CN102329259B - Preparation method of (1-benzhydryl-3-azetidinol) cyanoacetate - Google Patents
Preparation method of (1-benzhydryl-3-azetidinol) cyanoacetate Download PDFInfo
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- CN102329259B CN102329259B CN201110322579.XA CN201110322579A CN102329259B CN 102329259 B CN102329259 B CN 102329259B CN 201110322579 A CN201110322579 A CN 201110322579A CN 102329259 B CN102329259 B CN 102329259B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- KSZGPBFUBSHVTO-UHFFFAOYSA-N (1-benzhydrylazetidin-3-yl) 2-cyanoacetate Chemical compound C1C(OC(CC#N)=O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 KSZGPBFUBSHVTO-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 82
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 28
- MMAJXKGUZYDTHV-UHFFFAOYSA-N 1-benzhydrylazetidin-3-ol Chemical compound C1C(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MMAJXKGUZYDTHV-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000000126 substance Substances 0.000 claims abstract description 17
- 239000007788 liquid Substances 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 16
- 238000011049 filling Methods 0.000 claims description 16
- 230000002000 scavenging effect Effects 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 239000012190 activator Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 8
- 239000000945 filler Substances 0.000 claims description 7
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
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- 239000000843 powder Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- ZKFQEACEUNWPMT-UHFFFAOYSA-N Azelnidipine Chemical compound CC(C)OC(=O)C1=C(C)NC(N)=C(C(=O)OC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZKFQEACEUNWPMT-UHFFFAOYSA-N 0.000 abstract description 16
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- 230000003213 activating effect Effects 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 abstract 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 11
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- -1 -isopropyl ester Chemical class 0.000 description 5
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- 238000001514 detection method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 206010020772 Hypertension Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
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- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 2
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- 206010002383 Angina Pectoris Diseases 0.000 description 1
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- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 102000004016 L-Type Calcium Channels Human genes 0.000 description 1
- 108090000420 L-Type Calcium Channels Proteins 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- WRVRNZNDLRUXSW-UHFFFAOYSA-N acetic acid;prop-2-enoic acid Chemical compound CC(O)=O.OC(=O)C=C WRVRNZNDLRUXSW-UHFFFAOYSA-N 0.000 description 1
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- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- ZJLBPXHQYXCWNP-UHFFFAOYSA-N propan-2-one;propan-2-yl acetate Chemical compound CC(C)=O.CC(C)OC(C)=O ZJLBPXHQYXCWNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a preparation method of (1-benzhydryl-3-azetidinol) cyanoacetate, and relates to the technical field of application of azelnidipine in pharmaceutical and chemical technologies. The method comprises the steps of pumping 1-benzhydryl-3-azetidinol, cyanoacetic acid and an activating agent into a reaction kettle, pumping reaction liquid into an external circulation water removal system filled with a water removal agent in the reaction process for circulating water removal, and obtaining the (1-benzhydryl-3-azetidinol) cyanoacetate. In the reaction process, water generated in the reaction process can be effectively removed through an external circulation water removal device, the loss of the 1-benzhydryl-3-azetidinol and the cyanoacetic acid is reduced, the production with low energy consumption, simplicity and rapidness are realized, the yield of the obtained (1-benzhydryl-3-azetidinol) cyanoacetic ester is more than 93 percent, and the utilization rate of a reaction substrate is obviously improved.
Description
Technical field
The present invention relates to a kind of preparation method of 1-Benzydryl-3-azetidinyl cyanoacetate, relate to the applied technical field of Azelnidipine in the medication chemistry technology.
Background technology
1-Benzydryl-3-azetidinyl cyanoacetate (1-Benzydryl-3-azetidinyl cyanoacetate) is the intermediate of Azelnidipine (azelnidipine), is for its CAS number: 116574-14-2.
Azelnidipine (azelnidipine) chemical name: 2-amino-Isosorbide-5-Nitrae-dihydro-6-methyl-4-(3-nitro benzal)-3,5-pyridine dicarboxylic acid-3-(1-diphenyl-methyl-3-azetidinol) ester-5-isopropyl ester.Molecular formula is C
33H
34N
4O
6, molecular weight 582.65, CAS number: 123524-52-7, its chemical structural formula is as follows:
Azelnidipine be by Japan three altogether (Sankyo) companies and company of space section (Ube) developed jointly the Isosorbide-5-Nitrae-dihydropyridine calcium channel blocker of new generation of release in 2003, its selective action in
L-type calcium channel, chemical structure is similar to nifedipine, clinical systemic hypertension and the stenocardia of being used for the treatment of, minority is used for the treatment of congestive heart failure.It can excited tissue by suppressing that calcium ion enters, and causes peripheral blood vessel and coronary artery vasorelaxation.The diastole peripheral blood vessel effect of Azelnidipine is stronger than verapamil, but the effect of cardiac conduction is not so good as verapamil.It is the persistence calcium ion antagonist, the effect of tool coronary vasodilation and antihypertensive function.Adapt to treatment heart failure and hypertension danger picture, effect rapidly.To light disease or medium symptom essential hypertension, nephropathy accompanied with hypertension and severe hypertension patient's hypotensive effect curative effect is better.
Azelnidipine belongs to Isosorbide-5-Nitrae-dihydropyridine compounds, and according to Hantzsch pyridine building-up reactions principle, the synthetic route of main flow has following 2:
Route 1: take benzhydrylamine as starting raw material, carry out the nucleophilic addition(Adn) open loop with epoxy chloropropane, carry out intramolecular nucleophilic displacement reaction closed loop again and make 4, compound 4 generates ester 5 with cyanoacetic acid under the effect of DCC.Then, the cyano group of compound 5 and ethanol carry out addition, process making intermediate 2((1-benzhydryl-3-aza ring butyl with ammonium acetate again)-3,3-diamino acrylate acetate).Intermediate 2 and intermediate 3(2-(3-nitrobenzyl) acetone isopropyl acetate) the condensation ring-closure reaction obtains end product Azelnidipine 1.This route reaction mild condition, treatment process is simple, and side reaction is few, and yield is higher.
Synthetic route 1 reaction conditions is relatively gentleer, relatively is suitable for suitability for industrialized production.And 1-Benzydryl-3-azetidinyl cyanoacetate (ester 5) is as key intermediate essential in the synthetic route, and the raising of its yield will directly affect the productive rate of final product Azelnidipine.
Route 2: take benzhydrylamine as starting raw material, carry out the nucleophilic addition(Adn) open loop with epoxy chloropropane, carry out again intramolecular substitution reaction closed loop and make 4; compound 4 generates ester 5 with cyanoacetic acid under the effect of DCC; 5 become oxime with oxammonium hydrochloride, acetylize, and palladium carbon catalytic hydrogenolysis makes intermediate 2.Intermediate 2 and intermediate 3 condensation ring-closure reactions obtain end product Azelnidipine 1.Although this method reaction times is short, severe reaction conditions is difficult for monitoring in reaction process.
Report is comparatively single, as follows about Azelnidipine key intermediate 1-Benzydryl-3-azetidinyl cyanoacetate synthetic route at present:
1988, the people such as KOIKE HIROYUKI of Japan were dissolved in compound 4 and cyanoacetic acid among the THF, stirred, rear adding 1,3-dicyclohexylcarbodiimide (DCC) then is warming up to 55 ℃, continue stirring reaction 11 h, cooling is filtered, decompression steams solvent, residue is dissolved in ethyl acetate, washing, dried over anhydrous sodium carbonate, concentrating under reduced pressure, residuum silica gel column chromatography obtain yellow oily compound 5(93%) (JP63253082; EP0266922; CN87107150; ).The crude product of this operational path is the product that uses silica gel column chromatography to obtain, and the process for purification of column chromatography is unfavorable for suitability for industrialized production.
2007, the people such as Wu Guosheng improved the 1-Benzydryl-3-azetidinyl cyanoacetate synthetic method.Namely under nitrogen, compound 4, cyanoacetic acid add DCC in solution after the THF dissolving, 10 h that reflux, cooling is filtered, removal of solvent under reduced pressure, residue is dissolved in ethyl acetate, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, drying, get 1-Benzydryl-3-azetidinyl cyanoacetate, yield is the 95%(Chinese Journal of New Drugs, 2007,16 (12): 951-952).Though the yield of this processing method is improved, but increase nitrogen protection and back flow reaction, not only caused environmental pollution but also increased production cost.
