CN106188040B - A kind of Fevipiprant and its intermediate preparation method - Google Patents
A kind of Fevipiprant and its intermediate preparation method Download PDFInfo
- Publication number
- CN106188040B CN106188040B CN201610513858.7A CN201610513858A CN106188040B CN 106188040 B CN106188040 B CN 106188040B CN 201610513858 A CN201610513858 A CN 201610513858A CN 106188040 B CN106188040 B CN 106188040B
- Authority
- CN
- China
- Prior art keywords
- reaction
- mesyl
- fevipiprant
- preparation
- pyridine
- 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.)
- Active
Links
- 0 CCC1=C(C)N(CC2=C(C(F)(F)F)*#CC(*C)C=C2)**2=NC=CC3C12C3 Chemical compound CCC1=C(C)N(CC2=C(C(F)(F)F)*#CC(*C)C=C2)**2=NC=CC3C12C3 0.000 description 2
Classifications
-
- 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of Fevipiprant and its intermediate preparation method, it is characterised in that：The bromopyridine of 2 amino 3 and the trifluoromethylated benzaldehyde of 4 mesyl 2 first carry out condensation reaction and form Schiff base intermediate, again the amine of 3 bromine N (4 (mesyl) 2 (trifluoromethyl) phenyl) pyridine 2 is obtained through reduction reaction, the amine of 3 bromine N (4 (mesyl) 2 (trifluoromethyl) phenyl) pyridine 2 carries out Liv Ullmann ring closure reaction with methyl ester levulinate or ethyl levulinate, it is N [1 (4 ((methane) sulfonyl) 2 trifluoromethyls) 2 methyl 1H pyrrolo-es [2 to obtain Fevipiprant by saponification or decarboxylic reaction again, 3 b] 3 base of pyridine] acetic acid.For the present invention as a kind of brand-new Fevipiprant preparation methods, not only step is short, technological operation is convenient, product easy purification and easily amplification produce, and may also reach up the high yield of comparison, it is easy to accomplish Fevipiprant industrialized production.
Description
Technical field：
The present invention relates to the preparation method of a kind of organic synthesis bulk drug and its intermediate, one kind is specifically related to
Fevipiprant and its intermediate preparation method.
Background technology：
Fevipiprant, Chinese are [1- (4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acids H-
Pyrrolo- [2,3-b] pyridin-3-yl] acetic acid, English name is [1- (4- ((Methane) sulfonyl) -2-
Trifluoromethylbenzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid, CAS
It is as shown in Equation 1 for 872365-14-5, its structural formula.
Compound 1Fevipiprant is developed by Novartis, is a kind of prostaglandin D 2 receptor (DP2/CRTh2) inhibitor, can
Promote the integrality of airway epithelia, and airway of patient with asthma remodeling may be mitigated, be mainly used in treating asthma.It is dynamic by medicine generation
Mechanics (PK), security and tolerance test show extraordinary effect, proceed to III phase clinical stages in the U.S. at present,
It is a kind of very potential and treatment of market prospects slightly to moderate persistent asthma, moderate to severe atopic dermatitis and mistake
Quick property rhinitis medicine.
But had some limitations for Fevipiprant synthesis techniques, its synthetic method, patent
WO2005123731 is as follows for the main synthetic route of the medicine：
Using 4- methyl sulphonyl -2- trifluoromethylated benzaldehydes as raw material by reduction, bromo products therefrom and 2- methyl -
1H- pyrroles [2,3-b] and pyridin-3-yl-methyl acetate condensation, saponification or decarboxylation obtain target compound, but 2- methyl-
1H- pyrroles [2,3-b] and pyridin-3-yl-methyl acetate synthesis are difficult, itself need by multi-step complex reaction and cumbersome
Purifying, simultaneously because heterocycle resonance can occur in condensation step, pyridine ring alkylate by-product is caused to generate, the accessory substance highest
60% generation is had, is also not less than 40% even across optimization, the step needs to be only up to by complicated separation, yield
50% or so, and the substantial amounts of three wastes can be produced, because the route has significant limitation, to potential Fevipiprant
Industrialized production brings very big difficulty, therefore it is the current research for being badly in need of solving to find alternative brand-new synthetic route
Problem.
The content of the invention：
The defects of technical problems to be solved by the invention are to overcome existing Fevipiprant industrialized productions,
Provide a kind of easily Fevipiprant and its intermediate preparation method, technological operation convenience, the product easy purification of use
With easy amplification production, the high yield of comparison may also reach up.
Based on above-mentioned technical problem, the first aspect of the present invention purpose is to provide a kind of as shown in formula 1
Fevipiprant preparation method, it is characterised in that comprise the steps of：
(1), 2- amino -3- bromopyridines (compound 2) and 4- mesyl -2- trifluoromethylated benzaldehydes (compound 3) are first
Carry out condensation reaction and form Schiff base intermediate, then 3- bromo- N- (4- (mesyl) -2- (fluoroforms are obtained through reduction reaction
Base) phenyl)-pyridine -2- amine (compound 4)；
(2), the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (compound 4) and levulinic
Sour methyl esters or ethyl levulinate (compound 5) carry out Liv Ullmann ring closure reaction, then obtain N [1- by saponification or decarboxylic reaction
(4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl] acetic acid (chemical combination
Thing 1).
Reaction equation of the present invention is as follows：
In formula：
Compound 1 is：N [1- (4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-
B] pyridin-3-yl] acetic acid；
Compound 2 is：2- amino -3- bromopyridines；
Compound 3 is：4- mesyl -2- trifluoromethylated benzaldehydes；
Compound 4 is：The bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine；
Compound 5 is：Methyl ester levulinate or ethyl levulinate.
Preferably, using following technical scheme, more preferable effect can be obtained：
In step (1)：
Described condensation reaction, the dosage of 2- amino -3- bromopyridines (compound 2) is 4- mesyl -2- trifluoromethyls
1~2 times of benzaldehyde (compound 3) mole, the dosage of 2- amino -3- bromopyridines is more, and effect is better；
Described condensation reaction, it can be carried out in organic inert solvent or under condition of no solvent, preferably in organic inert
Being carried out in solvent, the organic inert solvent is selected from aromatic hydrocarbon, alkyl halide, alcohol, preferably one kind of ether equal solvent, aromatic hydrocarbon,
Particularly preferably toluene；The dosage of organic inert solvent is preferably 4- mesyl -2- trifluoromethylated benzaldehydes (compound 3)
1~100 times, preferably 8~20 times of mole；
Described condensation reaction, carried out preferably in the presence of catalyst, catalyst is selected from p-methyl benzenesulfonic acid, hydrochloric acid sulphur
Acid, preferably one kind of polyphosphoric acids, p-methyl benzenesulfonic acid, the dosage of catalyst is 4- mesyl -2- trifluoromethylated benzaldehydes
0.1~1 times of the mole of (compound 3), the dosage of catalyst is more, and effect is better；
Described condensation reaction, reaction temperature are 0~150 DEG C, and preferably 0~120 DEG C, the reaction time is preferably anti-to detect
Untill answering completely, preferably untill TLC detections reactant consumption is complete.
Described reduction reaction, carried out under solvent condition, the solvent of reduction reaction is preferably alcohol, particularly preferably second
Alcohol；
Described reduction reaction, reducing agent be selected from sodium borohydride, potassium borohydride, acetic acid sodium borohydride, sodium cyanoborohydride,
One kind of borine, preferably sodium borohydride；The dosage of reducing agent is 4- mesyl -2- trifluoromethylated benzaldehydes (compound 3)
0.25~10 times of mole, the more effects of dosage of reducing agent are better；
Described reduction reaction, reaction temperature are 0~100 DEG C, preferably 0~50 DEG C；Reaction time is preferably anti-to detect
Untill answering completely, preferably untill TLC detections reactant consumption is complete.
