CN113149907A - Synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one - Google Patents
Synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one Download PDFInfo
- Publication number
- CN113149907A CN113149907A CN202110279894.2A CN202110279894A CN113149907A CN 113149907 A CN113149907 A CN 113149907A CN 202110279894 A CN202110279894 A CN 202110279894A CN 113149907 A CN113149907 A CN 113149907A
- Authority
- CN
- China
- Prior art keywords
- bromo
- tetrahydro
- reaction
- benzazepin
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-ketone, belonging to the technical field of organic synthesis, wherein gamma-butyrolactone and benzene which are cheap and easy to obtain are used as starting raw materials to sequentially synthesize 2-bromo-1-tetralone, 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthylimine and 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-ketone. The synthesis method takes gamma-butyrolactone and benzene as starting raw materials, and 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-ketone is obtained through cyclization reaction, bromination reaction, oxime formation reaction and Beckmann rearrangement reaction respectively. The invention has the advantages of simple production process, low production cost, simple operation, less three wastes generation and less environmental pollution, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one.
Background
3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one is an important intermediate for synthesizing benazepril hydrochloride. Benazepril hydrochloride is an Angiotensin Converting Enzyme Inhibitor (ACEI) developed by Giba-Geigy, Switzerland, is mainly used for treating hypertension and congestive heart failure, and has the advantages of less adverse reaction and good safety. Benazepril hydrochloride is a national medical insurance B product, is the most widely used Angiotensin Converting Enzyme Inhibitor (ACEI) in the market of China at present, and is a first-line medicament for clinically treating hypertension in China.
The key intermediate for synthesizing the 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one is alpha-tetralone. There are three main methods reported in the literature for the synthesis of α -tetralone:
1, benzene butyric acid or benzene butyryl chloride is used as a starting material, and alpha-tetralone is generated through cyclization reaction, so that the price of the starting material is high, and the application of the strategy is limited.
2, tetrahydronaphthalene is used as an initial raw material, oxygen and/or air is used as an oxidant, a catalytic system is ferric ion, nitrate ion and N-hydroxyphthalimide are jointly used (CN 111606791) or N-hydroxyphthalimide and nitrite are jointly catalyzed (CN 107011133), but the synthesis strategy generally generates hydroxyl and poly-oxidation products and needs column chromatography purification, which limits the large-scale production.
3, using gamma-butyrolactone and benzene as initial raw materials in AlCl3Synthesizing alpha-tetralone under catalysis. The raw materials of the strategy are cheap and easy to obtain, and the process is also suitable for industrial production.
The synthesis strategies for synthesizing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one by using alpha-tetralone as a starting material are roughly divided into two types: one is to first form oxime, then carry out Beckmann rearrangement reaction, and finally carry out bromination reaction to obtain the target product. The other method is to carry out bromination and oxime formation reaction firstly and then carry out Beckmann rearrangement reaction to obtain a target product.
1. Taking alpha-tetralone as a starting material, firstly carrying out oxime forming reaction, then carrying out Beckmann rearrangement, and finally carrying out bromination reaction to obtain a target product. As described in the documents bio.med.chem.2015, 25, 3488, US6777550, US4575503, US4410520 and US 4473575.
2. Alpha-tetralone is used as an initial raw material, bromination and oxime formation reaction are firstly carried out, and finally Beckmann rearrangement is carried out to obtain a target product. As described in the Journal of Heterocyclic Chemistry, 1994, 31, 1545, CN105017154, US 5677297.
In the two strategies, a large amount of liquid bromine is used during bromination, and firstly, the liquid bromine is volatile in the use process, has strong toxicity and corrosiveness, and can stimulate eyes and respiratory mucosa. In the use process of the liquid bromine, higher requirements are also put forward for equipment and personnel. Secondly, after the liquid bromine reaction is finished, one molecule of hydrobromic acid is generated, so that the waste liquid is strongly acidic, which also increases the difficulty of waste liquid treatment.
Therefore, there is a need in the art to develop a new, more mild and efficient method for preparing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one.
Disclosure of Invention
The invention aims to solve the technical problems of one or more of troublesome post-treatment, lower yield, large environmental pollution, higher cost and the like in the existing synthesis method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-ketone.
The technical scheme of the invention is to provide a synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-ketone.
The invention provides a synthesis method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-ketone, which takes compound alpha-tetralone as a precursor, and respectively obtains the 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-ketone through bromination, oxime formation and Beckmann rearrangement reaction. The specific synthetic route is as follows:
the method specifically comprises the following steps:
1) synthesis of alpha-tetralone
Adding aluminum trichloride into benzene, adding gamma-butyrolactone while stirring, refluxing after the addition is completed until the reaction is complete, adding a hydrochloric acid solution for hydrolysis after the reaction is completed, stirring for 0.5-3 hours, then layering, washing an organic layer with water, alkali and water respectively to neutrality, performing rotary evaporation to remove benzene to obtain a crude product, and performing reduced pressure distillation on the crude product to obtain alpha-tetralone;
2) synthesis of 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide
S1, adding alpha-tetralone, HBr solution and H into a reaction bottle in sequence2O and methanol, adding Oxone into the mixture, reacting at 30-35 ℃ until the reaction is complete, and standing to separate out a lower organic phase; s2, adding methanol into the organic phase, adding hydroxylamine sulfate, adding water for dilution after the addition is finished, then carrying out heat preservation reaction at 25-40 ℃ for 60-90 hours, adding baking soda after the heat preservation reaction is finished, carrying out heat preservation reaction at 25-40 ℃ for 40-60 hours, filtering, washing a filter cake with water, and leaching with methanol to obtain a 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide crude product for later use;
3) synthesis of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one
Adding polyphosphoric acid into a reaction bottle, heating to 60-80 ℃ for later use, adding another reaction bottle, heating to 60-85 ℃ to dissolve a 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthylimine crude product and toluene, keeping the temperature and standing for 0.5-1 hour, separating out a water phase, directly adding the toluene phase into the polyphosphoric acid liquid, keeping the temperature at 75-90 ℃ for stirring reaction, cooling to room temperature after the reaction is finished, pouring out a toluene phase, adding water, keeping the temperature at 20-40 ℃, stirring for 1-3 hours, filtering, washing a filter cake with water, washing with saturated sodium bicarbonate, washing with water, and drying the filter cake to obtain a 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-one crude product;
4) refining of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one
Dissolving the crude product with methanol, adding activated carbon for decolorization, filtering decolorized mother liquor, removing half of methanol, cooling to a temperature lower than 10 ℃ for recrystallization, filtering, and drying filter cakes to obtain a pure product of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-one.
Preferably, the molar ratio of the gamma-butyrolactone, the benzene and the anhydrous aluminum trichloride is 1 (8-10) to (2-3).
Preferably, in the step 1), the concentration of the hydrochloric acid solution is 10wt%, and the addition amount of the hydrochloric acid solution is 1-2 times of the mass of the benzene.
Preferably, in step 2), the molar ratio of α -tetralone, HBr and Oxone is: 1: 2 (2-2.5), and the molar ratio of the alpha-tetralone to the hydroxylamine sulfate to the baking soda is 1:1: 1.5.
Preferably, the water and methanol are added in a mass ratio of 8:9 in the step of S1 and 3:5 in the step of S2.
Preferably, in step 3), the polyphosphoric acid is added in an amount of 3 to 8 times by weight of 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthylimine, and the volume ratio of toluene to water added is 3: 4.
Preferably, the adding amount of the activated carbon is 15-20% of the mass of the crude product of the 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one.
The invention has the following beneficial effects: simple operation, less generation of three wastes and less environmental pollution, and is more suitable for industrial production.
The invention has the advantages of being embodied in the synthetic process of 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthylimine. HBr is used for replacing liquid bromine, so that the difficulty of process operation is reduced, the generation of acid wastewater is reduced, and the recycling of a solvent can be realized.
Drawings
FIG. 1 is a GC spectrum of α -tetralone of example 1;
FIG. 2 is an HPLC chromatogram of crude 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide of example 1;
FIG. 3 is an HPLC chromatogram of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one of example 1;
FIG. 4 is a drawing showing a-tetralone of example 11HNMR spectrogram;
FIG. 5 is a scheme showing the preparation of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one in example 11HNMR spectrogram.
Detailed Description
In order to further explain the contents and features of the present invention, the following description is given with reference to the examples.
Example 1:
a synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-ketone comprises the following steps:
(1) synthesis of alpha-tetralone
Benzene (1500 g, 19.2 mol) was added to a reaction flask followed by aluminum trichloride (774 g, 5.81 mol) in portions, gamma-butyrolactone (200 g, 2.32 mol) was added with stirring, and reflux reaction was carried out at 80 ℃ for 24 hours. 2500 g of 10wt% hydrochloric acid solution is prepared, then reaction feed liquid is added in 3 batches, after the addition is finished, the mixture is stirred for 1.5 hours, and then layering is carried out, wherein a water layer is aluminum trichloride wastewater, an organic layer is washed by water and a saturated sodium bicarbonate aqueous solution respectively, and finally the organic layer is washed to be neutral by water. The benzene was removed by rotary evaporation to obtain 345 g of crude product (crude product is liquid). The crude product is distilled under reduced pressure to obtain alpha-tetralone (260 g, 1.78 mol), the GC diagram of which is shown in figure 1, the GC purity of the alpha-tetralone is 98.3 percent as shown in figure 1, and the alpha-tetralone is shown in figure 11The HNMR spectrum is shown in figure 4,1H NMR (400 MHz, CDCl3) : δ8.02(d, 1H, J = 7.6 Hz), 7.48-7.44(m, 1H), 7.29(t, 1H, J = 7.2 Hz ), 7.24(d, 1H, J = 8.0 Hz), 2.96(t, 2H, J = 6.0 Hz), 2.64 (t, 2H, J = 6.4 Hz), 2.16-2.10(m, 2H).
(2) synthesis of 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide
260 g (1.78 mol) of alpha-tetralone, HBr (48%, H) were sequentially added to the reaction flask2O, 3.56 mol), water (800 g) and methanol (900 g) were added in 3 portions to Oxone (2407 g, 3.92 mol) at room temperature, and the reaction was allowed to proceed with 72 hours incubation at a controlled temperature of 33-35 ℃. After the reaction, the lower organic phase is separated out by standing. Methanol (1500 g) was added thereto, and hydroxylamine sulfate (183 g, 1.78 mol) was added. After the addition, 900 mL of water was added for dilution, and the reaction was allowed to proceed at 30-32 ℃ for 85 hours. After the incubation reaction, sodium bicarbonate (224 g, 2.67 mol) was added and the incubation reaction was continued for 50 hours at 30-32 ℃. The solution is cooled to 10 ℃, filtered, the filter cake is washed by water and then is rinsed by 30% (v/v) methanol to obtain 1500g of wet 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide solid (about 425g of 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide is obtained according to 1.78 mol of alpha-tetralone), the HPLC spectrogram of the wet 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide is shown in figure 2, and the purity of the crude 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide is 87.8 percent as can be seen from figure 2.
(3) Synthesis of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one
Polyphosphoric acid (1700 g, 4 times weight) is added into a reaction bottle, the reaction bottle is heated to 65 ℃ for standby, 1500g of 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide wet product and 9L of toluene are added into another reaction bottle, the mixture is heated to 80 ℃ for dissolution, the water phase is separated after the mixture is kept warm and kept stand for 1 hour, the toluene phase is directly added into polyphosphoric acid liquid, and the mixture is stirred and reacted at 85 ℃. After the reaction is finished, cooling to room temperature, pouring out a toluene phase, adding 12L of water, keeping the temperature at about 35 ℃, stirring for 2 hours, filtering, washing filter cakes with water, saturated sodium bicarbonate and water for 1 time respectively, draining the filter cakes to obtain 280 g of wet 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-one, and drying to obtain 225 g of crude product.
(4) Purification of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one
Dissolving the crude product with methanol (3L), adding activated carbon 35 g for decolorization, filtering decolorized mother liquor, removing methanol to half, cooling to below 10 deg.C for recrystallization, filtering, oven drying filter cake at 40 deg.C under normal pressure to obtain pure 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one (191.5 g, 0.80 mol), and HPLC spectrogram is shown in figure 3, which shows that the product purity is 99.5%, and 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one in figure 31The HNMR spectrum is shown in figure 5,1H NMR (400 MHz, DMSO) : δ10.09(s, 1H), 7.30(dd, 2H, J = 9.2 Hz, 7.6 Hz), 7.18(t, 1H, J = 7.6 Hz), 7.05(d, 1H, J = 8.0 Hz), 4.62(dd, 1H, J = 10 Hz, 7.6 Hz), 2.85-2.75(m, 3H), 2.56-2.52 (m, 1H).
the results of the above examples are further illustrative of the present invention, but should not be construed as limiting the scope of the invention. All modifications and equivalents of the subject matter disclosed herein are intended to be included within the scope of the claims appended hereto.
Claims (7)
1. A synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one is characterized by sequentially comprising the following steps:
1) synthesis of alpha-tetralone
Adding aluminum trichloride into benzene, adding gamma-butyrolactone while stirring, refluxing after the addition until the reaction is complete, adding a hydrochloric acid solution for hydrolysis after the reaction is finished, stirring until the reaction is layered, washing an organic layer with water, washing with alkali and water respectively to be neutral, performing rotary evaporation to remove benzene to obtain a crude product, and performing reduced pressure distillation on the crude product to obtain alpha-tetralone;
2) synthesis of 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide
S1, adding alpha-tetralone, HBr solution and H into a reaction bottle in sequence2O and methanol, adding Oxone into the mixture, reacting at 30-35 ℃ until the reaction is complete, and standing to separate out an organic phase; s2, adding methanol into the organic phase, adding hydroxylamine sulfate, adding water for dilution after the addition is finished, then carrying out heat preservation reaction at 25-40 ℃ for 60-90 hours, adding baking soda after the heat preservation reaction is finished, carrying out heat preservation reaction at 25-40 ℃ for 40-60 hours, filtering, washing a filter cake with water, and leaching with methanol to obtain a 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide crude product for later use;
3) synthesis of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one
Adding polyphosphoric acid into a reaction bottle, heating to 60-80 ℃ for later use, adding a 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthylimine crude product and toluene into another reaction bottle, heating to 60-85 ℃ for dissolving, keeping the temperature, standing, separating out a water phase, directly adding the toluene phase into the polyphosphoric acid liquid, keeping the temperature at 75-90 ℃, stirring for reaction, cooling to room temperature after the reaction is finished, pouring out the toluene phase, adding water, keeping the temperature at 20-40 ℃, stirring for 1-3 hours, filtering, washing filter cakes with water, washing with saturated sodium bicarbonate, washing with water, and drying the filter cakes to obtain a 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-one crude product;
4) refining of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one
And dissolving the crude product by using methanol, adding activated carbon for decoloring, filtering, recrystallizing, and drying a filter cake after filtering to obtain a pure product of the 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-one.
2. The method of synthesizing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one according to claim 1, wherein: the molar ratio of gamma-butyrolactone, benzene and anhydrous aluminum trichloride is 1 (8-10) to 2-3.
3. The method of synthesizing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one according to claim 1, wherein: in the step 1), the concentration of the hydrochloric acid solution is 10wt%, and the addition amount of the hydrochloric acid solution is 1-2 times of the mass of benzene.
4. The method of synthesizing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one according to claim 1, wherein: in the step 2), the mol ratio of the alpha-tetralone, HBr and Oxone is as follows: 1: 2 (2-2.5), and the molar ratio of the alpha-tetralone to the hydroxylamine sulfate to the baking soda is 1:1: 1.5.
5. The method of synthesizing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one according to claim 1, wherein: in the step S1, the mass ratio of water to methanol was 8:9, and in the step S2, the mass ratio of water to methanol was 3: 5.
6. The method of synthesizing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one according to claim 1, wherein: in the step 3), the adding amount of the polyphosphoric acid is 3-8 times of the weight of the 2-bromo-3, 4-dihydro-N-hydroxy- (2H) -naphthalimide.
7. The method of synthesizing 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one according to claim 1, wherein: the adding amount of the activated carbon is 15-20% of the mass of the crude product of the 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepine-2-ketone, and the temperature during recrystallization is lower than 10 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110279894.2A CN113149907A (en) | 2021-03-16 | 2021-03-16 | Synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110279894.2A CN113149907A (en) | 2021-03-16 | 2021-03-16 | Synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113149907A true CN113149907A (en) | 2021-07-23 |
Family
ID=76887140
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110279894.2A Pending CN113149907A (en) | 2021-03-16 | 2021-03-16 | Synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113149907A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017154A (en) * | 2015-07-07 | 2015-11-04 | 丽水市南明化工有限公司 | Preparation method of 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepine-2-keto |
-
2021
- 2021-03-16 CN CN202110279894.2A patent/CN113149907A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017154A (en) * | 2015-07-07 | 2015-11-04 | 丽水市南明化工有限公司 | Preparation method of 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepine-2-keto |
| CN105017154B (en) * | 2015-07-07 | 2017-10-10 | 浙江博聚新材料有限公司 | The ketone preparation method of 1 benzazepines of one kind 3 bromine, 1,3,4,5 tetrahydrochysene 2H 2 |
Non-Patent Citations (1)
| Title |
|---|
| ARUN KUMAR MACHARLA等: "Oxidative bromination of ketones using ammonium bromide and oxone®", TETRAHEDRON LETTERS, vol. 53, no. 2, pages 191, XP028393251, DOI: 10.1016/j.tetlet.2011.11.011 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2019091179A1 (en) | Method for preparing florfenicol intermediate v and method for preparing florfenicol using intermediate v | |
| CN112079742B (en) | Method for preparing lidocaine through continuous reaction | |
| US20080249324A1 (en) | Process For Preparing 1,3-Dibromoacetone, 1-3-Dichloroacetone and Epichlorohydrin | |
| CN115260200B (en) | Preparation method of sitagliptin intermediate | |
| JPH04346988A (en) | Method for manufacturing 3-amino-9,13b-dihydro-1hdibenz (c,f)-imidazo-(1,5-1a)-azepine hydrochloride | |
| CN103435507B (en) | Preparation method of L-alpha-methyl-3,4-dihydroxyphenylalanine | |
| CN101723855A (en) | Method for synthesizing (7-methoxy-1-naphthyl) acetonitrile | |
| CN110790721B (en) | Synthetic method of ceftazidime side chain ethyl ester | |
| CN114539048B (en) | Carlong anhydride intermediate and preparation method of Carlong anhydride | |
| Gershon | Pyrimidines. II. Chlorinated pyrimidines derived from orotic acid | |
| CN113149907A (en) | Synthetic method of 3-bromo-1, 3,4, 5-tetrahydro-2H-1-benzazepin-2-one | |
| CA1058615A (en) | Process for benz(f)-2,5-oxazocines | |
| CN102702060A (en) | Racemization recovery method for by-products in split mother liquor of Vernakalant intermediates | |
| JPS638368A (en) | 4-benzyloxy-3-pyrroline-2-one-1-ylacetamide,manufacture and use | |
| CN105566223A (en) | Crude iminostilbene product recrystallization method | |
| CN114671859A (en) | Preparation method of rosuvastatin calcium and intermediate thereof | |
| CA1140138A (en) | Method of preparation of lower alkyl 4,10- dihydro-10-oxothieno[3,2-c][1]benzoxepin-8- acetate | |
| CN111302997B (en) | Method for preparing Raatinib intermediate by one-pot method | |
| CN110590677A (en) | Synthesis method of tinidazole | |
| CN112898133B (en) | Preparation method of trans-ketone intermediate | |
| CN114539201B (en) | Preparation method of Sibirer linking agent | |
| CN118515569B (en) | Method for preparing tetra (dimethylamino) ethylene by one step | |
| CN116178307B (en) | Synthesis method of 1- (2, 3-dichlorophenyl) piperazine hydrochloride | |
| CN113880701A (en) | Antidiabetic drug intermediate and preparation method thereof | |
| CN110105362B (en) | Safe and green folic acid synthesis method catalyzed by heteropoly acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |