CN104844514B - Diaryl pyrazole azole compound and preparation method and application - Google Patents
Diaryl pyrazole azole compound and preparation method and application Download PDFInfo
- Publication number
- CN104844514B CN104844514B CN201510264306.2A CN201510264306A CN104844514B CN 104844514 B CN104844514 B CN 104844514B CN 201510264306 A CN201510264306 A CN 201510264306A CN 104844514 B CN104844514 B CN 104844514B
- Authority
- CN
- China
- Prior art keywords
- methyl
- fluorophenyls
- isophthalic acid
- pyrazolyls
- methyl isophthalic
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
Abstract
The invention discloses diaryl pyrazole azole compound and preparation method and application, structure is as shown in logical formula (I)：Wherein, R1For hydrogen, halogen or methyl；R2For hydrogen, cyano group, trifluoromethyl or halogen；R3For hydrogen, halogen or itrile group；X such as above formulas are carbamyl, ghiourea group, methylamino or aminomethyl.The diaryl pyrazole azole compound of the present invention, especially 11aM01,11aM02,11M04,13aM01,16aM01,16aM02,16aM10,16aM11,16aM12,16aM15 have stronger cell growth inhibiting activity, 11aM03 to prostate gland cancer cell LNCaP and PC 3,12aM01,12aM02,16aM05,16aM06,16aM07,16aM08,16aM13,16aM16 have stronger selectivity to prostate gland cancer cell LNCaP cells, and these compounds may be used to prepare antineoplastic.
Description
Technical field
The present invention relates to organic compound synthesis and medical applications field, more particularly to diaryl pyrazole azole compound and its
Preparation method and application.
Background technology
Prostate cancer (prostate cancer, PCa) is one of most common tumour of male in the world, and the world
Upper the fourth-largest most common tumour, only in the U.S., just has 200,000 people to be diagnosed as prostate cancer, more than threescore every year
In male, just there is the disease that a meeting is diagnosed as this threat to life in average every five people.
The main method for the treatment of metastatic prostate cancer is that androgen removes therapy (androgen deprivation
Therapy, ADT, also known as castration therapy), including suppress the biosynthesis of androgen and using androgen receptor antagonists, so as to
The combination of androgen and acceptor is blocked, blocks the transcription and translation of downstream gene.Although androgen removes therapy for most of
Early prostate cancer the treatment works well, but after treatment after a while, most prostate cancer can all be consolidated
State is sprouted again, is changed into castration-resistant prostate cancer (castration resistance prostate cancer, CRPC), this
When androgen receptor antagonists, as Flutamide (Flutamide) and Nilutamide (Nilutamide) to prostate cancer there is no
Effect, and Bicalutamide (Bicalutamide) can be changed into partial excitatory activity, should stop applying androgen in this case
Remove therapy or use other androgen receptor antagonists, but En Zhalute (Enzalutamide) is in application a period of time
Resistance can be produced afterwards, therefore is designed the novel new androgen receptor antagonists of composite structure and had become active demand.
The content of the invention
For above-mentioned prior art, the invention provides a kind of Nonsteroic androgen that can suppress prostate cancer activity by
Body antagonist-diaryl pyrazole azole derivative, the present invention also provide the preparation method of the analog derivative and its use in pharmacy
On the way.
The present invention is achieved by the following technical solutions：
Diaryl pyrazole azole compound, structure are as follows such as logical formula (I)：
Wherein, R1For hydrogen, halogen or methyl；R2For hydrogen, cyano group, trifluoromethyl or halogen；R3For hydrogen, halogen or itrile group；X
If above formula is carbamyl, ghiourea group, methylamino or aminomethyl.
Preferably, R1For hydrogen, halogen or methyl；R2For hydrogen, cyano group, trifluoromethyl or halogen；R3For hydrogen, halogen or itrile group；
X such as above formulas are carbamyl, ghiourea group, methylamino or aminomethyl.
It is further preferred that the diaryl pyrazole azole compound of the present invention includes but is not limited to one of following compounds：
1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) thiocarbamide
(11aM01)
1- (3- trifluoromethyls) -3- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) thiocarbamide (11aM02)
1- (3,4- dicyanos phenyl) -3- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) thiocarbamide (11aM03)
1- (3- bromophenyls) -3- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) thiocarbamide (11aM04)
N- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) bromo- benzamides of -3- (12aM01)
N- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls)-(3- trifluoromethyls) benzamide (12aM02)
N- ((3- bromobenzyls) -3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) amine (13aM01)
N- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -3- bromanilines (16aM01)
N- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -3- 5-trifluoromethylanilines (16aM02)
4- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) phthalonitrile (16aM04)
3- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) cyanophenyl (16aM05)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of -4- (16aM06)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- aniline of -3- (16aM07)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- aniline of -4- (16aM08)
4- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) cyanophenyl (16aM09)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) bromo- aniline of -4- (16aM10)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -4- 5-trifluoromethylanilines (16aM11)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- 3- 5-trifluoromethylanilines (16aM12) of -4-
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the bromo- 4- of -3- (16aM13)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the chloro- 2- of -3- (16aM14)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) bromo- 2-aminotoluenes of -3- (16aM15)
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the chloro- 4- of -3- (16aM16)
It is its corresponding code name, for sake of convenience, above-mentioned bracket in bracket after above-mentioned preferable 22 compound names
In code name will be directly applied in this specification herein below.
The preparation method of above-mentioned diaryl pyrazole azole compound：
The preparation method of diaryl pyrazole azole compound of the present invention, comprises the following steps (synthetic route is as follows)：
Synthetic route：
R1、R2Or R3Structure it is identical or different, be all derived from following groups：Hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or nitrile
Base；
Reagent and reaction condition：(i)a：LiAlH4, THF；b：HCl；(ii)SOCl2, CH2Cl2；(iii) Acetone,
K2CO3, KI；(iv) diphenyl phosphate azide, absolute ethanol, dioxane；(v) NaOH, ethanol；(vi)CH2Cl2；
(vii) DMF, pyridine, THF；(viii) NaH, DMF；
Further, comprise the following steps that：
(i) the methyl isophthalic acid H- pyrazole-5-ethyl formates (4) of 3- (4- fluorophenyls) -1 are weighed, are dissolved with tetrahydrofuran.Weigh hydrogen
Change aluminium lithium, under condition of ice bath, be added to by several times in the tetrahydrofuran solution of intermediate 4, react at room temperature 15 minutes, detected with TLC
During without intermediate 4, reaction finishes, and frozen water is added dropwise under condition of ice bath into reaction solution, and now, decompression steams tetrahydrofuran, adjusts pH
To 1, when solution is no longer colloid, it is extracted with ethyl acetate three times, merges organic phase, organic phase is washed with saturated sodium-chloride, is done
Dry, filtering takes filtrate, and decompression steams organic solvent, obtains white solid, as midbody compound 14, the intermediate compound
The mol ratio of thing 4 and lithium aluminium hydride reduction is 1：(1~3), the lithium aluminium hydride reduction, tetrahydrofuran, the mass ratio of frozen water are 1：(20~
30)：(30~50)；
(ii) midbody compound 14 is weighed, is dissolved with dichloromethane, is slowly dropped into thionyl chloride, is reacted at room temperature 1 hour,
When TLC detections are without midbody compound 14, reaction finishes, and decompression steams dichloromethane and thionyl chloride obtains faint yellow solid, Gu
Body petroleum ether and re-crystallizing in ethyl acetate, it is midbody compound 15 to obtain faint yellow solid, midbody compound 14 and two
The mol ratio of chlorine sulfoxide is 1：The mass ratio of (1~5), thionyl chloride and dichloromethane is 1：(70~90)；
(iii) substituted aniline is weighed, with acetone solution, adds Anhydrous potassium carbonate and KI, and will be prepared in step ii
Midbody compound 15 be added thereto, be stirred at room temperature 8 hours, TLC reactions stop reaction, remove acetone under reduced pressure when finishing, Gu
Body water and ethyl acetate dissolving, divide and go aqueous phase, and organic phase is washed with saturated sodium-chloride, is dried, filtering, take filtrate, and decompression is steamed
Except organic solvent, target compound 16 is obtained with silica gel column chromatography separating purification.The eluent system is petroleum ether：Ethyl acetate=
10：1, the substituted aniline, midbody compound 15, the mol ratio 1 of Anhydrous potassium carbonate and KI：(0.8~2)：(0.8~
5)：(0.1~1), the mass ratio of the acetone, water and ethyl acetate is 1：(4~6)：(4~6)；
(iv) 3- (4- fluorophenyls) -1- methyl isophthalic acid H- pyrazoles -5- formic acid (5) is weighed, with dioxane and absolute second
Alcohol dissolves, and adds diphenyl phosphate azide, triethylamine, back flow reaction 7 hours, when TLC detections are without midbody compound 5, stops
Reaction, removes organic solvent under reduced pressure, now obtains dark brown liquid, uses the lemon of mass concentration 5% after being diluted with ethyl acetate respectively
Lemon acid, saturated sodium bicarbonate and saturated sodium-chloride washing, dry, filtering, take filtrate, remove organic solvent under reduced pressure, use silicagel column
Chromatography purify white solid is midbody compound 9.The eluent system is n-hexane：Ethyl acetate=3：1, institute
The mol ratio for stating midbody compound 5, diphenyl phosphate azide and triethylamine is 1：(1~3)：(1~6), the absolute
The mass ratio of ethanol and ethanol is 1：(0.8~3)；
(v) midbody compound 9 is weighed, is dissolved with ethanol, the sodium hydroxide solution dissolving of mass concentration 10% is added, returns
Stream reaction 5 hours, when TLC detections are without midbody compound 9, reaction solution is cooled to room temperature, removes ethanol under reduced pressure, adds distillation
Water, white solid is separated out, filtering, gained white solid is midbody compound 10, the midbody compound 9, ethanol, matter
The mass ratio for measuring the sodium hydroxide of concentration 10% and distilled water is 1：(20~30)：(10~30)：(30~50)；
(vi) midbody compound 10 is weighed, is dissolved with dichloromethane, aryl substitution isothiocyanates is weighed, uses dichloromethane
Alkane dissolves, and in the solution for the dichloromethane for being slowly dropped into midbody compound 10 under ice bath, drop finishes, and reacts at room temperature 7 hours, separates out
White solid, filtering, solid washs with dichloromethane, and dry white solid is target compound 11, the intermediate
The mol ratio of compound 10 and aryl substitution isothiocyanates is 1：(0.8~2)；
(vii) preparation of target compound 12：Substituted benzoyl chloride is weighed, is dissolved with tetrahydrofuran, is placed in constant pressure addition
In funnel.Midbody compound 10 is weighed, is dissolved with tetrahydrofuran, adds anhydrous pyridine, by constant pressure funnel under ice bath
Substituted benzene formyl solutions of chlorine be slowly dropped into the tetrahydrofuran solution of midbody compound 10, drop finish, remove ice bath, room temperature is anti-
Answer 2 hours, when TLC detections are without midbody compound 10, stop reaction, remove organic solvent, residue ethyl acetate under reduced pressure
After dissolving, organic phase is washed with saturated sodium bicarbonate solution, water and saturated sodium-chloride, is dried, and filtering, is taken filtrate, is removed under reduced pressure
Organic solvent, it is target compound 12 to obtain white solid with silica gel column chromatography separating purification, and the eluent system is petroleum ether：
Ethyl acetate=6：1, the mol ratio of the substituted benzoic acid, thionyl chloride and midbody compound 10 is 1：(1~5)：(0.8
~2), the volume ratio of the thionyl chloride, DMF, anhydrous pyridine and tetrahydrofuran is 1：(0.3~0.8)：(1~2)：(15~
20)；
(viii) midbody compound 10 is weighed, is dissolved with DMF, adds sodium hydride, stirring claims to there is no gas generation
Substitute benzyl bromine, dissolved with DMF, instilled at room temperature in the DMF solution of midbody compound 10, reacted at room temperature 16 hours, TLC inspections
When surveying unsubstituted benzyl bromine, stop reaction, reaction solution be poured into frozen water, separate out white solid, be extracted with ethyl acetate three times,
Merge organic phase, organic phase is washed with saturated sodium-chloride, is dried, and filtering, is taken filtrate, is removed organic solvent, silica gel column layer under reduced pressure
Analysis isolates and purifies to obtain faint yellow solid, as target compound 13, and the eluent system is n-hexane：Ethyl acetate=3：1, institute
The mol ratio for stating midbody compound, sodium hydride and substitution benzyl bromine is 1：(1~5)：(0.8~2)；
Preferably, in above-mentioned steps (i), the midbody compound 14 is 3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrroles
Oxazolyl) methanol；
Preferably, in above-mentioned steps (ii), the midbody compound 15 is 5- chloromethyls -3- (4- fluorophenyls) -1- first
Base -1H- pyrazoles；
Preferably, in above-mentioned steps (iii), the substituted aniline is 3- bromanilines, 3- 5-trifluoromethylanilines, 4- amino neighbour
Benzene dicarbonitrile, 3- aminobenzonitriles, 4- fluoroanilines, 3- chloroanilines, 4- chloroanilines, 4- aminobenzonitriles, 4- bromanilines, 4- trifluoromethyls
The chloro- 3- 5-trifluoromethylanilines of aniline, 4-, the bromo- 4- fluoroanilines of 3-, the chloro- 2- fluoroanilines of 3-, the bromo- 2-aminotoluenes of 3-, the chloro- 4- of 3-
Fluoroaniline；
Preferably, in above-mentioned steps (iv), the midbody compound 9 is (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrroles
Oxazolyl) urethanes；
Preferably, in above-mentioned steps (v), midbody compound 10 is (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazoles
Base) amine；
Preferably, in above-mentioned steps (vi), the aryl substitution isothiocyanates is 4- (isothiocyanate group) -2-
(trifluoromethyl) cyanophenyl, 4- (isothiocyanate group) phthalonitrile, 3- (isothiocyanate group) bromobenzene, 1- (isothiocyanates
Base) -3- trifluoromethylbenzenes；
Preferably, in above-mentioned steps (vii), the substituted benzoic acid is 3- bromobenzoic acids, 3- trifluoromethylbenzoic acids；
Preferably, in above-mentioned steps (viii), the substitution benzyl bromine is 3- bromobenzyl bromines；
1,3, the 5- tri- substituted pyrazolecarboxylic class compounds of the present invention, especially 11aM01,11aM02,11M04,13aM01,
16aM01,16aM02,16aM10,16aM11,16aM12,16aM15 have stronger to prostate gland cancer cell LNCaP and PC-3
Cell growth inhibiting activity, 11aM03,12aM01,12aM02,16aM05,16aM06,16aM07,16aM08,16aM13,
16aM16 has stronger selectivity to prostate gland cancer cell LNCaP cells, and these compounds may be used to prepare antineoplastic
Thing.
Compared with prior art, excellent results of the invention are：The present invention has synthesized the different diaryl pyrazole azole of structure
Compound, innovative point, which is to have obtained, has the structure of androgen receptor antagonist effect and prostatic cell growth inhibition effect complete
New pyrazole derivatives.Evaluation to prostate carcinoma cell growth inhibitory activity is using conventional MTT cytotoxicity assay method
(mtt assay), to the antagonistic activity of androgen receptor by determining androgen receptor target gene prostate-specific in LNCaP cells
Property antigen (PSA) expression lower percentage evaluated, as a result as shown in table 1.
Activity experiment result shows, diaryl pyrazole azole compound on prostate cancer cell LNCaP and PC-3 of the invention
There is obvious cell growth inhibiting activity, some compound on prostate cancer cell LNCaP cells have stronger selectivity, right
Androgen receptor has certain antagonistic activity.Connects chain X is growth suppression of the compound of ghiourea group for LNCaP and PC-3 cells
System activity is substantially better than corresponding connects chain as carbamyl, methylamino, the compound of aminomethyl, and even X is carbamyl for connection
Compound for LNCaP cells selectivity better than corresponding connects chain be ghiourea group, methylamino and aminomethyl compound,
Connects chain is that the compound of aminomethyl better than corresponding connects chain is ghiourea group, methylamino and carbamyl for AR antagonistic activity
The compound of base, for AR antagonistic activities when the phenyl ring contraposition on the bit substituent of pyrazole ring 5 has cyano group, fluorine, trifluoromethyl substitution
Preferably, wherein preferably, meta is preferable for AR antagonistic activities when having cyano group, chlorine to substitute, and is substituted with chlorine for activity when being substituted with cyano group
When activity it is best.Compound 11aM01,11aM02,11M04,13aM01,16aM01,16aM02,16aM07,16aM08,
The cell growth inhibiting activity of 16aM10,16aM11,16aM12,16aM13,16aM15 to prostate gland cancer cell LNCaP and PC-3
It is significantly better than that positive control medicine MDV3100 and Bicalutamide；Compound 11aM03,12aM02,16aM05,16aM06
It is better than positive control for LNCaP selectivity and wants MDV3100 and Bicalutamide.In addition, the hero of above-claimed cpd swashs
Plain receptor antagonist activity is weaker than positive control medicine, be probably the reason for this phenomenon due to diaryl pyrazole azole compound both
With endogenous androgens DHT competitive bindings AR AR signal paths can be blocked to suppress the growth of prostate gland cancer cell, also may be used
To suppress prostate carcinoma cell growth by other signal paths.
Numbering, structure and the active testing result of the diaryl pyrazole azole compound of table 1
Embodiment
The present invention is further described with reference to embodiment, with profit deeper into the understanding present invention and its advantage and effect, but
The embodiment is merely to illustrate the present invention rather than the limitation present invention.
The method be not described in detail in embodiment, reagent etc., are art conventional method, reagent.
The preparation of the midbody compound 14 of embodiment 1
Weigh 12mmol (1eq) midbody compounds 3- (4- fluorophenyls) -1- methyl isophthalic acid H- pyrazole-5-ethyl formates
5 in 100mL eggplant-shape bottles, are dissolved with 30mL tetrahydrofurans.Weigh 36mmol (1.37g, 3eq) lithium aluminium hydride, under condition of ice bath,
By several times be added in reaction solution, react at room temperature 15 minutes, with TLC detect without intermediate 4 when, reaction finishes, under condition of ice bath to
Frozen water 50mL is added dropwise in reaction solution, removes tetrahydrofuran under reduced pressure, pH to 1 is adjusted with 1mol/L HCl, when solution is no longer colloid, uses
Ethyl acetate (50mL × 3) is extracted, and merges organic phase, and organic phase is washed with saturated sodium-chloride, is dried, and filtering, decompression has steamed
Solvent, obtain white solid.
Intermediate therefor compound 4 is the methyl isophthalic acid H- pyrazole-5-ethyl formates of 3- (4- fluorophenyls) -1, accordingly, gained
3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methanol, it is specific as follows；
3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methanol (14)：White solid, yield：100%；Mp:112-
114℃；1H-NMR(600MHz,DMSO-d6)δ(ppm):7.783(dd,J1=8.4Hz, J2=5.4Hz, 2H), 7.203 (t, J
=9.0Hz, 2H), 6.597 (s, 1H), 5.323 (t, J=5.4Hz, 1H), 4.518 (d, J=5.4Hz, 2H), 3.824 (s,
3H)。
The preparation of the midbody compound 15 of embodiment 2
0.8mmol midbody compounds 14 are weighed in 50mL eggplant-shape bottles, is dissolved, is slowly dropped into 10mL dichloromethane
1.6mmol thionyl chlorides, react at room temperature 1 hour, when TLC detections are without midbody compound 14, reaction finishes, and decompression steams dichloro
Methane and thionyl chloride obtain faint yellow solid.
Intermediate therefor compound 14 is 3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methanol, accordingly, gained
Midbody compound is 5- chloromethyls -3- (4- fluorophenyls) -1- methyl isophthalic acid H- pyrazoles, specific as follows；
5- chloromethyls -3- (4- fluorophenyls) -1- methyl isophthalic acid H- pyrazoles (15)；Faint yellow solid, yield：100%；Mp:
124-126℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.799 (t, J=7.2Hz, 2H), 7.227 (t, J=7.2Hz,
2H),6.800(s,1H),4.953(s,2H),3.891(s,3H)。
The preparation of the target compound 16 of embodiment 3
0.8mmol (1eq) substituted anilines are weighed in 50mL eggplant-shape bottles, with 12mL acetone solutions, add 4mmol
(553mg, 5eq) Anhydrous potassium carbonate and 0.08mmol (13mg, 0.1eq) KI, by 0.8mmol (179mg, 1eq) intermediate
Compound 15 is added thereto, and is stirred at room temperature 8 hours, when TLC reactions finish, is stopped reaction, is removed acetone, solid 50mL under reduced pressure
Water and the dissolving of 50mL ethyl acetate, divide and go aqueous phase, and organic phase is washed with saturated sodium-chloride (30mL × 1), is dried, and filtering, takes filter
Liquid, removes the organic solvent in filtrate under reduced pressure, and gained solid obtains target compound 16 with silica gel column chromatography separating purification.It is described to wash
Lift-off system is petroleum ether：Ethyl acetate=10：1；
Substituted aniline used is 3- bromanilines, 3- 5-trifluoromethylanilines, 4- amino phthalonitrile, 3- aminobenzonitriles, 4-
The chloro- 3- trifluoromethylbenzenes of fluoroaniline, 3- chloroanilines, 4- chloroanilines, 4- aminobenzonitriles, 4- bromanilines, 4- 5-trifluoromethylanilines, 4-
The bromo- 4- fluoroanilines of amine, 3-, the chloro- 2- fluoroanilines of 3-, the bromo- 2-aminotoluenes of 3-, the chloro- 4- fluoroanilines of 3-；Intermediate therefor compound
15 be 5- chloromethyls -3- (4- fluorophenyls) -1- methyl isophthalic acid H- pyrazoles, after the combination of different material, has synthesized to obtain following 15
Individual target compound：
N- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -3- bromanilines (16aM01)；White solid,
Yield：40%；Mp:85-87℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.759(dd,J1=8.8Hz, J2=
5.6Hz, 2H), 7.196 (t, J=8.8Hz, 2H), 7.030 (t, J=8.0Hz, 1H), 6.844 (t, J=1.6Hz, 1H),
6.703(dd,J1=7.6Hz, J2=1.2Hz, 1H), 6.669 (dd, J1=8.4Hz, J2=2.0Hz, 1H), 6.621 (s, 1H),
6.447 (t, J=5.6Hz, 1H), 4.324 (d, J=5.6Hz, 2H), 3.839 (s, 3H).
N- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -3- 5-trifluoromethylanilines (16aM02)；In vain
Color solid, yield：34%；Mp:85-87℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.755(dd,J1=8.4Hz, J2
=5.6Hz, 2H), 7.299 (t, J=8.0Hz, 1H), 7.193 (t, J=8.8Hz, 2H), 6.959 (s, 1H), 6.938 (d, J=
8.8Hz, 1H), 6.858 (d, J=7.6Hz, 1H), 6.636 (m, 2H), 4.385 (s, 2H), 3.852 (s, 3H).
4- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) phthalonitrile (16aM04)；In vain
Color solid, yield：17%；Mp:224-226℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.786~7.712 (m, 4H),
7.262 (d, J=2.4Hz, 1H), 7.203 (t, J=8.8Hz, 2H), 7.042 (dd, J1=8.8Hz, J2=2.4Hz, 1H),
6.646 (s, 1H), 4.500 (d, J=5.6Hz, 2H), 3.843 (s, 3H).
3- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) cyanophenyl (16aM05)；White solid,
Yield：80%；Mp:129-131℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.759(dd,J1=8.4Hz, J2=
5.6Hz, 2H), 7.275 (d, J=8.0Hz, 1H), 7.193 (t, J=8.8Hz, 2H), 7.016 (s, 1H), 7.005 (d, J=
8.8Hz, 1H), 6.964 (d, J=7.2Hz, 1H), 6.662 (t, J=7.6Hz, 1H), 6.628 (s, 1H), 4.374 (d, J=
7.6Hz,2H),3.845(s,3H)。
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of -4- (16aM06)；White solid,
Yield：50%；Mp:115-117℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.759(dd,J1=8.8Hz, J2=
5.6Hz, 2H), 7.199 (t, J=8.8Hz, 2H), 6.939 (t, J=8.8Hz, 2H), 6.671 (dd, J1=8.8Hz, J2=
4.8Hz, 2H), 6.626 (s, 1H), 6.056 (t, J=6.0Hz, 1H), 4.286 (d, J=6.0Hz, 2H), 3.848 (s, 3H).
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- aniline of -3- (16aM07)；White solid,
Yield：63%；Mp:77-79℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.759(dd,J1=8.4Hz, J2=
7.2Hz, 2H), 7.201 (t, J=8.8Hz, 2H), 7.095 (t, J=8.0Hz, 1H), 6.703 (t, J=2.0Hz, 1H),
6.648 (d, J=1.6Hz, 1H), 6.629 (s, 1H), 6.578 (dd, J1=8.0Hz, J2=1.2Hz, 1H), 6.467 (t, J=
5.6Hz, 1H), 4.326 (d, J=5.6Hz, 2H), 3.846 (s, 3H).
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- aniline of -4- (16aM08)；White solid,
Yield：47%；Mp:106-108℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.758(dd,J1=8.8Hz, J2=
5.6Hz, 2H), 7.197 (t, J=8.8Hz, 2H), 7.114 (d, J=8.8Hz, 2H), 6.684 (d, J=8.8Hz, 2H),
6.618 (s, 1H), 6.344 (t, J=5.6Hz, 1H), 4.310 (d, J=6.0Hz, 2H), 3.843 (s, 3H).
4- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) cyanophenyl (16aM09)；White solid,
Yield：69%；Mp:194-196℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.763(dd,J1=9.2Hz, J2=
5.6Hz, 2H), 7.491 (d, J=8.8Hz, 2H), 7.199 (t, J=9.2Hz, 2H), 6.763 (d, J=8.8Hz, 2H),
6.636 (s, 1H), 4.420 (d, J=6.0Hz, 1H), 3.846 (s, 3H).
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) bromo- aniline of -4- (16aM10)；White solid,
Yield：63%；Mp:117-119℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.751(dd,J1=8.8Hz, J2=
5.6Hz, 2H), 7.208 (t, J=8.8Hz, 2H), 7.190 (d, J=8.8Hz, 2H), 6.454 (d, J=8.8Hz, 2H),
6.607 (s, 1H), 6.361 (t, J=5.6Hz, 1H), 4.301 (d, J=6.0Hz, 2H), 3.835 (s, 3H).
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -4- 5-trifluoromethylanilines (16aM11)；White
Solid, yield：29%；Mp:109-111℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.759(dd,J1=9.2Hz, J2
=5.6Hz, 2H), 7.399 (d, J=8.8Hz, 2H), 7.191 (t, J=9.2Hz, 2H), 6.893 (s, 1H), 6.785 (d, J=
8.8Hz,2H),6.634(s,1H),4.393(s,2H),3.849(s,3H)。
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- 3- 5-trifluoromethylanilines of -4-
(16aM12)；White solid, yield：8%；Mp:124-126℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.758
(dd,J1=8.8Hz, J2=5.6Hz, 2H), 7.372 (d, J=8.8Hz, 1H), 7.196 (t, J=8.8Hz, 2H), 7.096 (d,
J=2.8Hz, 1H), 6.911 (dd, J1=8.8Hz, J2=2.8Hz, 1H), 6.814 (t, J=5.2Hz, 1H), 6.629 (s,
1H), 4.393 (d, J=5.2Hz, 2H), 3.844 (s, 3H).
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the bromo- 4- of -3- (16aM13)；White
Solid, yield：14%；Mp:101-103℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.757(dd,J1=8.8Hz, J2
=5.6Hz, 2H), 7.195 (t, J=8.8Hz, 2H), 7.012 (t, J=8.8Hz, 1H), 6.922 (dd, J1=5.6Hz, J2=
2.8Hz, 1H), 6.932~6.911 (m, 1H), 6.616 (s, 1H), 6.300 (t, J=5.6Hz, 1H), 4.307 (d, J=
6.0Hz,2H),3.836(s,3H)。
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the chloro- 2- of -3- (16aM14)；White
Solid, yield：34%；Mp:87-89℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.749(dd,J1=8.8Hz, J2=
5.6Hz, 2H), 7.178 (t, J=8.8Hz, 2H), 6.950 (td, J1=8.0, J2=1.6Hz, 1H), 7.758 (td, J1=
8.0Hz,J2=1.2Hz, 1H), 6.688 (td, J1=8.0Hz, J2=1.2Hz, 1H), 6.599 (s, 1H), 6.453 (td, J1=
6.0Hz,J2=1.2Hz, 1H), 4.416 (d, J=6.0Hz, 2H), 3.858 (s, 3H).
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) bromo- 2-aminotoluenes of -3- (16aM15)；In vain
Color solid, yield：68%；Mp:108-110；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.751(dd,J1=8.4Hz, J2
=5.6Hz, 2H), 7.179 (t, J=8.8Hz, 2H), 6.903 (t, J=8.0Hz, 1H), 6.825 (d, J=8.0Hz, 1H),
6.606 (d, J=8.0Hz, 1H), 5.874 (t, J=4.8Hz, 1H), 4.393 (d, J=4.8Hz, 1H), 3.867 (s, 2H),
2.264(s,3H)。
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the chloro- 4- of -3- (16aM16)；White
Solid, yield：56%；Mp:121-123℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):7.759(dd,J1=8.4Hz, J2
=5.6Hz, 2H), 7.198 (t, J=8.8Hz, 2H), 7.134 (t, J=9.2Hz, 1H), 6.791 (dd, J1=6.0Hz, J2=
2.4Hz, 1H), 6.661~6.623 (m, 2H), 6.337 (t, J=5.2Hz, 1H), 4.309 (d, J=5.6Hz, 2H), 3.837
(s,3H)。
The preparation of the midbody compound 9 of embodiment 4
4.55mmol (1eq) midbody compound 5 is weighed, is dissolved with 15mL dioxane and 15mL absolutes ethanol,
Addition 5.92mmol (1.63g, 1.3eq) diphenyl phosphate azide, 5.92mmol (1.3eq) triethylamine, back flow reaction 7 hours,
When TLC detections are without midbody compound 5, stop reaction, remove organic solvent under reduced pressure, dark brown liquid is now obtained, with 40mL second
Citric acid (30mL × 3), saturated sodium bicarbonate (30mL × 3) and the saturation chlorine of mass concentration 5% are used after acetoacetic ester dilution respectively
Change sodium (30mL × 1) washing, dry, filtering, take filtrate, remove organic solvent under reduced pressure, gained solid is separated with silica gel column chromatography
Purify to obtain white solid.The eluent system is n-hexane：Ethyl acetate=3：1；
Intermediate therefor compound 5 is 3- (4- fluorophenyls) -1- methyl isophthalic acid H- pyrazoles -5- formic acid, accordingly, among gained
Body compound is (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) urethanes；It is specific as follows；
(3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) urethanes；White solid, yield：75%；Mp:
124-126℃；1H-NMR(600MHz,DMSO-d6)δ(ppm):9.678(s,1H),7.774(dd,J1=8.4Hz, J2=
6.0Hz, 2H), 7.206 (t, J=9.0Hz, 2H), 6.549 (s, 1H), 4.154 (q, J=7.2Hz, 2H), 1.254 (t, J=
7.2Hz,3H)。
The preparation of the midbody compound 10 of embodiment 5
4.9mmol (1eq) midbody compound 9 is weighed, is dissolved with 30mL ethanol, adds the hydroxide of mass concentration 10%
Sodium solution dissolves 30mL, back flow reaction 5 hours, when TLC detections are without midbody compound 9, reaction solution is cooled into room temperature, depressurized
Ethanol is evaporated off, adds distilled water, separates out white solid, filtering, gained white solid is midbody compound 10.
Intermediate therefor compound 9 is (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) urethanes, gained
Midbody compound is (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) amine；It is specific as follows；
(3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) amine；White solid, yield：80%；Mp：129-131℃；1H-NMR(600MHz,DMSO-d6)δ(ppm):7.673(dd,J1=8.4Hz, J2=6.0Hz, 2H), 7.148 (t, J=
9.0Hz,2H),5.563(s,1H),5.273(s,2H),3.553(s,3H)。
The preparation of the target compound 11 of embodiment 6
0.5mmol (1eq) midbody compound 10 is weighed, is dissolved with 10mL dichloromethane, weighs 0.5mmol (1eq) virtues
Base substitutes isothiocyanates, is dissolved with 5mL dichloromethane, be slowly dropped under ice bath midbody compound 10 dichloromethane it is molten
In liquid, drop finishes, and reacts at room temperature 7 hours, separates out white solid, filtering, solid is washed with dichloromethane, dry that white solid is
For target compound 11.
Aryl substitution isothiocyanates used is 4- (isothiocyanate group) -3- (trifluoromethyl) cyanophenyl, 1- (isothiocyanic acids
Ester group) -3- trifluoromethylbenzenes, 4- (isothiocyanate group) phthalonitrile, 3- (isothiocyanate group) bromobenzene；Intermediate therefor
Compound 10 is (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) amine, after the combination of different material, synthesized to obtain with
Lower 4 target compounds：
1- (4- cyano group -3- (trifluoromethyl) phenyl -) 3- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) thiocarbamide
(11aM01)；White solid, yield：76%；Mp:120-122℃；1H-NMR(600MHz,DMSO-d6)δ(ppm):10.757
(s,1H),10.143(s,1H),8.381(s,1H),8.122(s,2H),7.824(dd,J1=9.0Hz, J2=5.4Hz, 2H),
7.229 (t, J=9.0Hz, 2H), 6.732 (s, 1H), 3.730 (s, 3H).
1- (3- trifluoromethyls) -3- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) thiocarbamide (11aM02)；In vain
Color solid, yield：23%, Mp:160-162℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.294(s,1H),9.808
(s, 1H), 7.985 (s, 1H), 7.842~7.8.6 (m, 3H), 7.591 (t, J=8.0Hz, 1H), 7.511 (d, J=8.0Hz,
1H), 7.254~7.200 (m, 2H), 6.707 (s, 1H), 3.732 (s, 3H).
1- (3,4- dicyanos phenyl) -3- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) thiocarbamide (11aM03)；In vain
Color solid, yield：98%, Mp:116-118℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.739(s,1H),10.151
(s, 1H), 8.414 (s, 1H), 8.091 (d, J=0.8Hz, 2H), 7.821 (dd, J1=8.8Hz, J2=5.6Hz, 2H), 7.229
(t, J=8.8Hz, 2H), 6.720 (s, 1H), 3.730 (s, 3H).
1- (3- bromophenyls) -3- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) thiocarbamide (11aM04)；White is solid
Body, yield：36%, Mp:151-153℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.193(s,1H),9.710(s,
1H),7.985(s,1H),7.845(s,1H),7.816(dd,J1=8.8Hz, J2=5.6Hz, 2H), 7.486 (d, J=8.0Hz,
1H), 7.360 (d, J=8.0Hz, 1H), 7.315 (t, J=8.0Hz, 1H), 7.221 (t, J=8.8Hz, 2H), 6.680 (s,
1H),3.716(s,3H)。
The preparation of the target compound 12 of embodiment 7
The preparation of target compound 12：1mmol (1eq) substituted benzoyl chloride is weighed, is placed in the dissolving of 20mL tetrahydrofurans
In constant pressure funnel.Weigh 0.8mmol (0.8eq) midbody compound 10, with 15mL tetrahydrofurans dissolve, add 1mL without
Water pyridine, the substituted benzene formyl solutions of chlorine in constant pressure funnel is slowly dropped into the tetrahydrofuran of midbody compound under ice bath
In solution, drop finishes, and removes ice bath, reacts at room temperature 2 hours, when TLC detections are without midbody compound 10, stops reaction, decompression is steamed
Except organic solvent, the residue dissolving of 40mL ethyl acetate and 30mL saturated sodium bicarbonate solutions, divide and remove aqueous phase, organic phase water
(30mL × 3) and saturated sodium-chloride (30mL × 1) wash, and dry, and filtering, take filtrate, remove the organic solvent in filtrate under reduced pressure,
It is target compound 12 that remaining solid obtains white solid with silica gel column chromatography separating purification, and the eluent system is petroleum ether：
Ethyl acetate=6：1；
Aryl substitution substituted benzoic acid used is 3- bromobenzoic acids, 3- trifluoromethylbenzoic acids；Intermediate therefor compound
10 be (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) amine, after the combination of different material, has synthesized to obtain following 2
Target compound：
N- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) bromo- benzamides of -3- (12aM01)；White solid, production
Rate：54%, Mp:156-158℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.545 (s, 1H), 8.185 (t, J=
1.6Hz, 1H), 7.994 (d, J=8.0Hz, 1H), 7.966~7.806 (m, 3H), 7.539 (t, J=8.0Hz, 1H), 7.230
(t, J=8.8Hz, 2H), 6.720 (s, 1H), 3.758 (s, 3H).
N- (3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls)-(3- trifluoromethyls) benzamide (12aM02)；White
Solid, yield：45%, Mp:173-175℃；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.694(s,1H),8.341(s,
1H), 8.305 (d, J=7.6Hz, 1H), 8.027 (d, J=7.6Hz, 1H), 7.848~7.813 (m, 3H), 7.236 (t, J=
8.8Hz,2H),6.740(s,1H),3.768(s,3H)。
The preparation of the target compound 13 of embodiment 8
0.69mmol (1eq) midbody compound 10 is weighed, is dissolved with 15mL DMF, adds 1.265mmol (1.1eq)
60% sodium hydride, stirring weigh 0.76mmol (1.1eq) substitution benzyl bromines, dissolved with 5mL DMF, room to there is no gas generation
Temperature is lower to be instilled in the DMF solution of midbody compound 10, is reacted at room temperature 16 hours, when TLC detects unsubstituted benzyl bromine, is stopped anti-
Should, reaction solution is poured into 70mL frozen water, separates out white solid, frozen water is extracted three times with ethyl acetate (30mL × 3), is associated with
Machine phase, organic phase are washed with saturated sodium-chloride (30mL × 1), are dried, and filtering, are taken filtrate, are removed under reduced pressure organic molten in filtrate
Agent, silica gel column chromatography separating purification obtain faint yellow solid, as target compound 13, and the eluent system is n-hexane：Acetic acid
Ethyl ester=3：1.
Aryl substitution benzyl bromine used is 3- bromobenzyl bromines；Intermediate therefor compound 10 for (3- (4- fluorophenyls) -1- methyl -
1H-5- pyrazolyls) amine, gained target compound 13 is N- ((3- bromobenzyls) -3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazoles
Base) amine (13aM01)；It is specific as follows；
N- ((3- bromobenzyls) -3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) amine (13aM01)；White solid, production
Rate：27%, Mp:117-119℃；1H-NMR(600MHz,DMSO-d6)δ(ppm):7.661(dd,J1=8.4Hz, J2=
5.4Hz, 2H), 7.617 (s, 1H), 7.432 (t, J=8.4Hz, 2H), 7.305 (t, J=7.8Hz, 1H), 7.145 (t, J=
8.4Hz 2H), 6.261 (t, J=6.0Hz, 1H), 5.730 (s, 1H), 4.261 (d, J=6.0Hz, 2H), 3.621 (s, 3H).
Although the above-mentioned embodiment to the present invention is described, not to the limit of the scope of the present invention
System, one of ordinary skill in the art should be understood that on the basis of technical scheme those skilled in the art need not pay
Go out various modifications or deformation that creative work can make still within protection scope of the present invention.
Claims (6)
1. diaryl pyrazole azole compound, it is characterised in that its structure is as shown in logical formula (I)：
Wherein, R1 is hydrogen, halogen or methyl；R2 is hydrogen, cyano group, trifluoromethyl or halogen；R3 is hydrogen, halogen or itrile group；X is first
Amido or aminomethyl, structural formula are as implied above.
2. diaryl pyrazole azole compound according to claim 1, it is characterised in that：For one of following compounds：
N- ((3- bromobenzyls) -3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) amine (13aM01)；
N- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -3- bromanilines (16aM01)；
N- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -3- 5-trifluoromethylanilines (16aM02)；
4- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) phthalonitrile (16aM04)；
3- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) cyanophenyl (16aM05)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of -4- (16aM06)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- aniline of -3- (16aM07)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- aniline of -4- (16aM08)；
4- (((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) amino) cyanophenyl (16aM09)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) bromo- aniline of -4- (16aM10)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) -4- 5-trifluoromethylanilines (16aM11)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) chloro- 3- 5-trifluoromethylanilines (16aM12) of -4-；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the bromo- 4- of -3- (16aM13)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the chloro- 2- of -3- (16aM14)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) bromo- 2-aminotoluenes of -3- (16aM15)；
N- ((3- (4- fluorophenyls) -1- methyl isophthalic acid H-5- pyrazolyls) methyl) fluoro- aniline of the chloro- 4- of -3- (16aM16)；
It is its corresponding code name in bracket after compound name.
3. the preparation method of the diaryl pyrazole azole compound described in claim 1 or 2, it is characterised in that：Synthetic route is as follows
It is shown：
Comprise the following steps that：
(i) 3- (4- fluorophenyls) -1- methyl isophthalic acid H- pyrazole-5-ethyl formates, i.e. midbody compound 4 are weighed, uses tetrahydrofuran
Dissolving；Weigh lithium aluminium hydride reduction, under condition of ice bath, be added to by several times in the tetrahydrofuran solution of intermediate 4, react at room temperature 15 points
Clock, when being detected with TLC without midbody compound 4, reaction finishes, and frozen water is added dropwise under condition of ice bath into reaction solution, now, decompression
Tetrahydrofuran is steamed, adjusts pH to 1, when solution is no longer colloid, is extracted with ethyl acetate three times, merges organic phase, organic phase is used
Saturated sodium-chloride washs, and dries, and filtering, takes filtrate, removes the organic solvent in filtrate under reduced pressure, obtain white solid, is middle
Body compound 14, the mol ratio of the midbody compound 4 and lithium aluminium hydride reduction is 1：1~3, the lithium aluminium hydride reduction, tetrahydrofuran,
The mass ratio of frozen water is 1：20~30：30~50；
(ii) to the dichloromethane solution of midbody compound 14, thionyl chloride is slowly dropped into, is reacted 1 hour at 20-25 DEG C,
When TLC detections are without midbody compound 14, reaction finishes, and decompression steams dichloromethane and thionyl chloride obtains faint yellow solid, then
With petroleum ether and re-crystallizing in ethyl acetate, midbody compound 15, the mol ratio of midbody compound 14 and thionyl chloride are produced
For 1：1~5, the mass ratio of thionyl chloride and dichloromethane is 1：70~90；
(iii) substituted aniline is weighed, with acetone solution, add Anhydrous potassium carbonate and KI, and will be prepared in step ii
Intermediate compounds therefor 15 is added thereto, and is stirred at room temperature 8 hours, when TLC reactions finish, stops reaction, removes acetone under reduced pressure, and solid is used
Water and ethyl acetate dissolving, divide and go aqueous phase, and organic phase is washed with saturated sodium-chloride, is dried, and filtering, is taken filtrate, is removed filter under reduced pressure
Organic solvent in liquid, target compound 16 is obtained with silica gel column chromatography separating purification；The eluent system is petroleum ether：Acetic acid second
Ester=10：1, the substituted aniline, midbody compound 15, the mol ratio 1 of Anhydrous potassium carbonate and KI：0.8~2：0.8~
5：0.1~1, the mass ratio of the acetone, water and ethyl acetate is 1：4~6：4~6；
(iv) midbody compound 5 is weighed, is dissolved with dioxane and absolute ethanol, addition diphenyl phosphate azide, three
Ethamine, back flow reaction 7 hours, when TLC detections are without midbody compound 5, stop reaction, remove organic solvent under reduced pressure, obtain dark brown
Color liquid, washed respectively with the citric acid of mass concentration 5%, saturated sodium bicarbonate and saturated sodium-chloride after being diluted with ethyl acetate,
Dry, filtering, take filtrate, remove the organic solvent in filtrate under reduced pressure, obtaining white solid with silica gel column chromatography separating purification is
Midbody compound 9；The eluent system is n-hexane：Ethyl acetate=3：1, the midbody compound 5, nitrine di(2-ethylhexyl)phosphate
The mol ratio of phenyl ester and triethylamine is 1：1~3：1~6, the volume ratio of the absolute ethanol and dioxane is 1：0.8~
3；
(v) midbody compound 9 is weighed, is dissolved with ethanol, adds the dissolving of the sodium hydroxide solution of mass concentration 10%, back flow reaction
5 hours, when TLC detections are without midbody compound 9, reaction solution is cooled to room temperature, removes ethanol under reduced pressure, add distilled water, analysis
Go out white solid, filter, gained white solid is midbody compound 10, the midbody compound 9, ethanol, and quality is dense
The mass ratio spent for 10% sodium hydroxide and distilled water is 1：20~30：10~30：30~50；
(vi) midbody compound 10 is weighed, is dissolved with DMF, adds sodium hydride, stirring weighs substitution to there is no gas generation
Benzyl bromine, is dissolved with DMF, is instilled at room temperature in the DMF solution of midbody compound 10, is reacted at room temperature 16 hours, and TLC detection nothings take
During for benzyl bromine, stop reaction, reaction solution is poured into frozen water, separate out white solid, be extracted with ethyl acetate three times, merge organic
Phase, organic phase are washed with saturated sodium-chloride, are dried, and filtering, are taken filtrate, are removed the organic solvent in filtrate, silica gel column layer under reduced pressure
Analysis isolates and purifies to obtain faint yellow solid, as target compound 13, and the eluent system is n-hexane：Ethyl acetate=3：1, institute
The mol ratio for stating midbody compound, sodium hydride and substitution benzyl bromine is 1：1~5：0.8~2.
4. preparation method according to claim 3, it is characterised in that：In the step (iii), the substituted aniline is 3-
Bromaniline, 3- 5-trifluoromethylanilines, 4- amino phthalonitrile, 3- aminobenzonitriles, 4- fluoroanilines, 3- chloroanilines, 4- chloroanilines,
The chloro- 3- 5-trifluoromethylanilines of 4- aminobenzonitriles, 4- bromanilines, 4- 5-trifluoromethylanilines, 4-, the bromo- 4- fluoroanilines of 3-, the chloro- 2- of 3-
The bromo- 2-aminotoluene of fluoroaniline, 3- or the chloro- 4- fluoroanilines of 3-.
5. preparation method according to claim 3, it is characterised in that：
In the step (vi), the substitution benzyl bromine is 3- bromobenzyl bromines.
6. application of the diaryl pyrazole azole compound in the medicine of anti-prostate cancer is prepared described in claim 1 or 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510264306.2A CN104844514B (en) | 2015-05-21 | 2015-05-21 | Diaryl pyrazole azole compound and preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510264306.2A CN104844514B (en) | 2015-05-21 | 2015-05-21 | Diaryl pyrazole azole compound and preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104844514A CN104844514A (en) | 2015-08-19 |
| CN104844514B true CN104844514B (en) | 2017-11-10 |
Family
ID=53844552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510264306.2A Active CN104844514B (en) | 2015-05-21 | 2015-05-21 | Diaryl pyrazole azole compound and preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104844514B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107903213A (en) * | 2017-09-28 | 2018-04-13 | 山东大学 | 5 methyl 1H pyrazole derivatives and its preparation method and application |
| CN107935928B (en) * | 2017-12-06 | 2021-05-25 | 鲁东大学 | Total diphenylpyrazole and preparation method and application thereof |
| CN108727386A (en) * | 2018-07-16 | 2018-11-02 | 广州医科大学 | A kind of Pyrazolopyrimidines and its preparation method and application |
| CN114409898B (en) * | 2022-01-25 | 2023-09-29 | 浙江工业大学 | Amino-modified covalent triazinyl skeleton and preparation method and application thereof |
| CN114685371A (en) * | 2022-03-08 | 2022-07-01 | 四川大学 | Pyrazole carboxamide derivatives, their preparation and use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008060771A2 (en) * | 2006-10-02 | 2008-05-22 | National Health Research Institutes | Pyrazole compounds |
| CN103435553A (en) * | 2013-09-16 | 2013-12-11 | 中国药科大学 | Piperazine structure-based aryl formamide Raf kinase inhibitor and preparation method as well as application thereof |
| CN104592116A (en) * | 2014-11-28 | 2015-05-06 | 山东大学 | 1,3,5-trisubstituted pyrazole compounds, and preparation method and application thereof |
-
2015
- 2015-05-21 CN CN201510264306.2A patent/CN104844514B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008060771A2 (en) * | 2006-10-02 | 2008-05-22 | National Health Research Institutes | Pyrazole compounds |
| CN103435553A (en) * | 2013-09-16 | 2013-12-11 | 中国药科大学 | Piperazine structure-based aryl formamide Raf kinase inhibitor and preparation method as well as application thereof |
| CN104592116A (en) * | 2014-11-28 | 2015-05-06 | 山东大学 | 1,3,5-trisubstituted pyrazole compounds, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104844514A (en) | 2015-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104844514B (en) | Diaryl pyrazole azole compound and preparation method and application | |
| CN104968662B (en) | Azoles benzene derivative | |
| WO1995024410A1 (en) | Phosphonic diester derivative | |
| BRPI0517515B1 (en) | indoline compound, as well as methods for producing indoline compounds | |
| HUT59660A (en) | Process for producing biphenilyl derivatives and pharmaceutical compositions containing them as active components | |
| EP2907811A1 (en) | Process for manufacturing pyrimidine sulfamide derivatives | |
| CN106866528A (en) | A kind of method for preparing 4 amino quinoline derivatives | |
| US20150344506A1 (en) | Novel phosphinine oxide derivative and preparation method thereof | |
| JP2010505836A (en) | Thrombin receptor antagonists based on a modified tricyclic unit of himbacin | |
| CN105849106B (en) | Key intermediate and impurity in Eliquis synthesis：Eliquis diol ester | |
| Mansour et al. | Inversion kinetics of some E/Z 3-(benzylidene)-2-oxo-indoline derivatives and their in silico CDK2 docking studies | |
| CN103059010B (en) | Isosorbide-5-Nitrae-benzoxazinone-1,2,3-triazole compound with anti-mycotic activity and preparation method thereof | |
| CN103864772A (en) | Preparation method for rivaroxaban and intermediate thereof | |
| CN110041282A (en) | Related substance of Parecoxib Sodium and its preparation method and application | |
| CN102659629B (en) | Compound and application thereof in preparing erlotinib | |
| CN113416162B (en) | Double-chiral binaphthyl O-N-N tridentate ligand and preparation method thereof | |
| CN100522965C (en) | 8-arylamine-3H-imidazole [4,5-g] quinazoline derivatives and its solid phase synthesis method | |
| TWI687418B (en) | Crystallization of oxazole derivatives | |
| Sukalovic et al. | Interactions of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas with dopamine D2 and 5-hydroxytryptamine 5HT1A receptors | |
| CN107353266B (en) | A kind of preparation method that olefin(e) acid bromine lactonizes | |
| CN104974095B (en) | 2,4,5 polysubstituted glyoxaline compounds and preparation method | |
| Han et al. | Synthesis of highly substituted 2-imidazolines through a three-component coupling reaction | |
| CN104926807A (en) | Rivaroxaban related substance 'diamine' and synthesis method thereof | |
| CN110511208A (en) | Two nitrine indoline-like compound of N-2- pyridyl group -2,3- and its preparation and application | |
| CN105085431B (en) | 4 (4 first ammonia thiazolinyl phenyl) 3 morpholones and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |