CN1597662A - A kind of aromatic acid amide compound its preparation method and use - Google Patents
A kind of aromatic acid amide compound its preparation method and use Download PDFInfo
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Abstract
An arylamide kind of compounds with high anti-androgen activity for treating the diseases associated with androgen, such as prostatic cancer, prostatoplasia, acne, alopesia, etc, and their preparing process are disclosed.
Description
Technical field
The present invention relates to a class aromatic amine amide compound, this compounds has the androgen antagonist effect, can be used for the treatment of male sex hormone diseases associated such as prostate cancer, hyperplasia of prostate, acne, alopecia, hirsutism.
Background technology
Numerous disease is relevant with the male hormone level in elderly men.The male sex with advancing age, androgenic level can descend gradually in the health, is accompanied by that muscle reduces phenomenons such as sexual disorder in the body.On the contrary, the male sex hormone level is too high in the body also can bring some other disease, is exactly androgen-dependent disorders as hyperplasia of prostate and prostate cancer.Also have some other disease relevant with the male sex hormone level, contain androgen receptor in the human body skin hair follicle, these acceptors of some people are comparatively responsive to male sex hormone, cause alopecia; Androgen receptor is comparatively responsive in young adult's skin, causes the growth of acne.
Utilize androgen antagonist can treat the above-mentioned disease relevant with male sex hormone.The selectivity androgen antagonist is the research direction in this field, and having optionally to the androgen receptor of human body Different Organs, androgen antagonist is the target of this class medicinal design.Adopt the androgen antagonist treatment necessary often to above-mentioned disease.For example, since the century, operation is the main means of treatment prostatosis always, though curative effect better, mortality ratio is not high, but still brings in various degree infringement to the patient.For example thinking in the past that prostate gland secretion prostatic fluid participated in the composition of seminal fluid, and the atrophy of the elderly's sexual gland is excised harmless.But studies show that in recent years: prostate gland participates in the composition of seminal fluid except the secretion prostatic fluid; can also produce the panimmunity sphaeroprotein; synthetic contain anti-microbial effect contain the zinc polypeptide, and prostate gland also has the immunization barrier function that the protection reproductive system exempts from bacterium and pathogenic micro-organism invasion and attack.Usually treatment of prostate cancer is based on the excision operation on testis, but clinical study shows, simple excision testis, can reduce androgenic content in the blood, but can not reduce androgenic content in the prostata tissue significantly, this is can utilize the enzyme system of the steroidal of acth secretion for the raw material synthetic androgen because prostata tissue exists.Therefore, even taked the castration therapy, pharmacological agent also is very necessary for the prostate cancer anti-androgens.
A lot of medicines have the androgen antagonist effect, comprising steroidal class androgen antagonist medicine, and nonsteroidal androgen antagonist medicine and some natural plant extracts, the summary of this respect is extremely many, no longer discusses at this.
Nonsteroidal androgen antagonist medicine mostly is the aromatic amides compounds.
First-generation non-steroidal anti-androgens medicine commonly used clinically at present is mainly flutamide etc.Flutamide has another name called Drogenil, Sch-13521.Be a kind of non-steroid androgen antagonist, main influence relies on androgenic male sex's sexual accessory gland-----seminal vesicle and prostate gland.Being used for the treatment of prostate cancer clinically, having the androgen antagonist activity, is the non-steroidal antiandrogen of a brute force.In experimentation on animals, flutamide is specific to the effect of the gonophore that male sex hormone relies on.But dose is bigger, takes for a long time and can cause gynecomasty, with tumour and tenderness, and has nausea,vomiting,diarrhea, idol skin reaction can occur, the denatured hemoglobin anaemia, and white corpuscle and thrombocyte reduce.Have 30% patient transaminase and bilirubinic rising to occur approximately, a few patients has liver toxicity.In experimentation on animals, find, after rat is oral in a large number for a long time, can cause leydig cell tumor of testis.After the people took this product, as seen sperm number reduced in the seminal fluid.
Drogenil
Bicalutamide (bicalutamide) is a s-generation non-steroidal anti-androgens medicine.This medicine is a racemization isomer, and its activeconstituents is a levoisomer.This medicine nineteen ninety-five at first goes on the market in Britain, and curative effect is higher than flutamide, and side effect has reduced 70%.This product now and LHRH and with the treatment that is applied to advanced prostate cancer.Aspect treatment, bicalutamide has the androgen antagonist activity equally, the double blind random clinical study of doing with 813 patients that suffer from advanced prostate cancer shows, the analogue that this product of 50mg/ days adds LHRH can well be tolerated, and effect is strong and flutamide (250mg 3 times/day) adds the LHRH analogue, and it can reduce by 70% side effect simultaneously.This medicine is gone on the market in Britain with login name Casodex by Zeneca, with the coupling of LHRH analogue or with castrating operation coupling, the prostate cancer in treatment late period, recommended dose is 50mg.Recently, the bicalutamide of 150mg dosage gets permission to be used for the early prostate cancer patient, and it is identical that its effect and testis are cut place's art effect.Shown great application prospect.
Bicalutamide R-bicalutamide
Therefore aromatic amides has critical role in the research of androgen antagonist medicine.
Summary of the invention
The present invention seeks to seek a class and have the high aromatic amides compounds that contain amido replacement higher than existing pharmaceutical activity with the androgen receptor binding ability, can be used as and be used for the treatment of the disease relevant with male sex hormone, especially male prostate class disease is as prostate cancer and hyperplasia of prostate.
Another purpose of the present invention is the synthetic method that discloses this compounds.
Still a further object of the present invention provides the medical usage of this compounds.
Relate to compound with following general structure:
R1 wherein, R2 is CN, NO2, CF
3Deng electron-withdrawing group.
R3 wherein, R4 is a hydrogen atom, alkyl contains various substituent alkyl, aromatic base, and contain multiple substituent aromatic base.Comprise halogen, NO
2, CN, CF
3,
In above-mentioned molecule, a chiral atom is arranged on 2 of amidocarbonylation, its steric configuration can be raceme in the present invention, left-handed (R configuration) and dextrorotation (S configuration).
Compound involved in the present invention is synthetic by following route:
Aromatic amine compound with structural formula I can be by literature method (J.Med.Chem., 1988,31,954-959) and the alpha-acrylic acyl chloride reaction generate amide compound II, re-use metachloroperbenzoic acid, Peracetic Acid, trifluoro Peracetic Acid, hydrogen peroxide, benzoyl hydroperoxide and make oxygenant and be translated into epoxy compounds with structural formula II I; Epoxy compounds III and suitable aminated compounds are at ethanol, methyl alcohol, C
3-C
6Alcohol, dimethyl formamide, dimethyl sulfoxide (DMSO), THF, dioxane equal solvent under react and can obtain corresponding target compound.R1 wherein, R2, R3, R4 are as mentioned above.
Corresponding chipal compounds can prepare optically pure epoxy compounds 4 earlier, obtains with corresponding aminate reaction again.
Having optically active compound 1 can be by literature method (J.Med.Chem.2000,43,581-590) make, generate acyl chlorides 2 with the thionyl chloride reaction again, make compound with amino benzenes compounds according to above-mentioned literature method method again with structural formula 3, under the sodium hydroxide condition, generate epoxide 4, obtain target compound with corresponding aminated compounds reaction as stated above then with optical texture.R1 wherein, R2, R3, R4 is with above-mentioned identical.
Compound activity obtains as follows, and resulting compound is dissolved among the DMSO, is mixed with certain density compound mother liquor.With DMSO it is diluted to 6-8 concentration gradient, with damping fluid each concentration is diluted, 4 ℃ of preservations are until use.(Dihydrotestosterone DHT) joins in the damping fluid, and mixing is mixed with reaction solution with having radiolabeled dihydrotestosterone with androgen receptor.Each compound concentration gradient dilution liquid is joined respectively in the reaction solution, mixing, 4 ℃ of overnight incubation are fully reacted compound and DHT and androgen receptor.Add Hydroxylapitite (Bio-Rad) suspension, mixing is hatched 10 minutes for 4 ℃, and is centrifugal, discards the supernatant liquor that contains free DHT.Hydroxylapitite is last to be retained in the deposit seeds by being adsorbed in androgen receptor bonded DHT, thereby reaches the purpose of separation and combination and unconjugated radioligand.Add scintillation solution in precipitation, mixing, WALLAC MicroBeta Trilux 1450-023 liquid scintillation instrument (PerKinElmer) carry out radioactive intensity and detect.Numerical value according to detected each concentration gradient carries out data processing, obtains IC
50And K
iValue.
Concrete activity the results are shown in following table:
AR part radioligand is competed in conjunction with the result:
Activity data shows that the designed compound of the present invention is the active high androgen antagonist compounds of a class, and the activity of this compounds all is higher than the anti-androgens medicine of existing clinical application, even is higher than the active optical isomer of bicalutamide.The anti-androgens medicine that can be used as of this compounds is used clinically, is used for and the unusual diseases associated of male sex hormone, and as prostate cancer, hyperplasia of prostate, alopecia, acne and polychetes disease.
Embodiment
Experiment embodiment: following compound, but do not limit.
Epoxy compounds with compound III general structure by literature method by corresponding aminated compounds and vinylformic acid acyl chloride reaction, through oxidation obtain (J.Med.Chem.1988,31,954-959).Having optically active epoxy compounds 4 makes by literature method.
In the round-bottomed flask of 50ml, add benzylamine 0.40g, (1) 1g,, dehydrated alcohol 5ml is as solvent.Reflux, stir general about 1 hour of reaction times.The point plate is determined reaction end.TLC:PE: EA=2: 1, product point is more single, no raw material point.
After reaction was finished, cooling was drained, and obtains oily mater.It is a small amount of to add ethanol, heating for dissolving, and the adding concentrated hydrochloric acid is a small amount of, stir, concentrate, solid matter (hydrochloride), be crude product, use acetone recrystallization then, obtain the white powder material, oven dry is weighed, and is 499mg, this powder is slightly soluble in ethyl acetate, insoluble chloroform, mp:104-108 ℃, productive rate is about 35.77%.
1H-NMR(DMSO-d
6)：δ8.54(s，1H)，δ8.25(d，1H)，δ8.13(d，1H)，δ7.58(t，2H)，δ7.40(m，3H)，δ4.20(m，2H)，δ3.28(d，1H)，δ3.05(d，1H)，δ1.45(s，3H)。
In the round-bottomed flask of 50ml, add aniline 0.338ml, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, react 2 days (26 hours).The point plate is determined reaction end.The composition of developping agent is: PE: EA=2: 1.Discovery has 2 product points, and first o'clock dense than second o'clock, according to the experience of P-nethoxyaniline, can determine that be required point at first.
After reaction was finished, cooling was drained, and obtains oily mater, is dissolved in acetone, PE: EA=5: 1 crosses post.Obtain oily mater.Use the PE/EA periodic crystallisation.Cooling.Obtain white crystalline material, suction filtration, oven dry gets 409mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:114-116 ℃, productive rate is about 30.44%.
1H-NMR(DMSO-d
6)：δ8.43(s，1H)，δ8.20(d，1H)，δ8.05(d，1H)，δ7.00(t，2H)，δ6.62(d，2H)，δ6.45(t，1H)，δ3.42(d，1H)，δ3.14(d，1H)，δ1.40(s，3H)。
In the round-bottomed flask of 50ml, add para-fluoroaniline 0.355ml, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, react 1 day (15 hours).TLC PE: EA=2: 1 determines reaction end, and finding has 2 product points, determines first point that the position is required.
After reaction was finished, cooling concentrates, and obtains oily mater, PE: EA=6: 1 crossed post.Cross down required point, concentrate, obtain oily mater.Use the PE/EA periodic crystallisation.The refrigerator cooling.Obtain white crystalline material, suction filtration, oven dry gets 715mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:74-76 ℃, productive rate is about 50.70%.
1H-NMR(CDCl
3)：δ8.08(s，1H)，δ7.88(d，1H)，δ7.78(d，1H)，δ6.88(t，2H)，δ6.78(t，2H)，δ3.83(d，1H)，δ3.25(d，1H)，δ1.58(s，3H)。
In the round-bottomed flask of 50ml, add p-Chlorobenzoic acid amide 0.472g, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, react 2 days (26 hours).TLC PE: EA=2: 1 determines reaction end.Discovery has 2 product points, can determine first point that the position is required.
After reaction was finished, cooling concentrates, and obtains oily mater, is dissolved in acetone, PE: EA=6: 1 crossed post.Cross down required point, concentrate, obtain oily mater.Use the PE/EA periodic crystallisation.The refrigerator cooling.Obtain white crystalline material, suction filtration, oven dry gets 253mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:113-115 ℃, productive rate is about 17.20%.
1H-NMR(DMSO-d
6)：δ8.42(s，1H)，δ8.19(d，1H)，δ8.05(d，1H)，δ7.00(d，2H)，δ6.62(d，2H)，δ3.45(d，1H)，δ3.14(d，1H)，δ1.40(s，3H)。
In the round-bottomed flask of 50ml, add para-bromoaniline 0.637g, (1) 1g, dehydrated alcohol 5ml is as solvent.Stirring and refluxing is reacted 3 days (40 hours).TLC PE: EA=2: 1 determines reaction end.Discovery has 2 product points, can determine that be required point at first.
After reaction was finished, cooling was drained, and obtains oily mater, can't obtain crystallization with the method for hydrochloride.PE: EA=2: 1 crosses post.Cross down required point, concentrate, obtain oily mater.Use the PE/EA periodic crystallisation.The refrigerator cooling.Obtain white crystalline material, suction filtration, oven dry gets 209mg, and this solid (hydrochloride) is slightly soluble in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:179-182 ℃, productive rate is about 12.78%.
1H-NMR (DMSO-d
6): δ 8.42 (s, 1H), δ 8.20 (d, 1H), δ 8.05 (d, 1H), δ 7.10 (d, 2H), δ 6.60 (d, 2H), δ 3.40 (being covered) by the DMSO solvent peak, δ 3.15 (d, 1H), δ 1.40 (s, 3H).
In the round-bottomed flask of 50ml, add P-nethoxyaniline 0.456ml, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reacted general about 2 hours.TLC PE: EA=2: 1 reaction end.Discovery has 2 product points, can determine that be required point at first.
After reaction was finished, cooling concentrates, and obtains oily mater, PE: EA=3: 1 crossed post.Obtain oily mater.Use the PE/EA crystallization.The refrigerator cooling.Obtain white crystalline material, suction filtration, oven dry gets 1114mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:112-114 ℃, productive rate is about 76.58%.
1H-NMR(CDCl
3)：δ8.08(s，1H)，δ7.88(d，1H)，δ7.78(d，1H)，δ6.78(m，4H)，δ3.80(d，1H)，δ3.71(s，3H)，δ3.20(d，1H)，δ1.58(s，3H)。
In the round-bottomed flask of 50ml, add p-Nitroaniline 0.511g, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir general 4 days of the reaction times (50 hours).TLC PE: EA=2: 1 determines reaction end.Find still to have the not reaction of a large amount of raw materials.
After reaction was finished, cooling was drained, obtain oily mater, can't obtain crystallization, PE with the method for hydrochloride: EA=2: 1 crosses post, cross down required point, concentrate, obtain yellow substance, oven dry, get 500mg, this solid is dissolved in organic solvents such as ethyl acetate, and mp:147-149 ℃, productive rate is about 33.11%.
1H-NMR(DMSO-d
6)：δ8.42(s，1H)，δ8.21(d，1H)，δ8.05(d，1H)，δ7.90(d，2H)，δ6.78(d，2H)，δ3.60(d，1H)，δ3.35(d，1H)，δ1.40(s，3H)。
In the round-bottomed flask of 50ml, add m-trifluoromethyl aniline 0.47ml, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, general 10-12 of reaction times hour.TLC PE: EA=2: 1 determines reaction end.
After reaction was finished, cooling concentrates, and obtains oily mater, PE: EA=5: 1 crossed post.Cross down the main product object point, concentrate, obtain oily mater.Use the PE/EA crystallization.The refrigerator cooling.Obtain white crystalline material, suction filtration, oven dry gets 354mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:60-62 ℃, productive rate is about 22.20%.
1H-NMR(DMSO-d
6)：δ8.08(s，1H)，δ7.89(d，1H)，δ7.79(d，1H)，δ6.99(d，1H)，δ6.90(s，1H)，δ6.84(d，1H)，δ3.82(d，1H)，δ3.32(d，1H)，δ
In the round-bottomed flask of 50ml, add n-Butyl Amine 99 0.37ml, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir general about 45 minutes of reaction times.TLC PE: EA=2: 1 determines reaction end.Product point is more single, no raw material point.
After reaction was finished, cooling was drained, and obtains oily mater.It is a small amount of to add ethanol 2, and heating for dissolving adds the concentrated hydrochloric acid trace, stir, drain, solid matter (hydrochloride), be crude product, come recrystallization with acetone then, obtain the white powder material, oven dry is weighed, and is 447mg, this powder is slightly soluble in ethyl acetate, insoluble chloroform, mp:175-178 ℃, productive rate is about 35.21%.
1H-NMR (DMSO-d
6): δ 8.58 (s, 1H), δ 8.25 (d, 1H), δ 8.17 (d, 1H), δ 3.40 (overlapping) with the DMSO solvent peak, δ 3.15 (d, 1H), δ 2.90 (t, 2H), δ 1.63 (m, 2H), δ 1.50 (s, 3H), δ 1.30 (q, 2H), δ 0.88 (t, 3H).
In the round-bottomed flask of 50ml, add diethylamine 0.384ml, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reaction 2-3 hour.TLC PE: EA=2: 1 determines reaction end.Find that product point is apparent in view, it is more complete that raw material point reacts.
After reaction was finished, cooling was drained, and obtains oily mater, uses the PE/EA crystallization.The refrigerator cooling.Obtain white crystalline material, suction filtration, oven dry gets 902mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:54-56 ℃, productive rate is about 71.05%.
1H-NMR(CDCl
3)：δ8.10(s，1H)，δ7.92(d，1H)，δ7.78(d，1H)，δ3.26(d，1H)，δ2.60(w，4H)，δ2.48(d，1H)，δ1.40(s，3H)，δ1.00(m，6H)。
In the round-bottomed flask of 50ml, add morphine quinoline 0.322ml, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reaction 1-2 hour.TLC PE: EA=2: 1 determines reaction end.Find that product point is apparent in view, it is more complete that raw material point reacts.
After reaction was finished, cooling promptly had a large amount of white crystals to separate out, suction filtration, and oven dry gets 1314mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp.177-179 ℃, productive rate is about 99.34%.
1H-NMR(CDCl
3)：δ8.10(s，1H)，δ7.92(d，1H)，δ7.80(d，1H)，δ3.70(m，4H)，δ3.35(d，1H)，δ2.61(m，4H)，δ2.50(d，1H)，δ1.42(s，3H)。
In the round-bottomed flask of 50ml, add N methyl piperazine 0.410ml, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reacted 2 hours.TLC PE: EA=2: 1 determines reaction end.Find that product point is apparent in view, it is more complete that raw material point reacts.
After reaction is finished, cooling, draining becomes oily, uses the PE/EA crystallization, repeatable operation obtains the crystallization of white at last, suction filtration, oven dry, get 567mg, this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:93-96 ℃, productive rate is about 41.40%.
1H-NMR (DMSO-d
6): δ 8.50 (s, 1H), δ 8.25 (d, 1H), δ 8.08 (d, 1H), δ 2.71 (d, 1H), δ 2.58 (broad peak, 2H), δ 2.45 (d, 1H), δ 2.40 (broad peak, 2H), δ 2.20 (broad peak, 4H), δ 2.08 (s, 3H), δ 1.30 (s, 3H).
In the round-bottomed flask of 50ml, add cyano-aniline 0.444g, (1) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir general 2 days about half reaction times (about 30 hours).TLC PE: EA=2: 1 determines reaction end.Discovery has 2 product points, and second dense, so will obtain a little.
After reaction was finished, cooling was drained, and obtains oily mater, PE: EA=5: 1 crosses post.Cross following second point, drain, obtain oily mater.Use the PE/EA crystallization respectively.The refrigerator cooling.Crystallization.
In the round-bottomed flask of 50ml, add benzylamine 0.37g, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir reaction times 3-4 hour.TLC PE: EA=2: 1 determines reaction end.
After reaction was finished, cooling was drained, and obtains oily mater.It is a small amount of to add ethanol, and heating for dissolving adds the concentrated hydrochloric acid trace, jolting is drained, solid matter (hydrochloride), be crude product, come recrystallization with acetone then, obtain the white powder material, oven dry is weighed, and is 402mg, this powder is slightly soluble in ethyl acetate, insoluble chloroform, mp:195-198 ℃, productive rate is about 29.35%.
1H-NMR(DMSO-d
6)：δ8.56(s，1H)，δ8.25(d，1H)，δ8.20(d，1H)，δ7.58(t，2H)，δ7.40(m，3H)，δ4.20(m，2H)，δ3.28(d，1H)，δ3.00(d，1H)，δ1.42(s，3H)。
In the round-bottomed flask of 50ml, add aniline 0.321ml, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, react spend the night (10-12 hour).TLC PE: EA=2: 1 determines reaction end.Discovery has 2 product points, can determine first point that the position is required.
After reaction was finished, cooling was drained, and obtains oily mater, PE: EA=5: 1 crosses post.Cross down required point, drain, obtain oily mater.Use the PE/EA periodic crystallisation.The refrigerator cooling.Obtain the orange crystalline material, suction filtration, oven dry gets 758mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:71-73 ℃, productive rate is about 57.35%.
1H-NMR(CDCl
3)：δ8.05(s，1H)，δ7.97(s，2H)，δ7.20(m，2H)，δ6.78(m，3H)，δ3.85(d，1H)，δ3.30(d，1H)，δ1.58(s，3H)。
In the round-bottomed flask of 50ml, add para-fluoroaniline 0.331ml, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, react 1 day (15 hours).TLC PE: EA=2: 1 determines reaction end.Discovery has 2 product points, can determine first point that the position is required.
After reaction was finished, cooling was drained, and obtains oily mater, PE: EA=5: 1 crosses post.Cross down required point, drain, obtain oily mater.Use the PE/EA periodic crystallisation.The refrigerator cooling.Obtain the grey crystalline material, suction filtration, oven dry gets 1176mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:140-142 ℃, productive rate is about 84.98%.
1H-NMR(DMSO-d
6)：δ8.48(s，1H)，δ8.25(d，1H)，δ8.20(d，1H)，δ6.85(t，2H)，δ6.62(t，2H)，δ3.45(d，1H)，δ3.10(d，1H)，δ1.58(s，3H)。
In the round-bottomed flask of 50ml, add p-Chlorobenzoic acid amide 0.440g, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, react spend the night (10-12 hour).TLC PE: EA=2: 1 determines reaction end.Discovery has 2 product points, can determine first point that the position is required.
After reaction was finished, cooling was drained, and obtains oily mater, PE: EA=5: 1 crosses post.Cross down required point, drain, obtain oily mater.Use the PE/EA periodic crystallisation.The refrigerator cooling.Obtain the yellow crystal material, suction filtration, oven dry gets 622mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:114-116 ℃, productive rate is about 43.18%.
1H-NMR(DMSO-d
6)：δ8.48(s，1H)，δ8.24(d，1H)，δ8.17(d，1H)，δ7.00(d，2H)，δ6.65(d，2H)，δ3.45(d，1H)，δ3.14(d，1H)，δ1.40(s，3H)。
In the round-bottomed flask of 50ml, add para-bromoaniline 0.594g, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, react spend the night (10 hours).TLC PE: EA=2: 1 determines reaction end.Discovery has 2 main product points, can determine first point that the position is required.
After reaction was finished, cooling was drained, and obtains oily mater, PE: EA=4: 1 crosses post.Cross down required point, drain, obtain oily mater.Use the PE/EA periodic crystallisation.The refrigerator cooling.Obtain the yellow crystal material, suction filtration, oven dry gets 899mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:78-80 ℃, productive rate is about 56.40%.
1H-NMR(CDCl
3)：δ8.08(s，1H)，δ7.98(s，2H)，δ7.26(d，1H)，δ7.24(d，1H)，δ6.63(d，2H)，δ3.80(d，1H)，δ3.25(d，1H)，δ1.60(s，3H)。
In the round-bottomed flask of 50ml, add P-nethoxyaniline 0.425g, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reacted 6 hours.TLC PE: EA=2: 1 determines reaction end.Discovery has 2 product points.
After reaction was finished, cooling was drained, and obtains oily mater, PE: EA=3: 1 crosses post.Cross following 2 points respectively, drain respectively, obtain oily mater.Use the PE/EA crystallization respectively.The refrigerator cooling.First obtains the brown crystalline material, suction filtration, and oven dry gets 676mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:84-86 ℃, productive rate is about 47.43%.After determining structure, can affirm that be required material at first.
1H-NMR(CDCl
3)：δ8.08(s，1H)，δ7.95(t，2H)，δ6.78(m，4H)，δ3.85(d，1H)，δ3.75(s，3H)，δ3.20(d，1H)，δ1.58(s，3H)。
In the round-bottomed flask of 50ml, add p-Nitroaniline 0.477g, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir general 5 days of the reaction times (60 hours).TLC PE: EA=2: 1 determines reaction end.Find still to have the not reaction of a large amount of raw materials.
After reaction was finished, cooling was drained, and obtains oily mater, PE: EA=1.5: 1 crosses post.Cross down required point, drain, obtain the yellow oily material, obtain crystallization with the EA/PE periodic crystallisation, with the oven dry of material suction filtration, get 180mg, this solid is dissolved in organic solvents such as ethyl acetate, and mp:107-110 ℃, productive rate is about 12.78%.
1H-NMR(DMSO-d
6)：δ8.42(s，1H)，δ8.23(d，1H)，δ8.15(d，1H)，δ7.90(d，2H)，δ6.78(d，2H)，δ3.60(d，1H)，δ3.38(d，1H)，δ1.43(s，3H)。
In the round-bottomed flask of 50ml, add m-trifluoromethyl aniline 0.431ml, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, general 10-12 of reaction times hour.TLC PE: EA=2: 1 determines reaction end.
After reaction was finished, cooling was drained, and obtains oily mater, PE: EA=5: 1 crosses post.Cross down the main product object point, drain, obtain oily mater.Use the PE/EA crystallization.The refrigerator cooling.Obtain the yellow crystal material, suction filtration, oven dry gets 735mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:85-87 ℃, productive rate is about 47.24%.
1H-NMR(CDCl
3)：δ8.08(s，1H)，δ7.98(s，2H)，δ7.30(d，1H)，δ7.05(d，1H)，δ7.00(s，1H)，δ7.95(d，1H)，δ3.92(d，1H)，δ3.38(d，1H)，δ1.61(s，3H)。
In the round-bottomed flask of 50ml, add n-Butyl Amine 99 0.34ml, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reacted 2-3 hour.TLC PE: EA=2: 1 determines reaction end.
After reaction was finished, cooling was drained, and obtains oily mater.It is a small amount of to add ethanol, heating for dissolving, and the adding concentrated hydrochloric acid is a small amount of, jolting is drained, solid matter (hydrochloride), be crude product, use acetone recrystallization then, obtain the white powder material, oven dry is weighed, and is 502mg, this powder is slightly soluble in ethyl acetate, insoluble chloroform, mp:156-159 ℃, productive rate is about 40.07%.
1H-NMR (DMSO-d
6): δ 8.58 (s, 1H), δ 8.28 (d, 1H), δ 8.20 (d, 1H), δ 3.40 (overlapping) with the DMSO solvent peak, δ 3.15 (d, 1H), δ 2.90 (t, 2H), δ 1.63 (m, 2H), δ 1.50 (s, 3H), δ 1.28 (q, 2H), δ 0.85 (t, 3H).
In the round-bottomed flask of 0ml, add diethylamine 0.358ml, (2) g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reaction 1-2 hour.TLC PE: EA=2: 1 determines reaction end.Find that product point is apparent in view, it is more complete that raw material point reacts.
After reaction was finished, cooling was drained, and obtains oily mater, uses the PE/EA crystallization.The refrigerator cooling.Obtain the safran crystalline material very soon, suction filtration, oven dry gets 1110mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:84-86 ℃, productive rate is about 88.60%.
1H-NMR(CDCl
3)：δ8.10(s，1H)，δ8.00(s，2H)，δ3.38(d，2H)，δ2.65(m，4H)，δ2.56(d，1H)，δ1.45(s，3H)，δ1.05(t，6H)。
In the round-bottomed flask of 50ml, add morphine quinoline 0.301ml, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reaction 1-2 hour.TLC PE: EA=2: 1 determines reaction end.Find that product point is apparent in view, it is more complete that raw material point reacts.
After reaction was finished, cooling was drained, and obtains oily mater, uses the PE/EA crystallization.The refrigerator cooling.Obtain flaxen solid crystal, suction filtration, oven dry gets 305mg, and this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:162-165 ℃, productive rate is about 23.44%.
1H-NMR (CDCl
3): δ 8.10 (s, 1H), δ 7.98 (t, 2H), δ 3.65 (broad peak, 4H), δ 3.30 (d, 1H), δ 2.60 (broad peak, 4H), δ 2.45 (d, 1H), δ 1.40 (s, 3H).
In the round-bottomed flask of 50ml, add N methyl piperazine 0.383ml, (2) 1g, dehydrated alcohol 5ml is as solvent.Reflux, stir, reacted 2 hours.Point TLC PE: EA=2: 1 determines reaction end.Find that product point is apparent in view, it is more complete that raw material point reacts.
After reaction is finished, cooling, draining becomes oily, uses the PE/EA crystallization, repeatable operation obtains green crystallization at last, suction filtration, oven dry, get 688mg, this solid is dissolved in organic solvents such as ethyl acetate, methylene dichloride, chloroform, and mp:131-134 ℃, productive rate is about 51.11%.
1H-NMR (DMSO-d
6): δ 8.50 (s, 1H), δ 8.25 (d, 1H), δ 8.08 (d, 1H), δ 2.71 (d, 1H), δ 2.58 (broad peak, 2H), δ 2.45 (d, 1H), δ 2.40 (broad peak, 2H), δ 2.20 (broad peak, 4H), δ 2.08 (s, 3H), δ 1.30 (s, 3H).
Claims (7)
1. the amide compound that has following general structure:
R wherein
1, R
2Be CN, NO
2, CF
3Electron-withdrawing group, R
3, R
4Be hydrogen atom, alkyl contains various substituent alkyl, aromatic base, and contain multiple substituent aromatic base.
2, amide compound according to claim 1 is characterized in that working as R
1, R
2Be CN, NO
2, CF
3Electron-withdrawing group, R
3Be H, R
4For aromatic base, the aromatic base that contains one or more replacements comprise halogen, NO
2, CN, CF
3,
3, amide compound according to claim 1, the optical siomerism that it is characterized in that it are racemization, left-handed, isomer.
4, the preparation method of amide compound as claimed in claim 1 is made up of the following step:
Compound I I through the oxidising agent oxidation get epoxy compounds III again with aminated compounds in the presence of suitable solvent, react target compound.
5, the preparation method of amide compound according to claim 4 is characterized in that oxidising agent is metachloroperbenzoic acid, Peracetic Acid, trifluoro Peracetic Acid, hydrogen peroxide, benzoyl hydroperoxide oxygenant.
6,, it is characterized in that solvent is alcohol, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), the dioxane of ethanol, methyl alcohol and C3-C6 according to the preparation method of the described amide compound of claim 4.
7, the purposes of amide compound according to claim 4 is characterized in that the androgen antagonist medicine as treatment hyperplasia of prostate, alopecia, acne, crinosity.
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