In step (2)：
Described Liv Ullmann ring closure reaction, it can carry out in organic inert solvent or under condition of no solvent, preferably have
Carried out in machine atent solvent, the organic inert solvent is selected from DMF, DMA, N- methyl
Pyrrolidones, dimethyl sulfoxide (DMSO), aromatic hydrocarbon, halogenated hydrocarbons, ether, preferably one kind of second alcohol and water, DMA, have
The dosage of machine atent solvent is preferably the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (chemical combination
Thing 4) 1~100 times, preferably 8~20 times of mole；
Described Liv Ullmann ring closure reaction, is preferably carried out in the presence of catalyst and part, and the catalyst is selected from iodine
Change one kind of cuprous, stannous chloride, cuprous bromide, acetylacetone,2,4-pentanedione, preferably cuprous iodide, catalyst amount is the bromo- N- (4- of 3-
(mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (compound 4) 0.01~1 times of mole amount, catalyst uses
Amount is more, and effect is better；The part is selected from N, N- dimethylglycines, acetylacetone,2,4-pentanedione, proline, 2,2,6,6- tetramethyl -3,
One kind of 5- heptadione, preferably DMG；The dosage of part is the bromo- N- of 3- (4- (mesyl) -2- (three
Methyl fluoride) phenyl)-pyridine -2- amine (compound 4) 0.01~1 times of mole amount, the more effects of dosage of part are better；
Described Liv Ullmann ring closure reaction, reaction temperature be 0 DEG C~200 DEG C, preferably 60~150 DEG C, the reaction time compared with
It is good untill detection reaction completely, preferably untill TLC detections reactant consumption is complete.
Described saponification or decarboxylic reaction, carried out preferably under conditions of solvent, solvent is selected from alcohol, aromatic hydrocarbon, the one of ether
Kind, preferably ethanol；
The saponification or decarboxylic reaction, alkali are selected from sodium hydroxide, potassium hydroxide, preferably one kind of lithium hydroxide, hydrogen-oxygen
Change sodium；Acid is selected from hydrochloric acid and sulfuric acid；The dosage of saponification or decarboxylation reagent (acid or alkali) is the bromo- N- of 3- (4- (mesyl) -2-
(trifluoromethyl) phenyl)-pyridine -2- amine (compound 4) 1~5 times of mole amount, the more effects of dosage are better；
Described saponification or decarboxylic reaction, reaction temperature are 0 DEG C~150 DEG C, preferably 20~100 DEG C；Reaction time compared with
It is good untill detection reaction completely, preferably untill TLC detections reactant consumption is complete.
In the present invention, the method synthesis that described compound 2 can refer to document CN103664765 obtains.
In the present invention, described compound 3 can refer to the synthesis of document WO2007065684 methods and obtain.
Unless otherwise specified, reagent and raw material of the present invention are commercially available.
The beneficial effects of the present invention are：
(1), the invention provides a kind of brand-new Fevipiprant synthetic routes.
The present invention is first condensed using 2- amino -3- bromopyridines and 4- mesyl -2- trifluoromethylated benzaldehydes as raw material
React and form Schiff base intermediate, then through the reduction reaction acquisition bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl) -
Pyridine -2- amine；The bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (compound 4) and levulic acid
Methyl esters or ethyl levulinate carry out Liv Ullmann ring closure reaction, then obtain N [1- (4- ((methane) sulphurs by saponification or decarboxylic reaction
Acyl group) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl] acetic acid is Fevipiprant.
(2), synthetic route of the invention, the reagent or raw material of costliness can be avoided, operating method is simple and convenient, product is easily pure
Change, cost significantly reduces, is not only suitable for laboratory and prepares on a small quantity, also is adapted for industrialization large-scale production；Its may also reach up compared with
High yield.
Embodiment：
The present invention is further illustrated with embodiment below, but the present invention is not intended to be limited thereto.
In the present invention：Described normal temperature is 20~40 DEG C, and normal pressure is 0.8atm~1.2atm.
Embodiment 1：The preparation of the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (4).
4- mesyl -2- trifluoromethylated benzaldehydes (25.2g, 0.1mol) and 2- amino -3- bromopyridines (17.3g,
300mL toluene 0.1mol) is added, heat up 2h reflux water-dividings, and concentration toluene obtains faint yellow solid, is dissolved in 200mL ethanol, cold
But to 0 DEG C, it is added portionwise sodium borohydride (4.5g, 0.12mol), below 20 DEG C of temperature control, 12h is stirred at room temperature after finishing, is added dropwise full
It is quenched with ammonium chloride, dichloromethane extraction, anhydrous sodium sulfate drying, filtering, concentrates and obtained with re-crystallizing in ethyl acetate white solid
Body powder 37.2g, yield 91%.
