CN110156775A - A kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun - Google Patents
A kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun Download PDFInfo
- Publication number
- CN110156775A CN110156775A CN201810144681.7A CN201810144681A CN110156775A CN 110156775 A CN110156775 A CN 110156775A CN 201810144681 A CN201810144681 A CN 201810144681A CN 110156775 A CN110156775 A CN 110156775A
- Authority
- CN
- China
- Prior art keywords
- methyl
- pyridine
- base
- compound
- solvent
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
Abstract
The simple and convenient process for preparing of Buddhist nun is replaced the present invention relates to a kind of pyrrole former times, using N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- alkoxycarbonyl methyl pyridine or N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- cyano-methyl pyridine (II) and acetonitrile, the condensation reaction in the presence of alkali generates N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl picoline (III) to this method, compound III and nitromethane are condensed prepare compound IV, then it passes through and 2, 3- dichloropropylene aldehyde addition, the lower removing hydrogen chloride of alkali effect obtains compound V, finally hydrogenated reduction-cyclisation prepares pyrrole former times for Buddhist nun in the presence of catalyst.This method raw material is cheap and easy to get, and process flow is brief, easy to operate, and wastewater flow rate is few, product yield and purity is high, environmentally protective, is conducive to pyrrole former times for the industrialized production of Buddhist nun.
Description
Technical field
The simple and convenient process for preparing that Buddhist nun is replaced the present invention relates to a kind of pyrrole former times, belongs to technical field of medical chemistry.
Background technique
Pyrrole former times replaces Buddhist nun, Pexidartinib (I), and Chinese is [5- (the chloro- 1- hydrogen of 5--pyrrolo- [2,3-b] pyridine -3-
Ylmethyl)-pyridine -2- base]-(6- trifluoromethylpyridin -3- ylmethyl)-amine, the entitled [5- (5-chloro-1H- of English
pyrrolo[2,3-b]pyridine-3-ylmethyl)-pyridin-2-yl]-(6-trifuluoromethyl-pyridin-
3-ylmethyl)-amine is Japanese Sankyo Co. (Daiichi Sankyo Company) exploitation for controlling
Three phase of clinic for treating giant cell tumor of tendon sheath (TGCT) is grinding new drug.The breakthrough medicinal treatment that the medicine obtained FDA in 2015 is recognized
Card, goes on the road preferentially examined.Moreover, in November, 2017, which significantly reduces the swollen of patient in 3 clinical trial phases
Tumor size has reached Major Clinical terminal.The result of this clinical test supports it and treats giant cell tumor of tendon sheath (TGCT)
Potentiality.
Pyrrole former times is a CSF1R (colony-stimulating factor 1) inhibitor for Buddhist nun, can effectively inhibit CSF1 in conjunction with receptor.
It is previous the study found that giant cell tumor of tendon sheath is driven by the CSF1 of overexpression.Therefore, pyrrole former times is expected to for Buddhist nun from root
It is upper control disease generation, can not by operation be treated, avoid the high risk of actual operation, will to minimal invasive treatment with
Carry out very big improvement.
Chemical structural formula is as follows:
Currently, pyrrole former times for Buddhist nun synthetic route there are mainly two types of, be a small amount of preparation routes and newest of early stage research respectively
Feather weight preparation process route.
Document WO2008064265, WO2008063888, WO2008064255 are that Yuan Yan company is wide in early stage conceptual phase
A small amount of preparation routes when general screening reactive compound, the route are starting material through formylated with the chloro- 7- azaindole (1) of 5-
The reaction preparation chloro- 7- azaindole -3- formaldehyde (2) of 5-, then protects to obtain the chloro- 7- of 1- benzenesulfonyl -5- using benzenesulfonyl
Azaindole -3- formaldehyde (compound 3) then obtains compound 5, triethyl group with 2- amino -5- bromopyridine (compound 4) reaction
Silane reduction hydroxyl obtains compound 6, then reductive amination process occurs with 2- trifluoromethyl pyridine -5- formaldehyde (7) and obtains chemical combination
Object 8, deprotection obtain product pyrrole former times for Buddhist nun, total recovery only 0.4-1.4%, and obtain be milligram rank product.Accordingly
Synthetic route is referring to synthetic route 1.
Document WO2016179412 (Plexxikon Inc., the U.S. and Japanese Sankyo Co. are shared) reports original
The company feather weight of grinding prepares the process route for pyrrole former times replacing Buddhist nun, and the route is with the chloro- 7- azaindole of 5- and 2- bis- (tertbutyloxycarbonyl)
Amino -5- pyridine carboxaldehyde is raw material, acts on lower condensation in highly basic tert-pentyl alcohol potassium and generates compound 10, then also through triethylsilane
Former hydroxyl, trifluoroacetic acid take off Boc protecting group and obtain compound 11 and 2- trifluoromethyl pyridine -5- formaldehyde (7) generation reduction amination
Reaction obtains product pyrrole former times for Buddhist nun, and three-step reaction total recovery is 63.5%, and corresponding synthetic route is referring to synthetic route 2.
Both the above route is all the synthetic route of Yuan Yan company, using the chloro- 7- azaindole of the higher 5- of price and
2- trifluoromethyl pyridine -5- formaldehyde, product cost are higher.Make when wherein first route is early stage conceptual phase screening compound
Synthetic route, what is obtained is the product of milligram rank, and total recovery is low, and n-BuLi etc. has been used to compare danger in reaction route
The reagent of danger, and column chromatography has been used for multiple times during post-reaction treatment, be not suitable for heavy industrialization and generate.Article 2 road
Line is the synthesis technology that feather weight prepares the product.Reagent used in the process route is milder, and reaction condition is mild, total to receive
Rate is relatively high, but the route steps reaction time is too long, and production efficiency is low.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides the preparation method that a kind of pyrrole former times replaces Buddhist nun, and this method is easy to operate, low
It is cost, high yield, high-purity, environmentally protective.
Term explanation:
In this specification, the Roman number after the compound name is consistent with the Roman numerals of corresponding construction formula,
Using structural formula of compound as foundation.
Technical solution of the present invention is as follows:
A kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun, comprising the following steps:
(1) in the presence of solvent A and alkali A, N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5-G substituent group first
Yl pyridines (II) and acetonitrile are through condensation reaction generation N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl
Picoline (III)；
(2) in the presence of solvent B and catalyst A ', compound III and nitromethane condensation preparation N- (2- trifluoromethyl pyrrole
Pyridine -5- base) methyl-2-amino -5- [(3- nitro -2- cyano methyl) -2- acrylic] pyridine (IV)；
(3) in the presence of solvent C and catalyst B ', then compounds Ⅳ and 2,3- dichloropropylene aldehyde addition is acted in alkali B
Lower removing hydrogen chloride obtains compound V；
(4) in the presence of solvent D and catalyst C ', hydrogenating reduction-cyclisation prepares pyrrole former times for Buddhist nun (I).
Wherein, G is CN or COOR；R is-CH3、-C2H5、-C3H7、-C4H9Or-CH2Ph。
, according to the invention it is preferred to, solvent A described in step (1) is tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring
One of amyl ether, 1,2- dimethoxy-ethane, toluene, dimethylbenzene, 1,2- dichloroethanes or chlorobenzene or its any conjunction object；It is described
The mass ratio of solvent A and compound ii is (2-15): 1；It is further preferred that the mass ratio of the solvent A and compound ii is
(5-10):1。
, according to the invention it is preferred to, alkali A described in step (1) is sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, ammonia
Or mixtures thereof one of base lithium, lithium diisopropylamine (LDA).
, according to the invention it is preferred to, N- described in step (1) (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5-G
Substituent group picoline (II) is N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- cyano-methyl pyridine, N- (2- tri-
Fluoromethylpyridin -5- base) methyl-2-amino -5- methoxycarbonyl-methyl pyridine, N- (2- trifluoromethyl pyridine -5- base) methyl -2-
Amino -5- ethoxycarbonylmethyl group pyridine, N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- butyloxycarbonyl methyl pyrrole
Pyridine, N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- tert-Butoxycarbonylmethyl pyridine, N- (2- trifluoromethyl pyridine -
5- yl) methyl-2-amino -5- benzyloxycarbonyl-methyl pyridine.
, according to the invention it is preferred to, alkali A described in step (1), acetonitrile and N- (2- trifluoromethyl pyridine -5- base) methyl -
The molar ratio of 2- amino -5-G substituent group picoline (II) is (1.0-2.0): (1.0-2.0): 1.
, according to the invention it is preferred to, setting-up point described in step (1) is 20-110 DEG C, reaction time 2-10
Hour；It is further preferred that the setting-up point is 50-80 DEG C, the reaction time is 4-7 hours.
, according to the invention it is preferred to, solvent B described in step (2) is tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring
One of amyl ether, 1,2- dimethoxy-ethane, acetonitrile or chlorobenzene or its any conjunction object；The matter of the solvent B and compound III
Amount is than being (2-15): 1；It is further preferred that the solvent B and the mass ratio of compound III are (5-10): 1.
, according to the invention it is preferred to, catalyst A ' described in step (2) be piperidines, nafoxidine, morpholine, DBU, DBN,
4-dimethylaminopyridine, potassium tert-butoxide, sodium ethoxide, sodium methoxide；The molar ratio of the catalyst A ' and compound III is 5%-
20%.
, according to the invention it is preferred to, the molar ratio of nitromethane described in step (2) and compound III is (1.0-1.5):
1。
, according to the invention it is preferred to, nitromethane described in step (2) and compound III setting-up point are 0-90
DEG C, it reacts 2-8 hours, further preferred reaction temperature is 30-60 DEG C, is reacted 3-6 hours.
, according to the invention it is preferred to, solvent C described in step (3) is tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring
One of amyl ether, 1,2- dimethoxy-ethane, acetonitrile or chlorobenzene or its any conjunction object；The matter of the solvent C and compounds Ⅳ
Amount is than being (2-15): 1；It is further preferred that the mass ratio of the solvent C and compounds Ⅳ is (5-10): 1.
, according to the invention it is preferred to, catalyst B ' described in step (3) is piperidines, nafoxidine, morpholine, 1,8- phenodiazine
Miscellaneous bicyclic [5.4.0] 11 carbon -7- alkene (DBU), 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), 4- dimethylamino pyrrole
Pyridine；It is described to urge the mass ratio of catalyst B ' and compounds Ⅳ for 1%-10%.
, according to the invention it is preferred to, the molar ratio of 2,3- dichloropropylene aldehyde described in step (3) and compounds Ⅳ is
(1.0-1.5):1。
, according to the invention it is preferred to, compounds Ⅳ and 2 in step (3), 3- dichloropropylene aldehyde carries out Isosorbide-5-Nitrae-addition reaction
Temperature is 20-100 DEG C, is reacted 2-10 hours, and further preferred reaction temperature is 40-80 DEG C, is reacted 3-6 hours.
, according to the invention it is preferred to, alkali B described in step (3) is inorganic base or organic base, wherein inorganic base is selected from carbon
Sour potassium, sodium carbonate, sodium methoxide, sodium ethoxide, calcium carbonate, sodium hydroxide, potassium hydroxide, saleratus, sodium bicarbonate, bicarbonate
One of calcium, potassium acetate, sodium acetate, calcium acetate or combination, organic base are selected from one of trimethylamine, triethylamine, tri-n-butylamine or combination；
The molar ratio of the alkali B and compounds Ⅳ is (1.0-2.0): 1.
, according to the invention it is preferred to, elimination hcl reaction temperature described in step (3) is 0-80 DEG C, and reaction 2-6 is small
When, further preferred reaction temperature is 20-60 DEG C, is reacted 3-5 hours.
, according to the invention it is preferred to, solvent D described in step (4) is methanol, ethyl alcohol, acetonitrile, ethyl acetate, acetic acid uncle
Butyl ester, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring amyl ether, 1,2- dimethoxy second
One of alkane or its any conjunction object；The mass ratio of the solvent D and compound V is (2-15): 1；It is further preferred that institute
The mass ratio for stating solvent D and compound V is (5-10): 1.
, according to the invention it is preferred to, catalyst C ' described in step (4) is one of palladium charcoal or Raney Ni and ammonium chloride mixing
Object；Preferred palladium carbon catalyst dosage is the 0.5%~10% of formula (V) compound quality, further preferred palladium carbon catalyst
Dosage is 1%~5% mass ratio；Preferred raney nickel catalyst dosage is the 5%~25% of V compound quality of formula, further
Preferred raney nickel catalyst dosage is 10%~15% mass ratio；Preferred ammonium chloride dosage is the molar ratio of V compound of formula
For (0.1-1.0): 1.
, according to the invention it is preferred to, hydrogenating reduction-cyclization temperature is 0~80 DEG C in step (4), and Hydrogen Vapor Pressure is
0.1-0.5MPa reacts 3~10 hours.Further preferred reaction temperature is 30~60 DEG C, Hydrogen Vapor Pressure 0.1-0.3MPa, instead
It answers 4-8 hours.
The simple and convenient process for preparing that Buddhist nun is replaced the present invention provides a kind of pyrrole former times, utilizes N- (2- trifluoromethyl pyridine -5- base) first
Base -2- amino -5-G substituent group picoline and acetonitrile generate N- (2- trifluoromethyl in the presence of solvent and alkali, through condensation reaction
Pyridine -5- base) methyl-2-amino -5- Cyanoacetyl picoline, preparation N- (2- fluoroform is then condensed with nitromethane
Yl pyridines -5- base) methyl-2-amino -5- [(3- nitro -2- cyano methyl) -2- acrylic] pyridine (IV), then with 2,3- dichloro
Methacrylaldehyde addition is eliminated, and the hydrogenated reduction-cyclisation of products therefrom prepares pyrrole former times for Buddhist nun.Preparation step of the invention be described as with
Lower reaction route 3:
Wherein, G is CN or COOR；R is-CH3、-C2H5、-C3H7、-C4H9Or-CH2Ph。
Technical characterstic of the invention and the utility model has the advantages that
1. the present invention overcomes the prior art, there are expensive starting materials, ultralow temperature operation, the disadvantage that quantity of three wastes is big, product cost is high
End, the raw materials used in the present invention is cheap and easy to get, and process conditions are mild, easy to operate；Wastewater flow rate is few, environmentally protective, is a kind of advantageous
In the method that pyrrole former times replaces Buddhist nun's industrialized production.
2. gained intermediate N (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- cyano-acetamide ylmethyl of the invention
When pyridine and nitromethane are condensed, suitable nitromethane ratio and suitable temperature are most important for reduction by-product, nitre
Methylmethane is insufficient, and not exclusively, nitromethane is excessively easy to that series connection side reaction occurs with cyano for reaction；Nitre can be reduced when the temperature is excessively high
The activity difference of methylmethane and the reaction of carbonyl and cyano, causes yield and purity to reduce.
3. unit process selectivity involved in the present invention is high, product yield and purity is high, purity can reach 99% or more, always
Yield is up to 73% or more.
Specific embodiment
The present invention is described in detail with reference to embodiments, but the present invention is not only limited to this.
Embodiment is raw materials used and reagent is commercial product." % " in embodiment is mass percent, is illustrated
Except.
Embodiment 1:N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl picoline (III)
Preparation
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, reflux condensing tube and dropping funel, it is added 180 gram four
Between 40 to 45 DEG C, 32.5 grams of (0.1 mole) N- are added dropwise in hydrogen furans, 6.0 grams of acetonitriles, 15.0 grams of (0.13 mole) potassium tert-butoxides
The mixture of (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- methoxycarbonyl-methyl pyridine and 30 grams of tetrahydrofurans, drop
Finish, 55 to 60 DEG C are stirred to react 3 hours.20 to 25 DEG C are cooled to, with 20% aqueous ammonium chloride solution acid system pH value 4.0-
4.5,100 grams of methylene chloride are added, are layered, water layer is extracted with dichloromethane 3 times, 20 grams every time, merges organic phase, is distilled to recover
Methylene chloride obtains 28.9 grams of N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl picoline, receives
Rate is 86.5%, liquid phase purity 99.5%.
Embodiment 2:N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl picoline (III)
Preparation
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, reflux condensing tube and dropping funel, it is added 150 gram four
Between 50 to 55 DEG C, 29.2 grams of (0.1 mole) N- are added dropwise in hydrogen furans, 6.0 grams of acetonitriles, 15.0 grams of (0.13 mole) potassium tert-butoxides
The mixture of (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- cyano-methyl pyridine and 30 grams of tetrahydrofurans, drop finish, and 60
It is stirred to react 4 hours to 65 DEG C.20 to 25 DEG C are cooled to, with 20% aqueous ammonium chloride solution acid system pH value 4.0-4.5, is added
100 grams of methylene chloride, layering, water layer are extracted with dichloromethane 3 times, 20 grams every time, merge organic phase, be distilled to recover dichloromethane
Alkane, obtains 29.3 grams of N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl picoline, and yield is
87.7%, liquid phase purity 99.3%.
Embodiment 3:N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl picoline (III)
Preparation
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, reflux condensing tube and dropping funel, 160 grams of 2- are added
Methyltetrahydrofuran, 6.0 grams of acetonitriles, 10.0 grams of (0.15 mole) sodium ethoxides, between 50 to 55 DEG C, being added dropwise 33.9 grams, (0.1 rubs
You) N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- ethoxycarbonylmethyl group pyridine and 30 grams of 2- methyltetrahydrofurans
Mixture, drop finish, 50 to 55 DEG C are stirred to react 6 hours.20 to 25 DEG C are cooled to, with 20% aqueous ammonium chloride solution acid system
100 grams of methylene chloride are added in pH value 4.0-4.5, layering, and water layer is extracted with dichloromethane 3 times, 20 grams every time, merge organic phase,
It is distilled to recover methylene chloride, obtains 28.0 grams of N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl first
Yl pyridines, yield 83.8%, liquid phase purity 99.6%.
Embodiment 4:N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- [(3- nitro -2- cyano methyl) -2-
Acrylic] pyridine (IV) preparation
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, reflux condensing tube and dropping funel, it is added 200 gram four
Hydrogen furans, 33.5 grams of (0.1 mole) N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- cyano-acetamide ylmethyl pyrroles
Pyridine, 9.0 grams of (0.15 mole) nitromethanes, 1.5 grams of piperidines, 50 to 55 DEG C are stirred to react 4 hours.20 to 25 DEG C are cooled to, is used
20% aqueous ammonium chloride solution acid system pH value 4.0-4.5, is added 150 grams of methylene chloride, and layering, water layer is extracted with dichloromethane
3 times, 20 grams every time, merges organic phase, be distilled to recover methylene chloride, obtain 33.7 grams of N- (2- trifluoromethyl pyridine -5- base) first
Base -2- amino -5- [(3- nitro -2- cyano methyl) -2- acrylic] pyridine, yield 89.5%, liquid phase purity 99.5%.
Embodiment 5:N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- [(3- nitro -2- cyano methyl) -2-
Acrylic] pyridine (IV) preparation
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, reflux condensing tube and dropping funel, 200 grams of 2- are added
Methyltetrahydrofuran, 33.5 grams of (0.1 mole) N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl first
Yl pyridines, 9.0 grams of (0.15 mole) nitromethanes, 2.7 grams of potassium tert-butoxides, 35 to 40 DEG C are stirred to react 6 hours.Be cooled to 20 to
25 DEG C, with 20% aqueous ammonium chloride solution acid system pH value 4.0-4.5,100 grams of methylene chloride are added, are layered, water layer dichloro
Methane extracts 3 times, 20 grams every time, merges organic phase, is distilled to recover methylene chloride, obtains 33.9 grams of N- (2- trifluoromethyl pyridines-
5- yl) methyl-2-amino -5- [(3- nitro -2- cyano methyl) -2- acrylic] pyridine, yield 89.9%, liquid phase purity
99.3%.
Embodiment 6: the preparation of compound V
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, reflux condensing tube and dropping funel, 200 grams of 2- are added
Methyltetrahydrofuran, 37.5 grams of (0.1 mole) N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- [(3- nitro -2-
Cyano methyl) -2- acrylic] pyridine, 0.8 gram of DBU, 14.0 grams of (0.11 mole) 2,3- dichloropropylene aldehyde, 40 to 45 DEG C of stirrings
Reaction 4 hours.20 to 25 DEG C are cooled to, 15 grams of potassium carbonate are added, 20 to 25 DEG C are stirred to react 2 hours, it is added 100 grams of water, 100
Gram methylene chloride, layering, water layer are extracted with dichloromethane 3 times, 20 grams every time, merge organic phase, be distilled to recover methylene chloride, obtain
To 44.5 g of compound V, yield 95.6%, liquid phase purity 99.2%.
Embodiment 7: the preparation of compound V
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, reflux condensing tube and dropping funel, it is added 250 gram four
Hydrogen furans, 37.5 grams of (0.1 mole) N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- [(3- nitro -2- cyano first
Base) -2- acrylic] pyridine, 1.0 grams of piperidines, 14.0 grams of (0.11 mole) 2,3- dichloropropylene aldehyde, 50 to 55 DEG C are stirred to react 4
Hour.20 to 25 DEG C are cooled to, 7.0 grams of sodium methoxides are added, 30 to 35 DEG C are stirred to react 2 hours, it is added 100 grams of water, 100 gram two
Chloromethanes, layering, water layer are extracted with dichloromethane 3 times, 20 grams every time, merge organic phase, be distilled to recover methylene chloride, obtain
44.1 g of compound V, yield 94.7%, liquid phase purity 99.5%.
Embodiment 8: pyrrole former times replaces the preparation of Buddhist nun (I)
Addition 200 grams of methanol, 23.5 grams of (0.05 mole) compounds V into 500 milliliters of stainless steel pressure kettles, 0.5 gram
5% palladium-carbon catalyst, 1.5 grams of ammonium chlorides after nitrogen displacement three times, are passed through hydrogen, and holding Hydrogen Vapor Pressure is 0.2-0.3MPa,
30-35 DEG C is reacted 6 hours.Nitrogen is replaced three times, and palladium carbon is filtered to remove, and filtrate concentration is dry that 20.5 grams of pyrrole former times replace Buddhist nun, yield
98.1%, liquid phase purity 99.6%.
Embodiment 9: pyrrole former times replaces the preparation of Buddhist nun (I)
Addition 200 grams of isopropanols, 23.5 grams of (0.05 mole) compounds V into 500 milliliters of stainless steel pressure kettles, 3.0 grams
50% raney nickel catalyst, 2.0 grams of ammonium chlorides after nitrogen displacement three times, are passed through hydrogen, and holding Hydrogen Vapor Pressure is 0.2-
0.3MPa, 40-45 DEG C are reacted 4 hours.Nitrogen is replaced three times, is filtered to remove Raney Ni, filtrate concentration, dry 20.1 grams of pyrrole former times
For Buddhist nun, yield 96.2%, liquid phase purity 99.5%.
Comparative example: N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- [(3- nitro -2- cyano methyl) -2- third
Alkenyl] pyridine (IV) preparation
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer, reflux condensing tube and dropping funel, 200 grams of 2- are added
Methyltetrahydrofuran, 33.5 grams of (0.1 mole) N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- Cyanoacetyl first
Yl pyridines, 12.2 grams of (0.2 mole) nitromethanes, 2.7 grams of potassium tert-butoxides, 95 DEG C to 100 DEG C are stirred to react 6 hours.It is cooled to
20 to 25 DEG C, with 20% aqueous ammonium chloride solution acid system pH value 4.0-4.5,100 grams of methylene chloride are added, are layered, water layer is used
Methylene chloride extracts 3 times, 20 grams every time, merges organic phase, is distilled to recover methylene chloride, obtains 45.7 grams of dopes, outside liquid phase
Mark method N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- [(3- nitro -2- cyano methyl) -2- acrylic] pyridine contains
Amount is 52.2%, liquid yield 63.1%.
Analysis of conclusion:
From above embodiments and comparative example: present invention gained intermediate N (2- trifluoromethyl pyridine -5- base) methyl -
When 2- amino-5-cyano acetylmethyl pyridine and nitromethane are condensed, suitable nitromethane ratio and suitable temperature pair
In reducing, by-product is most important, and nitromethane is insufficient, and not exclusively, nitromethane is excessively easy to that series connection occurs with cyano secondary for reaction
Reaction；The activity difference that nitromethane and carbonyl and cyano reaction can be reduced when the temperature is excessively high, causes yield and purity to reduce.
Claims (9)
1. the simple and convenient process for preparing that a kind of pyrrole former times replaces Buddhist nun, comprising the following steps:
(1) in the presence of solvent A and alkali A, N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5-G replaces ylmethyl pyrrole
Pyridine (II) and acetonitrile are through condensation reaction generation N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- cyano-acetamide ylmethyl
Pyridine (III)；
(2) in the presence of solvent B and catalyst A ', compound III and nitromethane condensation preparation N- (2- trifluoromethyl pyridine-
5- yl) methyl-2-amino -5- [(3- nitro -2- cyano methyl) -2- acrylic] pyridine (IV)；
(3) in the presence of solvent C and catalyst B ', then compounds Ⅳ and 2,3- dichloropropylene aldehyde addition takes off under alkali B effect
Except hydrogen chloride obtains compound V；
(4) in the presence of solvent D and catalyst C ', hydrogenating reduction-cyclisation prepares pyrrole former times for Buddhist nun (I)；
Wherein, G is CN or COOR；R is-CH3、-C2H5、-C3H7、-C4H9Or-CH2Ph。
2. a kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun as described in claim 1, it is characterised in that in step (1), including it is following
Any one of condition is multinomial:
A1) solvent A is tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring amyl ether, 1,2- dimethoxy-ethane, toluene, two
One of toluene, 1,2- dichloroethanes or chlorobenzene or its any conjunction object；The mass ratio of the solvent A and compound ii is (2-
15):1；
A2) the alkali A is sodium methoxide, in sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium amide, lithium diisopropylamine (LDA)
Or mixtures thereof one kind；
A3) N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5-G substituent group picoline (II) is N- (2- tri-
Fluoromethylpyridin -5- base) methyl-2-amino -5- cyano-methyl pyridine, N- (2- trifluoromethyl pyridine -5- base) methyl -2- ammonia
Base -5- methoxycarbonyl-methyl pyridine, N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- ethoxycarbonylmethyl group pyridine,
N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- butyloxycarbonyl picoline, N- (2- trifluoromethyl pyridine -5-
Base) methyl-2-amino -5- tert-Butoxycarbonylmethyl pyridine, N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5- benzyloxy
Carbonvlmethyl pyridine；
A4) the alkali A, acetonitrile and N- (2- trifluoromethyl pyridine -5- base) methyl-2-amino -5-G substituent group picoline (II)
Molar ratio be (1.0-2.0): (1.0-2.0): 1；
A5) setting-up point is 20-110 DEG C, and the reaction time is 2-10 hours.
3. a kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun as claimed in claim 2, it is characterised in that in step (1), including it is following
Any one of condition is multinomial:
A1) mass ratio of the solvent A and compound ii is (5-10): 1；
A5) setting-up point is 50-80 DEG C, and the reaction time is 4-7 hours.
4. a kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun as described in claim 1, it is characterised in that in step (2), including it is following
Any one of condition is multinomial:
B1) the solvent B be tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring amyl ether, 1,2- dimethoxy-ethane, acetonitrile or
One of chlorobenzene or its any conjunction object；The solvent B and the mass ratio of compound III are (2-15): 1；
B2) the catalyst A ' is piperidines, nafoxidine, morpholine, DBU, DBN, 4-dimethylaminopyridine, potassium tert-butoxide, ethyl alcohol
Sodium, sodium methoxide；The molar ratio of the catalyst A ' and compound III is 5%-20%；
B3) molar ratio of the nitromethane and compound III is (1.0-1.5): 1；
B4) nitromethane and compound III setting-up point are 0-90 DEG C, are reacted 2-8 hours.
5. a kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun as claimed in claim 4, it is characterised in that in step (2), including it is following
Any one of condition is multinomial:
B1) the solvent B and the mass ratio of compound III are (5-10): 1；
B4) nitromethane and compound III setting-up point are 30-60 DEG C, are reacted 3-6 hours.
