promoter 2- (tributylstannyl) furan into a proper amount of organic solvent 1, 4-dioxane at room temperature, stirring, heating to 100 ℃, and keeping the temperature for reaction for 6 hours;
after the reaction is finished, filtering a reaction system obtained after the reaction is finished, pouring a filtrate into distilled water, adjusting the pH value of the obtained mixed solution to 7-8 under stirring, standing until no solid is precipitated, filtering to obtain a solid, fully washing for 2-3 times by using deionized water, and completely drying in vacuum to obtain the compound of the formula (III), wherein the yield is 97.6%, the purity is 92.2% by HPLC (high performance liquid chromatography), and the characterization data are the same as those of example 1.
Example 3
The reaction formula is the same as that of example 1, and the specific reaction process is as follows:
adding 100mmol of the compound of the formula (I), 170mmol of the compound of the formula (II), 8mmol of catalyst 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene, 15mmol of ligand L1, 150mmol of alkali triisopropanolamine and 4mmol of promoter 2- (tributylstannyl) furan into a proper amount of organic solvent 1, 4-dioxane at room temperature, stirring, heating to 80 ℃, and keeping the temperature for reaction for 9 hours;
after the reaction is finished, filtering a reaction system obtained after the reaction is finished, pouring a filtrate into distilled water, adjusting the pH value of the obtained mixed solution to be 7-8 under stirring, standing until no solid is precipitated, filtering to obtain a solid, fully washing for 2-3 times by using deionized water, and completely drying in vacuum to obtain the compound of the formula (III), wherein the yield is 97.5%, the purity is 92.1% by HPLC (high performance liquid chromatography), and the characterization data are the same as those of example 1.
Example 4
The reaction formula is the same as that of example 1, and the specific reaction process is as follows:
adding 100mmol of the compound of the formula (I), 190mmol of the compound of the formula (II), 6mmol of catalyst 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene, 12mmol of ligand L1, 160mmol of alkali triisopropanolamine and 5mmol of promoter 2- (tributylstannyl) furan into a proper amount of organic solvent 1, 4-dioxane at room temperature, stirring, heating to 90 ℃, and keeping the temperature for reaction for 7 hours;
after the reaction is finished, filtering a reaction system obtained after the reaction is finished, pouring a filtrate into distilled water, adjusting the pH value of the obtained mixed solution to 7-8 under stirring, standing until no solid is precipitated, filtering to obtain a solid, fully washing for 2-3 times by using deionized water, and completely drying in vacuum to obtain the compound of the formula (III), wherein the yield is 98.0%, the purity is 91.7% by HPLC (high performance liquid chromatography), and the characterization data are the same as those of example 1.
As can be seen from the above examples 1-4, according to the synthesis method of the present invention, the target product can be obtained with high yield, and the purity is greater than 90%, and the target product can be completely directly used for the next subsequent reaction.
In order to examine the influence of each technical feature on the final result, the following comprehensive examination is performed on each technical element.
Examples 5 to 20
Examples 5 to 8: except that catalyst 1,2,3,4, 5-Pentaphenyl-1' - (di-tert-butylphosphine) ferrocene was replaced with iron acetylacetonate (Fe (acac)3) Otherwise, the other operations were not changed, so that examples 1 to 4 were repeated, and examples 5 to 8 were obtained in this order.
Examples 9 to 12: examples 1-4 were repeated except that the catalyst 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphino) ferrocene was replaced with cyclooctatetraene iron tricarbonyl, and examples 9-12 were obtained in sequence.
Examples 13 to 16: examples 1 to 4 were repeated except that 1,2,3,4, 5-pentaphenyl-1' - (di-t-butylphosphino) ferrocene, a catalyst, was replaced with tris (2,2,6, 6-tetramethyl-3, 5-heptanedionato) iron, and examples 13 to 16 were obtained in this order.
Examples 17 to 20: examples 1-4 were repeated except that catalyst 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphino) ferrocene was replaced with tris (dibenzoylmethyl) iron, and examples 17-20 were obtained in sequence.
The results are shown in Table 1 below.
TABLE 1
It can be seen that 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene is the most effective catalyst in all catalysts, and other organic iron compounds cause significant yield reduction, especially the most significant reduction in tris (dibenzoylmethyl) iron.
Examples 21 to 32
Examples 21 to 24: the procedures were unchanged except for the replacement of ligand L1 with L2, thereby repeating examples 1-4 and obtaining examples 21-24 in sequence.
Examples 25 to 28: the procedures were unchanged except for the replacement of ligand L1 with L3, thereby repeating examples 1-4 and obtaining examples 25-28 in sequence.
Examples 29 to 32: the procedures were otherwise unchanged except that ligand L1 was omitted, thereby repeating examples 1-4 and obtaining examples 29-32 in sequence.
The results are shown in Table 2 below.
TABLE 2
It can be seen that although ligands L1-L3 have the same parent structure (all phenanthroline structures), the presence or absence and type of substituents thereon have significant impact on the final results, and even though the substitution of the bromine substituent in L1 with a methyl group gives L2, the effect is still significantly reduced, and the reduction is most significant when no substituent is present.
Examples 33 to 52
Examples 33 to 36: examples 1-4 were repeated, except that the base triisopropanolamine was replaced with potassium tert-butoxide, to give examples 33-36 in that order.
Examples 37 to 40: the procedures were unchanged except that the base triisopropanolamine was replaced with NaOH, thereby repeating examples 1-4 and obtaining examples 37-40 in sequence.
Examples 41 to 44: examples 1-4 were repeated except that the base triisopropanolamine was replaced with Tetramethylethylenediamine (TMEDA) to provide examples 41-44 in sequence.
Examples 45 to 48: the procedures were unchanged except that the base triisopropanolamine was replaced with diethanolamine, thereby repeating examples 1-4 to give examples 45-48 in sequence.
Examples 49 to 52: the procedures were unchanged except that the base triisopropanolamine was replaced with triethylamine, thereby repeating examples 1-4 and obtaining examples 49-52 in sequence.
The results are given in Table 3 below.
TABLE 3
It can be seen that of all the bases, triisopropanol has the best effect, while even diethanolamine, which is very similar thereto, has a significant decrease in effect, while Tetramethylethylenediamine (TMEDA) has the worst effect.
Examples 53 to 56
Examples 1-4 were repeated, with the exception that the promoter 2- (tributylstannyl) furan was omitted, to provide examples 53-56 in sequence.
As a result, it was found that the yield of the product was 88.1 to 89.5%, which was very significantly reduced as compared with examples 1 to 4, and this proved that the presence of the promoter could significantly improve the reaction effect, thereby greatly improving the product yield, which was unexpected.
Examples 57 to 63
Examples 1-4 were repeated except that the organic solvent 1, 4-dioxane was replaced with the other solvents of Table 4 below, to give the following examples 57-63, and the organic solvents used, the corresponding examples, and the product yields are shown in Table 4 below.
TABLE 4
It can be seen that 1, 4-dioxane has the best effect in all organic solvents, and other solvents, especially acetonitrile, have a certain reduction, and the product yield is already lower than 90%.
Purification by recrystallization example 1
S1: obtaining said compound of formula (III) according to example 1;
s2: adding the compound of the formula (III) obtained in the step S1 into a mixed solvent of chloroform and petroleum ether with a boiling range of 90-120 ℃ in a volume ratio of 1:4 at room temperature, wherein the ratio of the compound of the formula (III) in grams (g) to the mixed solvent in milliliters (ml) is 1:5, heating to 60 ℃ at a heating rate of 5 ℃/min, fully stirring until the compound is completely dissolved, stopping stirring and keeping the temperature for 35 min;
s3: after the heat preservation is finished, cooling to 8 ℃ at a cooling rate of 3 ℃/min, standing for 60 min at the temperature, filtering, fully washing the obtained needle crystal with deionized water for 2-3 times, fully drying in a vacuum oven completely to obtain the purified compound of the formula (III), wherein the purity of the compound of the formula (III) is 99.4% through HPLC (high performance liquid chromatography) determination.
Purification by recrystallization example 2
S1: obtaining said compound of formula (III) according to example 2;
s2: adding the compound of the formula (III) obtained in the step S1 into a mixed solvent of chloroform and petroleum ether with a boiling range of 90-120 ℃ in a volume ratio of 1:5 at room temperature, wherein the ratio of the compound of the formula (III) in grams (g) to the mixed solvent in milliliters (ml) is 1:7, heating to 70 ℃ at a heating rate of 5 ℃/minute, fully stirring until the compound is completely dissolved, stopping stirring and keeping the temperature for 25 minutes;
s3: after the heat preservation is finished, cooling to 12 ℃ at a cooling rate of 3 ℃/min, standing for 70 min at the temperature, filtering, fully washing the obtained needle crystal with deionized water for 2-3 times, fully drying in a vacuum oven completely to obtain the purified compound of the formula (III), wherein the purity of the compound of the formula (III) is 99.6% through HPLC (high performance liquid chromatography) determination.
Purification by recrystallization example 3
S1: obtaining said compound of formula (III) according to example 3;
s2: adding the compound of the formula (III) obtained in the step S1 into a mixed solvent of chloroform and petroleum ether with a boiling range of 90-120 ℃ in a volume ratio of 1:4.5 at room temperature, wherein the ratio of the compound of the formula (III) in grams (g) to the mixed solvent in milliliters (ml) is 1:6, heating to 65 ℃ at a heating rate of 5 ℃/min, fully stirring until the dissolution is complete, and stopping stirring and keeping the temperature for 30 minutes;
s3: after the heat preservation is finished, cooling to 10 ℃ at a cooling rate of 3 ℃/min, standing for 65 minutes at the temperature, then filtering, fully washing the obtained needle crystal with deionized water for 2-3 times, fully drying in a vacuum oven completely, thus obtaining the purified compound of the formula (III), and the purity of the compound of the formula (III) is 99.5% through HPLC (high performance liquid chromatography) determination.
Purification by recrystallization example 4
S1: obtaining the compound of formula (III) according to example 4;
s2: adding the compound of the formula (III) obtained in the step S1 into a mixed solvent of chloroform and petroleum ether with a boiling range of 90-120 ℃ in a volume ratio of 1:4.5 at room temperature, wherein the ratio of the compound of the formula (III) in grams (g) to the mixed solvent in milliliters (ml) is 1:6, heating to 70 ℃ at a heating rate of 5 ℃/min, fully stirring until the dissolution is complete, and stopping stirring and keeping the temperature for 35 minutes;
s3: after the heat preservation is finished, cooling to 9 ℃ at a cooling rate of 3 ℃/min, standing for 70 min at the temperature, filtering, fully washing the obtained needle crystal with deionized water for 2-3 times, fully drying in a vacuum oven completely to obtain the purified compound of the formula (III), wherein the purity of the compound of the formula (III) is 99.2% through HPLC (high performance liquid chromatography) determination.
In the following, key factors in the purification step of recrystallization are considered.
Comparative examples 1 to 16
Comparative examples 1 to 4: comparative purification examples 1 to 4 were obtained without changing the operation except that the temperature decreasing rate in step S3 of purification examples 1 to 4 by recrystallization was changed to 1 deg.C/min, respectively.
Comparative examples 5 to 8: comparative purification examples 5 to 8 were obtained without changing the operation except that the temperature decreasing rate in step S3 of purification examples 1 to 4 by recrystallization was changed to 2 deg.C/min, respectively.
Comparative examples 9 to 12: comparative purification examples 9 to 12 were obtained without changing the operation except that the temperature decreasing rate in step S3 of purification examples 1 to 4 by recrystallization was changed to 4 ℃ per minute, respectively.
Comparative examples 13 to 16: comparative purification examples 13 to 16 were obtained without changing the operation except that the temperature decreasing rate in step S3 of purification examples 1 to 4 by recrystallization was changed to 5 deg.C/min, respectively.
The purity of the final product obtained is shown in table 5 below.
TABLE 5
It can be seen that the temperature reduction rate in step S3 has a significant effect on the final product purity, with a temperature reduction rate of 3 ℃/min being optimal, and the product purity being lower when the deviation is greater than 3 ℃/min.
In conclusion, the invention provides a synthesis method and a recrystallization purification method of a temazepam intermediate compound, and the synthesis method can obtain a target product with high yield through a unique reaction system. The recrystallization purification method can obviously improve the purity of the product through a unique recrystallization method, provides a brand new method for purifying the compound, and has good application prospect and potential.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should also be understood that various alterations, modifications and/or variations can be made to the present invention by those skilled in the art after reading the technical content of the present invention, and all such equivalents fall within the protective scope defined by the claims of the present application.
Claims (6)
1. A synthetic method of a neurosurgical drug temazepam intermediate compound shown as a formula (III) below comprises the following steps: reacting a compound shown in the following formula (I) and a compound shown in the formula (II) in an organic solvent in the presence of a catalyst, a ligand, alkali and a promoter, and performing post-treatment after the reaction is finished to obtain the compound shown in the formula (III),
the catalyst is 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphine) ferrocene;
the ligand is of the formula L1,
the base is triisopropanolamine;
the promoter is 2- (tributylstannyl) furan;
the organic solvent is 1, 4-dioxane.
2. The method of synthesis of claim 1, wherein: the molar ratio of the compound of the formula (I) to the compound of the formula (II) is 1: 1.5-2.
3. The method of synthesis of claim 1, wherein: the molar ratio of the compound of the formula (I) to the catalyst is 1: 0.05-0.1.
4. The method of synthesis of claim 1, wherein: the molar ratio of the catalyst to the ligand is 1: 0.1-0.2.
5. The method of synthesis according to any one of claims 1 to 4, characterized in that: the molar ratio of the compound of the formula (II) to the base is 1: 1.2-1.8.
6. A recrystallization purification method of the compound of formula (III), the recrystallization purification method comprising the steps of:
s1: obtaining the compound of formula (III) according to the synthesis method of any one of claims 1-5;
s2: at room temperature, adding the compound of the formula (III) obtained in the step S1 into a mixed solvent of chloroform and petroleum ether with a boiling range of 90-120 ℃ in a volume ratio of 1:4-5, heating to 60-70 ℃ at a heating rate of 5 ℃/min, fully stirring until the compound is completely dissolved, stopping stirring, and keeping the temperature for 25-35 min;
s3: and after the heat preservation is finished, cooling to 8-12 ℃ at a cooling rate of 1-5 ℃/min, standing for 60-70 min at the temperature, filtering, fully washing the obtained needle crystal with deionized water for 2-3 times, and fully drying in a vacuum oven completely to obtain the purified compound of the formula (III).
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Non-Patent Citations (2)
| Title |
|---|
| Intramolecular Fe(II)-Catalyzed N Oor N N Bond Formation from Aryl Azides;Benjamin J. Stokes et al.;《Organic Letters》;20100527;第12卷(第12期);第2884-2887页 * |
| 阿普唑仑的化学合成;姚建新等;《郑州大学学报（医学版）》;20080731;第43卷(第4期);第791-793页 * |
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