CN107163046A - The preparation method of pyrido o-diazepamate derivative with anti-tumor function - Google Patents
The preparation method of pyrido o-diazepamate derivative with anti-tumor function Download PDFInfo
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- CN107163046A CN107163046A CN201710413656.XA CN201710413656A CN107163046A CN 107163046 A CN107163046 A CN 107163046A CN 201710413656 A CN201710413656 A CN 201710413656A CN 107163046 A CN107163046 A CN 107163046A
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- 0 CCOC(C(*(*C(CCC*(*)O)=C1)O)C1=O)=O Chemical compound CCOC(C(*(*C(CCC*(*)O)=C1)O)C1=O)=O 0.000 description 7
- TXWQWZUOYAQDRV-UHFFFAOYSA-N CCOC(c(c(O)c(CN(CC1)C(OC(C)(C)C)=O)c1n1)c1O)=O Chemical compound CCOC(c(c(O)c(CN(CC1)C(OC(C)(C)C)=O)c1n1)c1O)=O TXWQWZUOYAQDRV-UHFFFAOYSA-N 0.000 description 2
- KRGGGGSVCGEKSX-UHFFFAOYSA-N Oc1c(CNCC2)c2nc(O)c1 Chemical compound Oc1c(CNCC2)c2nc(O)c1 KRGGGGSVCGEKSX-UHFFFAOYSA-N 0.000 description 2
- RNTMOIQITYNDIV-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(Cl)=C2)=C1NC2=O)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(Cl)=C2)=C1NC2=O)=O RNTMOIQITYNDIV-UHFFFAOYSA-N 0.000 description 1
- KEUVTQPNJYHEHS-UHFFFAOYSA-N CCOC(C(C(C(CN(CC1)C(OC(C)(C)C)=O)=C1N1)=O)C1=O)=O Chemical compound CCOC(C(C(C(CN(CC1)C(OC(C)(C)C)=O)=C1N1)=O)C1=O)=O KEUVTQPNJYHEHS-UHFFFAOYSA-N 0.000 description 1
- PADPURGFWVMRMN-UHFFFAOYSA-N Clc1cc(Cl)nc2c1CNCC2 Chemical compound Clc1cc(Cl)nc2c1CNCC2 PADPURGFWVMRMN-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Abstract
The invention discloses a kind of preparation method of the pyrido o-diazepamate derivative with anti-tumor function, belong to pharmaceutical chemistry synthesis technical field.Technical scheme main points are：
Description
Technical field
The invention belongs to pharmaceutical chemical synthesis technical field, and in particular to a kind of new pyrrole with anti-tumor function
Pyridine and the preparation method of o-diazepamate derivative.
Background technology
The synthesis of organic heterocyclic molecule is that organic chemistry filed develops fast one branch in recent years with application, in doctor
Occupy highly important status in medicine, the development of agricultural chemicals.It is used as the important heterocyclic compound of a class, o-diazepamate class
Compound all plays very important effect in medicine, agricultural chemicals.The pyrazole derivatives spy such as have effect wide spectrum, drug effect strong
Point, has been received more and more attention.In field of medicaments, o-diazepamate class compound is to including cancer, asthma, joint
Many diseases including inflammation have curative effect；In pesticide field, there is o-diazepamate class compound desinsection, sterilization and weeding to live
Property.In addition, o-diazepamate analog derivative has also all been applied in industries such as papermaking, leather, washing, plastics, coating, with wide
Wealthy research and development prospect.Pyridine is also a kind of important nitrogen heterocyclic ring, because there is good bioactivity extensively should for it
For medical research.For example, its derivative can suppress as 5HT2A receptor antagonists, extracellular signal-regulated kinase
Agent, mammal P2X7 conditioning agents, and with anti-breast cancer cell MDA-MB-231 proliferation activities and suppress liver cancer cells
HepG2 propagation.Fluorine-containing aromatic ring group, occurs very frequently in many insecticide pesticides, such as double trifluoro worm urides.
This seminar by the method for Computer-Aided Drug Design, designed and synthesized a series of new have it is antitumor
The pyrido o-diazepamate derivative of function, and related activity test has been carried out to it.
