CN107880020B - 4- with platelet aggregation inhibitory activity replaces Benzodiazepine 2- ketone compounds and its supercritical preparation process - Google Patents
4- with platelet aggregation inhibitory activity replaces Benzodiazepine 2- ketone compounds and its supercritical preparation process Download PDFInfo
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Abstract
The invention discloses a kind of 4- to replace Benzodiazepine 2- ketone compounds and its supercritical preparation process, belongs to medicine intermediate synthesis technical field.Technical solution of the present invention main points are as follows: a kind of 4- substitution Benzodiazepine 2- ketone compounds have the following structure:
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of 4- substituted benzene with platelet aggregation inhibitory activity
And phenodiazine Zhuo 2- ketone compounds and its supercritical preparation process.
Background technique
Benzodiazepine structure has extensive physiological activity and pharmacological action, is the heat of current field of medicinal chemistry research
Point.Benzodiazepines compound has the effects that antianxiety, tranquilizing soporific, anticonvulsion, of flaccid muscles, is medically usually used in
The drug of sedative and treatment cardiovascular disease.
Supercritical fluid (supercriticalfluid SCF) refers to the stream more than critical-temperature and critical pressure
Body has unique physicochemical properties, the advantages of having both gas and liquid: viscosity is small be similar to gas, density greatly close to
Liquid, diffusion coefficient are tens times or even hundreds of times of liquid, therefore it has very strong solvability and good mobility
And transitivity, it is very sensitive in variation of the Near The Critical Point to temperature and pressure.Common supercritical fluid has CO2、NH3、
CH3OH、C2H5OH etc..Compared to traditional methodology of organic synthesis, supercritical fluid is mild with operating condition, catalyst is recyclable,
The features such as environmentally protective.
The design of this research and utilization supercritical fluid has synthesized a kind of 4- substitution Benzodiazepine 2- ketone compounds, the route
Have the characteristics that easy to operate, high income, carbonyl ortho position carbon atom has been activated by cleverly method, is easy the hydrogen above it
Be substituted, and carbonyl enable to be reduced back quickly as former state, with good industrial prospect, and to obtained compound into
Platelet aggregation inhibitory activity detection is gone.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of, and the 4- with platelet aggregation inhibitory activity replaces benzodiazepine *
Tall and erect 2- ketone compounds and its supercritical preparation process.
A kind of 4- with platelet aggregation inhibitory activity replaces Benzodiazepine 2- ketone compounds structure as shown in formula I:
In formula I, R is methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclohexyl.
A kind of 4- with platelet aggregation inhibitory activity replaces the overcritical preparation side of Benzodiazepine 2- ketone compounds
Method, it is characterised in that specific steps are as follows:
A, aniline and pivaloyl chloride are in supercritical CO2Middle generation acylation reaction generates N- phenyl trimethicone acetamide；N- benzene
Base pivaloyl amine is in overcritical CH3Addition reaction occurs with 4- pyridine carboxaldehyde under OH and obtains N- (2- (hydroxyl (4- pyridyl group)
Methyl) phenyl) pivaloyl amine；
B, N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine is in supercritical CO2In be oxidized, tie
Secondary carbon and the hydroxyl connected generate carbonyl after sloughing a molecule hydrogen on structure, obtain N- (2- (4- piperidone base) phenyl) front three
Yl acetamide；N- (2- (4- piperidone base) phenyl) pivaloyl amine sloughs tertiary bytyry down in acid condition and obtains 2-
(4- piperidone base) aniline；
C, 2- (4- piperidone base) aniline DCC effect under with Boc glycyl chlorine in overcritical CH3Replace in OH
Reaction generates N- (2- (4- piperidone base) phenyl) Boc amino acetamide；
D, N- (2- (4- piperidone base) phenyl) Boc amino acetamide reacts in THF with HCl, sloughs the same of Boc group
When at salt obtain N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate；
E, N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate is in supercritical CO2In, ketoamine occurs and is condensed
To -2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine table；
F, -2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine table withIn supercritical CO2
Middle generation condensation reaction generates compound
G, compoundWith iodo compound in overcritical CH3Occur to replace and slough in OH anti-
It should obtain compound
It further limits, the detailed process of step A are as follows: aniline, pivaloyl chloride and carbonic acid are added in supercritical reaction kettle
Potassium is passed through supercritical CO2Be stirred to react 30min in 30 DEG C, 20MPa, chloroform be added after fully reacting in system, after stirring from
The heart, organic phase are concentrated to get N- phenyl trimethicone acetamide；Obtained N- phenyl trimethicone acetamide and 4- pyridine carboxaldehyde
It is added in supercritical reaction kettle, is passed through overcritical CH3OH is stirred to react 2h in 220 DEG C, 15MPa, adds in system after fully reacting
Enter ethyl acetate, be centrifuged after stirring, organic phase is concentrated to get N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl
The crude product of amine, then sterling is obtained through column chromatography for separation.
