Article pubs.acs.org/OPRD
An Improved Synthesis of Nomegestrol Acetate He-Lin Lu,† Zong-Wen Wu,† Shu-Yong Song,† Xiao-Dan Liao,‡ Yan Zhu,*,§ and Yun-Sheng Huang*,† †
Guangdong Medical College School of Pharmacy, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan 523808, China Key Laboratory for South China Essential Oil Under the Ministry of Traditional Chinese Medicine, Zhanjiang 524018, China § Department of Reproductive Pharmacology, Shanghai Institute of Planned Parenthood Research, Shanghai 200032, China ‡
S Supporting Information *
ABSTRACT: Oral contraceptives (OCs) are synthetic steroids, or progestins, which are structurally related to testosterone or to progesterone. Many progestins have been synthesized and approved for OCs, hormonal replacement therapy (HRT), or the treatment of some gynecological disorders. Nomegestrol acetate (NOMAc) is a newly approved OC and has gained rapid acceptance in many countries for OC or HRT. The synthesis of NOMAc remains challenging and costly. We have developed a novel and improved procedure for the synthesis of NOMAc with a total of 11 steps and an overall good yield without the use of hazardous reagents.
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INTRODUCTION
RESULTS AND DISCUSSION The major challenge in synthesizing NOMAc is to put a hydroxyl at the α position on carbon 17. In addition to the osmium tetroxide oxidation method, there are three methods reported in the literature to convert a steroid 17-ketone structure to the corresponding 17α-hydroxy progesterone derivative. The first method is to react a cyanide compound to form the corresponding 17α-hydroxy-17β-cyano analogue, followed by a number of steps involving intramolecular cyclization and ring-opening or by reacting with methyl lithium/ether to give the desired structure.30 The second method involves the 17-ketosteroid reacting with acetylene/tBuOK to afford the 17β-hydroxy-17α-ethynyl analogue that is then transformed to the corresponding 17α-hydroxy progesterone structure with benzenesulfenyl chloride.31 The third method involves converting the 17β-hydroxy-17α-ethynyl steroid to the 21-ketone through the use of mercury(II) acetate and subsequently inverting the C-17 stereo configuration.32 The second method offers process advantages over the other two in terms of cost and potentially lower environmental impact. Thus, we selected the commercially readily available estrone as the starting material and designed a route based on the second method of sulfoxide−sulfenate rearrangement with a total of 11 steps to obtain the desired product in excellent overall yields and high purity (Scheme 1). Intermediate 4, also known as mestranol, was synthesized by methylation and subsequent acetylenylation in high yields. Compound 5 was easily prepared by reacting 4 with benzenesulfenyl chloride according to a modified procedure at 0 °C to room temperature.31 Though the exact stereochemistry of the allene of compound 5 is not clear, the C-13 NMR indicated that it should have at least 2 stereoisomers that were converted to the same compound 6 when they were treated by sodium methoxide, followed by trimethyl phosphite in excellent yield. The keto group of 6 was easily protected with
NOMAc belongs to a new generation of synthetic progestins that possess high affinities for progesterone receptor, low or no affinities for estrogen, androgen, glucocorticoid or mineralocorticoid receptors.1−3 Early synthetic progestins, such as norethynodrel (NOR), norethisterone (NET), levonorgestrel (LNG), norgestrel (NG), gestodene (GES), desogestrel (DSG), norgestimate (NGM), etc., were derived from the structure of testosterone (estranes and gonanes). Subsequently introduced progestins, such as medroxyprogesterone acetate (MPA), chlormadinone acetate (CMA), cyproterone acetate (CPA), promegestone, nomegestrol acetate (NOMAc), trimegestone (TMG), nestorone (NES), etc., were derived from the structure of progesterone (pregnanes and norpregnanes).4,5 The most recently developed progestins, also called the fourth generation, include dienogest (DNG), NOMAc, TMG, NES, which were derived from the structure of pregnane.4,6,7 Progestins inhibit ovulation by suppressing the natural production of menstrual-cycle hormones and are often used in combination with an estrogen which is added for better cycle control.8−19 Early generations of progestins had some offtarget side effects in addition to their beneficial therapies.20−24 Newly developed progestins are expected to have few or no undesired side effects and may be applied for treatment of many kinds of gynecological diseases.25−27 The synthesis of NOMAc has been a challenging and costly task due to the applications of some expensive reagents and lengthy synthetic routes. There are a couple of synthetic methods documented for the synthesis of NOMAc.28,29 The first one uses 17α-acetyloxy-19-norprogesterone as the starting material that is not available commercially.28 The second method requires the use of osmium tetroxide that is both expensive and environmentally hazardous.29 Here we report a newly developed synthetic method for nomegestrol acetate starting from readily available raw materials and affording good overall yields. © 2014 American Chemical Society
Received: December 11, 2013 Published: February 4, 2014 431
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Scheme 1. Synthesis of NOMAca
Reagents and conditions: a) Me2SO4/NaOH/acetone, reflux; b) t-BuOK/acetylene/THF, 0−5 °C; c) PhSCl/Et3N/DCM, 0 °C to RT; d) NaOMe/P(OMe)3/MeOH, reflux; e) ethylene glycol/p-TSA, RT; f) Na/liquid NH3, −60 °C; g) (AcO)2O, RT; h) CH(OEt)3/THF, RT; i) POCl3/DMF, −10 °C; j) NaBH4/MeOH, HCl, RT; k) Pd−C/EtOH, reflux. a
reacted with benzenesulfenyl chloride to form the corresponding 17α-ethynyl-17β-sulfenate intermediate that subsequently underwent a [2,3]-sigmatropic rearrangement to form the corresponding intermediate 5. Though benzenesulfenyl chloride can easily react with double and triple bonds, the 17βhydroxyl group is much more reactive, and as a result, the 17βsulfenate is the dominant product. Compound 5 underwent Michael addition with sodium methoxide to give an intermediate that underwent another [2,3]-sigmatropic rearrangement to afford the corresponding ketone analogue 6 after the treatment of hydrochloric acid. The subsequent transformations of intermediates 6 to 7, 8, 9, 10, 11, and 12 were carried out by conventional chemistry without any difficulties. The double bond isomerization of intermediate 12 to the desired product 1 was performed with the catalysis of palladium on active carbon.33,34 A possible palladium(0) catalytic mechanism involves coordination of the palladium to the double bond, hydride elimination, and dissociation of the palladium to result in the hydride migrated product. All the novel intermediates and the final product have been characterized by both 1H NMR and 13C NMR. There was no previous report of 1H NMR or 13C NMR spectral data for NOMAc or the intermediates involved in this route. An attempt to assign the 1H NMR spectra to the corresponding protons was unsuccessful due to the overcrowded and overlapped signals in the region between 1 to 3 ppm, which
ethylene glycol to form the intermediate 7 that was subsequently carried out Birch reduction at −60 °C with sodium in liquid ammonia to afford 8 in high yield. Intermediate 9 was obtained by acetylation of 8 and was subsequently reacted with triethyl orthoformate to give 10 in excellent yields in both steps. Compound 10 underwent Vilsmeier formylation at the C-6 position to afford compound 11 in good yield. Reduction of 11 with sodium borohydride gave intermediate 12 which then underwent a double bond isomerization by the catalysis of palladium on charcoal to afford the desired compound NOMAc (1). This synthetic route consists of a total of 11 steps and affords an overall yield of 18.8%, in which the conversion of 4 to 5 gave the lowest yield of 71% and has the potential for improvement due to the existence of two or more isomers that may actually not be necessary for purification. The last step of double bond isomerization affords the second lowest yield of 77%, mainly due to the repeated recrystallization to obtain the desired product with a purity of 99.8% (187 nm) or 99.4% (254 nm). The conversions of 9 to 10 and 11 to 12 both gave about 80% yield and should have the potential for improvement as well, since both are relatively conventional process chemistry. There was an in-depth discussion of the mechanisms involved in the sulfoxide−sulfenate rearrangement by VanRheenen and Shephard.31 Their proposed mechanisms can also explain the transformation of intermediate 4 to 5 and then to 6 in this synthesis. The 17α-ethynyl-17β-hydroxy intermediate 4 432
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Table 1. Assignment of 13C NMR spectra of compounds 5−12 and NOMAc (1) cmpd C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10 C-11 C-12 C-13 C-14 C-15 C-16 C-17 C-18 C-19 C-20 C-21 3-OMe SO-Ph
ethylenedioxy 17-OAc 3-OEt
6
7
8
12
1
126.26 111.58
5
126.30 111.51
126.29 111.41
36.49 35.49
36.48 35.41
28.87 27.33
28.54 26.59
39.05 37.19
37.51 26.97
113.83
113.83
113.78
124.63
124.67
99.63
93.33
122.82
121.77
29.77 27.73 38.74 43.74
29.84 27.86 38.65 43.37
29.94 27.72 38.51 43.34
26.55 27.78
26.11 30.38
26.31 31.55
30.09 26.59 40.27 49.02 42.47 25.96 31.16
30.26 26.56 40.36 48.80 42.36 26.04 31.00
117.47 30.47 37.06 43.26 41.32 26.32 31.08
29.10 35.83 43.17 42.48 26.42 30.50
27.54 40.12 47.30 43.22 26.07 30.28
139.56 41.00 45.56 41.06 24.92 30.26
54.43 24.62 35.86
49.61 23.75 33.61
49.85 22.70 32.79
49.28 23.74 33.46
50.35 23.67 31.08
51.24 23.76 31.29
50.98 23.71 30.90
50.62 23.59 30.88
48.66 23.16 30.98
18.81
15.57
14.66
15.43
14.42
14.32
14.31
14.38
14.19
27.96 55.22
21.09 55.22
27.85
26.36
26.42
26.53
26.39
26.40
21.25(Me)
21.26(Me) 62.31 (CH2) 14.63(Me)
21.22(Me)
21.20(Me)
104.89 55.22 129.14(o) 124.40(m) 130.70(p)
9
10
11
63.52 66.21
6-CHO 6-CH2 6-Me
21.24(Me) 63.23(CH2) 14.43(Me) 189.55
114.43 19.32
compounds,35−38 we assigned 35.86, 29.77, 27.78, 27.73, 26.55, and 24.61 ppm to C-16, C-6, C-12, C-7, C-11, and C-15, respectively. On the basis of the same criteria, we assigned each of the corresponding C-13 NMR spectra for compounds 6, 7, 8, 9, 10, 11, 12, and 1, as summarized in Table 1.