The content of the invention
Present invention solves the technical problem that there is provided, a kind of synthetic method is simple, and having for molecular structure novelty is antitumor
The preparation method of the pyrido o-diazepamate derivative of function.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of new pyrrole with anti-tumor function
Pyridine and the preparation method of o-diazepamate derivative, it is characterised in that concretely comprise the following steps：
A, N-Boc-4- piperidones and dimethyl carbonate react in the presence of potassium tert-butoxide obtains N-Boc-3- formic acid first
Ester -4- piperidones
B, N-Boc-3- methyl formate -4- piperidones are under ammonium acetate effect, and ketone carbonyl redox is changed into amino
Compound N-Boc-3- methyl formate -4- amino -3- alkene-piperidines
C, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines and chloroformyl ethyl acetate take under TEA effects
Generation reaction obtains compound N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
D, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines occur in the presence of potassium tert-butoxide
Intramolecular cyclization obtains compoundThen the compound carries out intramolecular in acid condition
Hydrogen migration and carbonyl reduction obtain compound
E、Under strongly acidic conditions, ester group and Boc groups are sloughed in heating, obtain compound
F、Under POCl3 effect, hydroxyl is replaced by chlorine obtains compound
G、Chloro carbon-to-nitrogen double bon is changed into amido link under concentrated hydrochloric acid effect and obtain compound
H、In the basic conditions, Boc amido protectings are carried out and obtains compound
I、Under cesium carbonate effect compound is obtained with iodomethane reaction
J、Reduction carbon-carbon double bond is obtained under Pd/C effects
K、Occur condensation with 4- pyridine carboxaldehydes and obtain compound
L、Compound is obtained with hydration hydrazine reaction
M、Intramolecular cyclization is carried out under Oxygen Condition and obtains compound
N、Slough Boc groups and obtain compound
O、Obtained with carboxylic acid compound in alkalescence condition reaction
Further limit, step A detailed process is：In reaction bulb, 1eq N-Boc-4- piperidones is added to
In the toluene of 10V volumes, 2eq dimethyl carbonate and 2eq potassium tert-butoxide are added, 70 DEG C of reaction 1h is heated to, is cooled to
Room temperature, adds water and is quenched, and it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, is spin-dried for
Obtain yellow oil N-Boc-3- methyl formate -4- piperidones
Further limit, step B detailed process is：1eq N-Boc-3- methyl formate -4- piperidones is added to 10
In the methanol of times volume, 3eq ammonium acetate is added, reaction is stayed overnight, be spin-dried for methanol, add the water of 3 times of volumes, dichloromethane extraction
Anhydrous sodium sulfate drying is used after extracting reaction solution, red oily liquids N-Boc-3- methyl formate -4- amino -3- is obtained after being spin-dried for
Alkene-piperidines
Further limit, step C detailed process is：By 1eq N-Boc-3- methyl formate -4- amino -3- alkene-piperidines
In the DCM for being added to 8 times of volumes, 1.05eq TEA is added, 10 DEG C are cooled to, 1.05eq 4- chloromethane ethyl acetoacetic acid second is added dropwise
Ester, room temperature reaction is stayed overnight, and adds the DCM dilute reaction solutions of 8 times of volumes, twice, anhydrous sodium sulfate drying is spin-dried for both obtaining for washing
Red oil product N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
Further limit, step D detailed process is：1eq N-Boc-3- methyl formate -4- carbamyl acetic acid second
Ester -3- alkene-piperidines is added in the THF of 10 times of volumes, then is added portionwise 2.0eq t-BuOK, reaction temperature control less than
25 DEG C, frozen water is added after reaction 1h and is quenched, it is 3 to adjust reaction solution pH with 2mol/L HCl, filtering, and it is white that vacuum drying obtains class