It further limits, the detailed process of step B are as follows: N- (2- (hydroxyl (4- pyridyl group) is added in supercritical reaction kettle
Methyl) phenyl) pivaloyl amine, it is passed through oxygen 1MPa and supercritical CO21h, fully reacting are stirred to react in 40 DEG C, 13MPa
Ethyl acetate is added in system afterwards, is centrifuged after stirring, organic phase is concentrated to get N- (2- (4- piperidone base) phenyl) trimethyl second
Amide；Obtained N- (2- (4- piperidone base) phenyl) pivaloyl amine is added to the mixed solution of ethyl alcohol and hydrochloric acid
In, it is stirred to react at room temperature, is heated to flowing back after stirring 2h, the reaction was continued 5h, TLC monitoring raw material have reacted
Entirely；Ethyl alcohol is evaporated off in vacuum concentration, then adjusts reaction solution pH > 7 with saturated sodium carbonate solution, then reaction solution three is extracted with dichloromethane
It is secondary, it is concentrated to get the crude product of 2- (4- piperidone base) aniline after merging organic phase, then obtain sterling through column chromatography for separation.
Further limit, the detailed process of step C are as follows: in supercritical reaction kettle be added 2- (4- piperidone base) aniline,
Boc glycyl chlorine and DCC are passed through overcritical CH3OH is stirred to react 1h in 240 DEG C, 10MPa, adds in system after fully reacting
Enter chloroform, is washed with 10% HCl solution and saturated sodium carbonate solution after agitation and filtration, be concentrated to give after separating organic phase respectively again
Sterling is obtained to N- (2- (4- piperidone base) phenyl) Boc amino acetamide crude product, then through column chromatography for separation.
It further limits, the detailed process of step D are as follows: in reaction flask, N- (2- (4- piperidone base) phenyl) Boc ammonia
Yl acetamide is added in the THF containing 4M HCl, is stirred to react 2h at room temperature, and TLC monitors raw material fully reacting, mistake
Reaction solution is filtered, filter cake is N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate.
It further limits, the detailed process of step E are as follows: N- (2- (4- piperidone base) benzene is added in supercritical reaction kettle
Base) glycyl amine hydrochlorate, sodium methoxide and methanol, it is passed through supercritical CO21h, fully reacting are stirred to react in 30 DEG C, 8MPa
Water and methylene chloride is added in system afterwards, is centrifuged after stirring, obtains 5- (4- pyridyl group) -1H- benzo [e] after organic phase concentration
[1,4] phenodiazine table -2 (3H) -one.