may require the use of 2D NMR techniques, such as correlation spectroscopy (COSY), nuclear Overhauser effect spectroscopy (NOESY), heteronuclear multiple bond coherence (HMQC), etc. But the 1H NMR signals from protons of the unsaturated carbon atoms, the OMe (on C-3), the Me (C-18), the Me (C21), the Me of the 17α-OAc, the methylene (on C-6), or the Me (on C-6) are clearly identified in the corresponding 1H NMR spectra (see the assignment in the Experimental Section and the corresponding spectra in the Supporting Information). On the other hand, the 13C NMR (DEPT) spectra nicely displayed each individual proton-attached carbon (such as CH3, CH, and CH2) signal. We have assigned each of the CH, CH2, and CH3 13C NMR signal to the corresponding carbon (Table 1). The 13C NMR spectrum of intermediate 5 clearly shows 9 CH carbon units with 5 from the SOPh aromatic portion (paraC 130.70 ppm, ortho-Cs 129.14 ppm, and meta-Cs 124.40 ppm), 3 from the ring A aromatic moiety (C-1 126.26 ppm, C2 111.58 ppm, and C-4 113.82 ppm), and 1 signal from the C21 (104.89 ppm). The 3 signals at 54.43, 43.74, and 38.74 ppm are assigned for the tertiary carbons C-14, C-9, and C-8 respectively. The OMe of the 3 position shows a signal at 55.22 ppm, whereas the C-18 carbon displays a signal at 18.81 ppm. The 13C NMR signals for the CH2 carbon units (C6,7,11,12,15,16) are not so obviously confirmed due to close or overlapped resonances that are very sensitive by even small structural changes. On the basis of several published reference
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CONCLUSIONS A novel and improved synthesis of the newly introduced contraceptive progestin NOMAc has been developed in 11 steps with a combined yield of 18.8%, or an average of more than 85% yield for each step. One of the key steps involved in the transformation of 17α-ethynyl-17β-hydroxy to the corresponding 17α-hydroxy-17β-acetyl steroid was accomplished by a process of double [2,3]-sigmatropic rearrangements. The resultant intermediate 6 was obtained in both excellent yield and good purity. This newly designed synthetic method has significant advantages, in terms of cost, safety, and environmental friendliness, over the previously documented methods that involved the use of highly toxic, flammable, or expensive reagents.
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EXPERIMENTAL SECTION General. All chemicals were purchased as reagent grade and used directly without further purification. The reactions were monitored by analytical thin-layer chromatography (TLC) on silica gel F254 glass plates and visualized under UV light (254
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mixture was cooled to room temperature and then poured into ice-cold 2 N HCl (1 L). The solid was filtered and recrystallized from ethyl acetate/petroleum ether to afford compound 6 as a white solid (41.00 g, yield 89%), mp 149−151 °C. 1H NMR (CDCl3, ppm): δ 7.21−7.23 (d, 1H), 6.72−6.75 (dd, 1H), 6.65−6.66 (dd, 1H), 3.80 (s, 3H), 2.85−2.92 (m, 2H), 2.70− 2.77 (dt, 2H), 2.25−2.39 (m, 5H), 1.89−2.00 (m, 4H), 1.64− 1.71 (m, 1H), 1.45−1.55 (m, 5H), 0.79 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 126.30 (C-1), 113.83 (C-4), 111.51 (C-2), 55.22 (OMe), 49.61 (C-14), 43.37 (C-9), 38.65 (C-8), 33.61 (C-16), 30.38 (C-12), 29.84 (C-6), 27.96 (C-21), 27.86 (C-7), 26.11 (C-11), 23.75 (C-15), 15.57 (C-18). 20,20-(Ethylenedioxy)-3-methoxy-17α-hydroxy-19norpregna-1,3,5(10)-triene (7). To a 500 mL round bottle was added DCM (300 mL), compound 6 (40.00 g, 0.12 mol), p-TSA (2.00 g, 0.012 mol), ethylene glycol (36.00 g, 0.58 mol), and trimethyl orthoformate (50.00 g, 0.47 mol). The reaction was stirred at room temperature for 2 h and then poured into water. The organic phase was separated, washed with brine, and dried over Na2SO4. The solid was removed, and the solution was concentrated to dryness. The crude product was recrystallized from methanol to afford compound 7 as a white solid (39.00 g, yield 88%, HPLC > 98%), mp 125−126 °C. 1H NMR (CDCl3, ppm): δ 7.22−7.24 (d, 1H), 6.72−6.74 (d, 1H), 6.66 (s, 1H), 4.07−4.10 (m, 2H), 3.89−3.97 (m, 2H), 3.80 (s, 3H), 2.87−2.91 (m, 2H), 2.24−2.34 (m, 4H), 1.76− 2.10 (m, 5H), 1.43−1.54 (m, 7H), 1.26−1.31 (m, 1H), 0.88 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 126.29 (C-1), 113.78 (C-4), 111.41 (C-2), 66.21 (OCH2−), 63.53 (−CH2O), 55.22 (OMe), 49.85 (C-14), 43.35 (C-9), 38.51 (C-8), 32.79 (C-16), 31.55 (C-12), 29.94 (C-6), 27.72 (C-7), 26.31 (C-11), 22.70 (C-15), 21.09 (C-21), 14.66 (C-18). 17α-Hydroxy-19-norpregna-4-ene-3,20-dione (8). Under nitrogen and at −60 °C, ammonia gas was bubbled into a 2-L bottle until about 1000 mL of liquid ammonia was collected. Sodium (16.00 g, 0.67 mol) was added, and the solution was stirred at −60 °C for 20 min. A solution of 7 (25.00 g, 0.067 mol) in THF (500 mL) was added dropwise. Then tert-butanol (100 mL) and ethanol (200 mL) were added, and the reaction was stirred at −60 °C until the complete disappearance of the raw material. Ethanol (200 mL) was added to quench the reaction, and the solution was left to warm to room temperature with a gas trap to collect the evaporated ammonia. The remaining solvent was concentrated, and the residue was added to a solution of THF (200 mL) and 1.3 N HCl (40 mL) and stirred at 60 °C for 20 min. The solvent was concentrated, and the residue was poured into water. The solid was collected by filtration and dried to give 8 (18.60 g, yield 87.7%, HPLC > 98%), mp 214−216 °C. 1H NMR (CDCl3, ppm): δ 5.80 (s, 1H), 2.64−2.67 (m, 2H), 2.30−2.50 (m, 2H), 2.22−2.26 (m, 4H), 2.05−2.15 (m, 1H), 1.71−1.78 (m, 5H), 1.54−1.58 (m, 4H), 1.34−1.37 (m, 2H), 1.15−1.25 (m, 3H), 0.89−0.91 (m, 1H), 0.75 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 124.63 (C-4), 49.28 (C-14), 49.01 (C-9), 42.46 (C10), 40.27 (C-8), 36.49 (C-1), 35.49 (C-2), 33.46 (C-16), 31.16 (C-12), 30.09 (C-6), 26.59 (C-7), 25.96 (C-11), 23.74 (C-15), 15.43 (C-18). 17α-Acetoxy-19-norpregna-4-ene-3,20-dione (9). To a 100 mL reaction bottle was added intermediate 8 (14.00 g, 0.044 mol), acetic anhydride (52.00 g, 0.51 mol), and p-TSA (0.30 g, 1.4 mmol). The reaction was stirred at room temperature for 24 h and then poured into water (200 mL). The solid was filtered and recrystallized from ethanol to give a
and 365 nm). Flash column chromatography was performed on silica gel (200−300 mesh). 1H NMR spectra were recorded with a Bruker Avance III 400 MHz NMR spectrometer at room temperature. Chemical shifts (in ppm) were recorded as parts per million (ppm) downfield to tetramethylsilane (TMS). The following abbreviations are used for multiplicity of NMR signals: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet, (dd) double doublet, (dt) double triplet, (dq) double quartet, (br) broad. 13C NMR or 13C attached-proton-test (13CApt) spectra were recorded with Bruker Avance III 400 MHz NMR spectrometer (100 MHz) and calibrated with CDCl3 (δ = 77.23 ppm). High-resolution mass spectra were recorded with a Waters LCT Premier XE mass spectrometer. 3-Methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17β-ol (4). 3-Methoxy-19-norpregna-1,3,5(10)- trien-20-yn-17β-ol was prepared according to a modified procedure of Wong et al.34 Estrone (100.00 g, 0.37 mol), acetone (500 mL), and 5 N NaOH (75 mL) was added to a three-neck 1-L round bottle. To the reaction mixture under stirring was added Me2SO4 (47.00 g, 0.37 mol) portionwise. The reaction was heated to reflux for 2 h and cooled to room temperature; the solid was filtered off and concentrated to dryness. The crude product was crystallized from ethyl acetate/petroleum ether to give estrone3-methyl ether as a white solid product 3 (103.00 g, yield 98%, HPLC > 98%), mp 167−169 °C (172−174 °C in ref 39). Compound 3 (100.00 g, 0.35 mol), THF (1000 mL), and potassium tert-butoxide (55.00 g, 1.40 mol) were added to a 2L four-neck round bottle and was stirred vigorously while acetylene gas was bubbled to the bottom at 0−20 °C for 2−2.5 h. The reaction mixture was poured into ice−water (2 L), and the solid was filtered, washed with water, and dried to afford 17α-ethinyl-17β-hydroxy analogue 4 as a white solid (107 g, yield 98%, HPLC > 97%), mp 154−155 °C (151−154 °C in reference 39). 3-Methoxy-21-(phenylsulfinyl)-19-norpregna-1(2),3(4),5(10),17(20),20-pentaene (5). To a 2-L round bottle was added 4 (100.00 g, 0.32 mol), DCM (1 L), and triethylamine (140 mL). The mixture was stirred until dissolution, phenylsulfenyl chloride (55.00 g, 0.38 mol) was added at 0 °C, and the reaction mixture was stirred at that temperature for 2 h. The mixture was poured into water (1 L), and the organic phase was separated, washed with saturated NaCl aqueous solution, and dried with Na2SO4. The solid was filtered off, and the solution was concentrated in vacuo to give an oily crude product that was recrystallized from ethyl acetate/petroleum ether to give a white solid product 5 (95.00 g, yield 71%), mp 267−270 °C. 1 H NMR (CDCl3, ppm): δ 7.67−7.69 (dd, 2H), 7.49−7.58 (m, 3H), 7.20−7.22 (d, 1H), 6.72−6.75 (dd, 1H), 6.65−6.66 (d, 1H), 6.17−6.19 (t, 1H), 3.80 (s, 3H), 2.88−2.92 (m, 2H), 2.74−2.80 (m, 1H), 2.57−2.64 (m, 1H), 2.34−2.38 (m, 1H), 2.23−2.27 (br, 1H), 1.93−1.95 (m, 2H), 1.73−1.79 (m, 2H), 1.41−1.57 (m, 5H), 0.95 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 130.70 (para-C of SOPh), 129.14 (2 ortho-Cs of SOPh), 126.26 (C-1), 124.40 (meta-Cs of SOPh), 113.82 (C4), 111.58 (C-2), 104.89 (C-21), 55.22 (OMe), 54.43 (C-14), 43.74 (C-9), 38.74 (C-8), 35.86 (C-16), 29.77 (C-6), 27.78 (C12), 27.73 (C-7), 26.55 (C-11), 24.62 (C-15), 18.81 (C-18). 3-Methoxy-17α-hydroxy-19-norpregna-1,3,5(10)trien-20-one (6). To a 2-L round bottle was added methanol (1 L), sodium methoxide (4.00 g, 0.074 mol), and 5 (60.00 g, 0.14 mol). The mixture was stirred and heated to reflux for 2−3 h; then trimethylphosphite (19.00 g, 0.15 mol) was added, and the reaction was stirred at reflux for an additional 2 h. The 434
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3H), 1.75−1.85 (m, 3H), 1.45−1.65 (m, 3H), 1.25−1.40 (m, 2H), 1.02−1.12 (dq, 1H), 0.69 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 122.82 (C-4), 111.43 (CH2 of 6′), 50.62 (C-14), 47.30 (C-9), 43.22 (C-10), 40.11 (C-8), 39.05 (C-1), 37.19 (C-2), 30.88 (C-16), 30.28 (C-12), 27.54 (C-7), 26.38 (C-21), 26.07 (C-11), 23.59 (C-15), 21.22 (Me of OAc), 14.37 (C-18). 6-Methyl-3,20-dioxo-19-norpregna-4,6-dien-17-yl acetate (1). To a 250 mL round bottle was added the above compound 12 (7.00 g, 0.019 mol), THF (50 mL), ethanol (10 mL), and 5% Pd−C (7.00 g, 54% water). The mixture was stirred at refluxing for 45 min, and then the solid catalyst was filtered off. The solution was concentrated to dryness, and the crude product was recrystallized from petroleum ether/ethyl acetate to afford a white solid 1 (5.40 g, yield 77%, HPLC > 99.8%), mp 214−215 °C. 1H NMR (CDCl3, ppm): δ 6.04 (s, 1H), 5.95 (s, 1H), 2.96−3.02 (dt, 1H), 2.54−2.58 (dd, 1H), 2.27−2.40 (m, 3H), 1.98−2.18 (m, 8H, including two large singlet peaks at 2.10 and 2.06, respectively), 1.78−1.95 (m, 7H, including a large singlet at 1.85), 1.52−1.63 (m, 2H), 1.38− 1.47 (m, 1H), 1.28−1.37 (dq, (1H), 1.15−1.25 (dq, 1H), 0.71 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 139.56 (C-7), 121.77 (C-4), 48.66 (C-14), 45.56 (C-9), 41.06 (C-10), 41.00 (C-8), 37.50 (C-1), 30.98 (C-16), 30.26 (C-12), 26.97 (C-2), 26.40 (C-21), 24.92 (C-11), 23.16 (C-15), 21.20 (Me of OAc), 19.32 (Me of 6′), 14.19 (C-18). MS (ES): 371 (M + 1). Elemental analysis: C 74.52, H 8.286 (calc: C 74.56, H 8.16). Optical rotation = −62.6 in absolute ethanol at 22 °C (EP 7.0 ref: −60 to −64 in absolute ethanol at 25 °C).
white solid product 9 (15.00 g, yield 95%, HPLC > 98%), mp 227−229 °C. 1H NMR (CDCl3, ppm): δ 5.87 (s, 1H), 2.96− 3.00 (t, 1H), 2.42−2.54 (m, 2H), 2.27−2.34 (m, 3H), 2.01− 2.14 (m, 7H), 1.87−1.98 (m, 3H), 1.73−1.81 (m, 3H), 1.56− 1.61 (m, 2H), 1.29−1.45 (m, 3H), 1.15−1.19 (dq, 1H), 0.95− 0.99 (dq, 1H), 0.72 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 124.66 (C-4), 50.35 (C-14), 48.80 (C-9), 42.36 (C-10). 40.36 (C-8), 36.48 (C-1), 35.41 (C-2), 31.08 (C-16), 31.00 (C-12), 30.26 (C-6), 26.56 (C-7), 26.36 (C-21), 26.04 (C-11), 23.67 (C-15), 21.25 (C-23), 14.42 (C-18). 3-Ethoxy-17α-acetoxy-19-norpregna-3,5-diene-20one (10). To a 500 mL round bottle was added intermediate 9 (14.00 g, 0.039 mol), THF (250 mL), triethyl orthoformate (14.00 g, 0.094 mol), and p-TSA (0.25 g, 1.45 mmol). The mixture was stirred at room temperature for 24 h and then was concentrated under reduced pressure to about 50 mL; methanol (20 mL) was added, and the flask was placed in a refrigerator overnight. The solid was collected by filtration to give product 10 (12.40 g, yield 80%), mp 161−163 °C. 1H NMR (CDCl3, ppm): δ 5.86 (s, 1H), 3.71−3.77 (q, 2H), 2.93− 2.98 (dt, 1H), 2.42−2.53 (m, 2H), 2.26−2.34 (m, 3H), 2.13 (s, 3H), 2.07 (s, 3H), 1.85−2.05 (m, 2H), 1.75−1.81 (m, 3H), 1.56−1.60 (m, 2H), 1.32−1.44 (m, 4H), 1.28−1.30 (t, 3H), 1.12−1.21 (dq, 1H), 0.93−1.02 (dq, (1H), 0.71 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 117.47 (C-6), 99.63 (C-4), 62.31 (OCH2− of OEt), 51.24 (C-14), 43.26 (C-9), 41.32 (C10), 37.06 (C-8), 31.29 (C-16), 31.07 (C-12), 30.47 (C-7), 28.87 (C-1), 27.33 (C-2), 26.42 (C-21), 26.32 (C-11), 23.76 (C-15), 21.26 (Me of OAc), 14.63 (Me of OEt), 14.32 (C-18). 6-Formyl-3-ethoxy-17α-acetoxy-19-norpregna-3,5diene-20-one (11). To a 100 mL round bottle was added intermediate 10 (12.00 g, 0.03 mol), DMF (50 mL). The mixture was stirred, and a solution of freshly prepared Vilsmeier reagent (6.50 g POCl3 was added to 18 mL of DMF dropwise at −10 °C) was added to the solution dropwise at −10 °C. The reaction was then poured into saturated aqueous NaHCO3 solution (200 mL). The product was extracted with DCM, washed, and dried with Na2SO4. The solvent was removed under reduced pressure, and the product was recrystallized from methanol to afford a light-yellow solid product 11 (10.80 g, yield 87%), mp 206−208 °C. 1H NMR (CDCl3, ppm): δ 10.25 (s, 1H), 6.37 (s, 1H), 3.86−3.98 (m, 2H), 2.92−2.97 (dt, 1H), 2.55−2.61 (dd, 1H), 2.21−2.40 (m, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 1.98−2.05 (m, 3H), 1.68−1.88 (m, 4H), 1.57− 1.63 (m, 1H), 1.20−1.45 (m, 7H, including a large triplet peak at 1.37−1.41), 0.97−1.06 (dq, 1H), 0.67 (s, 3H). 13C NMR (DEPT, CDCl3, ppm): δ 189.55 (CHO), 93.33 (C-4), 63.23 (OCH2− of OEt)), 50.98 (C-14), 43.16 (C-9), 42.47 (C-10), 35.83 (C-8), 30.89 (C-16), 30.50 (C-12), 29.10 (C-7), 28.54 (C-1), 26.59 (C-2), 26.53 (C-21), 26.42 (C-11), 23.71 (C-15), 21.24 (CH3 of OAc), 14.43 (CH3 of OEt), 14.31 (C-18). 6- Methlene-17α-acetoxy-19-norprogesterone (12). To a 500 mL round bottle was added intermediate 11 (10.50 g, 0.025 mol) and methanol (350 mL). The mixture was stirred at room temperature, and NaBH4 (1.13 g, 0.0299 mol) was added. The pH of the reaction mixture was adjusted to 4 with concentrated HCl; the reaction was then concentrated to about 50 mL and poured into water. The solid was collected by filtration and recrystallized from methanol to give a white solid product 12 (7.30 g, yield 79%), mp 197−198 °C. 1H NMR (CDCl3, ppm): δ 6.12 (s, 1H), 5.20 (s, 1H), 4.98 (s, 1H), 2.94−3.00 (dt, 1H), 2.46−2.53 (dt, 2H), 2.24−2.36 (m, 2H), 2.17−2.20 (dt, 1H), 2.13 (s, 3H), 2.06 (s, 3H), 1.92−2.04 (m,
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ASSOCIATED CONTENT
S Supporting Information *
Spectroscopic data (1H and 13C NMR) for intermediates and the product. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*Telephone: +86-0769-22896547. E-mail:
[email protected]. cn. *Telephone: +86-21-64438416. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was financially supported by the 12th 5-year National Science Research under the Ministry of Science and Technology of the People’s Republic of China (Grant No. 2012BAI31B01).
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REFERENCES
(1) Lello, S. Nomegestrol acetate: pharmacology, safety profile, and therapeutic efficacy. Drugs 2010, 70 (5), 541−559. (2) Ruan, X.; Seeger, H.; Mueck, A. O. The pharmacology of nomegestrol acetate. Maturitas 2012, 71, 345−353. (3) Mueck, A. O.; Sotruk-Ware, R. Nomegestrol acetate, a novel progestogen for oral contraception. Steroid 2011, 76, 531−539. (4) Ouzounian, S.; Verstraete, L.; Chabbert-Buffet, N. Thirdgeneration oral contraceptives: Future implications of current use. Expert Rev. Obstet. Gynecol. 2008, 3 (2), 190−201. (5) Sitruk-Ware, R. Pharmacological profile of progestins. Maturitas 2008, 61 (1−2), 151−157.
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(6) Stitruk-Ware, R.; Nath, A. The use of newer progestins for contraception. Contraception 2010, 82, 410−417. (7) Mansour, D. Review use of the new progestogens in contraception and gynaecology. Obstet. Gynecol. 2006, 8, 229−234. (8) Fleischman, D. S.; Navarrete, C. D.; Fessler, D. M. T. Oral contraceptives suppress ovarian hormone production. Psychol. Sci. 2010, 21 (5), 750−752. (9) Fruzzetti, F.; Tremollieres, F.; Bitzer, J. An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest. Gynecol. Endocrinol. 2012, 28 (5), 400−408. (10) Fruzzetti, F.; Bitzer, J. Review of clinical experience with estradiol in combined oral contraceptives. Contraception 2010, 81, 8− 15. (11) Borgelt, L. M.; Martell, C. W. Estradiol valerate/dienogest: a novel combined oral contraceptive. Clin. Ther. 2012, 34 (1), 37−55. (12) Pintiaux, A.; Gaspard, U.; Nisolle, M. Zoley, a combined oral contraceptive. Monophasic pill containing estradiol and nomegestrol acetate. Rev. Med. Liege. 2012, 67 (3), 152−156. (13) Christin-Maitre, S.; Serfaty, D.; Chabbert-buffet, N.; Ochsenbein, E.; Chassard, D.; Thomas, J. L. Comparison of a 24day and a 21-day pill regimen for the novel combined oral contraceptive, nomegestrol acetate and 17β-estradiol (NOMAc/E2): A double-blind randomized study. Hum. Reprod. 2011, 26 (6), 1338− 2011. (14) Mansour, D.; Verhoeven, C.; Sommer, W.; Weisberg, E.; Taneepanichskul, S.; Melis, G. B.; Sundstrom-Poromaa, I.; Korver, T. Efficacy and tolerability of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in a 24/4 regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen. Eur. J. Contracept. Reprod. Health Care 2011, 16 (6), 430−443. (15) Agren, U. M.; Anttila, M.; Maenpaa-Liukko, K.; Rantala, M-L; Tautiainen, H.; Sommer, W. F.; Mommers, E. Effects of a monophasic combined oral contraceptve containing nomegestrol acetate and 17βoestradiol in comparison to one containing levonorgestrel and ethinylestradiol on markers of endocrine function. Eur. J. Contracept. Reprod. Health Care 2011, 16 (6), 458−467. (16) Christin-Maitre, S.; Laroche, E.; Bricaire, L. A new contraceptive pill containing 17β-estradiol and nomegestrol acetate. Women’s Health 2013, 9 (1), 13−23. (17) Westhoff, C.; Kaunitz, A. M.; Korver, T.; Sommer, W.; Bahamondes, L.; Darney, P.; Verhoeven, C. Efficacy, safety, and tolerability of a monophasic oral contraceptive containing nomegestrol acetate and 17β-estradiol: A randomized control trial. Obstet. Gynecol. 2012, 119 (5), 989−999. (18) Yang, L. P. H.; Plosker, G. L. Nomegestrol acetate/estradiol in oral contraception. Drugs 2012, 72 (14), 1917−1928. (19) Gerrits, M. G. F.; Schnabel, P. G.; Post, T. M.; Peeters, P. A. M. Pharmacokinetic profile of nomegestrol acetate and 17β-estradiol after multiple and single dosing in healthy women. Contraception 2013, 193−200. (20) Vlieg, A. H.; Helmerhorst, F. M.; Vandenbroucke, J. P.; Doggen, C. J. M.; Rosendaal, F. R. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: Results of the MEGA case-control study. Br. Med. J. 2009, 339, b2921. (21) Nelson, H. D.; Humphrey, L. L.; Nygren, P.; Teutsch, S. M.; Allan, J. D. Postmenopausal hormone replacement therapy: Scientific review. J. Am. Med. Assoc. 2002, 288 (7), 872−881. (22) Rice, L. W. Hormone prevention strategies for breast, endometrial and ovarian cancers. Gynecol. Oncol. 2010, 118, 202−207. (23) Pasqualini, J. R. Progestins in the menopause in healthy women and breast cancer patients. Maturitas 2009, 62, 343−348. (24) Pasqualini, J. R. Breast cancer and steroid metabolizing enzymes: The role of progestogens. Maturitas 2009, 65S, S17−S21. (25) van Diepen, H. A. Preclinical pharmacological profile of nomegestrol acetate, a synthetic 19-nor-progesterone derivative. Reprod. Biol. Endocrinol. 2012, 10, 85.
(26) Persiani, P.; Radici, E.; Lombardi, P. A.; Lombardi, P. L. Use of nomegestrol acetate in the treatment of menstruation disorders: Our experience in 56 cases. Minerva Ginecol. 1997, 49 (4), 181−185. (27) Florio, P.; Imperatore, A.; Litta, P.; Franchini, M.; Calzolari, S.; Angioni, S.; Gabbanini, M.; Bruni, L.; Petraglia, F. The use of nomegestrol acetate in rapid preparation of endometrium before operative hysteroscopy in pre-menopausal women. Steroids 2010, 75, 912−917. (28) Gastaud, J. M. New derivatives of 17α-hydroxy, 19-norpregna4,6-diene-3,20-dione. French Patent FR2271833, 1975. (29) Tchernatinsky, C. New process for manufacturing derivatives of 17-alpha-hydroxy-19-norprogesterone and novel intermediates for use therein. PCT WO/1985/01504, 1985. (30) Livington, D. A.; Petre, J. E.; Bergh, C. L. Intermolecular cyanohydrin elaboration. Construction of corticosteroids from 17ketosteroids. J. Am. Chem. Soc. 1990, 112, 6449−6450. (31) VanRheenen, V.; Shephard, K. P. New synthesis of cortico steroids from 17-keto steroids: Application and stereochemical study of the unsaturated sulfoxide−sulfenate rearrangement. J. Org. Chem. 1979, 44, 1582−1584. (32) Rao, P. N.; Cessae, J. W.; Blye, R. P.; Kim, H. K. 11β-Substituted 13β-ethyl gonane derivatives exhibit reversal of antiprogestational activity. Steroids 1998, 63, 50−57. (33) Borszeky, K.; Mallat, T.; Baiker, A. Palladium-catalyzed enantioselective hydrogenation of alkenoic acids. Role of isomerization. Catal. Lett. 1999, 59, 95−97. (34) Larsen, C. R.; Grotjahn, D. B. Stereoselective alkene isomerization over one position. J. Am. Chem. Soc. 2012, 134, 10357−10360. (35) Ciuffreda, P.; Ferraboschi, P.; Verza, E.; Manzocchi, A. Total assignment of 1H and 13C NMR spectra of 13α- and 13β-estrone methyl ethers. Magn. Reson. Chem. 2001, 39, 648−650. (36) Reich, H. J.; Jautelat, M.; Messe, M. T.; Weigert, F. J.; Roberts, J. D. Nuclear magnetic resonance spectroscopy. Carbon-13 spectra of steroids. J. Am. Chem. Soc. 1969, 91 (26), 7445−7454. (37) Lancaster, R. W.; Harris, L. D.; Pearson, D. Fifty-year old samples of progesterone demonstrate the complex role of synthetic impurities in stabilizing a metastable polymorph. CrystEngComm 2011, 13, 1775−1777. (38) Korde, S. S.; Katoch, R.; Udasi, R. A.; Trivedi, G. K. Total assignment of 1H and 13C NMR spectra of pregnenolone and progesterone haptens using 2D NMR spectroscopy. Magn. Reson. Chem. 1999, 37, 594−597. (39) Wong, F. F.; Chuang, S. H.; Yang, S. C.; Lin, Y. H.; Tseng, W. E.; Lin, S. K.; Huang, J. J. One-pot ethynylation and catalytic desilylation in synthesis of mestranol and levonorgestrel. Tetrahedron 2010, 66, 4068−4072.
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NOTE ADDED AFTER ASAP PUBLICATION This paper was published ASAP on February 4, 2014, with an error in the Table of Contents graphic. The corrected version was reposted on February 18, 2014.
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