Color solid product
Further limit, step E detailed process is：In 10eq 6mol/L HCl solution, it is added portionwise 1.0eq's100 DEG C are heated to, reaction is stayed overnight, are spin-dried for reaction dissolvent, then washed with ether, is dried in vacuo
Obtain off-white powder
Further limit, step F detailed process is：To 5eq POCl3In be added portionwise 1.0eq's100 DEG C are heated to, reaction is stayed overnight, are spin-dried for POCl3Obtain Red oil product
Further limit, step G detailed process is：It is added to the 1,4- dioxies six of 4 times of volumes
In ring, the concentrated hydrochloric acid of 4 times of volumes is added, 100 DEG C are heated to, back flow reaction 2 days is spin-dried for adding the second of 10 times of volumes after solvent
Acetoacetic ester, is washed three times, is dried and is obtained brown solid after being spin-dried for
Further limit, step H detailed process is：1eq'sIt is added to the 1,4- of 10 times of volumes
In dioxane and the water of 10 times of volumes, then 3.0eq sodium carbonate and 1.5eq (Boc) is added portionwise2O, reacts at room temperature 10h
Afterwards, filter, then wash with ethyl acetate reaction solution is extracted with ethyl acetate after filter cake, then washed with sodium chloride solution, dried, revolved
Reaction solution is obtained
Further limit, step I detailed process is：1.0eq'sIt is added to 10 times of volumes
DMF in, add 1.5eq Cs2CO3, 1.3eq KI, room temperature reaction stays overnight, and adds frozen water and reaction solution, acetic acid is quenched
Ethyl ester extractive reaction liquid, sodium chloride solution washing, dries, is spin-dried for, then is beaten with ether, filters, and it is solid that vacuum drying obtains white
Body
Further limit, step J detailed process is：In autoclave, by 1.0eq'sAdd
To the methanol of 10 times of volumes, a certain amount of Pd/C is passed through hydrogen, reacting kettle inner pressure is reached 0.2MPa, is heated to 50 DEG C, returns
Stream reaction 5h, TLC monitoring raw material reaction is complete, and filtering reacting liquid is spin-dried for after solvent obtaining brown solid
Further limit, step K detailed process is：By compoundAdd in DMF, add
4- pyridine carboxaldehydes and a certain amount of triethylamine, are heated to backflow, complete through TLC monitoring raw material reactions after reaction a period of time,
Reaction solution, which is poured into frozen water, has a large amount of solids to separate out, and filter cake drying is obtained compound after suction filtration
Further limit, step L detailed process is：In reaction bulb, compoundAdd
In DMSO, a certain amount of hydrazine hydrate is added, at ambient temperature reaction a period of time, it is complete through TLC monitoring raw material reactions,
Reaction solution, which is poured into frozen water, has a large amount of solids to separate out, and filter cake drying is obtained compound after suction filtration
Further limit, step M detailed process is：In reaction bulb, compoundPlus
Enter in DMSO, backflow is heated under Oxygen Condition, it is reaction a period of time, complete through TLC monitoring raw material reactions, reaction solution is fallen
Enter in frozen water to have a large amount of solids to separate out, filter cake drying is obtained compound after suction filtration
Further limit, step N detailed process is：1.0eqIt is added to 10 times of volumes
Methanol and 10 volumes 12mol/L HCl/1, in 4- dioxane, room temperature reaction is stayed overnight, and is spin-dried for, ether washing, is obtained
Further limit, step O detailed process is：In reaction bulb,It is added in DMF, then
Triethylamine and carboxylic acid compound are added, 70 DEG C are heated to, reaction a period of time obtains compound
The synthetic route of pyrido o-diazepamate derivative of the present invention with anti-tumor function is：
The present invention has synthesized a series of new pyrido o-diazepamate derivative and has carried out antitumor activity test, hair
Now the derivative has good antitumor activity.