It further limits, the detailed process of step F are as follows: 5- (4- pyridyl group) -1H- benzo is added in supercritical reaction kettle
- 2 (3H) -one of [e] [1,4] phenodiazine table,And carbon tetrachloride, add quantitative acidulous catalyst to avoid
The hydrolysis of amide, is passed through supercritical CO2It is stirred to react 2h~4h in 30 DEG C, 8MPa~20MPa, is added in system after fully reacting
A certain amount of water (1eq), is then slowly dropped to reaction solution in ice n-heptanol solution, there is solid precipitation, and suction filtration obtains chemical combination
ObjectThe acidulous catalyst of the hydrolysis that can be avoided amide is phosphotungstic acid, silico-tungstic acid, phosphorus
Molybdic acid or ZrO2-TiO2。
It further limits, the detailed process of step G are as follows: be added in supercritical reaction kettleIodine
Substituted alkyl compound and methylene chloride are passed through overcritical CH3OH is stirred to react 2h in 240 DEG C, 10MPa, steams after fully reacting
A certain amount of ice water is added in solvent, has a large amount of solids to be precipitated, and suction filtration obtains compound
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
Aniline (10g, 0.107mol), pivaloyl chloride (14.24g, 0.118mol) and carbon are added in supercritical reaction kettle
Sour potassium (1.38g, 0.01mol), is passed through supercritical CO2It is stirred to react 30min in 30 DEG C, 20MPa, is added in system after fully reacting
Enter chloroform 50mL, be centrifuged after stirring, organic phase is concentrated to get N- phenyl trimethicone acetamide (19g, yield:99.63%) .MS
(ESI)m/z:177.1(M+H+).HNMR:(CDCl3) δ 7.35 (brs, 1H, NH), 7.53 (d, J=8Hz, 2H, Ar-H), 7.31
(t, J=8Hz, 2H, Ar-H), 7.09 (t, J=4Hz, 1H, Ar-H), 1.35 (s, 9H)
Embodiment 2
N- phenyl trimethicone acetamide (10g, 0.056mol) and 4- pyridine carboxaldehyde 10g are added in supercritical reaction kettle,
It is passed through overcritical CH3OH is stirred to react 2h in 220 DEG C, 15MPa, and ethyl acetate 50mL, stirring is added after fully reacting in system
After be centrifuged, organic phase is concentrated to get the crude product of N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine, then through column
Chromatography obtains sterling (13.1g, yield:82.11%) .MS (ESI) m/z:285.4 (M+H+).HNMR:(CDCl3)δ8.99
(brs, 1H, NH), 8.31 (d, J=6Hz, 2H, Ar-H), 8.11 (d, J=8Hz, 1H, Ar-H), 7.29-7.34 (m, 1H, Ar-
), H 8.31 (d, J=6Hz, 2H, Ar-H), 7.22 (d, J=5.2Hz, 2H, Ar-H), 8.31 (d, J=6Hz, 2H, Ar-H),
7.07 (d, J=3.6Hz, 2H, Ar-H), 5.79 (s, 1H), 1.04 (s, 9H)
Embodiment 3
In supercritical reaction kettle be added N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine (6g,
0.021mol), oxygen 1MPa and supercritical CO are passed through2It is stirred to react 1h in 40 DEG C, 13MPa, is added in system after fully reacting
Ethyl acetate 50mL is centrifuged after stirring, obtains N- (2- (4- piperidone base) phenyl) pivaloyl amine after organic phase concentration
(5.6g, yield:93.1%) .MS (ESI) m/z:283.4 (M+H+).1HNMR:(CDCl3)δ11.33(brs,1H,NH),
8.77-8.79 (m, 3H, Ar-H), 7.60 (t, J=7.6Hz, 1H, Ar-H), 7.46-7.49 (m, 3H, Ar-H), 7.06 (t, J=
7.2Hz,1H,Ar-H),1.04(s,9H).
Embodiment 4
In reaction flask, N- (2- (4- piperidone base) phenyl) pivaloyl amine (4.2g, 0.0154mol) is added to
It in the mixed solution of ethyl alcohol 35mL and hydrochloric acid 14mL, is stirred to react at room temperature, is heated to flowing back after stirring 2h, after
Continuous reaction 5h, TLC monitor raw material fully reacting；Vacuum concentration is evaporated off ethyl alcohol, then with saturated sodium carbonate solution adjust reaction solution pH >
7, then reaction solution is extracted with dichloromethane three times, the crude product of 2- (4- piperidone base) aniline is concentrated to get after merging organic phase, then
Sterling (2.4g, yield:80%) .MS (ESI) m/z:199.2 (M+H is obtained through column chromatography for separation+).HNMR:(CDCl3)δ
8.75-8.76 (m, 2H, Ar-H), 7.44 (d, 2H, Ar-H), 7.43 (d, 2H, Ar-H), 6.75 (d, 1H, J=8Hz, Ar-H),
6.57-6.61(m,1H,Ar-H),6.32(brs,2H,NH).
Embodiment 5
2- (4- piperidone base) aniline (2g, 0.01mol), Boc glycyl chlorine are added in supercritical reaction kettle
(3.8g, 0.02mol) and DCC (4.12g, 0.02mol), is passed through overcritical CH3OH is stirred to react 1h in 240 DEG C, 10MPa, instead
Chloroform 50mL should be added in completely rear system, be washed respectively with 10% HCl solution and saturated sodium carbonate solution again after agitation and filtration
It washs, is concentrated to get N- (2- (4- piperidone base) phenyl) Boc amino acetamide crude product after separating organic phase, then through column chromatography for separation
Obtain sterling (3.1g.yield:88%) .MS (ESI) m/z:356.4 (M+H+).HNMR:(CDCl3)δ11.46(brs,1H,
), NH 8.79 (t, 3H, J=4Hz, Ar-H), 8.72 (d, 1H, J=4Hz, Ar-H), 7.45-7.61 (m, 4H, Ar-H), 5.36
(brs, 1H, NH), 4.00 (d, J=8Hz, 2H), 1.45 (s, 9H)
Embodiment 6
In reaction flask, N- (2- (4- piperidone base) phenyl) Boc amino acetamide (2g, 0.0056mol) is added to
In THF 30mL containing 4M HCl, it being stirred to react 2h at room temperature, TLC monitors raw material fully reacting, filtering reacting liquid,
Filter cake is N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate (1.3g, yield:79%) MS (ESI) m/z:256.4
(M+H+).1HNMR:(CDCl3) δ 8.66 (t, 3H, J=4Hz, Ar-H), 8.43 (d, 1H, J=4Hz, Ar-H), 7.38-7.61
(m, 4H, Ar-H), 7.23 (brs, 1H, NH), 3.85 (d, J=8Hz, 2H), 1.53 (s, 2H)
Embodiment 7
In supercritical reaction kettle be added N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate (700mg,
2.41mmol), sodium methoxide (155.8mg, 2.88mmol) and methanol 15mL, are passed through supercritical CO2It is stirred to react in 30 DEG C, 8MPa
1h is added water 10mL and methylene chloride 10mL, is centrifuged after stirring in system after fully reacting, obtain 5- (4- after organic phase concentration
Pyridyl group) -2 (3H) -one (515mg, yield:90%) .MS (ESI) m/z:238.3 (M+H of -1H- benzo [e] [1,4] phenodiazine table+).1HNMR:(CDCl3) δ 9.37 (brs, 1H, NH), 8.68 (s, 2H, Ar-H), 7.54 (d, 1H, J=8Hz, Ar-H), 7.45
(s,2H,Ar-H),7.20-7.27(m,3H,Ar-H),4.38(s,2H).
Embodiment 8
- 2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine table is added in supercritical reaction kettle
(300mg,1.26mmol)、(247mg, 1.5mmol) and carbon tetrachloride 50mL, adds phosphotungstic acid
(0.126mmol), is passed through supercritical CO2It is stirred to react 2h in 30 DEG C, 15MPa, 1eq water is added after fully reacting in system, so
Reaction solution is slowly dropped in ice n-heptanol solution afterwards, there is solid precipitation, suction filtration obtains compound
(421mg, yield:87%) .MS (ESI) m/z:384.2 (M+H+).HNMR:(CDCl3)δ9.37(brs,1H,NH),8.68(s,
2H, Ar-H), 7.54 (d, 1H, J=8Hz, Ar-H), 7.45 (s, 2H, Ar-H), 7.20-7.40 (m, 8H, Ar-H), 3.81 (s,
2H),3.50(m,2H),3.33(m,3H),3.81(s,2H),2.88(m,1H),2.47(m,2H).
Embodiment 9
- 2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine table is added in supercritical reaction kettle
(300mg,1.26mmol)、(247mg, 1.5mmol) and carbon tetrachloride 50mL, adds silico-tungstic acid
(0.189mmol), is passed through supercritical CO2It is stirred to react 2h in 30 DEG C, 20MPa, 1eq water is added after fully reacting in system, so
Reaction solution is slowly dropped in ice n-heptanol solution afterwards, there is solid precipitation, suction filtration obtains compound
(388mg, yield:80%) .MS (ESI) m/z:384.2 (M+H+).
Embodiment 10
- 2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine table is added in supercritical reaction kettle
(300mg,1.26mmol)、(247mg, 1.5mmol) and carbon tetrachloride 50mL, adds phosphomolybdic acid
(0.126mmol), is passed through supercritical CO2It is stirred to react 4h in 30 DEG C, 8MPa, 1eq water is added after fully reacting in system, then
Reaction solution is slowly dropped in ice n-heptanol solution, there is solid precipitation, suction filtration obtains compound
(363mg, yield:75%) .MS (ESI) m/z:384.2 (M+H+).
Embodiment 11
- 2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine table is added in supercritical reaction kettle
(300mg,1.26mmol)、(247mg, 1.5mmol) and carbon tetrachloride 50mL, adds ZrO2-TiO2
(0.252mmol), is passed through supercritical CO2It is stirred to react 3h in 30 DEG C, 13MPa, 1eq water is added after fully reacting in system, so
Reaction solution is slowly dropped in ice n-heptanol solution afterwards, there is solid precipitation, suction filtration obtains compound
(435mg, yield:90%) .MS (ESI) m/z:384.2 (M+H+).
Embodiment 12
It is added in supercritical reaction kettle(460mg, 1.2mmol) is passed through overcritical CH3OH
It is stirred to react 2h in 240 DEG C, 10MPa, solvent is steamed after fully reacting, 20mL ice water is added, there are a large amount of solids to be precipitated, filters
To compound(161mg, yield:53%) .MS (ESI) m/z:255.1 (M+H+).HNMR:(CDCl3)δ
9.22 (brs, 1H, NH), 8.98 (s, 2H, Ar-H), 7.85 (m, 2H, Ar-H), 7.72 (m, 2H, Ar-H), 7.50 (d, 1H, J=
8Hz,Ar-H),7.26(m,1H,Ar-H),4.35(m,1H),1.88(m,3H).
Embodiment 13
It is added in supercritical reaction kettle(460mg, 1.2mmol), iodomethane (369mg,
1.3mmol) with methylene chloride 15mL, it is passed through overcritical CH3OH is stirred to react 2h in 240 DEG C, 10MPa, steams after fully reacting
20mL ice water is added in solvent, has a large amount of solids to be precipitated, and suction filtration obtains compound(260mg,yield:
85%) .MS (ESI) m/z:255.1 (M+H+).
Embodiment 14
The method in embodiment 1-13 is repeated, difference is using different iodo-alkyl compounds, to be made one
Series compound is specifically shown in Table 1.
Table 1:
Embodiment 15
Platelet aggregation inhibitory activity test
Healthy male rabbit is selected, it is random to be grouped.If normal and ticlopidine control group, gastric infusion, dosage 30mg/
kg-1.Normal group gives the CMC-Na that equivalent mass concentration is 0.5%.40mg/kg is injected intraperitoneally in 2h after administration-1Penta bar
Than appropriate sodium (1mL/kg-1) anesthesia, rabbit hearts position blood is acquired, the sodium citrate for being 3.8% with mass concentration is anticoagulant, respectively
Platelet rich plasma (PRP) and platelet poor plasma (PPP) are prepared, by adenosine diphosphate (ADP) (final concentration: 1.5 μm of ol/L-1) be added
With induced platelet aggregation, detected relative light transmission 5 minutes at 37 DEG C, the biggest impact during observation be used to calculate induction
Maximum platelet aggregation rate and inhibiting rate.Inhibiting rate (%)=(aggregation maximum value-test group aggregation of control group is maximum
Value)/control group aggregation maximum value * 100%.
As seen from the above table, the obtained target compound of the present invention has good platelet aggregation-against effect, part
Compound is horizontal close to ticlopidine.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. a kind of 3- with platelet aggregation inhibitory activity replaces Benzodiazepine 2- ketone compounds, it is characterised in that its molecule
Structural formula are as follows:Wherein R is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclohexyl.
2. a kind of 3- described in claim 1 with platelet aggregation inhibitory activity replaces Benzodiazepine 2- ketone compounds
Supercritical preparation process, it is characterised in that specific steps are as follows:
A, aniline and pivaloyl chloride are in supercritical CO2Middle generation acylation reaction generates N- phenyl trimethicone acetamide；N- phenyl front three
Yl acetamide is in overcritical CH3Addition reaction occurs with 4- pyridine carboxaldehyde under OH and obtains N- (2- (hydroxyl (4- pyridyl group) methyl)
Phenyl) pivaloyl amine；
B, N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine is in supercritical CO2In be oxidized, it is secondary in structure
Carbon and the hydroxyl connected generate carbonyl after sloughing a molecule hydrogen, obtain N- (2- (4- pyriconyl) phenyl) pivaloyl
Amine；N- (2- (4- pyriconyl) phenyl) pivaloyl amine sloughs tertiary bytyry in acid condition and obtains 2- (4- pyridone
Base) aniline；
C, 2- (4- pyriconyl) aniline DCC effect under with Boc glycyl chlorine in overcritical CH3Substitution reaction occurs in OH
Generate N- (2- (4- pyriconyl) phenyl) Boc amino acetamide；
D, N- (2- (4- pyriconyl) phenyl) Boc amino acetamide reacts in THF with HCl, while sloughing Boc group at
Salt obtains N- (2- (4- pyriconyl) phenyl) glycyl amine hydrochlorate；
E, N- (2- (4- pyriconyl) phenyl) glycyl amine hydrochlorate is in supercritical CO2In, ketoamine occurs and is condensed to yield 5-
(4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine -2 (3H) -one of Zhuo；
F, tall and erect -2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine withIn supercritical CO2Middle hair
Raw condensation reaction generates compound
G, compoundWith iodo compound in overcritical CH3Occur to replace and slough in OH to react
To compound
3. a kind of 3- with platelet aggregation inhibitory activity according to claim 2 replaces Benzodiazepine 2- ketone chemical combination
The supercritical preparation process of object, it is characterised in that the detailed process of step A are as follows: aniline, spy penta are added in supercritical reaction kettle
Acyl chlorides and potassium carbonate, are passed through supercritical CO2It is stirred to react 30min in 30 DEG C, 20MPa, chloroform is added after fully reacting in system,
It is centrifuged after stirring, organic phase is concentrated to get N- phenyl trimethicone acetamide；Obtained N- phenyl trimethicone acetamide and 4-
Pyridine carboxaldehyde is added in supercritical reaction kettle, is passed through overcritical CH3OH is stirred to react 2h in 220 DEG C, 15MPa, after fully reacting
Ethyl acetate is added in system, is centrifuged after stirring, organic phase is concentrated to get N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) three
The crude product of methylacetamide, then sterling is obtained through column chromatography for separation.
4. a kind of 3- with platelet aggregation inhibitory activity according to claim 2 replaces Benzodiazepine 2- ketone chemical combination
The supercritical preparation process of object, it is characterised in that the detailed process of step B are as follows: N- (2- (hydroxyl is added in supercritical reaction kettle
(4- pyridyl group) methyl) phenyl) pivaloyl amine, it is passed through oxygen 1MPa and supercritical CO2It is stirred to react in 40 DEG C, 13MPa
1h is added ethyl acetate, is centrifuged after stirring, organic phase is concentrated to get N- (2- (4- pyriconyl) benzene in system after fully reacting
Base) pivaloyl amine；Obtained N- (2- (4- pyriconyl) phenyl) pivaloyl amine is added to ethyl alcohol and hydrochloric acid
Mixed solution in, be stirred to react at room temperature, be heated to flowing back after stirring 2h, the reaction was continued 5h, TLC monitoring are former
Expect fully reacting；Ethyl alcohol is evaporated off in vacuum concentration, then adjusts reaction solution pH > 7 with saturated sodium carbonate solution, then be extracted with dichloromethane
Reaction solution three times, is concentrated to get the crude product of 2- (4- pyriconyl) aniline after merging organic phase, then obtains through column chromatography for separation pure
Product.
5. a kind of 3- with platelet aggregation inhibitory activity according to claim 2 replaces Benzodiazepine 2- ketone chemical combination
The supercritical preparation process of object, it is characterised in that the detailed process of step C are as follows: 2- (4- pyridine is added in supercritical reaction kettle
Ketone group) aniline, Boc glycyl chlorine and DCC, it is passed through overcritical CH3OH is stirred to react 1h, fully reacting in 240 DEG C, 10MPa
Chloroform is added in system afterwards, is washed, is separated organic with 10% HCl solution and saturated sodium carbonate solution respectively again after agitation and filtration
It is concentrated to get N- (2- (4- pyriconyl) phenyl) Boc amino acetamide crude product after phase, then obtains sterling through column chromatography for separation.
6. a kind of 3- with platelet aggregation inhibitory activity according to claim 2 replaces Benzodiazepine 2- ketone chemical combination
The supercritical preparation process of object, it is characterised in that the detailed process of step D are as follows: in reaction flask, N- (2- (4- pyriconyl)
Phenyl) Boc amino acetamide is added in the THF containing 4M HCl, is stirred to react 2h at room temperature, and TLC monitors raw material
Fully reacting, filtering reacting liquid, filter cake are N- (2- (4- pyriconyl) phenyl) glycyl amine hydrochlorate.
