3-羟基雌甾-1,3,5(10),15-四烯-17-酮的高效合成

doi:10.7503/cjcu20160869

摘要/Abstract

摘要：

以雌酚酮为原料, 以取代的苯甲酰作为雌酚酮酚羟基的保护基, 乙二醇为雌酚酮羰基的保护基, 经过溴代、脱溴和水解等5步反应, 通过优化反应路线、反应试剂及反应条件, 以65%的高收率制得3-羟基雌甾-1,3,5(10),15-四烯-17-酮. 中间体及目标产物的结构经过元素分析、核磁共振波谱(NMR)和电喷雾电离-质谱(ESI-MS)确证.

关键词: 3-羟基雌甾-1,3,5(10), 15-四烯-17-酮, 雌酚酮, 高收率

Abstract:

As an important intermediate, 3-hydroxyestra-1,3,5(10),15-tetraene-17-one is widely used in the field of natural product synthesis and drug discovery, especially in the synthesis of estetrol which is produced only by the fetal liver during human pregnancy. In recent years a number of clinical studies have shown that estetrol can be used for perimenopausal syndrome and the replacement of postmenopausal hormone, the prevention and treatment of osteoporosis and breast cancer, and the oral contraceptives. Although the synthesis have been reported, low yield and complex purification process are main problems. In order to overcoming the current shortcomings, the development of a new route is necessary. In this paper, estrone was used as starting materials, substituted benzoyl group was applied to protect the phenolic hydroxyl group of estrone and ethanediol to protect the keto group. Phenyltrimethylammonium tribromide was selected as the optimal brominating reagent after deep exploration of reaction agents and reaction conditions. Then debromination and hydrolysis reaction was carried out to obtain 3-hydroxyestra-1,3,5(10),15-tetraen-17-one. The total yield of synthetic route was 65% and the purification of the target compound was 99.8% which was confirmed by liguid chromatography-mass spectrometry(LC-MS). The structures of all intermediates and the target compound were confirmed by elemental analysis, nuclear magnetic resonance(¹H NMR, ¹³C NMR) and electrospray inoization-mass spectrometry(ESI-MS).

Key words: 3-Hydroxyestra-1,3,5(10), 15-tetraene-17-one, Estrone, High yield

中图分类号:

O629.23

TrendMD:

滕以龙, 孙晓红, 刘源发, 马海霞. 3-羟基雌甾-1,3,5(10),15-四烯-17-酮的高效合成. 高等学校化学学报, 2017, 38(5): 764.

TENG Yilong, SUN Xiaohong, LIU Yuanfa, MA Haixia. Highly Effective Method for Synthesis of 3-Hydroxyestra-1,3,5(10),15-tetraene-17-one^†. Chem. J. Chinese Universities, 2017, 38(5): 764.

图/表 5

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Compd.	Appearance	Yield(%)	ESI-MS, m/z	Elemental analysis(%, calcd.)
Compd.	Appearance	Yield(%)	ESI-MS, m/z	C	H
1	White solid	99.2	432.31(M+Na)⁺	73.40(73.43)	6.13(6.16)
2	White solid	98.4	449.24(M-H)^-	71.54(71.59)	6.41(6.45)
3	White solid	91.6	531.28(M-H)^-	60.91(60.97)	5.28(5.31)
4	White solid	83.4	311.15(M-H)^-	76.84(76.89)	7.71(7.74)
5	White solid	87.3	269.19(M+H)⁺, 267.07(M-H)^-	80.49(80.56)	7.44(7.51)

Compd.	Appearance	Yield(%)	ESI-MS, m/z	Elemental analysis(%, calcd.)
Compd.	Appearance	Yield(%)	ESI-MS, m/z	C	H
1	White solid	99.2	432.31(M+Na)⁺	73.40(73.43)	6.13(6.16)
2	White solid	98.4	449.24(M-H)^-	71.54(71.59)	6.41(6.45)
3	White solid	91.6	531.28(M-H)^-	60.91(60.97)	5.28(5.31)
4	White solid	83.4	311.15(M-H)^-	76.84(76.89)	7.71(7.74)
5	White solid	87.3	269.19(M+H)⁺, 267.07(M-H)^-	80.49(80.56)	7.44(7.51)

Compd.	¹H NMR(400 MHz), δ	¹³C NMR(100 MHz), δ
1	8.22—8.07(m, 2H), 7.56—7.45(m, 2H), 7.36(d, J=8.5 Hz, 1H), 7.00(d, J=8.5 Hz, 1H), 6.96(s, 1H), 3.05—2.87(m, 2H), 2.62—2.40(m, 2H), 2.41—2.28(m, 1H), 2.26—1.91(m, 4H), 1.73—1.41(m, 6H), 0.95(s, 3H)	220.72, 164.60, 148.66, 140.06, 138.16, 137.63, 131.52, 128.92, 128.11, 126.52, 121.60, 118.76, 50.45, 47.96, 44.19, 38.02, 35.87, 31.57, 29.44, 26.36, 25.79, 21.61, 13.85
2	8.20—8.10(m, 2H), 7.57—7.43(m, 2H), 7.36(d, J=8.5 Hz, 1H), 6.98(d, J=8.5 Hz, 1H), 6.94(s, 1H), 4.04—3.87(m, 4H), 2.98—2.84(m, 2H), 2.44—2.23(m, 2H), 2.14—2.01(m, 1H), 1.99—1.74(m, 4H), 1.73—1.62(m, 1H), 1.58—1.30(m, 5H), 0.92(s, 3H)	164.61, 148.46, 139.98, 138.45, 138.32, 131.52, 128.89, 128.20, 126.51, 121.49, 119.38, 118.52, 65.28, 64.60, 49.40, 46.11, 43.87, 38.70, 34.24, 30.70, 29.59, 26.80, 26.01, 22.38, 14.34
3	8.22—8.07(m, 2H), 7.57—7.43(m, 2H), 7.34(d, J=8.5 Hz, 1H), 6.98(d, J=8.5 Hz, 1H), 6.93(s, 1H), 4.58(dd, J=10.5, 4.1 Hz, 1H), 4.38—4.13(m, 2H), 4.10—3.90(m, 2H), 3.00—2.82(m, 2H), 2.46—2.08(m, 4H), 2.07—1.73(m, 3H), 1.57—1.34(m, 4H), 0.95(s, 3H)	164.59, 148.56, 140.02, 138.25, 137.81, 131.52, 128.91, 128.14, 126.39, 121.56, 118.65, 116.81, 66.57, 66.24, 55.31, 47.52, 45.70, 43.64, 38.14, 35.15, 30.62, 29.41, 26.56, 25.69, 14.65
4	8.99(s, 1H), 7.01(d, J=8.4 Hz, 1H), 6.49(d, J=8.4 Hz, 1H), 6.43(s, 1H), 6.23(d, J=5.9 Hz, 1H), 5.70(dd, J=5.9, 3.1 Hz, 1H), 3.98—3.65(m, 4H), 2.86—2.61(m, 2H), 2.39—1.92(m, 4H), 1.90—1.71(m, 1H), 1.60—1.19(m, 4H), 0.84(s, 3H)	155.45, 137.49, 135.78, 132.81, 130.68, 126.20, 119.15, 115.43, 113.15, 65.04, 64.02, 55.60, 49.66, 44.42, 36.28, 29.86, 29.32, 27.32, 25.83, 16.70
5	9.03(s, 1H), 7.84(d, J=6.0 Hz, 1H), 7.03(d, J=8.3 Hz, 1H), 6.50(d, J=8.3 Hz, 1H), 6.45(s, 1H), 6.04(dd, J=6.0, 3.0 Hz, 1H), 2.97—2.62(m, 2H), 2.54—2.48(m, 1H), 2.41—2.09(m, 3H), 1.86—1.27(m, 5H), 0.97(s, 3H)	212.44, 160.02, 155.57, 137.44, 131.32, 130.37, 126.20, 115.49, 113.23, 55.71, 51.24, 44.86, 35.76, 29.35, 29.18, 26.56, 25.54, 21.10

Compd.	¹H NMR(400 MHz), δ	¹³C NMR(100 MHz), δ
1	8.22—8.07(m, 2H), 7.56—7.45(m, 2H), 7.36(d, J=8.5 Hz, 1H), 7.00(d, J=8.5 Hz, 1H), 6.96(s, 1H), 3.05—2.87(m, 2H), 2.62—2.40(m, 2H), 2.41—2.28(m, 1H), 2.26—1.91(m, 4H), 1.73—1.41(m, 6H), 0.95(s, 3H)	220.72, 164.60, 148.66, 140.06, 138.16, 137.63, 131.52, 128.92, 128.11, 126.52, 121.60, 118.76, 50.45, 47.96, 44.19, 38.02, 35.87, 31.57, 29.44, 26.36, 25.79, 21.61, 13.85
2	8.20—8.10(m, 2H), 7.57—7.43(m, 2H), 7.36(d, J=8.5 Hz, 1H), 6.98(d, J=8.5 Hz, 1H), 6.94(s, 1H), 4.04—3.87(m, 4H), 2.98—2.84(m, 2H), 2.44—2.23(m, 2H), 2.14—2.01(m, 1H), 1.99—1.74(m, 4H), 1.73—1.62(m, 1H), 1.58—1.30(m, 5H), 0.92(s, 3H)	164.61, 148.46, 139.98, 138.45, 138.32, 131.52, 128.89, 128.20, 126.51, 121.49, 119.38, 118.52, 65.28, 64.60, 49.40, 46.11, 43.87, 38.70, 34.24, 30.70, 29.59, 26.80, 26.01, 22.38, 14.34
3	8.22—8.07(m, 2H), 7.57—7.43(m, 2H), 7.34(d, J=8.5 Hz, 1H), 6.98(d, J=8.5 Hz, 1H), 6.93(s, 1H), 4.58(dd, J=10.5, 4.1 Hz, 1H), 4.38—4.13(m, 2H), 4.10—3.90(m, 2H), 3.00—2.82(m, 2H), 2.46—2.08(m, 4H), 2.07—1.73(m, 3H), 1.57—1.34(m, 4H), 0.95(s, 3H)	164.59, 148.56, 140.02, 138.25, 137.81, 131.52, 128.91, 128.14, 126.39, 121.56, 118.65, 116.81, 66.57, 66.24, 55.31, 47.52, 45.70, 43.64, 38.14, 35.15, 30.62, 29.41, 26.56, 25.69, 14.65
4	8.99(s, 1H), 7.01(d, J=8.4 Hz, 1H), 6.49(d, J=8.4 Hz, 1H), 6.43(s, 1H), 6.23(d, J=5.9 Hz, 1H), 5.70(dd, J=5.9, 3.1 Hz, 1H), 3.98—3.65(m, 4H), 2.86—2.61(m, 2H), 2.39—1.92(m, 4H), 1.90—1.71(m, 1H), 1.60—1.19(m, 4H), 0.84(s, 3H)	155.45, 137.49, 135.78, 132.81, 130.68, 126.20, 119.15, 115.43, 113.15, 65.04, 64.02, 55.60, 49.66, 44.42, 36.28, 29.86, 29.32, 27.32, 25.83, 16.70
5	9.03(s, 1H), 7.84(d, J=6.0 Hz, 1H), 7.03(d, J=8.3 Hz, 1H), 6.50(d, J=8.3 Hz, 1H), 6.45(s, 1H), 6.04(dd, J=6.0, 3.0 Hz, 1H), 2.97—2.62(m, 2H), 2.54—2.48(m, 1H), 2.41—2.09(m, 3H), 1.86—1.27(m, 5H), 0.97(s, 3H)	212.44, 160.02, 155.57, 137.44, 131.32, 130.37, 126.20, 115.49, 113.23, 55.71, 51.24, 44.86, 35.76, 29.35, 29.18, 26.56, 25.54, 21.10

Substrate	Reagent	t/h	Solvent	Yield(%)
Estetrone	PyBr₃	12	HAc	<10
	PhMe₃NBr₃	12	THF	<10
	Br₂	3	DCM	<10
1	PyBr₃	12	HAc	25
	PhMe₃NBr₃	12	THF	65
	Br₂	3	DCM	60
2	PyBr₃	12	HAc	50
	PhMe₃NBr₃	12	THF	91.6
	Br₂	3	DCM	30