CN104356040A - Preparation method of 1-benzhydryl-3-hydroxylazetidine hydrochloride - Google Patents
Preparation method of 1-benzhydryl-3-hydroxylazetidine hydrochloride Download PDFInfo
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Abstract
The invention provides a preparation method of an azelnidipine intermediate, namely 1-benzhydryl-3-hydroxylazetidine hydrochloride. The preparation method comprises the following steps: 1) preparation of a reaction solution I: mixing dimethylaniline and epoxy chloropropane in proportion and adding an organic solvent to prepare the reaction solution I; 2) preparation of a reaction solution II: letting the reaction solution I react at 0-60 DEG C to prepare the reaction solution II; and 3) preparation of 1-benzhydryl-3-hydroxylazetidine hydrochloride: adding the reaction solution II into a microreactor by the use of a pump with flwo velocity of 1-200ml/min, heating to 60-250 DEG C at pressure of 0-2 MPa, completely reacting, and carrying out separation purification to obtain white crystals, namely 1-benzhydryl-3-hydroxylazetidine hydrochloride.
Description
Technical field
Medical art of the present invention, particularly, relates to a kind of preparation method of dihydropyridine type calcium antagonists azelnidipine intermediate 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride.
Background technology
1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is the key intermediate of synthesis Azelnidipine, Azelnidipine belongs to dihydropyridine (DHP) class calcium channel blocker (CCB), as a line hypertension therapeutic medicine, be widely used due to antihypertensive effect reliability.Azelnidipine is for target and developing with " hypotensive effect is gentle and lasting, and the desirable CCB hypotensor thing few to cardiac stimulation ".The hypotensive effect of this medicine and the DHP class CCB class medicine amlodipine of the third generation quite similar, acting duration is long and effect is gentle.But, Azelnidipine in the pharmacological property such as impact and vascular tissue's affinity of heart and amlodipine there are differences, be not easy to cause the excitement of the sympathetic nervous systems such as tachycardia and the sensitization of renin angiotensin (RA) system.In addition, research shows that Azelnidipine has diuretic properties, heart provide protection, renal protection and arteriosclerosis effect.The Azelnidipine of these features is had to be with historically new significance for hypertension therapeutic as this desirable channel blocking medicine.Be widely used in mild or medium symptom essential hypertension clinically, with renal tubal dysfunction hypertension and severe hypertension patient.
Along with pharmaceutical chemical development, 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is as a kind of intermediate of 3-azetidin alcohol hydrochloride, and its use is as follows:
3-azetidin alcohol hydrochloride is the key intermediate of wide spectrum fluoroquinolone antibiotic delafloxacin of new generation, delafloxacin shows anti-microbial activity widely to a large amount of high resistant organisms, as the replacement therapy medicine of multiple severe infections, comprise complicacy skin infections, Nosocomial Pneumonia, endocarditis and other very severe infection disorders, compared with other quinoline ketone antiseptic-germicides, more effective to gram-positive microorganism, particularly to the methicillin-resistant staphylococcus aureus (MRSA) of other methods for quinolones antibacterial agents resistances; Selected 100 kinds of most Development volue in 2009 and new medicinal products list; FDA declares publicly, and is appointed as by Rib-X company delafloxacin and has treatment acute bacterial skin and the qualification medication of skin structure infection (ABSSSI) and the acquired pneumonia day after tomorrow (CABP).Therefore, delafloxacin obtains 5 years extra exclusivities, and automatically can obtain according to " microbiotic incentive plan (GAIN) " right preferentially evaluated and enter and evaluate passage fast and evaluate.Rib-X company starts the III clinical trial phase of this wide spectrum fluoroquinolone antibiotics treatment ABSSSI the second half year in 2012.
3-azetidin alcohol hydrochloride is tebipenem pivoxil key intermediate, tebipenem pivoxil (TBPM-PI) is first oral preparations in carbapenem antibiotic, developed by Japanese Hui Shi Rieter Perfojet, within 2002, license to MingZhi fruit Co., Ltd's continual exploitation, in August, 2009 is in Japanese list marketing, compared with its activeconstituents tebipenem (TB-PM), the oral absorption rate of tebipenem pivoxil significantly improves.Compared with similar drug, the advantage of tebipenem pivoxil is: oral medication, substantially increases the adaptability of clinical application; There is lower Mlc, not easily cause the appearance of bacterial drug resistance; Untoward reaction is little, and drug safety is high, can be used for treatment childhood infection etc.
Patent CN200810159764.X discloses a kind of preparation method of 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride: by 183g xylidene(s), 100g epoxy chloropropane and 600ml methyl alcohol, add in 1000ml reaction flask, react 72 hours at 25 DEG C, reflux 72 hours at 65 DEG C, cold filtration obtains solid, washing with acetone, filtration, drying, yield is 65%.
The preparation method of the 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride of above-mentioned patent literature, reaction total time is long, and energy consumption is large, and yield is not high, and long-time backflow easily causes solvent to run off in a large number, increases cost and environmental pollution; Repeatability is not strong, is not suitable for stable large-scale production.
Summary of the invention
Technical problem to be solved by this invention is to provide the short and preparation method of the 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride that yield is high of a kind of reaction times.The method feature is simple to operate, cost is low, less energy consumption, yield are high, purity is high.
The present invention's adopted technical scheme that solves the problem is: a kind of preparation method of 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride, comprises the following steps:
A preparation method for 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride, is characterized in that, comprise the following steps:
1) preparation feedback liquid I: xylidene(s) and epoxy chloropropane are mixed in proportion, add organic solvent, obtained reaction solution I;
2) preparation feedback liquid II: by reaction solution I at 0 DEG C-60 DEG C obtained reaction solutions II of reaction;
3) 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is prepared: use the pump that flow velocity is 1-200ml/min to add in microreactor by reaction solution II, be heated to 60-250 DEG C, pressure 0-2MPa, after reacting completely, separation and purification obtains white crystal, obtains 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride.
Wherein, step 1) in, xylidene(s) mixes according to mol ratio 1:1-1:2 with epoxy chloropropane, preferred molar ratio 1:1.3.
Further, described step 1) temperature of reaction be 0-30 DEG C, be preferably 20-25 DEG C, step 2) temperature of reaction be preferably 25-30 DEG C.
Further, preparation reaction solution II step 2 of the present invention) in, the reaction times is 1-72 hour, and be preferably 40-50 hour, more excellent is 48 hours.
Further, step 3 of the present invention) temperature of reaction is 60-250 DEG C, temperature is higher, and yield is higher, and be preferably 220-240 DEG C, optimum is 230 DEG C.
Organic solvent of the present invention is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, propyl alcohol, isopropylcarbinol, the trimethyl carbinol, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform, toluene, dimethylbenzene, methyl-sulphoxide, N, one or more mixed solvent in dinethylformamide, sherwood oil, one or more the mixed solvent in particular methanol, ethanol, Virahol, propyl carbinol.
Step 3 of the present invention) in reaction pressure be preferred 1.8MPa.
Pump of the present invention comprises ram pump, surge pump, syringe pump or peristaltic pump.Reaction solution II adds in microreactor by the pump that use flow velocity of the present invention is 1-200ml/min, and flow velocity selects 10-100ml/min, preferred 50-70ml/min, more preferably 60ml/min.
Reactor of the present invention is microchannel flow reactor.
Purification procedures of the present invention comprises: concentrating under reduced pressure, and cooling, crystallization, filtration, ethyl acetate cleaning, drying, obtain white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride.
Concentrating under reduced pressure in purification procedures of the present invention, is transferred in rotatory evaporator by the reaction solution of collection, and vacuum concentration removes half solvent.
Cooling in purification procedures of the present invention, crystallization, filtration, ethyl acetate washing, drying, liquid after underpressure distillation is cooled to 0 DEG C of crystallization, filter, then ethyl acetate washing crystal is used, filter, drying, obtains white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride.
1-diphenyl-methyl-3-hydroxy azetidine hydrochloride yield of the present invention is 74%-77%; Purity is greater than 99%; Production capacity is 0.68kg-1.84kg/h.
The advantage that the present invention has: reaction yield is high, improve raw material availability, solvent can reuse, therefore cost significantly reduces; Method is simple to operation, production process safety, and speed of response, temperature are easy to control; Production capacity is high, and flow reactor does not have scale effect, reproducible; The three wastes are few, belong to typical friendly process.
The advantage of microreactor of the present invention: microreactor and microchannel flow reactor, floor space is little, only 2 square metres, can realize 24 hours continuous seepage uninterrupted, without scale effect, reproducible; Temperature, pressure are easy to control, and especially for heat release, stronger reaction of absorbing heat, advantage is especially obvious, and safety coefficient is high.
Content set forth in the present invention, solves the problems of traditional reactor production model, as: autoclave produces long reaction time, and efficiency is low; Reaction intermediate can not transform completely, yield is low.
Embodiment
Below in conjunction with embodiment, to the detailed description further of the present invention's do, but embodiments of the present invention are not limited thereto.
The HPLC of 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride test of the present invention:
Model: Agilent 1100; Detector: G1321A; Chromatographic column: GeminiC18,4.0x250mm; Moving phase: 0.1TFA/H2O:MeCN=70:30; Column temperature: 25 DEG C; Flow velocity: 1ml/min; Product retention time: 5.4min.
Production capacity of the present invention: the time ratios that the product weight prepared and reaction solution charging complete.Reaction yield of the present invention: the product weight of real income and the ratio of theoretical yield.
Embodiment 1:
1) reaction solution I is prepared: get benzhydrylamine (1500g, 8.19mol) add in 5L four-hole boiling flask, temperature control 20-25 DEG C, add 1.5L methyl alcohol, add epoxy chloropropane (984.52g again, 10.64mol), stir, xylidene(s) and epoxy chloropropane are 1:1.3 according to mol ratio.
2) preparation feedback liquid II: reaction solution I is reacted in 27 ± 2 DEG C of situations obtained reaction solution II after 48 hours, benzhydrylamine has 99% to be converted into intermediate state B, and only the benzhydrylamine of surplus trace, generates without other impurity.Reaction equation is:
3) 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is prepared: temperature of reactor is raised to 230 DEG C, pressure is set to 1.8MPa, the pump that flow velocity is 1-200ml/min is used to add in microreactor by reaction solution II, flow rate set is 70ml/min, after 1.1 minutes, reaction solution flows out microreactor, is collected in container for storing liquid, continues to be fed to run out of all materials.
Separation and purification: reaction solution is transferred in rotatory evaporator, temperature is kept to be 40 DEG C, concentrating under reduced pressure falls half solvent, is cooled to 0 DEG C, separates out a large amount of solid, filter, obtain light yellow crystal, with the making beating of 1000ml ethyl acetate, filter, again with the cleaning of 500ml ethyl acetate, obtain white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride 1695.25g.Reaction equation is:
Test: mass spectrum: MS (M+H+): m/z275.7.
Nucleus magnetic resonance: 1HNMR:3.62 (S, 2H), 4.10 (S, 2H), 4.46 (S, 1H), 5.76 (S, 1H), 6.21 (S, 1H), 7.20-7.43 (b, 10H).
HPLC: purity 99.8%.
Yield: theoretical yield is 2257.33g, actual output is 1695.25g, and yield is 75.10%.
Embodiment 2:
1) reaction solution I is prepared: get benzhydrylamine (1500g, 8.19mol) add in 5L four-hole boiling flask, temperature control 20-25 DEG C, add 1.5L ethanol, add epoxy chloropropane (984.52g again, 10.64mol), stir, xylidene(s) and epoxy chloropropane are 1:1.3 according to mol ratio.
2) preparation feedback liquid II: reaction solution I is reacted in 27 ± 2 DEG C of situations obtained reaction solution II after 50 hours.
3) 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is prepared: temperature of reactor is raised to 230 DEG C, pressure is set to 2MPa, the pump that flow velocity is 1-200ml/min is used to add in microreactor by reaction solution II, flow rate set is 60ml/min, after 1.2 minutes, reaction solution flows out microreactor, is collected in container for storing liquid, continues to be fed to run out of all materials.
Separation and purification: reaction solution is transferred in rotatory evaporator, temperature is kept to be 55 DEG C, concentrating under reduced pressure falls half ethanol, is cooled to 0 DEG C, separates out a large amount of solid, filter, obtain light yellow crystal, with the making beating of 1000ml ethyl acetate, filter, again with the cleaning of 500ml ethyl acetate, obtain white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride 1741.43g.
Test: mass spectrum: MS (M+H+): m/z275.7.
Nucleus magnetic resonance: 1HNMR:3.77 (S, 2H), 4.14 (S, 2H), 4.46 (S, 1H), 5.88 (S, 1H), 6.15 (S, 1H), 7.34-7.93 (b, 10H).
HPLC: purity 99.7%.
Yield: theoretical yield is 2257.33g, actual output is 1741.43g, and yield is 77.16%.
Embodiment 3:
1) reaction solution I is prepared: get benzhydrylamine (1000g, 5.46mol) add in 5L four-hole boiling flask, water-bath temperature control 20-25 DEG C, add 1.5L propyl carbinol, add epoxy chloropropane (656.35g again, 7.09mol), stir, xylidene(s) and epoxy chloropropane are 1:1.3 according to mol ratio.
2) preparation feedback liquid II: reaction solution I is reacted in 30 DEG C of situations obtained reaction solution II after 40 hours.
3) 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is prepared: temperature of reactor is raised to 230 DEG C, pressure is set to 1.8MPa, the pump that flow velocity is 1-200ml/min is used to add in microreactor by reaction solution II, flow rate set is 50ml/min, after 1.2 minutes, reaction solution flows out microreactor, is collected in container for storing liquid, continues to be fed to run out of all materials.
Separation and purification: reaction solution is transferred in rotatory evaporator, temperature is kept to be 65 DEG C, concentrating under reduced pressure falls half solvent, is cooled to 0 DEG C, separates out a large amount of solid, filter, obtain light yellow crystal, with the making beating of 1000ml ethyl acetate, filter, again with the cleaning of 500ml ethyl acetate, obtain white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride 1741.43g.
Test: mass spectrum: MS (M+H+): m/z275.7.
Nucleus magnetic resonance: 1HNMR:3.65 (S, 2H), 4.13 (S, 2H), 4.56 (S, 1H), 5.92 (S, 1H), 6.22 (S, 1H), 7.33-7.78 (b, 10H).
HPLC: purity 99.9%.
Yield: theoretical yield is 1504.88g, actual output is 1116.67g, and yield is 74.20%.
Embodiment 4:
Above-mentioned reaction solution II is reacted respectively in 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130 DEG C, 140 DEG C, 150 DEG C, 160 DEG C, 170 DEG C, 180 DEG C, 200 DEG C, 220 DEG C, 240 DEG C situations, yield is respectively: 1.51%, 2.29%, 3.11%, 4.40%, 7.39%, 13.56%, 15.31%, 19.24%, 25.41%, 30.46%, 41.78%, 49.20%, 57.86%, 66.43%, 76.45%, 75.52%, 220 DEG C with 240 DEG C of situations under with 230 DEG C, yield does not have considerable change.
Embodiment 5:
1) reaction solution I is prepared: get benzhydrylamine (150g, 0.819mol) add in 1L four-hole boiling flask, temperature control 20-25 DEG C, add 200ml ethanol, add epoxy chloropropane (75.73g again, 0.819mol), stir, xylidene(s) and epoxy chloropropane are 1:1 according to mol ratio.
2) preparation feedback liquid II: reaction solution I is reacted in 27 ± 2 DEG C of situations obtained reaction solution II after 48 hours.
3) 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is prepared: temperature of reactor is raised to 230 DEG C, pressure is set to 2MPa, the pump that flow velocity is 1-200ml/min is used to add in microreactor by reaction solution II, flow rate set is 50ml/min, after 1.8 minutes, reaction solution flows out microreactor, is collected in container for storing liquid, continues to be fed to run out of all materials.
Separation and purification: reaction solution is transferred in rotatory evaporator, temperature is kept to be 55 DEG C, concentrating under reduced pressure falls half ethanol, is cooled to 0 DEG C, separates out a large amount of solid, filter, obtain light yellow crystal, with the making beating of 100ml ethyl acetate, filter, again with the cleaning of 50ml ethyl acetate, obtain white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride 146.82g.
Test: mass spectrum: MS (M+H+): m/z275.7.
Nucleus magnetic resonance: 1HNMR:3.67 (S, 2H), 4.04 (S, 2H), 4.33 (S, 1H), 5.77 (S, 1H), 6.10 (S, 1H), 7.32-7.89 (b, 10H).
HPLC: purity 99.5%.
Yield: theoretical yield is 225.70g, actual output is 146.82g, and yield is 65.05%.
Embodiment 6:
1) reaction solution I is prepared: get benzhydrylamine (100g, 0.546mol) add in 1L four-hole boiling flask, water-bath temperature control 25 DEG C, add 150ml propyl carbinol, add epoxy chloropropane (101g again, 1.091mol), stir, xylidene(s) and epoxy chloropropane are 1:2 according to mol ratio.
2) preparation feedback liquid II: reaction solution I is reacted in 27 DEG C of situations obtained reaction solution II after 45 hours.
3) 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is prepared: temperature of reactor is raised to 230 DEG C, pressure is set to 1.8MPa, the pump that flow velocity is 1-200ml/min is used to add in microreactor by reaction solution II, flow rate set is 70ml/min, after 1.1 minutes, reaction solution flows out microreactor, is collected in container for storing liquid, continues to be fed to run out of all materials.
Separation and purification: reaction solution is transferred in rotatory evaporator, temperature is kept to be 70 DEG C, concentrating under reduced pressure falls half solvent, is cooled to 0 DEG C, separates out a large amount of solid, filter, obtain light yellow crystal, with the making beating of 100ml ethyl acetate, filter, again with the cleaning of 50ml ethyl acetate, obtain white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride 111.46g.
Test: mass spectrum: MS (M+H+): m/z275.7.
Nucleus magnetic resonance: 1HNMR:3.62 (S, 2H), 4.20 (S, 2H), 4.53 (S, 1H), 5.89 (S, 1H), 6.25 (S, 1H), 7.38-7.82 (b, 10H).
HPLC: purity 99.7%.
Yield: theoretical yield is 150.4g, actual output is 111.46g, and yield is 74.11%.
Comparative example 1:
Getting benzhydrylamine (100g, 0.55mol) adds in 500ml four-hole boiling flask, temperature control 25 DEG C, add 100ml methyl alcohol, then add epoxy chloropropane (65.64g, 0.71mol), stir, xylidene(s) and epoxy chloropropane are 1:1.3 according to mol ratio.65 DEG C of backflows 72 hours are raised to again after reaction solution is reacted 72 hours in 25 ± 2 DEG C of situations.
Separation and purification: reaction solution is transferred in rotatory evaporator, temperature is kept to be 40 DEG C, concentrating under reduced pressure falls half solvent, is cooled to 0 DEG C, separates out a large amount of solid, filter, obtain light yellow crystal, with the making beating of 100ml ethyl acetate, filter, again with the cleaning of 50ml ethyl acetate, obtain white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride 79.93g.
Test: mass spectrum: MS (M+H+): m/z275.7.
Nucleus magnetic resonance: 1HNMR:3.77 (S, 2H), 4.14 (S, 2H), 4.48 (S, 1H), 5.90 (S, 1H), 6.19 (S, 1H), 7.22-7.79 (b, 10H).
HPLC: purity 97.8%.
Yield: theoretical yield is 150.49g, actual output is 79.93g, and yield is 53.11%.
Comparative example 2:
Getting benzhydrylamine (50g, 0.27mol) adds in 250ml there-necked flask, temperature control 25 DEG C, add 50ml methyl alcohol, then add epoxy chloropropane (32.82g, 0.35mol), stir, xylidene(s) and epoxy chloropropane are 1:1.3 according to mol ratio.Reaction solution is raised to 65 DEG C immediately, refluxes 72 hours.
Separation and purification: reaction solution is transferred in rotatory evaporator, temperature is kept to be 40 DEG C, concentrating under reduced pressure falls half solvent, is cooled to 0 DEG C, separates out solid, filter, obtain light yellow crystal, with the making beating of 100ml ethyl acetate, filter, again with the cleaning of 50ml ethyl acetate, obtain white crystalline solid 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride 42.02g.
Test: mass spectrum: MS (M+H+): m/z275.7.
Nucleus magnetic resonance: 1HNMR:3.78 (S, 2H), 4.07 (S, 2H), 4.48 (S, 1H), 5.78 (S, 1H), 6.20 (S, 1H), 7.34-7.68 (b, 10H).
HPLC: purity 98.3%.
Yield: theoretical yield is 75.24g, actual output is 42.02g, and yield is 55.84%.
Contrast from above-mentioned example 1-6 and comparison example 1-2, can find out, traditional method prepares 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride, reaction yield is 53.11%-55.84%, and preparation method's reaction yield of 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride of the present invention is 74.20%-77.16%, and the reaction times is short, and temperature is more easy to control, reaction process is continuous, can realize scale operation.
Claims (10)
1. a preparation method for 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride, is characterized in that, comprise the following steps:
1) preparation feedback liquid I: xylidene(s) and epoxy chloropropane are mixed in proportion, add solvent, obtained reaction solution I;
2) preparation feedback liquid II: by reaction solution I at 0 DEG C-60 DEG C obtained reaction solutions II of reaction;
3) 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride is prepared: use the pump that flow velocity is 1-200ml/min to add in microreactor by reaction solution II, be heated to 60-250 DEG C, pressure 0-2MPa, after reacting completely, separation and purification obtains white crystal, obtains 1-diphenyl-methyl-3-hydroxy azetidine hydrochloride.
2. preparation method according to claim 1, is characterized in that, the mol ratio of described xylidene(s) and epoxy chloropropane is 1:1-1:2.
3. preparation method according to claim 2, is characterized in that, the mol ratio of described xylidene(s) and epoxy chloropropane is 1:1.3.
4. preparation method according to claim 1, is characterized in that, the temperature of reaction of described step 1) is 0-30 DEG C, step 2) temperature of reaction 25-30 DEG C, the temperature of reaction of step 3) is 220-240 DEG C.
5. preparation method according to claim 1, it is characterized in that, one or more the mixed solvent in methyl alcohol, ethanol, Virahol, propyl carbinol, water, propyl alcohol, isopropylcarbinol, the trimethyl carbinol, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform, toluene, dimethylbenzene, methyl-sulphoxide, DMF, sherwood oil selected by described solvent.
6. preparation method according to claim 1, is characterized in that, described step 2) preparation feedback liquid II reaction times is 40-50 hour.
7. preparation method according to claim 1, is characterized in that, in described step 3), temperature of reaction is 230 DEG C, and pressure is 1.8Mpa, and purification procedures comprises: concentrating under reduced pressure, cooling, crystallization, filtration, ethyl acetate washing, drying.
8. preparation method according to claim 1, is characterized in that, described pump comprises ram pump, surge pump, syringe pump or peristaltic pump, and flow velocity is chosen as 10-100ml/min.
9. preparation method according to claim 8, is characterized in that, the flow velocity of described pump is 50-70 ml/min.
10. preparation method according to claim 1, is characterized in that, described microreactor is microchannel flow reactor.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543061A (en) * | 2016-10-20 | 2017-03-29 | 威海迪素制药有限公司 | The preparation method of 3 alcohol of N benzhydryl ring fourths heterocycle |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402598A (en) * | 2008-11-13 | 2009-04-08 | 青岛黄海制药有限责任公司 | Improved method for preparing 1-benzhydryl-3-aza ring butanol |
| CN102153553A (en) * | 2010-02-11 | 2011-08-17 | 山东轩竹医药科技有限公司 | Oral administration carbapenem compound containing amino sulfonamide-azetidine |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
-
2014
- 2014-09-17 CN CN201410475496.8A patent/CN104356040A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402598A (en) * | 2008-11-13 | 2009-04-08 | 青岛黄海制药有限责任公司 | Improved method for preparing 1-benzhydryl-3-aza ring butanol |
| CN102153553A (en) * | 2010-02-11 | 2011-08-17 | 山东轩竹医药科技有限公司 | Oral administration carbapenem compound containing amino sulfonamide-azetidine |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
Non-Patent Citations (2)
| Title |
|---|
| KOZIKOWSKI, ALAN P.等: "Synthesis of novel four-membered ring amino acids as modulators of the N-methyl-D-aspartate (NMDA) receptor complex", 《SYNLETT》 * |
| V. V. R. M. KRISHNA REDDY,等: "Improved Process for the Preparation of 1-Benzhydrylazetidin-3-ol: Development of an Efficient Synthesis and Identification of Process-related Impurities and/or Intermediates", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543061A (en) * | 2016-10-20 | 2017-03-29 | 威海迪素制药有限公司 | The preparation method of 3 alcohol of N benzhydryl ring fourths heterocycle |
| CN106543061B (en) * | 2016-10-20 | 2019-08-16 | 威海迪素制药有限公司 | The preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol |
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Application publication date: 20150218 |