7. a kind of 3- with platelet aggregation inhibitory activity according to claim 2 replaces Benzodiazepine 2- ketone chemical combination
The supercritical preparation process of object, it is characterised in that the detailed process of step E are as follows: N- (2- (4- pyrrole is added in supercritical reaction kettle
Pyridine ketone group) phenyl) glycyl amine hydrochlorate, sodium methoxide and methanol, it is passed through supercritical CO2It is stirred to react 1h in 30 DEG C, 8MPa,
Water and methylene chloride is added after fully reacting in system, is centrifuged after stirring, obtains 5- (4- pyridyl group) -1H- after organic phase concentration
Benzo [e] [1,4] phenodiazine -2 (3H) -one of Zhuo.
8. a kind of 3- with platelet aggregation inhibitory activity according to claim 2 replaces Benzodiazepine 2- ketone chemical combination
The supercritical preparation process of object, it is characterised in that the detailed process of step F are as follows: 5- (4- pyridine is added in supercritical reaction kettle
Base) tall and erect -2 (3H) -one of -1H- benzo [e] [1,4] phenodiazine,And carbon tetrachloride, add quantitative faintly acid
Catalyst is passed through supercritical CO to avoid the hydrolysis of amide22h~4h, fully reacting are stirred to react in 30 DEG C, 8MPa~20MPa
A certain amount of water is added in system afterwards, then reaction solution is slowly dropped in ice n-heptanol solution, has solid precipitation, filters
To compoundThe acidulous catalyst of the hydrolysis that can be avoided amide is phosphotungstic acid, silicon tungsten
Acid, phosphomolybdic acid or ZrO2-TiO2。
9. a kind of 3- with platelet aggregation inhibitory activity according to claim 2 replaces Benzodiazepine 2- ketone chemical combination
The supercritical preparation process of object, it is characterised in that the detailed process of step G are as follows: be added in supercritical reaction kettleIodo-alkyl compound and methylene chloride are passed through overcritical CH3OH stirs anti-in 240 DEG C, 10MPa
2h is answered, steams solvent after fully reacting, a certain amount of ice water is added, there are a large amount of solids to be precipitated, suction filtration obtains compound
10. a kind of 3- with platelet aggregation inhibitory activity as described in claim 1 replaces Benzodiazepine 2- ketone chemical combination
Object is preparing the application in medicament for resisting platelet aggregation.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3182066A (en) * | 1964-04-09 | 1965-05-04 | Hoffmann La Roche | Aminophenyl-pyridyl ketones |
| US3644419A (en) * | 1969-12-05 | 1972-02-22 | Hoffmann La Roche | 2 3 4 9 - tetrahydro - 9 -phenyl-oxazirino-(2 3-d)(1 4)benzodiazepines and preparation thereof |
| CN103435562A (en) * | 2013-08-26 | 2013-12-11 | 华东理工大学 | 6-substituted benzodiazepine-2,4-diketone compound and application thereof |
| CN107163045A (en) * | 2017-06-05 | 2017-09-15 | 穆开蕊 | The preparation method of piperidines with platelet aggregation-against function and the triazole compound of pyrido 1,2,3 |
| CN107260733A (en) * | 2017-06-05 | 2017-10-20 | 侯茜茜 | The preparation method of new medicament for resisting platelet aggregation of the one kind containing 1,6 dihydropyridine 3 (2H) ketone structures |
-
2017
- 2017-11-29 CN CN201711220510.XA patent/CN107880020B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3182066A (en) * | 1964-04-09 | 1965-05-04 | Hoffmann La Roche | Aminophenyl-pyridyl ketones |
| US3644419A (en) * | 1969-12-05 | 1972-02-22 | Hoffmann La Roche | 2 3 4 9 - tetrahydro - 9 -phenyl-oxazirino-(2 3-d)(1 4)benzodiazepines and preparation thereof |
| CN103435562A (en) * | 2013-08-26 | 2013-12-11 | 华东理工大学 | 6-substituted benzodiazepine-2,4-diketone compound and application thereof |
| CN107163045A (en) * | 2017-06-05 | 2017-09-15 | 穆开蕊 | The preparation method of piperidines with platelet aggregation-against function and the triazole compound of pyrido 1,2,3 |
| CN107260733A (en) * | 2017-06-05 | 2017-10-20 | 侯茜茜 | The preparation method of new medicament for resisting platelet aggregation of the one kind containing 1,6 dihydropyridine 3 (2H) ketone structures |
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