CN107383070A - The preparation method of piperidines with anti-hepatitis function and the adjoining fluorobenzene Zn complex of pyridine chain - Google Patents
The preparation method of piperidines with anti-hepatitis function and the adjoining fluorobenzene Zn complex of pyridine chain Download PDFInfo
- Publication number
- CN107383070A CN107383070A CN201710413119.5A CN201710413119A CN107383070A CN 107383070 A CN107383070 A CN 107383070A CN 201710413119 A CN201710413119 A CN 201710413119A CN 107383070 A CN107383070 A CN 107383070A
- Authority
- CN
- China
- Prior art keywords
- reaction
- added
- boc
- piperidines
- volumes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 0 C**(C)(C)C1=C(*)*(C(C)(C)C)C(CC*(*)C2)=C2C1c1ccccc1N Chemical compound C**(C)(C)C1=C(*)*(C(C)(C)C)C(CC*(*)C2)=C2C1c1ccccc1N 0.000 description 2
- MLXYBVIJKKMVCN-UHFFFAOYSA-N CC(C)(C)N(C(CCN(C1)C(OC(C)(C)C)=O)=C1C(C1)c(cccc2)c2F)C1=O Chemical compound CC(C)(C)N(C(CCN(C1)C(OC(C)(C)C)=O)=C1C(C1)c(cccc2)c2F)C1=O MLXYBVIJKKMVCN-UHFFFAOYSA-N 0.000 description 2
- CDMHXNOTNGEKFJ-UHFFFAOYSA-N CC(C(Cl)=C1)=C(CCNC)NC1=O Chemical compound CC(C(Cl)=C1)=C(CCNC)NC1=O CDMHXNOTNGEKFJ-UHFFFAOYSA-N 0.000 description 1
- VIMJESRFDSKMKN-UHFFFAOYSA-N CC(C)(C)N(C(CCN(C1)C(OC(C)(C)C)=O)=C1C(C1)Cl)C1=O Chemical compound CC(C)(C)N(C(CCN(C1)C(OC(C)(C)C)=O)=C1C(C1)Cl)C1=O VIMJESRFDSKMKN-UHFFFAOYSA-N 0.000 description 1
- TXWQWZUOYAQDRV-UHFFFAOYSA-N CCOC(c(c(O)nc(CC1)c2CN1C(OC(C)(C)C)=O)c2O)=O Chemical compound CCOC(c(c(O)nc(CC1)c2CN1C(OC(C)(C)C)=O)c2O)=O TXWQWZUOYAQDRV-UHFFFAOYSA-N 0.000 description 1
- JBGYTULBRFBFRC-UHFFFAOYSA-N CNC(NCC(CCNC1)=C1C1C(CCC=C2)=C2F)=C1NN Chemical compound CNC(NCC(CCNC1)=C1C1C(CCC=C2)=C2F)=C1NN JBGYTULBRFBFRC-UHFFFAOYSA-N 0.000 description 1
- GBWJABCKRQVFDK-UHFFFAOYSA-N O=C1NC(CCNC2)=C2C(Cl)=C1 Chemical compound O=C1NC(CCNC2)=C2C(Cl)=C1 GBWJABCKRQVFDK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic System without C-Metal linkages
Abstract
The invention discloses the preparation method of a kind of piperidines with anti-hepatitis function and the adjoining fluorobenzene Zn complex of pyridine chain, belong to pharmaceutical chemistry synthesis technical field.Technical scheme main points are：The present invention has the advantages that compared with prior art：Synthetic method of the present invention is simple, molecular structure is novel and resulting compound
Description
Technical field
The invention belongs to pharmaceutical chemical synthesis technical field, and in particular to a kind of new piperazine with anti-hepatitis function
Pyridine and the preparation method of the adjoining fluorobenzene-Zn complex of pyridine chain.
Background technology
In recent years, heterocyclic compound due to structure is changeable, active high, toxicity is low and as medicine and the master of agricultural chemicals innovation
Stream, plurality of new varieties just continuously put goods on the market, and study on the synthesis is more towards baroque condensed hetero ring, double miscellaneous
Ring and poly-heterocyclic compounds.Piperidines and pyridine compounds are all the nitrogen-containing heterocycle compounds for having good biological activity, extensively should
For medicine and the study on the synthesis of agricultural chemicals.Piperidines is mainly used in synthesis medicine, agricultural chemicals and rubber chemicals, is mainly used in pesticide industry
It is a kind of selective non-hormone-type thiocarbamic acid class herbicide in synthesis herbicides for use in paddy dimepiperate, there is hair very much
Exhibition prospect.It is used to synthesize medicine for digestive system hydrochloric acid acetyl Roxatidine, cardiovascular disease medicine Dipyridmole in pharmaceuticals industry
Deng.It is used to synthesize the super vulcanization accelerator bis-pentamethylenethiuram tetrasulfide of thiurams in Rubber Chemicals Industries, two is thio
Super accelerator pentamethylene aminodithioformic acid piperidinium salt of Carbamates etc..Other piperidines can also synthesize a variety of new
Type fine-chemical intermediate, many products belong to the centre of small tonnage newly developed, the medicine of high added value, agricultural chemicals and auxiliary agent
Body, such as pipecoline, 3- aminomethylpiperidines, 4- hydroxy piperidines.Pyridine is also a kind of important nitrogen heterocyclic ring, because it has
Good bioactivity is widely used in medical research.For example, its derivative can be used as 5HT2A receptor antagonists, cell
External signal regulatory protein kinase inhibitor, mammal P2X7 conditioning agents, and increase with anti-breast cancer cell MDA-MB-231
Grow activity and suppress the propagation of hepatocellular carcinoma H22.Fluorine-containing aromatic ring group, occur in many insecticide pesticides very frequently, such as
Double trifluoro worm urides.
Our laboratories have synthesized a series of piperidines with anti-hepatitis function and the adjoining fluorine of pyridine chain by new method
Benzene-Zn complex, and carried out corresponding bioactivity detection.
The content of the invention
Present invention solves the technical problem that there is provided, a kind of synthetic method is simple, and molecular structure novelty has anti-hepatitis
The piperidines of function and the preparation method of the adjoining fluorobenzene-Zn complex of pyridine chain.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of new piperazine with anti-hepatitis function
The molecular structure of pyridine and the adjoining fluorobenzene-Zn complex of pyridine chain is：
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of new piperazine with anti-hepatitis function
Pyridine and the preparation method of the adjoining fluorobenzene-Zn complex of pyridine chain, it is characterised in that concretely comprise the following steps：
A, N-Boc-4- piperidones reacts with dimethyl carbonate in the presence of potassium tert-butoxide obtains N-Boc-3- formic acid first
Ester -4- piperidones
B, N-Boc-3- methyl formates -4- piperidones under ammonium acetate effect, into amino changed by ketone carbonyl redox
Compound N-Boc-3- methyl formate -4- amino -3- alkene-piperidines
C, N-Boc-3- methyl formates -4- amino -3- alkene-piperidines takes with chloroformyl ethyl acetate under TEA effects
Generation reaction obtains compound N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
D, N-Boc-3- methyl formates -4- carbamyl ethyl acetate -3- alkene-piperidines occurs 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 substituted to obtain compound by chlorine
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、React with iodo-tert-butane to obtain compound under cesium carbonate effect
J、Carbon-carbon double bond hydrogenating reduction is set to obtain compound under Pd/C effects
K、React to obtain compound with adjacent fluorobenzoic boric acid
L、React to obtain compound with azido compound
M、Slough Boc groups and the tert-butyl group obtains compound
N、Obtained with zinc chloride complex 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, water quenching is added to go out, 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 overnight, is spin-dried for methanol, adds 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
It is added in the DCM of 8 times of volumes, adds 1.05eq TEA, be cooled to 10 DEG C, 1.05eq 4- chloromethane ethyl acetoacetic acid second is added dropwise
Ester, room temperature reaction overnight, add the DCM dilute reaction solutions of 8 times of volumes, and washing twice, anhydrous sodium sulfate drying, is spin-dried for both obtaining
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 2.0eq t-BuOK is added portionwise, reaction temperature control less than
25 DEG C, addition frozen water is quenched after reacting 1h, and it is 3 to adjust reaction solution pH with 2mol/L HCl, and filtering, 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 overnight, is spin-dried for reaction dissolvent, then is 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 overnight, is 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, is heated to 100 DEG C, back flow reaction 2 days, is spin-dried for adding after solvent the second of 10 times of volumes
Acetoacetic ester, washing three times, are dried and obtain 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, react at room temperature 10h
Afterwards, filter, then reaction solution is extracted with ethyl acetate after washing filter cake with ethyl acetate, then washed with sodium chloride solution, dried, rotation
Reaction solution obtains
Further limit, step I detailed process is：1.0eq'sIt is added to 10 times of volumes
In DMF, 1.5eq Cs is added2CO3, 1.3eq iodine band tertiary butane, overnight, reaction solution, second is quenched in addition frozen water for room temperature reaction
Acetoacetic ester extractive reaction liquid, sodium chloride solution washing, dries, is spin-dried for, then is beaten with ether, filters, and vacuum drying obtains white
Solid
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, hydrogen is passed through, reacting kettle inner pressure is reached 0.2MPa, be heated to 50 DEG C, returned
Stream reaction 5h, TLC monitoring raw material reaction is complete, filtering reacting liquid, brown solid is obtained after being spin-dried for solvent
Further limit, step K detailed process is：By 1.0eq'sIt is added to 20 times of volumes
In THF, 3eq 1mol/L potassium phosphate and 1.2eq adjacent fluorobenzoic boric acid are added, is heated to 100 DEG C, reaction is stayed overnight, acetic acid
Ethyl ester extracts, and dries, is spin-dried for rear column chromatography for separation and obtains
Further limit, step L detailed process is：In reaction bulb, 1.0eq'sIt is added to
In the tert-butyl alcohol of 20 times of volumes, 3.0eq potassium carbonate and 1.2eq TMSN are added3, after reacting a period of time at room temperature,
TLC monitoring raw material reactions are complete, obtain compound
Further limit, step M detailed process is：In reaction bulb, by 1.0eq'sAdd
Enter the HCl/1 to the methanol of 10 times of volumes and the 12mol/L of 10 volumes, in 4- dioxane, room temperature reaction overnight, is spin-dried for, second
Ether washs, and obtains
Further limit, step N detailed process is：Nitrogen is passed through into the ultrasonic response container for being provided with agitating device
Gas, then add dissolved withDichloromethane solution, after adding ammoniacal liquor, in 25 DEG C to ultrasonic response container
The middle methanol solution being added dropwise dissolved with zinc chloride, agitating device and ultrasonic generator, ultrasonic wave hair are opened during dropwise addition
The setpoint frequency of generating apparatus is 80KHz, and it is clear state to drip rear solution, stops stirring, keeps ultrasonic generator
Work on, be cooled to 0 DEG C of standing reaction solution, open the steam vent on ultrasonic response container, keep the nitrogen that is passed through from
Steam vent is discharged, and nitrogen is discharged ultrasonic response container with reaction dissolvent, there is a clear crystal precipitation, and crystallization is complete after 5h
Entirely, reaction solution is filtered, filter cake is washed repeatedly to wash away unnecessary zinc chloride with methanol, and filter cake obtains after drying at room temperature
The synthesis of the piperidines and the adjoining fluorobenzene-Zn complex of pyridine chain that have anti-hepatitis function of new tool of the present invention
Route is：
The present invention has synthesized a kind of new piperidine and the adjoining fluorobenzene-Zn complex of pyridine chain and has carried out antihepatitic activity survey
Examination, it is found that the complex has good antihepatitic activity.
Embodiment
The above of 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, adds carbonic acid two
Methyl esters 18g (0.2mol) and potassium tert-butoxide 22g (0.2mol), 70 DEG C of reaction 1h are heated to, room temperature is cooled to, adds water 100mL to quench
Go out, it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, is spin-dried for obtaining yellow oil
Shape thing N-Boc-3- methyl formate -4- piperidones 25g
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, overnight, TLC monitoring raw material reactions are complete, are spin-dried for methanol, water 900mL are added, with two for reaction
Chloromethanes 300mL extractive reactions liquid three times, uses anhydrous sodium sulfate drying after merging organic phase, red oily liquids is obtained after being spin-dried for
N-Boc-3- methyl formate -4- amino -3- alkene-piperidines 25g
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, is cooled to 10 DEG C, 4- chloroformyl ethyl acetate 16g is slowly added dropwise
(0.105mol), overnight, TLC monitoring raw material reactions are complete, add dichloromethane 200mL dilute reaction solutions, water for room temperature reaction
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
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 less than 25 DEG C, after reacting 1h
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
Embodiment 5
In reaction bulb, the HCl solution 200mL in 6mol/L is added, then be added portionwise
34g (0.1mol), 100 DEG C are heated to, reaction overnight, is spin-dried for reaction dissolvent, then is washed with ether, and vacuum drying obtains off-white color
Solid15g
Embodiment 6
In closed reaction bulb, it is added portionwise into POCl3 50g (0.5mol)16g
(0.1mol), 100 DEG C are slowly heated to, overnight, after TLC monitoring raw material reactions completely, vacuum is spin-dried for POCl3 and obtained for reaction
Red oil product16g
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, is heated to 100 DEG C, back flow reaction 2 days, after TLC monitoring raw material reactions completely,
It is spin-dried for solvent and concentrate is added the ethyl acetate of 10 times of volumes, washing three times, separates organic phase, dries and obtains palm fibre after being spin-dried for
Color solid
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 portionwise2O 33g (0.15mol), after reacting at room temperature 10h, TLC monitoring is former
Material reaction is complete, filtering reacting liquid, then uses ethyl acetate 200mL extractive reactions liquid three after washing filter cake with ethyl acetate 100mL
It is secondary, then washed with sodium chloride solution, dry, rotation reaction solution obtains20g
Embodiment 9
In reaction solution,28g (0.1mol) is added in DMF 300mL, adds carbonic acid
Caesium 50g (0.15mol), iodo-tert-butane 24g (0.13mol), overnight, TLC monitoring raw material reactions are complete, add ice for room temperature reaction
Water 100mL is quenched reaction solution, ethyl acetate 200mL extractive reactions liquid three times, saturated nacl aqueous solution 200mL washing reaction liquids,
Dry, be spin-dried for, then be beaten with ether, filtered, vacuum drying obtains white solid26g
Embodiment 10
, will in autoclave34g (0.1mol) is added in methanol 300mL, adds Pd/
C6g, with hydrogen is passed through after nitrogen displacement reactor air, pressure in kettle is reached 0.25MPa, be heated to 50 DEG C, react 5h,
TLC monitoring raw material reactions are complete, filter reaction solution, and concentration filtrate obtains23g。
Embodiment 11
, will in reaction solution34g (0.1mol) is added in THF500mL, adds 3eq's
1mol/L potassium phosphate and 1.2eq neck fluorobenzoic boric acid, 100 DEG C are heated to, reaction overnight, ethyl acetate extraction, is dried, is spin-dried for
Column chromatography for separation obtains afterwards45g
Embodiment 11
In reaction bulb,32g (0.1mol) is added in tert-butyl alcohol 400mL, adds carbon
Sour K42 g (0.3mol) and TMSN314g (0.12mol), after reacting a period of time at room temperature, TLC monitoring raw materials have reacted
Entirely, reaction solution is poured into water 500mL, merges organic phase, solvent is evaporated off and obtains with ethyl acetate 200mL extractive reactions liquid three times
To compound29g
Embodiment 12
, will in reaction bulb35g (0.1mol) is added to methanol 300mL's and 12mol/L
In HCl/1,4- dioxane 200mL, overnight, TLC monitoring raw material reactions are complete, are spin-dried for, ether washing concentrate for room temperature reaction,
Obtain17g
Embodiment 13
Nitrogen is passed through in the ultrasonic response container for being reversely provided with agitating device, is then added dissolved with compound51g dichloromethane solution 500mL, after adding ammoniacal liquor 100mL, in 25 DEG C to ultrasonic response container
In methanol solution 500mL dissolved with zinc chloride 50g is slowly added dropwise, open agitating device during dropwise addition and ultrasonic wave fill
Put, the setpoint frequency of ultrasonic generator is 80KHz, and it is clear state to drip rear solution, stops stirring, keeps ultrasonic wave
Generating means works on, and slow cooling to 0 DEG C of standing reaction solution, opens the steam vent on ultrasonic response container, keeps logical
The nitrogen entered is discharged from steam vent, nitrogen is discharged ultrasonic response container with a certain amount of reaction dissolvent, gradually has colourless
Crystal is separated out, and crystallization is complete after 5h, filters reaction solution, and filter cake is washed repeatedly to wash away unnecessary zinc salt with methanol, and filter cake is in room
Obtained after being dried under temperature48g。
Embodiment 15
Pharmacodynamic study
In order to evaluate and compare Tiopronin andPharmacodynamics, using four chlorinations
Carbon, D-Gal (DAG) cause acute and chronic liver injury model, total protein T-P, white with transaminase GOT, GPT in serum
Albumin A LB, Archon ratio A/G and tissue in hydroxyproline, sialic acid, liver collagen content change be turned to changes of liver function,
The evaluation index of liver tissue fibrosis, and binding of pathological histological examination, are evaluated the pharmacodynamics of the two.Drug design one
Serial Isodose is compared observation, is administered with injecting pathway, observes in preventive administration and chronic treatment administration
The operative condition of the two, as a result shows under mode：
Effect to acute hepatic injury model：
(1) effect of acute liver is caused to carbon tetrachloride：Through being administered to
After medicine, 37.5-150mg/kg can substantially suppress CCl4Rise (the P of serum GOT and GPT caused by caused acute liver damage<
0.05、P<0.01), showTo CCl4Caused acute liver damage has significant protection to make
With.Under same experimental condition, Tiopronin 150mg/kg is to CCl4Equally there is caused acute liver damage significant protection to make
With.
(2) effect of acute liver is caused to D-Gal (DAG)
Prevention effect：After preventive vaccination is administered, high dose 150mg/kg energy
Rise (the P of the obvious serum GOT suppressed caused by DAG caused by acute liver damage and GPT<0.05、P<0.01), showAcute liver damage caused by DAG can be suppressed, there is significant protective effect.Same experiment
Under the conditions of, Tiopronin 75-150mg/kg equally has significant protective effect to acute liver damage caused by DAG.
Therapeutic action：After treating 32h,37.5-150mg/kg it can substantially suppress DAG
Rise (the P of serum GPT caused by caused hepatic injury<0.05、P<0.01), showIt is short
After phase treatment, there is the restitution of part to the liver function of damage.Under same experimental condition, 75-150mg/kg pairs of Tiopronin
Hepatic injury caused by DAG, after short, equally there is the restitution of part to the liver function of damage.
After treating 7d,37.5-150mg/kg it can substantially suppress liver caused by DAG
Rise (the P of serum GPT, GOT caused by damage<0.05、P<0.01), showFor a long time
After treatment, there is preferable restitution to the liver function of damage.Under same experimental condition, 37.5-150mg/kg pairs of Tiopronin
Hepatic injury caused by DAG, after long-term treatment, equally there is preferable restitution to the liver function of damage.
Effect to chronic liver damage model：
For continuous drug administration by injection after 1 month, 50-100mg/kg dosage makes elevated turn
Ammonia enzyme ALT, AST significantly reduce (P<0.05、P<0.01), 100mg/kg dosage makes the ALB of reduction significantly raise (P<0.01), show
Write the ratio (P that rise A/G is reversed<0.01)；25-100mg/kg dosage significantly reduces elevated sialic acid content (P<0.01),
100mg/kg dosage significantly reduces elevated hydroxyproline content (P<0.01).Show
Chronic liver injury is caused to have significant therapeutic effect in carbon tetrachloride.Under same experimental condition, Tiopronin 100mg/kg is to tetrachloro
Changing carbon causes chronic liver injury equally to have significant therapeutic effect.
Conclusion：Drug administration by injection is for caused by carbon tetrachloride, D-Gal
Acute and chronic hepatic injury has significant a prevention or therapeutic action, and the dosage and intensity of effect are suitable or approximate with Tiopronin.
Embodiment above describes the general principle of the present invention, main features and advantages, 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 piperidines and the adjoining fluorobenzene-Zn complex of pyridine chain with anti-hepatitis function, it is characterised in that specific
Step is：
A, N-Boc-4- piperidones reacts with dimethyl carbonate in the presence of potassium tert-butoxide obtains N-Boc-3- methyl formates -4-
Piperidones；
B, for N-Boc-3- methyl formates -4- piperidones under ammonium acetate effect, ketone carbonyl redox obtains compound into amino
N-Boc-3- methyl formate -4- amino -3- alkene-piperidines；
C, with chloroformyl ethyl acetate under TEA effects substitution occurs for N-Boc-3- methyl formates -4- amino -3- alkene-piperidines instead
Compound N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines should be obtained；
D, molecule occurs in the presence of potassium tert-butoxide for N-Boc-3- methyl formates -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 substituted to obtain compound by chlorine
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、React with iodo-tert-butane to obtain compound under cesium carbonate effect
J、Carbon-carbon double bond hydrogenating reduction is set to obtain compound under Pd/C effects
K、React to obtain compound with adjacent fluorobenzoic boric acid
L、React to obtain compound with azido compound
M、Slough Boc groups and the tert-butyl group obtains compound
N、Obtained with zinc chloride complex reaction
2. the preparation of the piperidines according to claim 1 with anti-hepatitis function and the adjoining fluorobenzene-Zn complex of pyridine chain
Method, it is characterised in that step A detailed process is：In reaction bulb, 1eq N-Boc-4- piperidones is added to 10V bodies
In long-pending toluene, 2eq dimethyl carbonate and 2eq potassium tert-butoxide are added, 70 DEG C of reaction 1h is heated to, is cooled to room temperature,
Water quenching is added to go out, it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, 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- first
Sour methyl esters -4- piperidones is added in the methanol of 10 times of volumes, adds 3eq ammonium acetate, and reaction overnight, is spin-dried for methanol, added
Enter the water of 3 times of volumes, use anhydrous sodium sulfate drying after dichloromethane extractive reaction liquid, red oily liquids N- is obtained after being spin-dried for
Boc-3- methyl formate -4- amino -3- alkene-piperidines；Described step C detailed process is：By 1eq N-Boc-3- formic acid first
Ester -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, is added dropwise
1.05eq 4- chloroformyl ethyl acetate, room temperature reaction overnight, add the DCM dilute reaction solutions of 8 times of volumes, wash twice,
Anhydrous sodium sulfate drying, be spin-dried for both Red oil product N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene -
Piperidines；Described step D detailed process is：1eq N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene -
Piperidines is added in the THF of 10 times of volumes, then 2.0eq t-BuOK is added portionwise, and reaction temperature control is reacted less than 25 DEG C
Add frozen water after 1h 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 overnight, is spin-dried for reaction dissolvent, then washed with ether
Wash, vacuum drying obtains off-white powderDescribed step F detailed process is：To 5eq POCl3In
It is added portionwise 1.0eq's100 DEG C are heated to, reaction overnight, is spin-dried for POCl3Obtain Red oil product
3. the preparation of the piperidines according to claim 1 with anti-hepatitis function and the adjoining fluorobenzene-Zn complex of pyridine chain
Method, it is characterised in that step G detailed process is：It is added to the 1,4- dioxane of 4 times of volumes
In, the concentrated hydrochloric acids of 4 times of volumes is added, is heated to 100 DEG C, back flow reaction 2 days, is spin-dried for adding after solvent the acetic acid of 10 times of volumes
Ethyl ester, washing three times, are dried and obtain brown solid after being spin-dried forDescribed step H detailed process is：
1eq'sIt is added in Isosorbide-5-Nitrae-dioxane of 10 times of volumes and the water of 10 times of volumes, then is added portionwise
3.0eq sodium carbonate and 1.5eq (Boc)2O, after reacting at room temperature 10h, filtering, then use acetic acid after washing filter cake with ethyl acetate
Ethyl ester extractive reaction liquid, then washed with sodium chloride solution, dry, rotation reaction solution obtainsDescribed step
Suddenly I detailed process is：1.0eq'sIt is added in the DMF of 10 times of volumes, adds 1.5eq's
Cs2CO3, 1.3eq iodine band tertiary butane, overnight, reaction solution, ethyl acetate extractive reaction liquid, chlorine is quenched in addition frozen water for room temperature reaction
Change sodium solution washing, dry, be spin-dried for, then be beaten with ether, filtered, vacuum drying obtains white solid
4. the preparation of the piperidines according to claim 1 with anti-hepatitis function and the adjoining fluorobenzene-Zn complex of pyridine chain
Method, it is characterised in that step J detailed process is：In autoclave, by 1.0eq'sIt is added to 10
The methanol of times volume, a certain amount of Pd/C, is passed through hydrogen, reacting kettle inner pressure is reached 0.2MPa, is heated to 50 DEG C, backflow is anti-
5h is answered, TLC monitoring raw material reactions are complete, filtering reacting liquid, brown solid obtained after being spin-dried for solventInstitute
The step K stated detailed process is：By 1.0eq'sIt is added in the THF of 20 times of volumes, adds
3eq 1mol/L potassium phosphate and 1.2eq adjacent fluorobenzoic boric acid, 100 DEG C are heated to, reaction overnight, ethyl acetate extraction, is done
It is dry, it is spin-dried for rear column chromatography for separation and obtains
5. the preparation of the piperidines according to claim 1 with anti-hepatitis function and the adjoining fluorobenzene-Zn complex of pyridine chain
Method, it is characterised in that step L detailed process is：In reaction bulb, 1.0eq'sIt is added to 20 times
In the tert-butyl alcohol of volume, 3.0eq potassium carbonate and 1.2eq TMSN are added3, after reacting a period of time at room temperature, TLC prisons
It is complete to control raw material reaction, obtains compoundDescribed step M detailed process is：In reaction bulb
In, by 1.0eq'sIt is added to the methanol of 10 times of volumes and the 12mol/L of 10 volumes HCl/1,4-
In dioxane, room temperature reaction overnight, is spin-dried for, and ether washing, is obtained
6. the preparation of the piperidines according to claim 1 with anti-hepatitis function and the adjoining fluorobenzene-Zn complex of pyridine chain
Method, it is characterised in that step N detailed process is：Nitrogen is passed through into the ultrasonic response container for being provided with agitating device,
Then add dissolved withDichloromethane solution, add ammoniacal liquor after, in 25 DEG C into ultrasonic response container
The methanol solution dissolved with zinc chloride is added dropwise, agitating device and ultrasonic generator are opened during dropwise addition, ultrasonic wave occurs
The setpoint frequency of device is 80KHz, and it is clear state to drip rear solution, stop stirring, keep ultrasonic generator after
Continuous work, 0 DEG C of standing reaction solution is cooled to, opens the steam vent on ultrasonic response container, keep the nitrogen that is passed through from row
Stomata is discharged, and nitrogen is discharged ultrasonic response container with reaction dissolvent, there is a clear crystal precipitation, and crystallization is complete after 5h,
Reaction solution is filtered, filter cake is washed repeatedly to wash away unnecessary zinc chloride with methanol, and filter cake obtains after drying at room temperature
7. tool according to claim 1 has the piperidines of anti-hepatitis function and the system of the adjoining fluorobenzene-Zn complex of pyridine chain
Preparation Method, it is characterised in that the specific synthetic route in preparation process is：
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710413119.5A CN107383070A (en) | 2017-06-05 | 2017-06-05 | The preparation method of piperidines with anti-hepatitis function and the adjoining fluorobenzene Zn complex of pyridine chain |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710413119.5A CN107383070A (en) | 2017-06-05 | 2017-06-05 | The preparation method of piperidines with anti-hepatitis function and the adjoining fluorobenzene Zn complex of pyridine chain |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107383070A true CN107383070A (en) | 2017-11-24 |
Family
ID=60333007
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710413119.5A Withdrawn CN107383070A (en) | 2017-06-05 | 2017-06-05 | The preparation method of piperidines with anti-hepatitis function and the adjoining fluorobenzene Zn complex of pyridine chain |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107383070A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09291034A (en) * | 1996-02-27 | 1997-11-11 | Yoshitomi Pharmaceut Ind Ltd | Condensed pyridine compound and its use as medicine |
-
2017
- 2017-06-05 CN CN201710413119.5A patent/CN107383070A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09291034A (en) * | 1996-02-27 | 1997-11-11 | Yoshitomi Pharmaceut Ind Ltd | Condensed pyridine compound and its use as medicine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107428754A (en) | Two ring Quinazol derivatives | |
| CN106699690B (en) | A kind of pleuromutilin derivative and its preparation method and application with acyl piperazine base side chain | |
| WO2013020460A1 (en) | Atazanavir preparation method | |
| CN106543054A (en) | A kind of pleuromutilin derivative with 2 amino second mercapto alcohol side chains and its production and use | |
| CN107383070A (en) | The preparation method of piperidines with anti-hepatitis function and the adjoining fluorobenzene Zn complex of pyridine chain | |
| CN107260719A (en) | A kind of preparation method of Antihepatitis medicament piperidines and the diazetidine Zn complex of pyrido 1,2 | |
| CN104211666B (en) | 2,3 epoxy succinyl aminated compounds, preparation method and use | |
| CN107163045A (en) | The preparation method of piperidines with platelet aggregation-against function and the triazole compound of pyrido 1,2,3 | |
| CN107235973A (en) | The preparation method of the adjoining fluorobenzene calcium composition of piperidones chain with pharmaceutical activity | |
| CN107245077A (en) | The preparation method of piperidines with insecticidal activity and the adjoining fluorobenzene analog derivative of pyridine chain | |
| CN109503518A (en) | A kind of substituted double aromatic radical amide compounds and its preparation method and application | |
| CN107474021A (en) | Oxadiazine derivatives and its preparation method and application | |
| CN106977512A (en) | The method for preparing the smooth free alkali of horse sieve | |
| CN107325099A (en) | The preparation method of piperidines with insecticidal activity and the triazole derivative of 4,5 dihydro of pyrido 1,2,3 | |
| CN107266442A (en) | The preparation method of piperidines with antitumor activity and pyridine compounds and their | |
| CN107286160A (en) | A kind of preparation method of the piperidines of Antihepatitis medicament and pyrido pyrazoles Zn complex | |
| CN107163046A (en) | The preparation method of pyrido o-diazepamate derivative with anti-tumor function | |
| CN107286159A (en) | The preparation method of piperidines with pharmaceutical activity and chloro-pyridine calcium composition | |
| CN107235974A (en) | The preparation method of piperidine sulfonamide calcium composition with pharmaceutical activity | |
| CN110372615A (en) | A kind of pleuromutilin derivative and preparation and application with 2- amino benzenethiol and 1,2,3- triazole side chain | |
| CN107266443A (en) | The preparation method of piperidines with PVC stabilizer function and pyridone tin complex | |
| CN107266444A (en) | The preparation method of piperidines with pharmaceutical activity and pyridine calcium composition | |
| CN107188892A (en) | The preparation method of piperidines with platelet aggregation-against function and pyridine compounds | |
| CN104774161B (en) | Polypeptide, protein PEG dressing agent synthetic methods | |
| CN107739381A (en) | Curcuma zedoary 01 derivatives and its application in antineoplastic is prepared |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20171124 |
|
| WW01 | Invention patent application withdrawn after publication |