Highly Effective Method for Synthesis of 3-Hydroxyestra-1,3,5(10),15-tetraene-17-one†

doi:10.7503/cjcu20160869

Abstract

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

CLC Number:

O629.23

TrendMD:

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

Figures/Tables 5

References 25

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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