CN103275013A - Novel nitrogenous heterocycle sulfamide derivative type aromatizing enzyme inhibitor and preparation method thereof - Google Patents
Novel nitrogenous heterocycle sulfamide derivative type aromatizing enzyme inhibitor and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a novel nitrogenous heterocycle sulfamide derivative type aromatizing enzyme inhibitor and a preparation method thereof. The preparation method comprises the following steps of: (1) synthesizing an amino alcohol compound; (2) synthesizing an aryl sulfamide compound; and (3) synthesizing a novel nitrogenous heterocycle sulfamide derivative. The primary research on the compounds obtained by the method shows that most of the compounds have an inhibition effect on aromatizing enzyme, and the inhibition effect of part of the compounds is more excellent than that of the first-line medicament letrozole used at present, so the compounds to be protected by the invention are effective lead compounds of aromatizing enzyme inhibitor medicaments and may be developed to become new aromatizing enzyme inhibitor medicaments.
Description
Technical field
The invention belongs to technical field of chemistry, relate to a kind of novel azaheterocyclic sulfone amide derivative type arimedex and preparation method thereof.
Background technology
Mammary cancer is a kind of even life-threatening common disease of WomanHealth and frequently-occurring disease of having a strong impact on.The treatment of mammary cancer, it is main mainly taking at present operation, chemotherapy, radiotherapy, endocrine therapy and molecular targeted therapy etc. are auxiliary Colligation Therapy Mode.Endocrine therapy has developed into a kind of important treatment means in breast cancer treatment, and particularly, after hormone receptor is found, endocrinotherapy for breast cancer can purposive selection measurable curative effect.And the appearance of arimedex enters endocrine therapy brand-new epoch.
Aromatizing enzyme is present in the endoplasmic reticulum of cell, be a kind ofly male sex hormone (Androstenedione and testosterone) can be converted to the cytochrome P 450 enzymes of oestrogenic hormon (being converted to respectively oestrone and estradiol), to regulating balance and the conversion of sexual hormoue in body, very important effect arranged.The specific aromatizing enzyme that acts on of arimedex, can effectively suppress estrogenic generation, and the metabolism of other steroid hormones is not produced to interference, and the disease that treatment is caused because oestrogenic hormon is excessive has very outstanding curative effect.Now, some effective arimedexs have been used for the treatment of the dependent mammary cancer of hormone in clinical.The application clinically of third generation arimedex, promote from the two wires adjuvant therapy medicaments to the first-line treatment medicine gradually, and the effect of arimedex more and more comes into one's own.Except mammary cancer, aromatizing enzyme and ovarian cancer, carcinoma of endometrium, the excessive syndromes of aromatizing enzyme and aromatizing enzyme shortage syndromes etc. also may have important relationship.If the activity of aromatizing enzyme in body is too high, can cause oestrogenic hormon and androgenic unbalance, make boy produce female's breast disease, can produce sexual prematurity and macromastia to girl, and the illness such as obesity associated therewith, early ageing, liver illness, hyperthyroidism, also all relevant to estrogenic over-conversion with male sex hormone.Masculinity and femininity no matter, reason of short and small stature nearly all with cause that because hormone is unbalance epiphysis is closed relevant in advance.And the variation of gene C YP19 may produce the enzymoprivic problem of aromatize, male sex hormone accumulation may cause that the girl baby's is manlike; The adult female there will be primary amenorrhea; Be characterized in: the patient is of imposing stature, and the stone age delays, osteoporosis etc.
Although arimedex is had outstanding performance in clinical, better than some original effect of drugs.But they are also often relevant with some disadvantageous side effects, as bone density loss, bone pain, inhibition bone forming, increase the symptoms such as danger of osteoporosis, fracture.
In addition, resistance is a very important problem, and research shows that some patient with breast cancers are after accepting the arimedex treatment, early stage, effectively tumour reduced, but along with administration time extends, tumour has also obtained the tolerance of Endocrine, and restarts growth.
Therefore, research and develop new arimedex particularly the nonsteroidal arimedex important meaning is arranged.
Summary of the invention
In order to overcome defect of the prior art, solve the problems of the technologies described above, the invention provides a kind of novel azaheterocyclic sulfone amide derivative type arimedex and preparation method thereof.
Its technical scheme is as follows:
A kind of novel azaheterocyclic sulfone amide derivative type arimedex has following general structure:
A kind of preparation method of novel azaheterocyclic sulfone amide derivative type arimedex comprises the following steps:
(1) alkamine compound is synthetic
Reaction conditions A: under nitrogen protection and 0 ℃; raw material amino acid is dissolved in anhydrous tetrahydro furan; careful gradation adds LAH; reaction reheats backflow 4-10h from 0 ℃ slowly rises to room temperature; the TCL detection reaction is complete, in reaction system, adds while stirring the frozen water mark NaOH aqueous solution, has the sticky solid material to generate; wash solid by ethyl acetate after filtration, after the merging organic phase, use anhydrous MgSO
4Drying, obtain corresponding amino alcohol after the evaporated under reduced pressure solvent,
Reaction conditions B: under 0 ℃ of nitrogen protection, by raw material amino acid and NaBH
4Be dissolved in anhydrous tetrahydro furan, carefully add and be dissolved with I
2Anhydrous tetrahydrofuran solution, after reaction system reflux 8-18h, be down to room temperature, careful methyl alcohol to the solution that drips is clarified, then continues reaction 1h, evaporated under reduced pressure solvent, then repeatedly extract with methylene dichloride to the KOH aqueous solution that adds 20% in Residual reactants, merge organic phase and also use MgSO
4Drying, obtain corresponding amino alcohol after the hot water bath solvent evaporated;
(2) the yellow amides of aryl is synthetic
Corresponding amino alcohol compound is dissolved in to anhydrous methylene chloride, after being down to 0 ℃, first add triethylamine, slowly drip again corresponding arylsulfonyl chlorine compound, after slowly rising to room temperature, continue reaction 6-12h to TLC detection raw material reaction complete, after the evaporated under reduced pressure solvent, thick sherwood oil for product: ethyl acetate=20-10: 1 (volume ratio) is eluent, through 100-200 order silica gel column chromatography, separates and obtains the yellow amides of corresponding aryl;
(3) the novel azaheterocyclic sulfone amide derivative is synthetic
The yellow amides of corresponding aryl is dissolved in methylene dichloride, after being down to 0 ℃, first add anhydrous triethylamine, slowly drip again methylsulfonyl chloride, after slowly rising to room temperature, continue reaction 8-15h to TLC detection raw material reaction complete, the evaporated under reduced pressure solvent, the thick not purified direct use of product is dissolved in toluene or anhydrous 1, the 4-dioxane, add imidazoles or triazole again, be heated to 60 ℃ of reaction 12-20h, it is complete that TLC detects raw material reaction, the evaporated under reduced pressure solvent, thin up, repeatedly extract by ethyl acetate, merges organic phase and use anhydrous Na
2SO
4Drying, the evaporated under reduced pressure solvent, thick product sherwood oil: ethyl acetate: the volume ratio of methyl alcohol=1: 5-12: 0.5-2 is eluent, through 200-300 order silica gel column chromatography, separates and obtains corresponding novel azaheterocyclic sulfone amide derivative.
Beneficial effect of the present invention: the preliminary study of gained compound shows; its major part is inhibited to aromatizing enzyme; the restraining effect of part of compounds is better than the first-line drug letrozole (Letrozole used now; positive control); therefore; the compound of this patent wish protection will be effective lead compound of arimedex class medicine, likely develop into new arimedex class medicine.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is described in more detail.
A kind of novel azaheterocyclic sulfone amide derivative type arimedex has following general structure:
A kind of preparation method of novel azaheterocyclic sulfone amide derivative type arimedex comprises the following steps:
(1) alkamine compound is synthetic
Reaction conditions A: under nitrogen protection and 0 ℃; raw material amino acid is dissolved in anhydrous tetrahydro furan; careful gradation adds LAH; reaction reheats backflow 4-10h from 0 ℃ slowly rises to room temperature; the TCL detection reaction is complete, in reaction system, adds while stirring the frozen water mark NaOH aqueous solution, has the sticky solid material to generate; wash solid by ethyl acetate after filtration, after the merging organic phase, use anhydrous MgSO
4Drying, obtain corresponding amino alcohol after the evaporated under reduced pressure solvent,
Reaction conditions B: under 0 ℃ of nitrogen protection, by raw material amino acid and NaBH
4Be dissolved in anhydrous tetrahydro furan, carefully add and be dissolved with I
2Anhydrous tetrahydrofuran solution, after reaction system reflux 8-18h, be down to room temperature, careful methyl alcohol to the solution that drips is clarified, then continues reaction 1h, evaporated under reduced pressure solvent, then repeatedly extract with methylene dichloride to the KOH aqueous solution that adds 20% in Residual reactants, merge organic phase and also use MgSO
4Drying, obtain corresponding amino alcohol after the hot water bath solvent evaporated;
(2) the yellow amides of aryl is synthetic
Corresponding amino alcohol compound is dissolved in to anhydrous methylene chloride, after being down to 0 ℃, first add triethylamine, slowly drip again corresponding arylsulfonyl chlorine compound, after slowly rising to room temperature, continue reaction 6-12h to TLC detection raw material reaction complete, decompression is steamed after solvent, thick sherwood oil for product: ethyl acetate=20-10: 1 (volume ratio) is eluent, through 100-200 order silica gel column chromatography, separates and obtains the yellow amides of corresponding aryl;
(3) the novel azaheterocyclic sulfone amide derivative is synthetic
The yellow amides of corresponding aryl is dissolved in methylene dichloride, after being down to 0 ℃, first add anhydrous triethylamine, slowly drip again methylsulfonyl chloride, after slowly rising to room temperature, continue reaction 8-15h to TLC detection raw material reaction complete, the evaporated under reduced pressure solvent, the thick not purified direct use of product is dissolved in toluene or anhydrous 1, the 4-dioxane, add imidazoles or triazole again, be heated to 60 ℃ of reaction 12-20h, it is complete that TLC detects raw material reaction, the evaporated under reduced pressure solvent, thin up, repeatedly extract by ethyl acetate, merges organic phase and use anhydrous Na
2SO
4Drying, the evaporated under reduced pressure solvent, thick product sherwood oil: ethyl acetate: the volume ratio of methyl alcohol=1: 5-12: 0.5-2 is eluent, through 200-300 order silica gel column chromatography, separates and obtains corresponding novel azaheterocyclic sulfone amide derivative.
Novel azaheterocyclic sulfone amide derivative example
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：8.09(1H，s)，7.85-7.80(3H，m)，7.65-7.57(3H，m)，7.38-7.30(5H，m)，6.92(1H，s)，5.43-5.40(1H，dd)，3.69-3.62(1H，m)，3.44-3.38(2H，m).
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：8.12(1H，s)，8.07(1H，s)，7.80-7.73(3H，m)，7.69-7.59(2H，m)，7.40-7.33(5H，m)，5.46-5.43(1H，dd)，3.59-3.50(1H，m)，3.45-3.39(2H，m).
Molecular formula C
18H
19N
3O
2S
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：7.99-7.95(1H，t)，7.83(1H，s)，7.69-7.67(2H，d)，7.39-7.36(2H，d)，7.39-7.33(5H，m)，6.90(1H，s)，5.42-5.37(1H，dd)，3.65-3.55(1H，m)，3.38-3.29(2H，m)，2.37(3H，s).
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：8.06(1H，s)，8.01(1H，s)，7.72-7.68(2H，d)，7.41-7.37(2H，d)，7.39-7.33(5H，m)，5.50-5.44(1H，dd)，3.67-3.60(1H，m)，3.45-3.38(2H，m)，2.31(3H，s).
Molecular formula C
21H
19N
3O
2S
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.59-8.58(1H，d)，8.47-8.46(1H，d)，8.24-8.22(1H，d)，8.14-8.12(1H，d)，8.10-8.07(1H，m)，7.80(1H，s)，7.69-7.61(3H，m)，7.33-7.27(5H，m)，6.87(1H，s)，5.41-5.38(1H，m)，3.74-3.70(1H，m)，3.48-3.41(2H，m).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.09(1H，s)，8.03(1H，s)，8.45-8.44(1H，d)，8.25-8.23(1H，d)，8.15-8.12(1H，d)，8.11-8.08(1H，m)，7.67-7.60(3H，m)，7.35-7.29(5H，m)，5.43-5.39(1H，m)，3.75-3.73(1H，m)，3.47-3.40(2H，m).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.46(1H，s)，8.39-8.37(2H，d)，8.04-8.02(2H，d)，7.82(1H，s)，7.35-7.29(5H，m)，6.88(1H，s)，5.43-5.39(1H，dd)，3.77-3.72(1H，m)，3.55-3.51(2H，m).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.07(1H，s)，8.02(1H，s)，8.37-8.35(2H，d)，8.02-8.00(2H，d)，7.37-7.30(5H，m)，5.41-5.37(1H，dd)，3.76-3.72(1H，m)，3.54-3.50(2H，m).
Molecular formula C
18H
19N
3O
3S
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：7.89(1H，s)，7.82(1H，s)，7.74-7.71(2H，d)，7.37-7.28(5H，m)，7.11-7.08(2H，d)，6.89(1H，s)，5.52-5.37(1H，dd)，3.83(3H，s)，3.61-3.54(1H，m)，3.33-3.31(2H，m).
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：8.07(1H，s)，8.02(1H，s)，7.79-7.72(2H，d)，7.40-7.35(5H，m)，7.18-7.10(2H，d)，5.55-5.40(1H，dd)，3.88(3H，s)，3.68-3.63(1H，m)，3.50-3.42(2H，m).
Molecular formula C
17H
16BrN
3O
2S
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.18(1H，s)，7.89(1H，s)，7.80-7.78(2H，d)，7.73-7.71(2H，d)，7.67-7.58(5H，m)，6.93(1H，s)，5.44-5.40(1H，t)，3.71-3.64(2H，m)，3.51-3.43(2H，m).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.10(1H，s)，8.05(1H，s)，7.81-7.79(2H，d)，7.74-7.72(2H，d)，7.69-7.59(5H，m)，5.44-5.40(1H，t)，3.71-3.64(2H，m)3.49-3.40(2H，m).
Molecular formula C
17H
16FN
3O
2S
1H-NMR(400MHz，MeOD)δ(ppm)：7.86-7.90(2H，m)，7.36-7.39(3H，m)，7.26-7.35(5H，m)，7.18(1H，s)，6.99(1H，s)，5.44-5.48(1H，m)，3.71-3.77(1H，m)，3.55-3.59(2H，m).
1H-NMR(400MHz，MeOD)δ(ppm)：8.08(1H，s)，8.01(1H，s)，7.91-7.85(2H，m)，7.36-7.39(2H，m)，7.26-7.35(5H，m)，5.54-5.48(1H，m)，3.81-3.75(1H，m)，3.63-3.58(2H，m).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.36(1H，s)，8.01-7.99(2H，d)，7.96-7.94(2H，d)，7.84(1H，s)，7.34-7.29(5H，m)，6.89(1H，s)，5.44-5.40(1H，d)，3.75-3.70(1H，d)，3.54-3.49(2H，m).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.06(1H，s)，8.00(1H，s)，8.11-7.98(2H，d)，7.86-7.80(2H，d)，7.34-7.29(5H，m)，5.49-5.42(1H，d)，3.81-3.73(1H，d)，3.64-3.54(2H，m).
Molecular formula C
19H
21N
3O
2S
1H-NMR(400MHz，MeOD)δ(ppm)：7.50(1H，s)，7.28-7.30(2H，d)，7.02-7.04(5H，m)，6.93(1H，s)，6.88-6.90(2H，d)，6.80(1H，s)，4.05-4.10(1H，dd)，3.88-3.93(1H，dd)，3.59-3.62(2H，m)，2.58-2.63(1H，dd)，2.39-2.45(1H，dd)，2.27(3H，s).
1H-NMR(400MHz，MeOD)δ(ppm)：8.09(1H，s)，8.05(1H，s)，7.27-7.31(2H，d)，7.03-7.05(5H，m)，6.87-6.90(2H，d)，4.04-4.09(1H，dd)，3.86-3.91(1H，dd)，3.57-3.60(2H，m)，2.56-2.61(1H，dd)，2.38-2.44(1H，dd)，2.27(3H，s).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.01-7.99(1H，d)，7.85(1H，s)，7.67-7.63(2H，m)，7.57-7.51(3H，m)，7.39-7.36(3H，m)，7.19-7.15(2H，m)，6.87(1H，s），4.07-4.02(1H，dd)，4.00-3.91(1H，m)，3.59-3.63(2H，m)，2.85-2.80(1H，dd)，2.67-2.62(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.10(1H，s)，8.05(1H，s)，7.72-7.63(2H，m)，7.65-7.59(3H，m)，7.42-7.38(2H，m)，7.28-7.19(3H，m)，4.12-4.08(1H，dd)，4.06-3.95(1H，m)，3.57-3.60(2H，m)，2.95-2.89(1H，dd)，2.75-2.70(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.46-8.43(1H，m)，8.28-8.26(1H，d)，8.10-8.08(1H，d)，8.00-7.98(1H，m)，7.85-7.83(1H，d)，7.78-7.77(1H，d)，7.66-7.60(2H，m)，7.47-7.43(1H，t)，7.11(1H，s)，6.89-6.82(5H，m)，4.11-4.07(1H，dd)，4.01-3.96(1H，dd)，3.82-3.80(1H，m)，3.46-3.44(1H，m)，2.61-2.57(1H，dd)，2.43-2.40(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.06(1H，s)，8.00(1H，s)，8.29-8.27(1H，d)，8.11-8.09(1H，d)，7.99-7.96(1H，m)，7.83-7.81(1H，d)，7.75-7.74(1H，d)，7.64-7.58(2H，m)，7.46-7.42(1H，t)，6.88-6.83(4H，m)，4.09-4.06(1H，dd)，4.00-3.97(1H，dd)，3.83-3.81(1H，m)，3.45-3.43(1H，m)，2.60-2.56(1H，dd)，2.43-2.41(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.45-8.43(1H，d)，8.14-8.12(2H，d)，7.66(1H，s)，7.65-7.63(2H，d)，7.18-7.17(1H，s)，7.13-7.06(4H，m)，6.89(1H，s)，4.20-4.16(1H，dd)，4.07-4.02(1H，dd)，3.81(1H，s)，3.30-3.32(1H，m)，2.79-2.74(1H，dd)，2.60-2.55(1H，dd).
Molecular formula C
17H
17N
5O
4S
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.08(1H，s)，8.03(1H，s)，8.15-8.13(2H，d)，7.65-7.63(2H，d)，7.13-7.06(5H，m)，4.20-4.16(1H，dd)，4.07-4.02(1H，dd)，3.81(1H，s)，3.30-3.32(1H，m)，2.79-2.74(1H，dd)，2.60-2.55(1H，dd).
1H-NMR(400MHz，MeOD)δ(ppm)：7.61(1H，s)，7.45-7.56(2H，d)，7.15-7.19(3H，d)，7.07(1H，s)，7.00-7.03(2H，m)，6.93(1H，s)，6.86-6.63(2H，d)，4.18-4.22(1H，dd)，4.00-4.06(1H，dd)，3.86(3H，s)，3.68-3.72(1H，m)，3.32-3.33(1H，m)，2.71-2.76(1H，dd)，2.52-2.58(1H，dd).
1H-NMR(400MHz，MeOD)δ(ppm)：8.07(1H，s)，8.01(1H，s)，7.60-7.51(2H，d)，7.22-7.13(2H，d)，7.13-7.03(5H，m)，4.30-4.25(1H，dd)，4.15-4.09(1H，dd)，3.91(3H，s)，3.76-3.66(1H，m)，3.31-3.34(1H，m)，2.79-2.73(1H，dd)，2.61-2.56(1H，dd).
1H-NMR(400MHz，MeOD)δ(ppm)：7.55(1H，s)，7.30-7.33(2H，d)，7.20-7.23(2H，d)，6.98-7.06(5H，m)，6.87-6.89(1H，d)，6.83(1H，s)，4.11-4.16(1H，dd)，3.94-3.99(1H，dd)，3.63-3.66(2H，m)，2.65-2.69(1H，dd)，2.37-2.43(1H，dd).
1H-NMR(400MHz，MeOD)δ(ppm)：8.05(1H，s)，8.00(1H，s)，7.34-7.31(2H，d)，7.24-7.21(2H，d)，7.05-6.99(5H，m)，4.15-4.11(1H，dd)，3.98-3.95(1H，dd)，3.67-3.64(2H，m)，2.68-2.66(1H，dd)，2.42-2.35(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.06-8.04(1H，d)，7.56(1H，s)，7.49-7.45(2H，dd)，7.16-7.11(4H，m)，7.08(1H，s)，7.04-7.03(2H，m)，6.84(1H，s)，4.09-4.04(1H，dd)，3.97-3.92(1H，dd)，3.67-3.65(2H，m)，2.69-2.64(1H，dd)，2.51-2.46(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.08(1H，s)，8.04(1H，s)，7.55-7.48(2H，dd)，7.25-7.18(5H，m)，7.12-7.06(2H，m)，4.16-4.09(1H，dd)，3.99-3.95(1H，dd)，3.75-3.66(1H，m)，2.78-2.70(2H，dd)，2.63-2.57(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：7.69(1H，s)，7.56-7.59(3H，m)，7.11(1H，s)，7.03-7.06(4H，m)，6.98-7.00(2H，m)，6.93(1H，s)，4.26-4.31(1H，dd)，4.10-4.15(1H，dd)，3.79-3.85(2H，m)，2.80-2.84(1H，dd)，2.52-2.55(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.09(1H，s)，8.04(1H，s)，7.67-7.61(2H，m)，7.30-7.26(2H，m)，7.15-7.10(3H，m)，7.08-7.01(2H，m)，4.37-4.30(1H，dd)，4.22-4.18(1H，dd)，3.89-3.82(2H，m)，2.95-2.88(1H，dd)，2.63-2.57(1H，dd).
1H-NMR(400MHz，MeOD)δ(ppm)：7.52(1H，s)，7.33-7.27(5H，m)，7.18-7.10(2H，d)，7.07-7.01(2H，m)，6.95(1H，s)，6.88(1H，s)，4.08-3.93(2H，m)，3.72-3.66(2H，m)，2.75-2.68(1H，dd)，2.58-2.50(1H，dd)，2.22(3H，s).
1H-NMR(400MHz，MeOD)δ(ppm)：8.06(1H，s)，8.01(1H，s)，7.39-7.30(5H，m)，7.21-7.16(2H，d)，7.10-7.06(2H，d)，4.05-3.96(2H，m)，3.78-3.70(2H，m)，2.88-2.81(1H，dd)，2.62-2.55(1H，dd)，2.25(3H，s).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.02-7.98(1H，d)，7.65(1H，s)，7.35-7.28(5H，m)，7.22-7.18(2H，m)，7.15-7.08(2H，m)，6.89(1H，s)，4.13-4.08(1H，dd)，4.03-3.96(1H，dd)，3.78-3.70(2H，m)，2.82.2.74(1H，dd)，2.63-2.56(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.07(1H，s)，8.01(1H，s)，7.39-7.30(5H，m)，7.32-7.25(2H，m)，7.18-7.10(2H，m)，4.20-4.15(1H，dd)，4.09-4.01(1H，dd)，3.86-3.78(2H，m)，2.88-2.81(1H，dd)，2.69-2.61(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.01(1H，s)，7.72(1H，s)，7.42-7.36(5H，m)，7.36-7.30(2H，d)，7.08-7.01(2H，d)，6.97(1H，s)，4.36-4.30(1H，dd)，4.19-4.12(1H，dd)，3.92-3.86(2H，m)，2.91-2.85(1H，dd)，2.61-2.54(1H，dd).
1H-NMR(400MHz，DMSO-d
6)δ(ppm)：8.09(1H，s)，8.03(1H，s)，7.45-7.39(5H，m)，7.39-7.31(2H，d)，7.15-7.09(2H，d)，4.65-4.59(1H，dd)，4.25-4.18(1H，dd)，4.03-3.95(2H，m)，2.99-2.92(1H，dd)，2.73-2.66(1H，dd).
The steric isomer of gained compound has identical or very similar nmr spectrum data, therefore be omitted.The aromatic enzyme-tion suppressioning activity detected result of part of compounds is as shown in table 1.
Table 1
The above; it is only preferably embodiment of the present invention; protection scope of the present invention is not limited to this; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses, the simple change of the technical scheme that can obtain apparently or equivalence are replaced and are all fallen within the scope of protection of the present invention.
Claims (2)
1. a novel azaheterocyclic sulfone amide derivative type arimedex is characterized in that having following general structure:
2. the preparation method of a novel azaheterocyclic sulfone amide derivative type arimedex claimed in claim 1, is characterized in that, comprises the following steps:
(1) alkamine compound is synthetic
Reaction conditions A: under nitrogen protection and 0 ℃; raw material amino acid is dissolved in anhydrous tetrahydro furan; careful gradation adds LAH; reaction reheats backflow 4-10h from 0 ℃ slowly rises to room temperature; the TCL detection reaction is complete, in reaction system, adds while stirring the frozen water mark NaOH aqueous solution, has the sticky solid material to generate; wash solid by ethyl acetate after filtration, after the merging organic phase, use anhydrous MgSO
4Drying, obtain corresponding amino alcohol after the evaporated under reduced pressure solvent,
Reaction conditions B: under 0 ℃ of nitrogen protection, by raw material amino acid and NaBH
4Be dissolved in anhydrous tetrahydro furan, carefully add and be dissolved with I
2Anhydrous tetrahydrofuran solution, after reaction system reflux 8-18h, be down to room temperature, careful methyl alcohol to the solution that drips is clarified, then continues reaction 1h, evaporated under reduced pressure solvent, then repeatedly extract with methylene dichloride to the KOH aqueous solution that adds 20% in Residual reactants, merge organic phase and also use MgSO
4Drying, obtain corresponding amino alcohol after the hot water bath solvent evaporated;
(2) the yellow amides of aryl is synthetic
Corresponding amino alcohol compound is dissolved in to anhydrous methylene chloride, after being down to 0 ℃, first add triethylamine, slowly drip again corresponding arylsulfonyl chlorine compound, after slowly rising to room temperature, continue reaction 6-12h to TLC detection raw material reaction complete, after the evaporated under reduced pressure solvent, thick product is with using sherwood oil: the ethyl acetate volume ratio is 20-10: 1 eluent, through 100-200 order silica gel column chromatography, separate and obtain the yellow amides of corresponding aryl;
(3) the novel azaheterocyclic sulfone amide derivative is synthetic
The yellow amides of corresponding aryl is dissolved in methylene dichloride, after being down to 0 ℃, first add anhydrous triethylamine, slowly drip again methylsulfonyl chloride, after slowly rising to room temperature, continue reaction 8-15h to TLC detection raw material reaction complete, the evaporated under reduced pressure solvent, the thick not purified direct use of product is dissolved in toluene or anhydrous 1, the 4-dioxane, add imidazoles or triazole again, be heated to 60 ℃ of reaction 12-20h, it is complete that TLC detects raw material reaction, the evaporated under reduced pressure solvent, thin up, repeatedly extract by ethyl acetate, merges organic phase and use anhydrous Na
2SO
4Drying, the evaporated under reduced pressure solvent, thick product sherwood oil: ethyl acetate: the volume ratio of methyl alcohol=1: 5-12: 0.5-2 is eluent, through 200-300 order silica gel column chromatography, separates and obtains corresponding novel azaheterocyclic sulfone amide derivative.
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| US4908455A (en) * | 1984-04-03 | 1990-03-13 | Sumitomo Chemical Company, Limited | Method for producing an optically active azolyl-α β-unsaturated alcohol |
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