6. a kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun as described in claim 1, it is characterised in that in step (3), including it is following
Any one of condition is multinomial:
C1) solvent C be tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring amyl ether, 1,2- dimethoxy-ethane, acetonitrile or
One of chlorobenzene or its any conjunction object；The mass ratio of the solvent C and compounds Ⅳ is (2-15): 1；
C2) the catalyst B ' is piperidines, nafoxidine, morpholine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0]
(DBU), 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), 4-dimethylaminopyridine；It is described to urge catalyst B ' and compound
IV mass ratio is 1%-10%；
C3) molar ratio of the 2,3- dichloropropylene aldehyde and compounds Ⅳ is (1.0-1.5): 1；
C4) compounds Ⅳ and 2, it is 20-100 DEG C that 3- dichloropropylene aldehyde, which carries out Isosorbide-5-Nitrae-addition reaction temperature, is reacted 2-10 hours；
C5) the alkali B is inorganic base or organic base, wherein inorganic base is selected from potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, carbon
One of sour calcium, sodium hydroxide, potassium hydroxide, saleratus, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate, calcium acetate or
Combination, organic base are selected from one of trimethylamine, triethylamine, tri-n-butylamine or combination；The molar ratio of the alkali B and compounds Ⅳ is
(1.0-2.0):1；
C6) the elimination hcl reaction temperature is 0-80 DEG C, is reacted 2-6 hours.
7. a kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun as claimed in claim 6, it is characterised in that in step (3), including it is following
Any one of condition is multinomial:
C1) mass ratio of the solvent C and compounds Ⅳ is (5-10): 1；
C4) compounds Ⅳ and 2, it is 40-80 DEG C that 3- dichloropropylene aldehyde, which carries out Isosorbide-5-Nitrae-addition reaction temperature, is reacted 3-6 hours；
C6) the elimination hcl reaction temperature is 20-60 DEG C, is reacted 3-5 hours.
8. a kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun as described in claim 1, it is characterised in that in step (4), including it is following
Any one of condition is multinomial:
D1) the solvent D be methanol, ethyl alcohol, acetonitrile, ethyl acetate, tert-butyl acetate, methylene chloride, chloroform, carbon tetrachloride,
One of tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring amyl ether, 1,2- dimethoxy-ethane or its any conjunction object；It is described
The mass ratio of solvent D and compound V is (2-15): 1；
D2) the catalyst C ' is one of palladium charcoal or Raney Ni and ammonium chloride mixt；Wherein palladium carbon catalyst dosage is formula
(V) the 0.5%~10% of compound quality；Raney nickel catalyst dosage is the 5%~25% of V compound quality of formula；Chlorination
Ammonium dosage is that the molar ratio of V compound of formula is (0.1-1.0): 1；
D3) hydrogenating reduction-cyclization temperature is 0~80 DEG C, Hydrogen Vapor Pressure 0.1-0.5MPa, is reacted 3~10 hours.
9. a kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun as claimed in claim 8, it is characterised in that in step (4), including it is following
Any one of condition is multinomial:
D1) mass ratio of the solvent D and compound V is (5-10): 1；
D2) the catalyst C ' is one of palladium charcoal or Raney Ni and ammonium chloride mixt；Wherein palladium carbon catalyst dosage is formula
(V) the 1%~5% of compound quality；Raney nickel catalyst dosage is the 10%~15% of V compound quality of formula；Ammonium chloride
Dosage is that the molar ratio of V compound of formula is (0.1-1.0): 1；
D3) hydrogenating reduction-cyclization temperature is 30~60 DEG C, Hydrogen Vapor Pressure 0.1-0.3MPa, is reacted 4-8 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810144681.7A CN110156775A (en) | 2018-02-12 | 2018-02-12 | A kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810144681.7A CN110156775A (en) | 2018-02-12 | 2018-02-12 | A kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110156775A true CN110156775A (en) | 2019-08-23 |
Family
ID=67635197
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810144681.7A Pending CN110156775A (en) | 2018-02-12 | 2018-02-12 | A kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110156775A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111978245A (en) * | 2020-09-15 | 2020-11-24 | 上海毕得医药科技有限公司 | Preparation method of 3-fluoro-2-isobutyl pyridine |
| CN113444083A (en) * | 2020-03-25 | 2021-09-28 | 上海天慈国际药业有限公司 | Preparation method of small molecule tyrosine kinase inhibitor |
| CN113816956A (en) * | 2021-10-26 | 2021-12-21 | 湖北工业大学 | Synthesis method of pexidaltinib |
| WO2022263801A1 (en) | 2021-06-15 | 2022-12-22 | Johnson Matthey Public Limited Company | Process for preparing pexidartinib |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006092032A2 (en) * | 2005-03-03 | 2006-09-08 | Universidade Federal Do Rio De Janeiro - Ufrj | PHARMACEUTICAL COMPOSITIONS CONTAINING 1-METHYL-3,6,7,8-TETRAHYDROPIRAZOLO[3,4-b]PIRROLO[4,3-d]PYRIDINE-6,8-DIONE DERIVATIVES, USE, AND PROCESS FOR PREPARING THEM |
| CN101784191A (en) * | 2007-04-26 | 2010-07-21 | 先正达参股股份有限公司 | 4-aza indole derivatives and their use as fungicides |
| CN103917235A (en) * | 2011-05-17 | 2014-07-09 | 普莱希科公司 | Kinase modulation and indications therefor |
| CN107531706A (en) * | 2015-05-06 | 2018-01-02 | 普莱希科公司 | Adjust the synthesis of 1H pyrrolo-es [2,3 b] pyridine derivate of kinases |
-
2018
- 2018-02-12 CN CN201810144681.7A patent/CN110156775A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006092032A2 (en) * | 2005-03-03 | 2006-09-08 | Universidade Federal Do Rio De Janeiro - Ufrj | PHARMACEUTICAL COMPOSITIONS CONTAINING 1-METHYL-3,6,7,8-TETRAHYDROPIRAZOLO[3,4-b]PIRROLO[4,3-d]PYRIDINE-6,8-DIONE DERIVATIVES, USE, AND PROCESS FOR PREPARING THEM |
| CN101784191A (en) * | 2007-04-26 | 2010-07-21 | 先正达参股股份有限公司 | 4-aza indole derivatives and their use as fungicides |
| CN103917235A (en) * | 2011-05-17 | 2014-07-09 | 普莱希科公司 | Kinase modulation and indications therefor |
| CN107531706A (en) * | 2015-05-06 | 2018-01-02 | 普莱希科公司 | Adjust the synthesis of 1H pyrrolo-es [2,3 b] pyridine derivate of kinases |
Non-Patent Citations (2)
| Title |
|---|
| N. L. NAM等: "Condensation of 1-substituted 5-aminopyrazoles with β-dicarbonyl compounds", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
| 王志会等: "氮杂吲哚合成", 《化学进展》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113444083A (en) * | 2020-03-25 | 2021-09-28 | 上海天慈国际药业有限公司 | Preparation method of small molecule tyrosine kinase inhibitor |
| CN111978245A (en) * | 2020-09-15 | 2020-11-24 | 上海毕得医药科技有限公司 | Preparation method of 3-fluoro-2-isobutyl pyridine |
| WO2022263801A1 (en) | 2021-06-15 | 2022-12-22 | Johnson Matthey Public Limited Company | Process for preparing pexidartinib |
| CN113816956A (en) * | 2021-10-26 | 2021-12-21 | 湖北工业大学 | Synthesis method of pexidaltinib |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110156775A (en) | A kind of pyrrole former times replaces the simple and convenient process for preparing of Buddhist nun | |
| CN109020881A (en) | A kind of Ah pa replaces the preparation method of Buddhist nun | |
| CN107337634B (en) | A kind of preparation method of Abbe Seeley midbody compound | |
| CN112592356A (en) | Method for synthesizing lornoxicam | |
| CN102432590A (en) | Method for synthesizing thiophene ethylamine | |
| CN109608468B (en) | Tofacitinib citrate impurity, and synthesis method and application thereof | |
| CN113816841A (en) | Preparation method of cyclopropyl methyl ketone | |
| CN112441932A (en) | Preparation method of bisoprolol fumarate impurity | |
| CN105693603A (en) | Improved indacaterol maleate preparation technology | |
| CN116621810A (en) | Process for preparing 2-methyl nicotine | |
| CN110684028B (en) | Preparation method of 2, 6-diazabicyclo [3,3,0] octane compound | |
| CN113620868A (en) | Torasemide new impurity and preparation method thereof | |
| CN105884625B (en) | A kind of synthetic method of R- salmeterols | |
| CN110218189B (en) | Abelide intermediate and simple preparation method of Abelide | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN109879800B (en) | Preparation process of bepotastine drug intermediate | |
| CN114163348A (en) | Synthesis method of aminoacyl-substituted L-phenylalanine | |
| CN108129414B (en) | Preparation method of mosapride citrate intermediate | |
| CN113956266A (en) | Method for synthesizing tetrodotoxin on large scale | |
| CN113861202B (en) | Large-scale preparation process of pterosin | |
| CN112321599B (en) | Synthesis method of drug intermediate 7-oxo-2-azaspiro [3.5] nonane | |
| CN109293649A (en) | A kind of preparation method of Sony's Ji cloth intermediate and Sony's Ji cloth | |
| CN111620875B (en) | Preparation process of imidazopyrazine compound | |
| CN109810052A (en) | A kind of highly selective Ah pa replaces the simple and convenient process for preparing of Buddhist nun | |
| JP2015513360A (en) | Compound JK12A and its production |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190823 |