HNMR(300MHz,CDCl3)δ:8.35~8.41 (s, 1H, PyH), 8.08~8.09 (d, 1H, PyH), 7.86~
7.93 (m, 2H, PyH), 6.98~7.01 (d, 1H, PhH), 6.73~6.75 (d, 1H, PyH), 6.31 (br, 1H, NH), 3.89
(s,2H,CH2), 3.38 (s, 3H, CH3)。
HPLC:98.9%.
Embodiment 2：The preparation of the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (4).
4- mesyl -2- trifluoromethylated benzaldehydes (25.2g, 0.1mol) and 2- amino -3- bromopyridines (17.3g,
300mL toluene 0.1mol) is added, heat up 2h reflux water-dividings, and concentration toluene obtains faint yellow solid, is dissolved in 200mL tetrahydrofurans
In, 0 DEG C is cooled to, is added portionwise sodium borohydride (4.5g, 0.12mol), below 20 DEG C of temperature control, 12h is stirred at room temperature after finishing, is dripped
Add saturated ammonium chloride to be quenched, dichloromethane extraction, anhydrous sodium sulfate drying, filtering, concentrate and obtained with re-crystallizing in ethyl acetate white
Color solid powder 30.0g, yield 73%.
HPLC:98.1%.
Embodiment 3：The preparation of the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (4).
4- mesyl -2- trifluoromethylated benzaldehydes (25.2g, 0.1mol) and 2- amino -3- bromopyridines (17.3g,
300mL toluene 0.1mol) is added, heat up 2h reflux water-dividings, and concentration toluene obtains faint yellow solid, is dissolved in 200mL tetrahydrofurans
In, it is cooled to 0 DEG C, is added dropwise 1M borines tetrahydrofuran solution (120mL, 0.12mol), below 20 DEG C of temperature control, finishes rear room temperature and stir
12h is mixed, saturated ammonium chloride is added dropwise and is quenched, dichloromethane extraction, anhydrous sodium sulfate drying, filtering, is concentrated and with ethyl acetate weight
Crystallize to obtain white solid powder 34.5g, yield 81%.
HPLC:98.5%.
Embodiment 5：N [1- (4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-b]
Pyridin-3-yl] acetic acid (1) preparation.
The bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (40.9g, 0.1mol) and acetyl
Methyl propionate (13.0g, 0.1mol) adds 300mL DMFs, adds cuprous iodide (1.9g, 0.01mol)
With DMG (1.0g, 0.01mol), after nitrogen displacement, 120 degree of reaction 12h are warming up to, are added after cooling
200mL saturated aqueous common salts, and extracted with ethyl acetate, organic phase is concentrated to give pale yellow powder, added by washing, drying
100mL ethanol and 100mL water, add sodium hydroxide (8g, 0.2mol) and be warming up to 60 degree of reaction 2h, be cooled to 0 DEG C, 4N is added dropwise
It is 2 that hydrochloric acid, which is acidified to pH, filtering, and washs solid with ethanol, and obtained crude product obtains sterling 34.5g by ethyl alcohol recrystallization, receives
Rate 81%.
HNMR(300MHz,d6-DMSO)δ:12.3(br,1H,CO2), H 8.24 (s, 1H, PhH), 8.11~8.12 (d,
1H, PhH), 8.00~8.02 (d, 1H, PyH), 7.91~7.93 (d, 1H, PyH), 7.09~7.10 (d, 1H, PhH), 6.46~
6.48(d,1H,PhH),5.73(s,2H,NCH2), 3.70 (s, 2H, CH 2CO2H), 3.30 (s, 3H, CH3)。
HPLC:99.9%.
Embodiment 6：N [1- (4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-b]
Pyridin-3-yl] acetic acid (1) preparation.
The bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (40.9g, 0.1mol) and acetyl
Dimethyl malenate (18.8g, 0.1mol) add 300mL DMFs, add cuprous iodide (1.9g,
0.01mol) and DMG (1.0g, 0.01mol), after nitrogen displacement, 120 degree of reaction 12h are warming up to, after cooling
200mL saturated aqueous common salts are added, and are extracted with ethyl acetate, organic phase is passed through washing, dried, and is concentrated to give pale yellow powder,
100mL ethanol and 100mL water are added, sodium hydroxide (8g, 0.2mol) is added and is warming up to 60 degree of reaction 2h, be cooled to 0 DEG C, drop
It is 2 to add 4N hydrochloric acid to be acidified to pH, filtering, and washs solid with ethanol, and obtained crude product obtains sterling 34.1g through ethyl alcohol recrystallization,
Yield 80%.