2009, the people such as Chen Guobin were dissolved in compound 4 and cyanoacetic acid among the THF, stirred the lower DCC that in batches adds, be warming up to 55 ℃, react 10 h, cooling, filter, decompression steams solvent, and residue is dissolved in ethyl acetate, washing, anhydrous sodium sulfate drying, underpressure distillation gets 1-Benzydryl-3-azetidinyl cyanoacetate, and yield is 90%(chemical industry and engineering, 2009,26 (1): 15-18).This processing method considers that DCC is dissolved in the exothermic effect of THF and has adopted the mode of batch charging, but yield has no raising.
2010, the people such as Liu Jianfeng were dissolved in itrile group acetic acid and compound 4 among the THF, and stirring and dissolving adds DCC again, 55 ℃ of lower 11 h that stir.With the reactant cooling, filter, with a small amount of THF flush cake, merging filtrate, concentrating under reduced pressure, residue is dissolved in ethyl acetate, washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain sticky shape product liquid, need not building-up reactions (Chinese pharmaceutical chemistry magazine, 2010,20 (3): 192-194) that purifying is directly used in follow-up Azelnidipine.This processing method has been omitted some crude product refinings and has been processed, and causes impurity in products more.
Generally speaking, in the prior art from compound 4 to compound these steps of 5 reactions can follow water generates, and then the forward of inhibited reaction carries out, and reduced compound
5Yield.Therefore, how effectively to remove the water that produces in the reaction process, become further raising reaction yield, the necessary means that reduces production costs.
Summary of the invention
It is the method for raw material production 1-Benzydryl-3-azetidinyl cyanoacetate by 1-diphenyl-methyl-3-azetidinol and cyanoacetic acid that technical purpose of the present invention provides a kind of, so that the water that produces in the reaction process can be removed effectively, reduce the loss of 1-diphenyl-methyl-3-azetidinol and cyanoacetic acid, realize less energy-consumption, simply, produce quickly, obtain the transformation efficiency of product 1-Benzydryl-3-azetidinyl cyanoacetate greater than 93%, the reaction substrate utilization ratio obviously improves.
For realizing technical purpose of the present invention, technical scheme of the present invention is as follows.
A kind of chemical mechanism type is the preparation method of the 1-Benzydryl-3-azetidinyl cyanoacetate shown in the III, be that the 1-diphenyl-methyl-3-azetidinol of I, cyanoacetic acid and the activator that chemical structural formula is II pump into heating and stirring reaction in the reactor that contains solvent with chemical structural formula, to react in the whole reaction process feed liquid at the uniform velocity pump into circulate in the outer circulation water scavenging system dewater after, the reaction feed liquid passes back in the reactor again and to continue reaction; Cooling removed by filter precipitation after reaction finished; The filtrate decompression distillating recovering solvent, gained residuum acetic acid ethyl dissolution, washing, dry rear underpressure distillation, obtaining faint yellow material is that chemical structural formula is the crude product of the 1-Benzydryl-3-azetidinyl cyanoacetate of III;
。
Further, the preparation method of 1-Benzydryl-3-azetidinyl cyanoacetate of the present invention also comprises the step that obtains the sterling of 1-Benzydryl-3-azetidinyl cyanoacetate behind the crude product recrystallization of 1-Benzydryl-3-azetidinyl cyanoacetate.
The mole proportioning of the reaction of 1-diphenyl-methyl of the present invention-3-azetidinol and cyanoacetic acid is 1:1～1:6.
Activator of the present invention comprises EDC or DCC.
The mole proportioning of 1-diphenyl-methyl of the present invention-3-azetidinol and activator is 1:1～1:3.
Solvent of the present invention comprises THF or methylene dichloride, and its add-on is for so that add behind each reactant that the starting point concentration of 1-diphenyl-methyl-3-azetidinol is the amount of 2～3mol/L in the whole reaction system.
Temperature of reaction of the present invention is 30～90 ℃.
Reaction times of the present invention is 5～15 h.
Outer circulation water scavenging system of the present invention refers to the filled column of single filling water-removal agent filler, the perhaps filled column series combination of two and above filling water-removal agent filler, perhaps the filled column parallel combination of two and above filling water-removal agent filler.
Further, described water-removal agent comprises molecular sieve, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate or anhydrous magnesium sulfate.
The flow velocity that reaction material liquid pump of the present invention enters to load the external circulating system of water-removal agent per hour is 0.2～1.2 times of molar weight of 1-diphenyl-methyl-initial molar weight of 3-azetidinol in the reaction system.
Beneficial effect of the present invention is:
(1) the outer circulation water scavenging system of filling water-removal agent filler of the present invention, not only water-removal agent is cheap, change, regenerate and be convenient, and owing to water-removal agent can not introduced reaction system, therefore the 1-Benzydryl-3-azetidinyl cyanoacetate that obtains by present method just can directly carry out subsequent reactions through simple recrystallization purifying and prepare Azelnidipine, the Product Green environmental protection can be widely used in the industry of fine chemicals and industrial chemicals etc.
(2) the outer circulation water scavenging system of the filling water-removal agent of the present invention's design, can design arbitrarily according to the throughput of reactor size, quantity and array mode except water column, and select different water-removal agents, to satisfy the requirement of the water of removing continuously, efficiently the reaction system generation.
(3) the present invention has suppressed the reverse hydrolysis reaction of reaction product 1-Benzydryl-3-azetidinyl cyanoacetate effectively owing in time having removed efficiently water, has improved product yield.And used reaction reagent toxicity is little, and the utmost point is beneficial to suitability for industrialized production.
Description of drawings
Fig. 1 is the schematic diagram of technical solution of the present invention.
Being labeled as among the figure: 1-raw material storage tank; The 2-pump; The 3-reactor; The 4-mechanical stirring device; 5-outer circulation water scavenging system; 6-product discharging control valve.
Embodiment
Embodiment 1
As shown in Figure 1, technical solutions according to the invention are as follows.
At first in raw material storage tank 1 be that the 1-diphenyl-methyl-3-azetidinol of I, cyanoacetic acid and the activator that chemical structural formula is II prepare for subsequent use according to mol ratio with chemical structural formula.Before the reaction, pump in the reactor 3 that contains solvent by pump 2 reaction raw materials that the proportioning in the raw material storage tank 1 is good, heat and open mechanical stirring device 4 stirrings and begin reaction, to react in the whole reaction process feed liquid with another pump 2 at the uniform velocity pump into circulate in the outer circulation water scavenging system 5 dewater after, the reaction feed liquid passes back in the reactor 3 again and to continue reaction; Cool off material after reaction finishes and emit material by product discharging control valve 6, remove by filter precipitation; The filtrate decompression distillating recovering solvent, gained residuum acetic acid ethyl dissolution, washing, dry rear underpressure distillation, obtaining faint yellow material is that chemical structural formula is the crude product of the 1-Benzydryl-3-azetidinyl cyanoacetate of III;
The technical scheme of the present embodiment is with embodiment 1, and its Parameter Conditions and reaction result are as follows.
The outer circulation water scavenging system of the present embodiment is the water column that removes of single filling water-removal agent, and except water column is of a size of 1 m * internal diameter 0.12 m, the filling rate of water-removal agent is 80%.
Reaction substrate and product HPLC method for qualitative and quantitative detection are: Hyper 0DS2 C
18(250 mm * 0.46 mm * 5 μ m) chromatographic column; Moving phase: methyl alcohol: water=70:30; Column temperature: 30 ℃; Flow velocity: 1 mL/min; Sample size: 20 μ L; UV detects wavelength: 222 nm.
With 1-diphenyl-methyl-3-azetidinol and the cyanoacetic acid mol ratio with 1:1, it is for subsequent use that 1-diphenyl-methyl-3-azetidinol and activator DCC are hybridly prepared into reaction substrate with the mol ratio three of 1:1.5.2.71 kg hybrid reaction substrates are pumped in the reactor that contains THF, and the add-on of THF is for so that add behind each reactant that the starting point concentration of 1-diphenyl-methyl-3-azetidinol is the amount of 2 mol/L in the whole reaction system; Be heated to 90 ℃ of violent stirring reactions, to react in the reaction process feed liquid take flow velocity as reaction system per hour in the flow of 1.2 times of molar weights of 1-diphenyl-methyl-initial molar weight of 3-azetidinol pass into the outer circulation water scavenging system that is filled with Calcium Chloride Powder Anhydrous and return in the reactor, stop after reacting 8 h, the discharge valve at the bottom of the unlatching still is emitted feed liquid.Remove under reduced pressure and reclaim unnecessary THF, residuum is measured through HPLC, and the 1-Benzydryl-3-azetidinyl cyanoacetate yield is 91.3%.
The technical scheme of the present embodiment is with embodiment 1, and its Parameter Conditions and reaction result are as follows.
The outer circulation water scavenging system of the present embodiment be two filling water-removal agents except the water column parallel combination, except water column is of a size of 1 m * internal diameter 0.12 m, the filling rate of water-removal agent is 80%.
Reaction substrate and product HPLC method for qualitative and quantitative detection and operation are all identical with embodiment 2, and the implementation step that changes activator solvent water-removal agent and each operating parameters is as follows:
With 1-diphenyl-methyl-3-azetidinol and the cyanoacetic acid mol ratio with 1:2, it is for subsequent use that 1-diphenyl-methyl-3-azetidinol and activator EDC are hybridly prepared into reaction substrate with the mol ratio three of 1:2.3.68 kg hybrid reaction substrates are pumped in the reactor that contains methylene dichloride, and the add-on of methylene dichloride is for so that add behind each reactant that the starting point concentration of 1-diphenyl-methyl-3-azetidinol is the amount of 3 mol/L in the whole reaction system; Be heated to 60 ℃ of violent stirring reactions, to react in the reaction process feed liquid take flow velocity as reaction system per hour in the flow of 0.2 times of molar weight of 1-diphenyl-methyl-initial molar weight of 3-azetidinol pass into the outer circulation water scavenging system that is filled with anhydrous sodium sulphate and return in the reactor, stop after reacting 5 h, the discharge valve at the bottom of the unlatching still is emitted feed liquid.Remove under reduced pressure and reclaim unnecessary methylene dichloride, residuum is measured through HPLC, and the 1-Benzydryl-3-azetidinyl cyanoacetate yield is 92.5%.
Embodiment 4
The technical scheme of the present embodiment is with embodiment 1, and its Parameter Conditions and reaction result are as follows.
The outer circulation water scavenging system of the present embodiment be two filling water-removal agents except the water column series combination, except water column is of a size of 1 m * internal diameter 0.12 m, the filling rate of water-removal agent is 80%.
Reaction substrate and product HPLC method for qualitative and quantitative detection and operation are all identical with embodiment 2, and the implementation step that changes activator solvent water-removal agent and each operating parameters is as follows:
With 1-diphenyl-methyl-3-azetidinol and the cyanoacetic acid mol ratio with 1:6, it is for subsequent use that 1-diphenyl-methyl-3-azetidinol and activator DCC are hybridly prepared into reaction substrate with the mol ratio three of 1:3.6.84 kg hybrid reaction substrates are pumped in the reactor that contains methylene dichloride, and the add-on of methylene dichloride is for so that add behind each reactant that the starting point concentration of 1-diphenyl-methyl-3-azetidinol is the amount of 2.7mol/L in the whole reaction system; Be heated to 50 ℃ of violent stirring reactions, to react in the reaction process feed liquid take flow velocity as reaction system per hour in the flow of 1 times of molar weight of 1-diphenyl-methyl-initial molar weight of 3-azetidinol pass into the outer circulation water scavenging system that is filled with anhydrous magnesium sulfate and return in the reactor, stop after reacting 15 h, the discharge valve at the bottom of the unlatching still is emitted feed liquid.Remove under reduced pressure and reclaim unnecessary THF, residuum is measured through HPLC, and the 1-Benzydryl-3-azetidinyl cyanoacetate yield is 90.1%.
The technical scheme of the present embodiment is with embodiment 1, and its Parameter Conditions and reaction result are as follows.
The outer circulation water scavenging system of the present embodiment be three filling water-removal agents except the water column parallel combination, except water column is of a size of 1 m * internal diameter 0.12 m, the filling rate of water-removal agent is 80%.
Reaction substrate and product HPLC method for qualitative and quantitative detection and operation are all identical with embodiment 2, and the implementation step that changes activator solvent water-removal agent and each operating parameters is as follows:
With 1-diphenyl-methyl-3-azetidinol and the cyanoacetic acid mol ratio with 1:4, it is for subsequent use that 1-diphenyl-methyl-3-azetidinol and activator EDC are hybridly prepared into reaction substrate with the mol ratio three of 1:1.4.55 kg hybrid reaction substrates are pumped in the reactor of the THF that contains 2.0 L, be heated to 30 ℃ of violent stirring reactions, to react in the reaction process feed liquid take flow velocity as reaction system per hour in the flow of 0.8 times of molar weight of 1-diphenyl-methyl-initial molar weight of 3-azetidinol pass into the outer circulation water scavenging system that is filled with molecular sieve and return in the reactor, stop after reacting 10 h, the discharge valve at the bottom of the unlatching still is emitted feed liquid.Remove under reduced pressure and reclaim unnecessary THF, residuum is measured through HPLC, and the 1-Benzydryl-3-azetidinyl cyanoacetate yield is 91.8%.
Embodiment 6
The described resistates acetic acid ethyl dissolution that obtains at last of embodiment 2-5, underpressure distillation after the filtrate organic layer drying minute is got in washing, and obtaining faint yellow material is that chemical structural formula is the crude product of the 1-Benzydryl-3-azetidinyl cyanoacetate of III.
Crude product is added an amount of dehydrated alcohol, and-5 ℃ of preservations 1～2 day were the sterling crystallization that recrystallization can obtain 1-Benzydryl-3-azetidinyl cyanoacetate.
Claims (8)
1. preparation method that chemical structural formula is the 1-Benzydryl-3-azetidinyl cyanoacetate shown in the III, be that the 1-diphenyl-methyl-3-azetidinol of I, cyanoacetic acid and the activator that chemical structural formula is II pump into heating and stirring reaction in the reactor that contains solvent with chemical structural formula, in the whole reaction process reaction material liquid pump being entered circulates in the outer circulation water scavenging system dewater after, the reaction feed liquid passes back into and continues reaction in the reactor; Cooling removed by filter precipitation after reaction finished; The filtrate decompression distillating recovering solvent, gained residuum acetic acid ethyl dissolution, washing, dry rear underpressure distillation, obtaining faint yellow material is that chemical structural formula is the crude product of the 1-Benzydryl-3-azetidinyl cyanoacetate of III;
Wherein, described outer circulation water scavenging system is the filled column of single filling water-removal agent filler, the perhaps filled column series combination of two and above filling water-removal agent filler, perhaps the filled column parallel combination of two and above filling water-removal agent filler;
Described water-removal agent is molecular sieve, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate or anhydrous magnesium sulfate;
The flow velocity that described reaction material liquid pump enters to load the external circulating system of water-removal agent per hour is 0.2～1.2 times of molar weight of 1-diphenyl-methyl-initial molar weight of 3-azetidinol in the reaction system.
2. preparation method according to claim 1 characterized by further comprising the step that obtains the sterling of 1-Benzydryl-3-azetidinyl cyanoacetate behind the crude product recrystallization with 1-Benzydryl-3-azetidinyl cyanoacetate.
3. preparation method according to claim 1 is characterized in that the mole proportioning of the reaction of described 1-diphenyl-methyl-3-azetidinol and cyanoacetic acid is 1:1～1:6.
4. preparation method according to claim 1 is characterized in that described activator comprises EDC or DCC.
5. preparation method according to claim 1 is characterized in that the mole proportioning of described 1-diphenyl-methyl-3-azetidinol and activator is 1:1～1:3.
6. preparation method according to claim 1 is characterized in that described solvent comprises THF or methylene dichloride, and its add-on is for so that add behind each reactant that the starting point concentration of 1-diphenyl-methyl-3-azetidinol is the amount of 2～3 mol/L in the whole reaction system.
7. preparation method according to claim 1 is characterized in that described temperature of reaction is 30～90 ℃.
8. preparation method according to claim 1 is characterized in that the described reaction times is 5～15 h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87107150A (en) * | 1986-10-09 | 1988-05-04 | 三共株式会社 | Dihydrogen pyridine derivative and its production and use |
| CN101570468A (en) * | 2009-06-15 | 2009-11-04 | 天津市康科德科技有限公司 | Method for preparing pesticide residue grade chromatographic ethanol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87107150A (en) * | 1986-10-09 | 1988-05-04 | 三共株式会社 | Dihydrogen pyridine derivative and its production and use |
| CN101570468A (en) * | 2009-06-15 | 2009-11-04 | 天津市康科德科技有限公司 | Method for preparing pesticide residue grade chromatographic ethanol |
Non-Patent Citations (2)
| Title |
|---|
| 吴国生等.阿折地平的合成.《中国新药杂志》.2007,第16卷(第12期),950-952. |
| 阿折地平的合成;吴国生等;《中国新药杂志》;20071231;第16卷(第12期);950-952 * |
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