Embodiment
The above to the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
In reaction bulb, N-Boc-4- piperidones 20g (0.1mol) is added in toluene 200mL, carbonic acid two is added
Methyl esters 18g (0.2mol) and potassium tert-butoxide 22g (0.2mol), is heated to 70 DEG C of reaction 1h, is cooled to room temperature, the 100mL that adds water quenches
Go out, it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, be spin-dried for obtaining yellow oil
Shape thing N-Boc-3- methyl formate -4- piperidones 25g；1HNMR(400MHz,CD3Cl)δ:3.81 (s, 1H), 3.71 (d, J=
8.4Hz, 1H), 3.68 (d, J=8.4Hz, 1H), 3.45 (s, 3H), 3.07-3.05 (m, 2H), 2.76-2.73 (m, 2H), 1.37
(s,9H).MS-ESI(m/z):258.3[M+H+]。
Embodiment 2
In reaction bulb, N-Boc-3- methyl formate -4- piperidones 25g (0.1mol) are added in methanol 300mL, then
Ammonium acetate 22g (0.3mol) is added, reaction is stayed overnight, TLC monitoring raw material reactions are complete, are spin-dried for methanol, water 900mL added, with two
Chloromethanes 300mL extractive reactions liquid three times, merges and anhydrous sodium sulfate drying is used after organic phase, red oily liquids is obtained after being spin-dried for
N-Boc-3- methyl formate -4- amino -3- alkene-piperidines 25g；1HNMR(400MHz,CD3Cl)δ:8.56(s,2H),3.93(s,
2H),3.77(s,3H),3.57-3.55(m,2H),2.16-2.13(m,2H),1.37(s,9H).MS-ESI(m/z):257.3[M
+H+]。
Embodiment 3
In reaction bulb, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines 26g (0.1mol) is added to dichloromethane
In alkane 200mL, TEA11g (0.11mol) is added, 10 DEG C are cooled to, 4- chloroformyl ethyl acetate 16g is slowly added dropwise
(0.105mol), room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, add dichloromethane 200mL dilute reaction solutions, water
Wash twice, anhydrous sodium sulfate drying, be spin-dried for both obtaining Red oil product N-Boc-3- methyl formate -4- carbamyl acetic acid second
Ester -3- alkene-piperidines 25g；1HNMR(400MHz,CD3Cl)δ:4.71(s,2H),3.93(s,2H),3.79(s,3H),3.57-
3.55(m,2H),3.53(s,2H),2.16-2.13(m,2H),1.37(s,9H),1.29(s,3H).MS-ESI(m/z):371.4
[M+H+]。
Embodiment 4
In reaction bulb, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines 37g (0.1mol)
It is added in THF400mL, then t-BuOK 23g (0.2mol) is added portionwise, reaction temperature control is reacted after 1h less than 25 DEG C
Add frozen water 300mL to be quenched, it is 3 to adjust reaction solution pH with 2mol/L HCl, and filtering, vacuum drying obtains off-white powder production
Product32g；1H NMR(400MHz,DMSO-d6)δ:11.51(s,1H),5.35(s,1H),
4.71 (s, 2H), 4.33 (d, J=4.0Hz, 2H), 3.66-3.62 (m, 2H), 3.25 (d, J=12.0Hz, 2H), 1.41-1.39
(m,9H),1.33-1.32(m,3H)。
Embodiment 5
In reaction bulb, the HCl solution 200mL in 6mol/L is added, then be added portionwise
34g (0.1mol), is heated to 100 DEG C, reaction is stayed overnight, and is spin-dried for reaction dissolvent, then is washed with ether, and vacuum drying obtains off-white color
Solid15g；1H NMR(400MHz,DMSO-d6)δ:11.47(s,1H),5.95(s,1H),5.41(s,
1H), 3.86-3.85 (m, 2H), 3.71 (d, J=12.0Hz, 2H), 3.11-3.09 (m, 2H), 1.90 (s, 1H).
Embodiment 6
In closed reaction bulb, it is added portionwise into POCl3 50g (0.5mol)16g
(0.1mol), is slowly heated to 100 DEG C, reaction is stayed overnight, and vacuum is spin-dried for POCl3 and obtains Red oil product16g；1H NMR(400MHz,DMSO-d6)δ:7.61 (s, 1H), 3.81 (s, 2H), 3.37 (d, J=
12.0Hz,2H),3.13-3.12(m,2H),1.87(s,1H)。
Embodiment 7
In the reaction bulb with thermometer and stirring,20g is added to 1,4- dioxane
In 100mL, concentrated hydrochloric acid 100mL is slow added into, 100 DEG C are heated to, back flow reaction 2 days is spin-dried for after solvent adding 10 times of volumes
Ethyl acetate, wash three times, dry be spin-dried for after obtain brown solid 1H NMR(400MHz,CDCl3)δ:
8.17 (s, 1H), 6.62 (s, 1H), 3.35 (s, 2H), 2.96 (d, J=12.0Hz, 2H), 2.07-2.05 (m, 2H) .MS-ESI
(m/z):185.6[M+H+]。
Embodiment 8
In reaction bulb,18g (0.1mol) is added to 1,4- dioxane 200mL and water 200mL
In, then sodium carbonate 30g (0.3mol) and (Boc) is added portionwise2After O 33g (0.15mol), room temperature reaction 10h, TLC monitoring is former
Material reaction is complete, filtering reacting liquid, then is washed with ethyl acetate 100mL after filter cake with ethyl acetate 200mL extractive reactions liquid three
It is secondary, then washed with sodium chloride solution, dry, rotation reaction solution is obtained20g；1H NMR(400MHz,
DMSO-d6)δ:6.61 (s, 1H), 3.93 (s, 2H), 3.54 (s, 3H), 3.57 (d, J=12.0Hz, 2H), 2.07-2.05 (m,
2H),1.39(s,9H)。
Embodiment 9
In reaction solution,28g (0.1mol) is added in DMF 300mL, adds carbonic acid
Caesium 50g (0.15mol), KI 20g (0.13mol), room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, add frozen water
Reaction solution is quenched in 100mL, and ethyl acetate 200mL extractive reactions liquid three times, saturated nacl aqueous solution 200mL washing reaction liquids are done
It is dry, it is spin-dried for, then be beaten with ether, filter, vacuum drying obtains white solid26g
Embodiment 10
, will in autoclave30g (0.1mol) is added in methanol 300mL, adds catalyst
Pd/C 6g, are passed through hydrogen, reacting kettle inner pressure is reached 0.2MPa, are heated to 50 DEG C, back flow reaction 5h, TLC monitoring raw material is anti-
Should be complete, filtering reacting liquid is spin-dried for after solvent obtaining brown solid27g
Embodiment 12
In reaction bulb, by compound30g (0.1mol) is added in DMF200mL, adds 4-
Pyridine carboxaldehyde 12.5 (0.12mol) and triethylamine 10mL, are heated to backflow, through TLC monitoring raw material reactions after reaction a period of time
Completely, reaction solution is poured into frozen water has a large amount of solids to separate out, and filter cake drying is obtained compound after suction filtration
Embodiment 13
In reaction bulb, compound40g (0.1mol) is added in DMSO 150mL, then is added
Enter hydrazine hydrate 50mL, at ambient temperature reaction a period of time, it is complete through TLC monitoring raw material reactions, reaction solution is poured into frozen water
In there are a large amount of solids to separate out, filter cake drying is obtained compound after suction filtration
Embodiment 14
In reaction bulb, compound41g (0.1mol) is added in DMSO 150mL,
Backflow is heated under Oxygen Condition, reaction a period of time, complete through TLC monitoring raw material reactions, reaction solution, which is poured into frozen water, to be had
A large amount of solids are separated out, and filter cake drying is obtained compound after suction filtration33g
Embodiment 15
, will in reaction bulb40g (0.1mol) is added to methanol 400mL's and 12mol/L
In HCl/1,4- dioxane 400mL, room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, are spin-dried for, ether washing concentrate,
Obtain22g；1H NMR(400MHz,DMSO-d6)δ:11.96(s,1H),5.47(s,1H),3.33
(s,2H),2.95-2.94(m,2H),2.79-2.71(m,4H),2.75(s,1H),2.61-2.55(m,4H),2.06-2.05
(m,2H),1.92-1.90(m,4H),1.67-1.65(m,4H).MS-ESI(m/z):293.8[M+H]+。
Embodiment 16
In reaction bulb,26g (0.1mol) is added in DMF, adds triethylamine 20g
(0.2mol) and benzoic acid 12g (0.1mol), is heated to after 70 DEG C, reaction 3h through the reaction of TLC monitoring raw materials completely, reaction solution
It is poured into water, with chloroform 200mL extractive reactions liquid three times, is spin-dried for obtaining compound after merging organic phase
31g；1H NMR(400MHz,DMSO-d6)δ:11.98(s,1H),8.04-8.02(m,2H),7.70(s,1H),7.63-7.62
(m, 2H), 5.44 (s, 1H), 4.01 (d, J=4.0Hz, 1H), 3.93 (d, J=4.0Hz, 2H), 3.54 (s, 2H), 2.79-
2.71(m,4H),2.78(s,1H),2.61-2.57(m,4H),2.07-2.05(m,2H),1.67-1.65(m,4H),1.54-
1.50(m,4H).MS-ESI(m/z):397.9[M+H+]。
Embodiment 17
Antitumor activity is tested
Growth period breast cancer cell MCF-7, lung cell A549 and hepatocellular carcinoma H22 are collected, is determined with MTS methods
The active anticancer of compound, by cell with (every milliliter 4 × 10 of debita spissitudo4Individual cell) it is added in 96 porocyte culture plates and (contains
10% tire calf serum obtains nutrient solution and is made into individual cells suspension), it is 5% in 37 DEG C, volumetric concentration after cultivating 24 hours
CO2Under the conditions of compound effects 72 hours with various concentrations, it is then that MTS (final mass concentration 2mg/mL) and DMS is (final
30 μM of molar concentration) mixture be directly added into celliferous culture medium, continue to put incubator and be incubated 4h.Act on after 4h, abandon
Supernatant is removed, 150 μ LDMSO are added per hole, vibration, cell survival rate is supervised by it to the metabolin that MTS is acted in enzyme linked immunological
The absorptivity surveyed under instrument 490nm wavelength is determined.
Embodiment above describes general principle, principal character and the advantage of the present invention, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (7)
1. the preparation method of the pyrido o-diazepamate derivative with anti-tumor function, it is characterised in that concretely comprise the following steps：
A, N-Boc-4- piperidones and dimethyl carbonate react in the presence of potassium tert-butoxide obtains N-Boc-3- methyl formates -4-
Piperidones；
B, N-Boc-3- methyl formate -4- piperidones are under ammonium acetate effect, and ketone carbonyl redox obtains compound into amino
N-Boc-3- methyl formate -4- amino -3- alkene-piperidines；
It is anti-that under TEA effects substitution occurs for C, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines and chloroformyl ethyl acetate
Compound N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines should be obtained；
Molecule occurs in the presence of potassium tert-butoxide for D, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
Interior cyclization obtains compoundThen the compound carries out intramolecular hydrogen turn in acid condition
Move and carbonyl reduction obtains compound
E、Under strongly acidic conditions, ester group and Boc groups are sloughed in heating, obtain compound
F、Under POCl3 effect, hydroxyl is replaced by chlorine obtains compound
G、Chloro carbon-to-nitrogen double bon is changed into amido link under concentrated hydrochloric acid effect and obtain compound
H、In the basic conditions, Boc amido protectings are carried out and obtains compound
I、Under cesium carbonate effect compound is obtained with iodomethane reaction
J、Reduction carbon-carbon double bond is obtained under Pd/C effects
K、Occur condensation with 4- pyridine carboxaldehydes and obtain compound
L、Compound is obtained with hydration hydrazine reaction
M、Intramolecular cyclization is carried out under Oxygen Condition and obtains compound
N、Slough Boc groups and obtain compound
O、Obtained with carboxylic acid compound in alkalescence condition reactionR is
Benzene, adjacent fluorobenzene and to trifluoromethylbenzene.
2. the preparation method of the pyrido o-diazepamate derivative according to claim 1 with anti-tumor function, its
The detailed process for being characterised by step A is：In reaction bulb, 1eq N-Boc-4- piperidones is added to the toluene of 10V volumes
In, 2eq dimethyl carbonate and 2eq potassium tert-butoxide are added, 70 DEG C of reaction 1h is heated to, is cooled to room temperature, adds water and be quenched,
It is 7 with 1mol/L HCl regulation reaction solutions pH, ethyl acetate is extracted, and after anhydrous sodium sulfate drying, is spin-dried for obtaining yellow oil
N-Boc-3- methyl formate -4- piperidones；Described step B detailed process is：By 1eq N-Boc-3- methyl formates -4-
Piperidones is added in the methanol of 10 times of volumes, adds 3eq ammonium acetate, and reaction is stayed overnight, and is spin-dried for methanol, adds 3 times of volumes
Water, anhydrous sodium sulfate drying is used after dichloromethane extractive reaction liquid, red oily liquids N-Boc-3- formic acid is obtained after being spin-dried for
Methyl esters -4- amino -3- alkene-piperidines；Described step C detailed process is：By 1eq N-Boc-3- methyl formate -4- amino -
3- alkene-piperidines is added in the DCM of 8 times of volumes, adds 1.05eq TEA, is cooled to 10 DEG C, and 1.05eq 4- chloromethanes are added dropwise
Ethyl acetoacetic acid ethyl ester, room temperature reaction is stayed overnight, and adds the DCM dilute reaction solutions of 8 times of volumes, is washed twice, anhydrous sodium sulfate drying,
It is spin-dried for both obtaining Red oil product N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines.
3. the preparation method of the pyrido o-diazepamate derivative according to claim 1 with anti-tumor function, its
The detailed process for being characterised by step D is：1eq N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperazine
Pyridine is added in the THF of 10 times of volumes, then 2.0eq t-BuOK is added portionwise, and reaction temperature control reacts 1h less than 25 DEG C
Add frozen water afterwards to be quenched, it is 3 to adjust reaction solution pH with 2mol/L HCl, and filtering, vacuum drying obtains off-white powder productDescribed step E detailed process is：In 10eq 6mol/L HCl solution, add in batches
Enter 1.0eq's100 DEG C are heated to, reaction is stayed overnight, are spin-dried for reaction dissolvent, then washed with ether
Wash, vacuum drying obtains off-white powder
4. the preparation method of the pyrido o-diazepamate derivative according to claim 1 with anti-tumor function, its
The detailed process for being characterised by step F is：To 5eq POCl3In be added portionwise 1.0eq'sIt is heated to
100 DEG C, reaction is stayed overnight, and is spin-dried for POCl3Obtain Red oil productDescribed step G detailed process
For：In the Isosorbide-5-Nitrae-dioxane for being added to 4 times of volumes, the concentrated hydrochloric acid of 4 times of volumes is added, is heated to
100 DEG C, back flow reaction 2 days is spin-dried for adding the ethyl acetate of 10 times of volumes after solvent, washed three times, dries and obtain palm fibre after being spin-dried for
Color solidDescribed step H detailed process is：1eq'sIt is added to 10 times of bodies
In long-pending Isosorbide-5-Nitrae-dioxane and the water of 10 times of volumes, then 3.0eq sodium carbonate and 1.5eq (Boc) is added portionwise2O, room temperature
React after 10h, filtering, then washed with ethyl acetate reaction solution is extracted with ethyl acetate after filter cake, then washed with sodium chloride solution,
Dry, rotation reaction solution is obtained
5. the preparation method of the pyrido o-diazepamate derivative according to claim 1 with anti-tumor function, its
The detailed process for being characterised by step I is：1.0eq'sIn the DMF for being added to 10 times of volumes, then add
Enter 1.5eq Cs2CO3, 1.3eq KI, room temperature reaction stays overnight, and adds frozen water and reaction solution, ethyl acetate extractive reaction is quenched
Liquid, sodium chloride solution washing, dries, is spin-dried for, then is beaten with ether, filters, and vacuum drying obtains white solidDescribed step J detailed process is：In autoclave, by 1.0eq's
The methanol of 10 times of volumes is added to, a certain amount of Pd/C is passed through hydrogen, reacting kettle inner pressure is reached 0.2MPa, is heated to 50
DEG C, back flow reaction 5h, TLC monitoring raw material reaction is complete, and filtering reacting liquid is spin-dried for after solvent obtaining brown solidDescribed step K detailed process is：By compoundAdd in DMF, then add
Enter 4- pyridine carboxaldehydes and a certain amount of triethylamine, be heated to backflow, it is complete through TLC monitoring raw material reactions after reaction a period of time,
Reaction solution, which is poured into frozen water, has a large amount of solids to separate out, and filter cake drying is obtained compound after suction filtration
6. the preparation method of the pyrido o-diazepamate derivative according to claim 1 with anti-tumor function, its
The detailed process for being characterised by step L is：In reaction bulb, compoundAdd in DMSO, then add
Enter a certain amount of hydrazine hydrate, at ambient temperature reaction a period of time, it is complete through TLC monitoring raw material reactions, reaction solution is poured into
There are a large amount of solids to separate out in frozen water, filter cake drying is obtained compound after suction filtrationDescribed step
M detailed process is：In reaction bulb, compoundAdd in DMSO, add under Oxygen Condition
Heat is to flowing back, and reaction a period of time, complete through TLC monitoring raw material reactions, reaction solution, which is poured into frozen water, has a large amount of solids to separate out,
Filter cake drying is obtained compound after suction filtrationDescribed step N detailed process is：1.0eqIt is added in the methanol of 10 times of volumes and the 12mol/L of 10 volumes HCl/1,4- dioxane,
Room temperature reaction is stayed overnight, and is spin-dried for, ether washing, is obtainedDescribed step O detailed process is：：Anti-
Answer in bottle,It is added in DMF, adds triethylamine and carboxylic acid compound, is heated to 70 DEG C, reaction
A period of time obtains compound
7. the preparation method of the pyrido o-diazepamate derivative according to claim 1 with anti-tumor function, its
The specific synthetic route being characterised by preparation process is：
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