HPLC:99.8%.
Embodiment 7：N [1- (4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-b]
Pyridin-3-yl] acetic acid (1) preparation.
The bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (40.9g, 0.1mol) and acetyl
Methyl propionate (13.0g, 0.1mol) adds 300mL DMFs, adds cuprous iodide (3.8g, 0.02mol)
With DMG (2.0g, 0.02mol), after nitrogen displacement, 120 degree of reaction 12h are warming up to, are added after cooling
200mL saturated aqueous common salts, and extracted with ethyl acetate, organic phase is concentrated to give pale yellow powder, added by washing, drying
100mL ethanol and 100mL water, add sodium hydroxide (8g, 0.2mol) and be warming up to 60 degree of reaction 2h, be cooled to 0 DEG C, 4N is added dropwise
It is 2 that hydrochloric acid, which is acidified to pH, filtering, and washs solid with ethanol, and obtained crude product obtains sterling 34.1g, yield through ethyl alcohol recrystallization
80%.
HPLC:99.9%.
Embodiment 8：N [1- (4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-b]
Pyridin-3-yl] acetic acid (1) preparation.
The bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (40.9g, 0.1mol) adds
300mL DMFs, add cuprous iodide (1.9g, 0.01mol) and 2,2,6,6- tetramethyl -3,5- heptan two
Ketone (3.6g, 0.02mol), after nitrogen displacement, 120 degree of reaction 12h are warming up to, add 200mL saturated aqueous common salts after cooling, and with
Ethyl acetate extracts, and organic phase is passed through washing, dried, and is concentrated to give pale yellow powder, adds 100mL ethanol and 100mL water, then
Add sodium hydroxide (8g, 0.2mol) and be warming up to 60 degree of reaction 2h, be cooled to 0 DEG C, it is 2 that 4N hydrochloric acid, which is added dropwise, and is acidified to pH, filtering,
And solid is washed with ethanol, obtained crude product obtains sterling 30.2g, yield 71% through ethyl alcohol recrystallization.
HPLC:99.6%.
Embodiment 9：N [1- (4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-b]
Pyridin-3-yl] acetic acid (1) preparation.
The bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (40.9g, 0.1mol) adds
300mL DMFs, add cuprous iodide (1.9g, 0.01mol) and proline (1.2g, 0.01mol), nitrogen
After gas displacement, 120 degree of reaction 12h are warming up to, 200mL saturated aqueous common salts are added after cooling, and extracted with ethyl acetate, organic phase
By washing, dry, be concentrated to give pale yellow powder, add 100mL ethanol and 100mL water, add sodium hydroxide (8g,
60 degree of reaction 2h 0.2mol) are warming up to, are cooled to 0 DEG C, it is 2 that 4N hydrochloric acid, which is added dropwise, and is acidified to pH, filtering, and solid with ethanol washing
Body, obtained crude product obtain sterling 33.2g, yield 78% through ethyl alcohol recrystallization.
HPLC:99.8%.
Embodiment 10：N [1- (4- ((methane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-
B] pyridin-3-yl] acetic acid (1) preparation.
The bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (40.9g, 0.1mol) adds
300mL DMFs, add cuprous iodide (1.9g, 0.01mol) and DMG (1.0g,
0.01mol), after nitrogen displacement, 120 degree of reaction 12h is warming up to, 200mL saturated aqueous common salts are added after cooling, and with ethyl acetate
Extraction, organic phase are concentrated to give pale yellow powder, add 100mL acetic acid and 100mL concentrated hydrochloric acids, be warming up to by washing, drying
Back flow reaction 6h, 0 DEG C is cooled to, adds 100mL elutriations crystalline substance, filtering, and solid is washed with ethanol, obtained crude product is through ethanol weight
Crystallize to obtain sterling 33.2g, yield 78%.
HPLC:99.1%.
