CN113816913A - Preparation method of oxazepam intermediate - Google Patents
Preparation method of oxazepam intermediate Download PDFInfo
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- CN113816913A CN113816913A CN202111142826.8A CN202111142826A CN113816913A CN 113816913 A CN113816913 A CN 113816913A CN 202111142826 A CN202111142826 A CN 202111142826A CN 113816913 A CN113816913 A CN 113816913A
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- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229960004535 oxazepam Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 81
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 17
- 238000007670 refining Methods 0.000 claims abstract description 13
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 239000002798 polar solvent Substances 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 10
- 238000004321 preservation Methods 0.000 claims abstract description 10
- 239000000463 material Substances 0.000 claims abstract description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000012043 crude product Substances 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 12
- 238000004537 pulping Methods 0.000 claims description 9
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 8
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- -1 alkali metal acetate Chemical class 0.000 claims description 4
- 235000011056 potassium acetate Nutrition 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 abstract description 11
- 230000010933 acylation Effects 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000010865 sewage Substances 0.000 abstract description 4
- 230000008707 rearrangement Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000006462 rearrangement reaction Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FYRWUTOZBRWYCS-UHFFFAOYSA-N (7-chloro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl) acetate Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(OC(=O)C)N=C1C1=CC=CC=C1 FYRWUTOZBRWYCS-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229940001470 psychoactive drug Drugs 0.000 description 2
- 239000004089 psychotropic agent Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960003188 temazepam Drugs 0.000 description 2
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000029650 alcohol withdrawal Diseases 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
Abstract
The invention discloses a preparation method of an oxazepam intermediate, which comprises the steps of adding acetic anhydride and anhydrous acetate into 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide in an aprotic polar solvent, stirring and heating for carrying out heat preservation reaction, cooling, separating out materials, and refining to obtain the oxazepam intermediate shown in the formula I. The method carries out acylation and rearrangement under the formed homogeneous system, improves the reaction yield, greatly reduces the consumption of acetic anhydride, and reduces the cost of raw materials and the cost of sewage treatment; in addition, the reaction is stable in a homogeneous system, the safety is obviously improved, and the method is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of preparation of medical intermediates, in particular to a preparation method of an oxazepam intermediate.
Background
Oxazepam (Oxazepam) is a benzodiazepine
Sedative hypnotic, which is mainly used for treating anxiety, insomnia and alcohol withdrawal clinically. The advantages of oxazepam are mainly embodied in that the metabolic process is simple, and the influence of age and liver function is small; the half-life period is short, and the accumulation in the body is not easy to occur; the drug is less addictive, and is especially suitable for patients with mild liver function damage and the elderly.
Oxazepam intermediate 7-chloro-5-phenyl-3-acetoxy-2, 3-dihydro-1-H-1, 4-benzodiazepin-2-one, CAS No.: 1824-74-4, which has the structural formula:
7-chloro-5-phenyl-3-acetoxy-2, 3-dihydro-1-H-1, 4-benzodiazepine-2-one is a key intermediate for the preparation of oxazepam and is also an oxazepam impurity B specified in European pharmacopoeia EP 8.0.
The oxazepam intermediate 7-chloro-5-phenyl-3-acetoxyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-2-one is prepared by acylation and rearrangement reactions of 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide serving as a raw material under the action of acetic anhydride. The synthetic route is as follows:
the acylation and rearrangement process of the oxazepam product is characterized in that 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide and acetic anhydride react at the high temperature of 97-100 ℃ to prepare the oxazepam product, wherein the mass ratio of the 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide to the acetic anhydride is 1: 14.05. The prior art mainly has the defects of large acetic anhydride consumption, pasty heterogeneous state of a reaction system when the acetic anhydride consumption is lower than the reaction temperature, difficult temperature control caused by severe temperature rise of the system when the reaction temperature is close to the reaction temperature, larger impurities of a target product, difficult recycling of acid-containing mother liquor, increased sewage treatment burden and the like.
During the acylation and rearrangement process preparation process of benzodiazepines psychotropic drugs, including oxazepam, lorazepam, temazepam, chlordiazepam and the like, reaction raw materials and acetic anhydride are adopted to simultaneously generate oxygen acylation reaction and acetoxyl transposition rearrangement reaction under the high-temperature condition of 80-100 ℃, other solvents and catalysts are not added in the prior art of the reaction, and the reaction is directly carried out under the high-temperature condition by taking the greatly excessive acetic anhydride as an acylating agent and also as a solvent, wherein the mass ratio of substances of a reaction substrate and the acetic anhydride is up to 1: about 15.
In the literature, "research on synthesis process of chlordiazepam" (pharmaceutical research, 2017, 36, 485 and 489), a reaction substrate substance is added in a ratio of 1: 15.04 and keeping the temperature of 100 ℃ for reaction for 3 hours to carry out acylation and rearrangement reaction.
In the literature, synthesis of the hypnotic agent temazepam (proceedings of the university of medical science in China 1997, 28, 201-203), the reaction substrate substances are added in a quantity ratio of 1: and (3) carrying out heat preservation reaction on 15.8 times of acetic anhydride at the temperature of 97-100 ℃ for 1 hour for acylation and rearrangement reaction.
The technicians generally think that the acylation and rearrangement reaction of benzodiazepine psychotropic drugs only needs to be carried out under the condition that a reaction substrate exists in the presence of single acetic anhydride with large excess, and the prior art has the following defects: the material system can only present a homogeneous state in a high-temperature environment, but the violent heat release of the material system increases the temperature control difficulty and is easy to generate organic impurities under the high-temperature condition, thereby influencing the purity of a target compound; the mother liquor generated after the reaction can not be recycled, and the sewage treatment cost of enterprises is increased.
Disclosure of Invention
The invention aims to provide a preparation method of an oxazepam intermediate, which is used for solving at least one of the problems.
In view of this, the scheme of the invention is as follows:
a preparation method of an oxazepam intermediate comprises the following steps: adding acetic anhydride and anhydrous acetate into the compound of the formula II in an aprotic polar solvent, stirring and heating to perform heat preservation reaction, and then cooling, separating out and refining to obtain an oxazepam intermediate as shown in the formula I; the preparation method comprises the following steps:
further, the dosage ratio of the compound shown in the formula II to acetic anhydride is 1 g: (0.6-1) ml.
Further, the compound of formula II and the aprotic polar solvent are used in a ratio of 1 g: (0.6-1) ml.
Further, the aprotic polar solvent is one or both of dimethylformamide and dimethylacetamide.
Further, the mass ratio of the compound of the formula II to the alkali metal acetate is 1: (0.1-0.2). Preferably, the alkali metal acetate is anhydrous sodium acetate and/or anhydrous potassium acetate.
Further, the reaction is carried out for 1.5 to 2.5 hours at the temperature of between 95 and 100 ℃ and is cooled to between-5 and 5 ℃ after the reaction is finished.
Further, the material separating process is to add water for material separating, and the mass ratio of the water to the compound of the formula II is (0.2-0.8): 1.
further, the refining process is that the crude product is pulped in a mixed solvent of ethanol and water to obtain the oxazepam intermediate. Preferably, the mass ratio of the total volume of the mixed solvent to the compound of formula II is (2-5) ml: 1g, wherein the volume ratio of ethanol to water in the mixed solvent is (4-2): 1.
compared with the prior art, the invention has the following effects:
1. the invention improves the conversion rate of the oxazepam acylation rearrangement reaction under the condition of greatly reducing the using amount of acetic anhydride, and obtains a high-purity product; meanwhile, the discharge amount of acid-containing wastewater is greatly reduced, and the raw material cost and the sewage treatment cost are obviously reduced;
2. according to the invention, dimethylformamide or dimethylacetamide is used as a reaction solvent, and acylation and rearrangement reactions are carried out under the condition that anhydrous acetate is used as a catalyst, so that a homogeneous reaction system is formed, the phenomenon of severe cascade rise does not occur in the reaction process due to stable temperature, the production safety is obviously improved, and the method is suitable for large-scale industrial production.
Detailed Description
In order to make the objects, technical solutions and advantageous effects of the present invention more apparent, the present invention is further described in detail with reference to the following detailed description. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The invention provides a method for preparing an oxazepam intermediate (formula I) from 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide (formula II), which comprises the following steps:
the preparation method comprises the following steps:
s1, adding anhydrous acetate into 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide (hereinafter referred to as a compound of a formula II), acetic anhydride and an aprotic polar solvent, stirring, heating to 95-100 ℃, then carrying out heat preservation reaction for 1.5-2.5H, cooling to-5 ℃ after the reaction is finished, more preferably, adding water, precipitating, filtering and washing to obtain a target product crude product; the aprotic polar solvent is dimethylformamide and/or dimethylacetamide, and the proportion of the compound shown in the formula II to the aprotic polar solvent is 1 g: (0.6-1.0) ml; the mixture ratio of the compound shown in the formula II to acetic anhydride is 1 g: (0.6-1.0) ml; the mass ratio of the compound shown in the formula II to the anhydrous acetate is 1: (0.1 to 0.2); the mass ratio of the water added in the material separating process to the compound shown in the formula II is (0.2-0.8): 1, preferably (0.4-0.6): 1.
s2, pulping and refining the crude product of the target product in the step S1 in a mixed solvent of ethanol and water to obtain a product; the ratio of the mixed solvent to the compound of formula II is (2-5) ml: 1g of a compound; ethanol and water in the mixed solvent are mixed according to the following formula (4-2): 1 by volume.
The 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide is prepared according to a preparation method introduced in the national raw material medicine process compilation (the national institute of medicine and administration, nineteen-eight-year) page 797-799, and is purified to the purity of 99.9 wt%.
Example 1
Adding 30g of 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide, 24ml of acetic anhydride, 24ml of dimethylformamide and 3g of anhydrous sodium acetate into a reaction bottle in sequence, stirring, heating to 95-100 ℃, and then carrying out heat preservation reaction for 2 hours. Cooling to 0 ℃, dropwise adding 12g of water, continuing stirring at-5-0 ℃ for 0.5 hour after the addition is finished, standing for more than 2 hours, filtering, and washing with water to obtain an oxazepam intermediate crude product. And adding the crude product into a mixed solvent of 90ml ethanol and 30ml water, pulping and refining to obtain 31.8g of oxazepam intermediate, wherein the HPLC purity is 99.4%, and the yield is 92.4%.
Example 2
Adding 30g of 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide, 18ml of acetic anhydride, 20ml of dimethylformamide, 10ml of dimethylacetamide and 4.5g of anhydrous potassium acetate into a reaction bottle in sequence, stirring and heating to 95-100 ℃, and then carrying out heat preservation reaction at 95-100 ℃ for 2.5 hours. Cooling to-5 ℃, dropwise adding 18g of water, continuing stirring at-5-0 ℃ for 0.5 hour after the addition is finished, standing for more than 2 hours, filtering, and washing with water to obtain an oxazepam intermediate crude product. And adding the crude product into a mixed solvent of 40ml of ethanol and 20ml of water, pulping and refining to obtain 31.6g of oxazepam intermediate, wherein the HPLC purity is 99.1%, and the yield is 91.9%.
Example 3
Adding 7g of chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide, 30ml of acetic anhydride, 18ml of dimethylacetamide, 3g of anhydrous potassium acetate and 3g of anhydrous sodium acetate into a reaction bottle in sequence, stirring and heating to 95-100 ℃, and then carrying out heat preservation reaction for 1.5 hours. Cooling to 5 ℃, dropwise adding 15g of water, continuing stirring at-5-0 ℃ for 0.5 hour after the addition is finished, standing for more than 2 hours, filtering, and washing with water to obtain an oxazepam intermediate crude product. And adding the crude product into a mixed solvent of 40ml of ethanol and 20ml of water, pulping and refining to obtain 31.7g of oxazepam intermediate, wherein the HPLC purity is 99.2%, and the yield is 92.2%.
Comparative example 1
Adding 30g of 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide, 24ml of acetic anhydride, 24ml of dimethylformamide and 3g of anhydrous sodium acetate into a reaction bottle in sequence, stirring, heating, and carrying out heat preservation reaction at 88-92 ℃ for 2 hours. Cooling to 0 ℃, dropwise adding 12g of water, continuing stirring at-5-0 ℃ for 0.5 hour after the addition is finished, standing for more than 2 hours, filtering, and washing with water to obtain an oxazepam intermediate crude product. And adding the crude product into a mixed solvent of 90ml ethanol and 30ml water, pulping and refining to obtain 21.6g of oxazepam intermediate, wherein the HPLC purity is 87.4%, and the yield is 62.8%.
Comparative example 2
30g of 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide, 24ml of acetic anhydride, 24ml of dimethylformamide and 3g of anhydrous sodium acetate are sequentially added into a reaction bottle, stirred and heated to 102 ℃ and 106 ℃ for heat preservation reaction for 2 hours. Cooling to 0 ℃, dropwise adding 12g of water, continuing stirring at-5-0 ℃ for 0.5 hour after the addition is finished, standing for more than 2 hours, filtering, and washing with water to obtain an oxazepam intermediate crude product. And adding the crude product into a mixed solvent of 90ml ethanol and 30ml water, pulping and refining to obtain 25.3g of oxazepam intermediate, wherein the HPLC purity is 90.5%, and the yield is 73.5%.
Comparative example 3
Adding 30g of 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide, 48ml of acetic anhydride and 3g of anhydrous sodium acetate into a reaction bottle in sequence, stirring and heating to 95-100 ℃, keeping the temperature and reacting for 2 hours, flushing materials and temperature fluctuation appear in the reaction process, the temperature in a 95-100 ℃ interval is difficult to keep, and the highest reaction temperature is increased to 121 ℃. Cooling to 0 ℃, dropwise adding 12g of water, continuing stirring at-5-0 ℃ for 0.5 hour after the addition is finished, standing for more than 2 hours, filtering, and washing with water to obtain an oxazepam intermediate crude product. And adding the crude product into a mixed solvent of 90ml ethanol and 30ml water, pulping and refining to obtain 18.7g of oxazepam intermediate, wherein the HPLC purity is 93.5%, and the yield is 54.4%.
Comparative example 4
Adding 30g of 7-chloro-2-oxo-5-phenyl-2, 3-dihydro-1-H-1, 4-benzodiazepine-4-oxide, 24ml of acetic anhydride and 24ml of dimethylformamide into a reaction bottle in sequence, stirring and heating to 95-100 ℃ for reaction, flushing materials and temperature fluctuation appear in the reaction process, cooling to 0 ℃ after reacting for 2 hours, dropwise adding 12g of water, continuing to stir at-5-0 ℃ for 0.5 hour after adding is finished, standing for more than 2 hours, filtering, and washing with water to obtain an oxazepam intermediate crude product. And adding the crude product into a mixed solvent of 90ml ethanol and 30ml water, pulping and refining to obtain 22.3g of oxazepam intermediate, wherein the HPLC purity is 89.2%, and the yield is 64.8%.
It can be seen from examples 1-3 that the preparation method provided by the present invention can obtain a product with a yield of more than 91% and a purity of more than 99%, and thus, under a homogeneous system formed by adding dimethylformamide and/or dimethylacetamide, the addition of anhydrous acetate for catalytic acylation has a significant effect on improving the reaction rate and selectivity, and only a small amount of acetic anhydride is required, which is greatly reduced compared with the existing process.
In comparative examples 1-2, the yield and purity of the obtained product were greatly reduced by increasing and decreasing the reaction temperature, respectively, as compared to example 1, and thus 95-100 ℃ was found to be a preferable reaction temperature. Compared with the example 1, the method has the advantages that a homogeneous system cannot be formed when the aprotic polar solvent is not added, the temperature fluctuation is serious, side reactions are caused, and the purity and the yield of the product are obviously influenced; in comparison with example 1, in the case of example 4, the substrate is not completely converted without adding the catalyst, and the yield and purity are greatly affected.
The invention is not limited to the description and embodiments, and additional advantages and modifications will readily occur to those skilled in the art, so that the invention is not limited to the specific details, representative apparatus, and examples shown and described herein, without departing from the spirit and scope of the general concept as defined by the appended claims and their equivalents.
Claims (10)
1. A preparation method of an oxazepam intermediate is characterized by comprising the following steps: adding acetic anhydride and anhydrous acetate into the compound of the formula II in an aprotic polar solvent, stirring and heating to perform heat preservation reaction, and then cooling, separating out and refining to obtain an oxazepam intermediate as shown in the formula I;
wherein the structural formula of formula I is:
the compound of formula II has the structural formula:
2. the process according to claim 1, wherein the compound of formula II and acetic anhydride are used in a ratio of 1 g: (0.6-1) ml.
3. The process according to claim 1, wherein the compound of formula II and the aprotic polar solvent are used in a ratio of 1 g: (0.6-1) ml.
4. The method according to claim 1, wherein the aprotic polar solvent is one or both of dimethylformamide and dimethylacetamide.
5. The method according to claim 1, wherein the mass ratio of the compound of formula II to the alkali metal acetate is 1: (0.1-0.2).
6. The method according to claim 5, wherein the alkali metal acetate is anhydrous sodium acetate and/or anhydrous potassium acetate.
7. The preparation method of claim 1, wherein the reaction is carried out at 95-100 ℃ for 1.5-2.5h, and the temperature is reduced to-5 ℃ after the reaction.
8. The preparation method according to claim 1, wherein the material separating process is water separation, and the mass ratio of water to the compound of the formula II is (0.2-0.8): 1.
9. the preparation method of claim 1, wherein the refining process comprises pulping the crude product in a mixed solvent of ethanol and water to obtain the oxazepam intermediate.
10. The method according to claim 8, wherein the mass ratio of the total volume of the mixed solvent to the compound of formula II is (2-5) ml: 1g, wherein the volume ratio of ethanol to water in the mixed solvent is (4-2): 1.
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