Claims (10)
1. a kind of Fevipiprant preparation method, it is characterised in that comprise the steps of：
(1), 2- amino -3- bromopyridines and 4- mesyl -2- trifluoromethylated benzaldehydes first carry out condensation reaction and form schiff bases
Intermediate, then obtain 3- bromo- N- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine through reduction reaction；
In step (1)：Described condensation reaction, carried out in organic inert solvent, reaction temperature is 0~150 DEG C, described organic
Atent solvent is selected from one kind of aromatic hydrocarbon, alkyl halide or ether solvents, and the dosage of organic inert solvent is 4- mesyl -2- trifluoros
1~100 times of the mole of tolyl aldehyde；
In step (1)：Described condensation reaction, carried out in the presence of catalyst, catalyst is selected from p-methyl benzenesulfonic acid, hydrochloric acid sulphur
Acid, one kind of polyphosphoric acids, the dosage of catalyst are the mole of 4- mesyl -2- trifluoromethylated benzaldehydes (compound 3)
0.1~1 times；
(2), the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine and methyl ester levulinate or acetyl
Ethyl propionate carries out Liv Ullmann ring closure reaction, then it is N [1- (4- ((first to obtain Fevipiprant by saponification or decarboxylic reaction
Alkane) sulfonyl) -2- trifluoromethyls) -2- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl] acetic acid；
In step (2)：Described Liv Ullmann ring closure reaction, is carried out in polar solvent, and reaction temperature is 0 DEG C~200 DEG C, described
Polar solvent is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO) or ethanol
One kind, the dosage of polar solvent is mole of the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine
1~100 times of amount；
In step (2)：Described Liv Ullmann ring closure reaction, is carried out in the presence of catalyst and part, and catalyst is selected from iodate
One kind of cuprous, stannous chloride or cuprous bromide, catalyst amount are the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) benzene
Base)-pyridine -2- amine (compound 4) 0.01~1 times of mole amount；The part is selected from N, N- dimethylglycines, acetyl
Acetone, proline, 2, one kind of 2,6,6- tetramethyl -3,5- heptadione, the dosage of part for the bromo- N- of 3- (4- (mesyl) -
2- (trifluoromethyl) phenyl)-pyridine -2- amine (compound 4) 0.01~1 times of mole amount.
A kind of 2. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (1)：It is described
Condensation reaction, the dosage of 2- amino -3- bromopyridines (compound 2) is 4- mesyl -2- trifluoromethylated benzaldehyde (compounds
3) 1~2 times of mole.
A kind of 3. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (1)：It is described
Condensation reaction, the reaction time with TLC detection reactant consumption it is complete untill.
A kind of 4. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (1)：It is described
Reduction reaction, carried out under solvent condition, the solvent of reduction reaction is alcohol.
A kind of 5. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (1)：It is described
Reduction reaction, reducing agent be selected from sodium borohydride, potassium borohydride, acetic acid sodium borohydride, sodium cyanoborohydride, one kind of borine,
The dosage of reducing agent is 0.25~10 times of the mole of 4- mesyl -2- trifluoromethylated benzaldehydes (compound 3).
A kind of 6. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (1)：It is described
Reduction reaction, reaction temperature be 0~100 DEG C, the reaction time with TLC detection reactant consumption it is complete untill.
A kind of 7. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (2)：It is described
Liv Ullmann ring closure reaction, the reaction time with TLC detection reactant consumption it is complete untill.
A kind of 8. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (2)：It is described
Saponification or decarboxylic reaction, carried out under conditions of solvent, solvent be selected from alcohol, aromatic hydrocarbon, one kind of ether.
A kind of 9. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (2)：It is described
Saponification or decarboxylic reaction, alkali are selected from sodium hydroxide, potassium hydroxide, one kind of lithium hydroxide, and acid is selected from hydrochloric acid and sulfuric acid；Acid or alkali
Dosage for the bromo- N- of 3- (4- (mesyl) -2- (trifluoromethyl) phenyl)-pyridine -2- amine (compound 4) mole 1
~5 times of amounts.
A kind of 10. Fevipiprant according to claim 1 preparation method, it is characterised in that：In step (2)：It is described
Saponification or decarboxylic reaction, reaction temperature be 0 DEG C~150 DEG C, the reaction time with TLC detection reactant consumption it is complete untill.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610513858.7A CN106188040B (en) | 2016-06-28 | 2016-06-28 | A kind of Fevipiprant and its intermediate preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610513858.7A CN106188040B (en) | 2016-06-28 | 2016-06-28 | A kind of Fevipiprant and its intermediate preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106188040A CN106188040A (en) | 2016-12-07 |
| CN106188040B true CN106188040B (en) | 2018-03-23 |
Family
ID=57464324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610513858.7A Active CN106188040B (en) | 2016-06-28 | 2016-06-28 | A kind of Fevipiprant and its intermediate preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106188040B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JOP20190223A1 (en) * | 2017-04-01 | 2019-09-26 | Novartis Ag | Process for preparing 1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1h-pyrrolo [2,3-b]pyridin-3-yl-acetic acid |
| WO2019011336A1 (en) * | 2017-07-14 | 2019-01-17 | 苏州科睿思制药有限公司 | Crystal form of qaw-039, preparation method and use thereof |
| CN108484595B (en) * | 2018-02-27 | 2021-03-30 | 天津科技大学 | Simple synthesis method of asthma medicine Fevipiprant |
| CN110467612B (en) * | 2018-05-09 | 2020-09-25 | 新发药业有限公司 | Simple preparation method of prostaglandin D2 receptor inhibitor compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123731A2 (en) * | 2004-06-17 | 2005-12-29 | Novartis Ag | Pyrrolopyridine derivatives and their use as crth2 antagonists |
-
2016
- 2016-06-28 CN CN201610513858.7A patent/CN106188040B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123731A2 (en) * | 2004-06-17 | 2005-12-29 | Novartis Ag | Pyrrolopyridine derivatives and their use as crth2 antagonists |
Non-Patent Citations (2)
| Title |
|---|
| A Convenient Palladium-Catalyzed Azaindole Synthesis;Raoul De Gasparo etal;《Synlett》;20141114;第26卷;supporting information第2页第1段 * |
| A mild method for the regioselective bromination of 2-aminopyridines;Tong Xu etal;《Tetrahedron Letters》;20140722;第55卷;support information * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106188040A (en) | 2016-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106188040B (en) | A kind of Fevipiprant and its intermediate preparation method | |
| CN104892509B (en) | Nuo get Si Ta preparation method | |
| CN103058993B (en) | Chlorantraniliprole preparation method | |
| CN109942576B (en) | Irbinitinib and preparation method of intermediate | |
| CN105294601B (en) | Thioamide analog compound and its synthetic method | |
| EP3133061B1 (en) | Florfenicol synthesizing method | |
| CN105732444B (en) | A kind of his synthetic method of Baily department | |
| CN110204486A (en) | A kind of synthetic method of quinoline | |
| CN103641722B (en) | A kind of production method of adjacent nitro bromobenzyl | |
| WO2013020460A1 (en) | Atazanavir preparation method | |
| CN102267994B (en) | Preparation method of moxifloxacin hydrochloride known impurity | |
| CN105237458B (en) | A kind of preparation method of polysubstituted indole derivatives | |
| CN109553518B (en) | Preparation method of substituted phenylacetic acid derivative | |
| CN105693802A (en) | Preparation method of 16 beta-methyl steroid | |
| CN106543144B (en) | A kind of industrialized process for preparing of dabigatran etcxilate | |
| CN105693632B (en) | A kind of preparation method of polysubstituted quinoxaline derivant | |
| CN105566260B (en) | A kind of preparation method of frusemide | |
| WO2013104546A1 (en) | Process for the synthesis of etoricoxib | |
| CN106674142A (en) | Preparation methods of parecoxib sodium and intermediate thereof | |
| CN106631885A (en) | 4-formaldoxime benzoate derivative preparation method | |
| CN106883192B (en) | The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification | |
| CN103539728A (en) | Synthesis method of lansoprazole drug intermediate chloromethyl pyridine derivative | |
| CN103664940A (en) | Preparation method of moxifloxacin impurity | |
| CN106478624A (en) | A kind of purification process of moxifloxacin hydrochloride | |
| CN102382165A (en) | Preparation method of dutasteride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |