An α,β-unsaturated ketone alkylation and efficient reduction protocol for the synthesis of 3α-hydroxy-3β-methyl-4,4-dimethyl-5α-21-bromo-19-nor-pregnan-20-one

Abstract

Alkyl-substituted testosterone derivatives are promising platforms for new drug discovery in medicinal chemistry. This approach provides a simple and efficient method for introducing an alkyl substituent to steroids at the C-4 position. In this study, the novel compound 3α-hydroxy-3β-methyl-4,4-dimethyl-5α-21-bromo-19-nor-pregnan-20-one is synthesized from 19-nor-testosterone. The protocol involves methylation of the dienolate, reduction of the alkene, the Grignard reaction of the carbonyl group, a Wittig reaction, hydroboration with BH₃, the oxidation and bromination with a 49% overall yield. For the methylation and reduction steps, the effects of the base, solvent, and reactant ratio on the conversion and yield are investigated. The structures of the synthesized compounds are determined by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) (electrospray ionization (ESI)).

Keywords

α,β-unsaturated ketone alkylation reduction 4,4-dimethyl-3α-hydroxy-3β-methyl-5α-21-bromo-19-nor-pregnan-20-one 19-nor-testosterone synthesis

Introduction

Steroids are natural products with cyclopentane polyhydrophenanthrene structures and are widely employed in the field of medicinal chemistry.^1
–3 For example, important steroids such as cholesterol, progesterone, estradiol, and hydrocortisone (Figure 1) have various physiological activities, such as promoting bone growth,⁴ anti-inflammatory,⁵ and management of levels of water and salt.⁶ In addition, with rapid developments in synthetic chemistry, more and more novel steroid compounds are developed, which play increasingly important roles in the prevention and treatment of cardiovascular diseases,^7,8 hypoglycemia,⁹ malaria,¹⁰ human immunity,¹¹ and digestive disorders.¹²

Figure 1.

The chemical structures of several important steroids.

During intensive studies on steroid biological activities, scientists have found that introducing nitrogen atoms or functional groups onto the polyhydrophenanthrene framework can impact unique properties or improve physiological activities over the parent compounds. In particular, the structure of the A-ring plays a crucial role in the study of antirheumatic, paralytic, and antitumor drugs. Apart from ring aromatization and extension, many progesterone and 19-nor-progesterone drugs are also prepared by alkylating the A-ring with new groups and by subsequently introducing nitrogen-containing heterocyclic functional groups such as pyrazoline, thiazole, and oxazole with high physiological activity to the novel steroid C-17 branched chains.^13,14 Further screening of their activity, selectivity, and toxicity will be beneficial for the discovery and invention of new antitumor, anti-inflammatory, and antibacterial drugs. For example, it has been found that C-3 alkylation on the steroid A-ring can improve the overall pharmacokinetics (PK) parameters and reduce potential toxicity by eliminating the possibility of partial oxidation of hydroxy groups to ketones, preventing further metabolism and reducing the possibility of secondary elimination pathways.¹⁵ Steroid derivatives with C-4 dimethylation show significant antifungal activity against Fusarium oxysporum in soybean sudden death syndrome.¹⁶ Our previous studies have indicated that 3α-hydroxy-3β-methyl-4,4-dimethyl-5α-21-bromo-19-nor-pregnan-20-one is a key intermediate for the synthesis of novel positive allosteric modulators (PAM) of synaptic and extrasynaptic GABA_A.

Alkyl-substituted testosterone derivatives represent promising platforms for new drug discovery in medicinal chemistry. There have been some reports on modification at C-2 or C-3 of the A-ring (Scheme 1);^17,18 however, alkylation of C-4 is complicated and reported rarely.

Scheme 1.

Alkylation of progesterone derivatives at the C-2 and C-3 positions.

It is well-known that alkylation of α,β-unsaturated ketones ortho to the carbonyl with alkylating agents followed by reduction of the alkene affords α-alkyl-substituted ketone derivatives.^19,20 In a reverse process, Schmidt et al.²¹ disclosed the C-4 monoalkylation of the steroid alkene 1 (Scheme 2). Lithium was added to a solution of 4-cholesten-3-one (1) in anhydrous THF and ammonia at −78 °C. After warming to −35 °C and stirring for another 4 h under nitrogen, 1 was reacted with iodomethane at −78 °C. When the reaction was complete, the solvent was evaporated, and the residue was extracted with diethyl ether and purified by flash column to give 2 as colorless crystals. However, this method uses dangerous lithium reagents at extremely low temperatures and gives only a 39% yield. Furthermore, the reaction time is long and the side reactions were proven. In addition, several dimethyl products were obtained that were difficult to purify.

Scheme 2.

Reported method for the C-4 alkylation of steroids.

Herein, we disclose a new method for steroid bis-C-4 alkylation via an α,β-unsaturated ketone alkylation and an efficient reduction protocol. The obtained novel compound, 4,4-dimethyl-3α-hydroxy-3β-methyl-5α-21-bromo-19-nor-pregnan-20-one (3), which represents a new class of progestin receptor ligand for drug discovery is synthesized from the starting material 19-nor-testosterone (9). The developed method avoids harsh reaction conditions and low yields. Overall, it is a selective, efficient, and sustainable route for the synthesis of novel steroid derivatives with C-4 alkylation that employs a safe procedure, short reaction times, and has prospects for the discovery of new steroid drugs.

Results and discussion

Alkylation of a dienolate followed by reduction of the resulting alkene can be used for preparing α-alkyl-substituted ketone derivatives. As shown in Scheme 3, retrosynthetic analysis suggests that the novel compound 3 can be synthesized by bromination of testosterone 4, which is the typical method for introducing a halogen at the carbonyl α-position. Compound 4 could be obtained by reaction of compound 5 with MeMgBr and hydrolysis using aqueous NH₄Cl, and the compound 5 could be prepared from compound 6 by reactant with diethyl cyanophosphonate and LiCN in tetrahydrofuran. The key intermediate 7 can be synthesized by alkylation and reduction of commercially available 19-nor-testosterone (9) (see below).

Scheme 3.

Retrosynthetic analysis of compound 3.

Based on the retrosynthetic analysis of compound 3, experiments revealed that reactant of 6 with diethyl cyanophosphonate and LiCN in tetrahydrofuran gave cyanide 5. However, attempts to convert compound 5 into the 17-acetyl derivative 4 by reaction with methylmagnesium bromide were not successful, even with 4.0 equiv. MeMgBr followed by treatment with aqueous NH₄Cl; the target compound 4 was obtained in only low yields because of serious side products. Further optimization was achieved on acetylation of compound 6 and a suitable method was obtained by vinyl oxidation. The new synthetic strategy is illustrated in Scheme 4.

Scheme 4.

The synthetic strategy toward compound 3.

In this new synthetic route, compound 9 was treated with potassium t-butoxide and iodomethane to give 4,4-dimethyltestosterone (8) in 95% yield. Consideration of the alkylation selectivity revealed that the initially product was a mixture of mono and dimethyl compounds, and the reaction required excess iodomethane under strong alkaline conditions to go to completion. Olefinic reduction of compound 8 generated the key intermediate 7 in a good yield of 92%. To avoid carbonyl reduction as a side reaction, mild conditions with 5% Pd/C and a low temperature were employed. Following a Grignard reaction of 7, compound 6 was obtained in a good yield of 90%. For the purpose of forming a complex with a protecting group on the C-17 carbonyl to increase the steric effects, methyl aluminum bis (2,6-di-t-butyl-4-methylphenoxide) (MAD) was introduced to ensure that the Grignard reaction only occurred at the C-3 position. Next, compound 11 was synthesized by the Wittig reaction with ethyl triphenylphosphonium bromide in THF. This was followed by hydroboration with borane and oxidation with pyridinium chlorochromate (PCC) to afford compound 4 as a single unassigned stereoisomer in 73% yield (three steps). Finally, the target compound 3 was obtained by bromination with Br₂/HBr from compound 4 in satisfactory yield of 86%. The structures of the intermediates and products were characterized by melting point, ¹H NMR, ¹³C NMR, and HRMS.

For the alkylation step, the side product of 4-monomethyl testosterone 12 is easily generated, and the reaction selectivity determines the yield of compound 8. The effects of different methylating agents, substrate ratios, solvents, and temperatures were investigated, and the results are summarized in Table 1.

Table 1.

Optimization of the alkylation conditions for the preparation of 8.


Entry	Alkylating agent(equiv.)^a	Base(equiv.)	Solvent	Tem(°C)	Time(h)	Selectivity8/(12+8)^b	Yield (%)^c
1	(CH₃O)₂SO₂ (2.0)	NaOCH₃ (3.0)	1,4-dioxane	100	12	–	–
2	(CH₃O)₂SO₂ (2.0)	n-BuLi (3.0)	diethyl ether	0	8	41	22
3	(CH₃O)₂SO₂ (3.0)	n-BuLi (4.0)	diethyl ether	20	8	68	36
4	CH₃I (2.0)	K₂CO₃ (3.0)	Acetone	25	12	54	48
5	CH₃I (2.0)	NaOCH₃ (3.0)	1,4-dioxane	25	12	68	60
6	CH₃I (2.0)	t-BuOK (3.0)	acetone	25	12	75	69
7	CH₃I (2.0)	t-BuOK (3.0)	Dimethyl sulfoxide	25	12	64	58
8	CH₃I (2.0)	t-BuOK (3.0)	t-butanol	25	8	82	78
9	CH₃I (2.5)	t-BuOK (3.0)	t-butanol	25	8	89	85
10	CH₃I (3.0)	t-BuOK (3.0)	t-butanol	25	8	95	92
11	CH₃I (3.0)	t-BuOK (4.0)	t-butanol	60	8	97	95
12	CH₃I (3.0)	t-BuOK (4.0)	t-butanol	60	12	97	95

Molar ratio.

HPLC peak area ratio: compound 8/compound 8 and compound 12 × 100%.

Isolated yield based on 9.

First, the standard alkylating agent (CH₃O)₂SO₂ was selected and different bases and solvents were screened (Table 1, entries 1–3). The results showed that when NaOCH₃ was used as the base, no reaction occurred, even at 100 °C for 12 h. Using n-BuLi in diethyl ether solvent, the alkylating agent (CH₃O)₂SO₂ gave unsatisfactory reaction selectivity (68%) and poor a product yield (36%). Next, the active alkylating agent CH₃I was investigated with different bases including K₂CO₃, NaOCH₃, and t-BuOK, with t-BuOK being the best (Table 1, entries 4–12). The reaction selectivity and yield of 8 were only 54% and 48% with K₂CO₃ (Table 1, entry 4). The base use of t-BuOK led to a 75% yield with 69% selectivity (Table 1, entry 6). With t-BuOK as the base, the solvent was further optimized with t-butanol proving to be optimized (Table 1, entry 8). To further improve the yield of compound 8, the amounts of CH₃I and t-BuOK were investigated (Table 1, entries 9–11), with 3.0 alkylating agent and 4.0 equiv. of the base ensuring the best yield of 95%. When the reaction time was increased from 8 to 12 h, the yield and selectivity of 8 was maintained with no obvious increase (Table 1, entry 12). Thus, the optimum reaction conditions were established as follows: CH₃I (3.0 equiv.) as the alkylating agent, t-BuOK (4.0 equiv.) as the base, and t-butanol as the solvent at 40 °C for 8 h.

For the reduction step, several methods for the direct reduction of the alkene to an alkyl group are known in the literature. High-pressure hydrogenation with the Raney Ni and Pd/C is the most efficient method for alkene reduction. Thus, experiments were carried out to explore suitable reduction conditions for the preparation of compound 7 (Table 2).

Table 2.

Optimization of reduction conditions for preparation of 7.


Entry	Catalyst(w/w)^a	Solvent	H₂ pressure(MPa)	Selectivity7/(13+7)^b	Yield(%)^c
1	Ni (0.05)	Methanol	0.5	69	61
2	Ni (0.05)	Methanol	1.0	47	40
3	5% Pd/C (0.05)	Methanol	0.5	74	65
4	5% Pd/C (0.05)	Tetrahydrofuran	0.5	81	73
5	5% Pd/C (0.05)	Ethyl acetate	0.5	86	75
6	5% Pd/C (0.05)	Ethyl acetate	0.4	87	76
7	5% Pd/C (0.05)	Ethyl acetate	0.2	96	92
8	5% Pd/C (0.05)	Ethyl acetate	0.1	97	92

w/w: catalyst dry weight/compound 8 weight; all reactions proceed at room temperature for 12 h.

HPLC peak area ratio: compound 7/compound 7 and compound 13 × 100%.

Isolated yield based on compound 8.

Reduction with 5% Raney-Ni in methanol was initially tested. The results demonstrated that a low H₂ pressure gave a moderate yield of 61% (Table 2, entry 1), while a higher pressure gave a lower yield of 40% due to poor reaction selectivity (Table 2, entry 2). Reductions with 5% Pd/C as the catalyst were also evaluated. The effects of different solvents were studied first (Table 2, entries 3–5). Ethyl acetate was found to be the most suitable solvent giving a higher yield of 73% (Table 2, entry 5). By further optimizing the reaction pressure (entries 5–8), the yield of compound 7 was significantly increased to 92% (entry 8). The results indicated that decreasing the H₂ pressure was beneficial to improve the reaction selectivity. The optimum reduction conditions for the reduction were established as follows: 5% Pd/C (0.05 w/w) as the catalyst, ethyl acetate as the solvent, a 0.1 MPa H₂ atmosphere, and a reaction time of 12 h.

Conclusion

In conclusion, we have developed an α,β-unsaturated ketone alkylation and an efficient reduction protocol for the synthesis of 4,4-dimethyl-3α-hydroxy-3β-5α-methyl-21-bromo-19-nor-pregnan-20-one without the need for hazardous alkyllithium reagents at extremely low reaction temperatures. The protocol involves methylation of a dienolate, alkene reduction, a Grignard reaction on a carbonyl group, a Wittig reaction, reduction with borane, and oxidation and bromination with a 49% overall yield. This work provides a new method for the synthesis of novel steroid derivatives modified at C-4 with the advantages of readily available reagents, relatively mild reaction conditions and moderate-to-good yields.

Experimental

All analytical reagents are commercially available (Macklin, J&K Scientific, and Aladdin) and were used directly without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates (GF-254), and the products were purified by silica gel column chromatography (200~300 mesh). Melting points were measured on a YRT-3 melting point apparatus using the capillary method without correction. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance DPX-spectrometer at 300 or 400 MHz in CDCl₃ or DMSO-d₆ with tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are reported in parts per million (ppm), coupling constants are expressed in Hz. High-resolution mass spectra (HRMS-ESI) were obtained using Agilent 1100 LC/MS Spectrometry Services.

4,4-dimethyl-5-ene-norandrostenedione (8)

Potassium t-BuOK (164.9 g, 1.47 mol) was added in portions to a solution of 100 g (367 mmol) of 19-nor-testosterone (9) and 1.5 L of t-butanol with mechanical stirring at 20–25 ℃. After the addition was complete, the pale-colored mixture was stirred at 25 ℃ for 30 min. A solution of iodomethane (156.3 g, 1.1 mol) in 100 mL of t-butanol was added dropwise to the reaction mixture. The reaction vessel was sealed, and the contents were stirred at 60 ℃ for 8 h. After cooling to 20 ℃, the mixture was quenched with 200 mL of saturated ammonium chloride solution. The ammonia was allowed to evaporate under reduced pressure, and the residue was diluted with 300 mL of H₂O and extracted with EtOAc (3 × 400 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 7/1) to give 8 as a white solid (104.7 g, 95%). M.p. 146–147 °C (lit. 139–145 °C).^{22
¹}H NMR (400 MHz, CDCl₃): δ 5.69-5.66 (m, 1H), 2.74-2.60 (m, 1H), 2.48 (m, 1H), 2.42-2.25 (m, 3H), 2.25-1.91 (m, 4H), 1.91-1.77 (m, 1H), 1.76-1.43 (m, 3H), 1.43-1.24 (m, 7H), 1.23 (s, 3H), 0.96-0.92 (m, 4H). ¹³C NMR (100 MHz, CDCl₃): δ 220.8, 214.3, 144.6, 119.3, 51.2, 50.7, 47.8, 45.92, 39.8, 37.3, 35.8, 35.6, 31.4, 31.1, 29.9, 28.7, 26.7, 21.7, 21.7, 13.7. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₈O₂Na: 323.1982; found: 323.1996.

The side product 4-methyl-4-ene-norandrostenedione (12) was obtained as a white solid. M.p. 157–158 °C. ¹H NMR (400 MHz, CDCl₃): δ 3.02-2.95 (m, 1H), 2.53-2.42 (m, 2H), 2.33-2.19 (m, 2H), 2.16-2.05 (m, 2H), 2.04-1.91 (m, 4H), 1.87 (dd, J = 9.1, 2.6 Hz, 1H), 1.82 (t, J = 1.6 Hz, 3H), 1.68-1.47 (m, 4H), 1.36-1.27 (m, 3H), 1.18-1.10 (m, 1H), 0.95 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 220.5, 199.2, 158.4, 129.1, 50.3, 49.6, 47.8, 43.4, 40.0, 36.2, 35.8, 31.4, 31.0, 29.9, 25.7, 25.6, 21.6, 13.8, 10.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₂₆O₂Na: 309.1825; found: 309.1877.

4,4-Dimethyl-5α-19-norandrostanedione (7)

5% Pd/C (5.0 g, dry weight, 0.05 w/w) was added to a solution of compound 8 (100.0 g, 333.1 mmol) in EtOAc (600 mL). After replacement of nitrogen, 0.1 MPa H₂, the mixture was stirred at room temperature for 12 h. The mixture was then filtered and the filtrate was concentrated in vacuo to afford compound 7 as a white solid (92.6 g, 92%). M.p. 128–130 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 2.65-2.61 (m, 1H), 2.43-2.36 (m, 1H), 2.20-2.17 (m, 1H), 2.11-1.97 (m, 2H), 1.85-1.79 (m, 3H), 1.73-1.60 (m, 2H), 1.53-1.47 (m, 2H), 1.36-1.22 (m, 4H), 1.21-1.09 (m, 4H), 1.01 (s, 3H), 0.95-0.92 (m, 3H), 0.83 (s, 3H), 0.71-0.63 (m, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ 220.3, 215.3, 51.9, 50.1, 48.7, 47.6, 37.4, 35.8, 31.8, 31.0, 29.9, 25.7, 25.3, 22.5, 21.7, 20.5, 13.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₃₀O₂Na: 325.2138; found: 325.2189.

3α-Hydroxy-4,4-dimethyl-5α-19-norandrostane-17-one (13)

As the byproduct, the total reduction product 13 was obtained as a pale white solid. M.p. 150–151 °C ¹H NMR (400 MHz, CDCl₃): δ 3.27-3.18 (m, 1H), 2.45-2.41 (m, 1H), 2.08 (dt, J = 18.8, 9.0 Hz, 1H), 1.99-1.71 (m, 7H), 1.60-1.35 (m, 4H), 1.31-1.07 (m, 5H), 1.01 (s, 4H), 0.94-0.75 (m, 8H), 0.69-0.56 (m, 1H).¹³C NMR (100 MHz, CDCl₃): δ 221.4, 78.0, 50.6, 49.4, 47.8, 40.6, 40.2, 38.7, 35.9, 31.6, 30.1, 29.1, 25.3, 25.2, 21.7, 13.8, 13.3. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₃₂O₂Na: 327.2300; found: 327.2378.

3α-Hydroxy-3β-methyl-4,4-dimethyl-5α-19-norandrostane-17-one (6)

A solution of compound 7 (25.0 g, 82.7 mmol) in 500 mL of anhydrous toluene was added slowly to the MAD solution (620 mL, 248.1 mmol, 0.4 M in toluene) under a nitrogen atmosphere at −78 ℃. After the addition was complete, the mixture was stirred for 1 h at −78 ℃ and then MeMgBr (82.7 mL, 248.1 mmol, 3.0 M in THF) was added dropwise at a temperature below −75 ℃. The mixture was then stirred for a further 12 h at the same temperature after dropping finished. The reaction was quenched by adding 150 mL of saturated aqueous ammonium chloride solution. After the addition was complete, the mixture was stirred vigorously and then filtrated. Next, 300 mL of water was added to the filtrate, the organic phase was separated, and the aqueous phase was extracted with EtOAc (3 × 300 mL). The combined organic phase was and washed with water (3 × 200 mL) and brine (2 × 200 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1 v/v) to give compound 6 as a white solid (23.7 g, 90%). M.p. 162–163 °C. ¹H NMR (400 MHz, CDCl₃): δ 2.67-2.53 (m, 1H), 2.52-2.41 (m, 1H), 2.34-2.22 (m, 1H), 2.21-2.04 (m, 1H), 2.02-1.68 (m, 6H), 1.60 (s, 1H), 1.57-1.37 (m, 3H), 1.36-1.16 (m, 8H), 1.14-1.04 (m, 4H), 1.03-0.85 (m, 7H), 0.80-0.63 (m, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 221.6, 71.1, 50.7, 48.3, 47.8, 46.9, 46.7, 45.3, 43.6, 40.2, 40.1, 35.9, 31.6, 30.1, 29.4, 28.1, 25.3, 25.1, 21.6, 13.8, 11.7. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₃₄O₂Na: 341.2457; found: 341.2468.

3α-Hydroxy-3β-methyl-4,4-dimethyl-5α-17-vinyl-19-norandrostane (11)

A solution of 500 mL of anhydrous THF and ethyl triphenylphosphine bromide (97.6 g, 262.8 mmol) was added to 200 mL of toluene and potassium t-butanol (29.6 g, 262.9 mmol) dropwise under an N₂ atmosphere at −10 to −5 ℃ with stirring for 20 min. After the addition was complete, the reaction mixture was stirred for 30 min at the same temperature. A solution of compound 6 (20.0 g, 62.8 mmol) in 200 mL tetrahydrofuran was added dropwise. The reaction mixture was warmed to 50–55 ℃ and stirred for 5 h. The reaction mixture was cooled to room temperature and quenched with 200 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with EtOAc, and the combined organic layer was washed with water, dried over anhydrous Na₂SO₄, and concentrated to give the crude product, which was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 15/1 to 10/1) to afford 11 as a pale solid (18.5 g, 89%). M.p. 107–108 °C. ¹H NMR (400 MHz, CDCl₃): δ 5.14 (q, J = 8.0 Hz, 1H), 2.40-2.36 (m, 1H), 2.26-2.17 (m, 2H), 1.90-1.88 (m, 1H), 1.81-1.74 (m, 3H), 1.69-1.66 (m, 4H), 1.60-1.45 (m, 3H), 1.26-1.14 (m, 8H), 1.08-1.04 (m, 3H), 0.92-0.86 (m, 11H), 0.68-0.61 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 150.6, 113.2, 74.1, 55.4, 44.6, 41.7, 41.5, 40.9, 39.1, 37.4, 36.8, 31.5, 27.9, 26.9, 26.1, 25.3, 25.2, 24.3, 20.5, 16.9, 13.1, 11.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₃₉O: 331.3001; found: 331.2979.

3α-Hydroxy-3β-methyl-4,4-dimethyl-5α-19-nor-pregnan-20-ol (10)

To a solution of 400 mL of anhydrous THF and compound 11 (12.0 g, 33.3 mmol) was added dropwise BH₃THF (190 mL, 190.0 mmol, 1.0 M in THF) at −10 to −5 ℃. After the addition was complete, the mixture was stirred for 30 min, then warmed to 20–25 ℃ and stirred for 8 h. The reaction was quenched by adding 150 mL of aqueous saturated ammonium chloride solution below 5 ℃. The mixture was extracted with EtOAc (3 × 200 mL), and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give crude compound 10 product as a pale solid, which was used directly without further purification.

3α-Hydroxy-3β-methyl-4,4-dimethyl-5α-19-nor-pregnan-20-one (4)

To a solution of 200 mL of dried dichloromethane and compound 10 (8.0 g, 23.0 mmol) was added PCC (14.9 g, 69 mmol) portionwise at a temperature below 5 ℃ under an N₂ atmosphere. The reaction was warmed to 15–20 ℃ and stirred for 5 h. Following completion of the reaction, it was quenched with 100 mL of saturated aqueous sodium thiosulfate solution, and the organic layer was separated and washed with brine. The combined organic phase was dried over anhydrous Na₂SO₄ and concentrated under vacuum to give a crude residue, which was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 15/1 to 10/1) to afford 4 as an off-white solid (7.0 g, 82%, two steps). M.p. 187–188 °C. ¹H NMR (400 MHz, CDCl₃): δ 2.54 (t, J = 9.0 Hz, 1H), 2.22-2.13 (m, 4H), 2.04-2.01 (m, 1H), 1.91-1.80 (m, 2H), 1.78-1.59 (m, 6H), 1.52-1.37 (m, 2H), 1.30-1.27 (m, 2H), 1.22-1.20 (m, 3H), 1.17-0.98 (m, 5H), 0.93-0.90 (m, 8H), 0.67-0.63 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 209.7, 74.6, 63.9, 55.9, 49.3, 48.5, 44.3, 41.0, 40.8, 40.7, 39.2, 36.8, 31.5, 31.5, 28.3, 26.3, 26.0, 24.2, 22.9, 22.8, 22.1, 16.3, 13.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₃₉O₂: 347.2950; found: 347.2986.

3α-Hydroxy-3β-methyl-4,4-dimethyl-5α-21-bromo-19-nor-pregnan-20-one (3)

To a solution of 100 mL of methanol, compound 4 (5.0 g, 14.4 mmol) and 3.0 mL of hydrobromic acid (HBr, 48%) was added bromine (3.5 g, 21.6 mmol) dropwise at −5 ℃. Then, residual mixture was stirred for 4 h at 10–15 ℃, and then the reaction was quenched by slowly adding 50 mL of aqueous saturated NaHCO₃ solution. The mixture was extracted with EtOAc and washed with brine (2 × 60 mL). The combined organic layer was then dried over anhydrous Na₂SO₄ and concentrated to dryness to give a crude residue that was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 7/1) to afford 3 as a white solid (5.3 g, 86%). M.p. 148–149 °C. ¹H NMR (400 MHz, CDCl₃): δ 3.93 (d, J = 3.0 Hz, 2H), 2.84 (t, J = 8.8 Hz, 1H), 2.25-2.17 (m, 1H), 2.00-1.68 (m, 8H), 1.53-1.36 (m, 4H), 1.31-1.13 (m, 5H), 1.09 (s, 4H), 0.93-0.70 (m, 8H), 0.66 (s, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 202.1, 74.6, 60.6, 55.8, 49.3, 48.5, 45.1, 40.8, 39.0, 36.8, 35.9, 31.4, 29.7, 28.3, 26.2, 25.9, 24.3, 23.7, 22.9, 22.1, 16.3, 14.1, 13.7. HRMS (ESI): m/z [M + K]⁺ calcd for C₂₃H₃₇BrO₂K: 463.1614; found: 463.1601.

Supplemental Material

sj-docx-1-chl-10.1177_17475198231204213 – Supplemental material for An α, β-unsaturated ketone alkylation and efficient reduction protocol for the synthesis of 3α-hydroxy-3β-methyl-4,4-dimethyl-5α-21-bromo-19-nor-pregnan-20-one

Supplemental material, sj-docx-1-chl-10.1177_17475198231204213 for An α, β-unsaturated ketone alkylation and efficient reduction protocol for the synthesis of 3α-hydroxy-3β-methyl-4,4-dimethyl-5α-21-bromo-19-nor-pregnan-20-one by Mingguang Zhang, Wenlong Wang, Chen Guo and Chunhuan Jiang in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors are grateful to the Integration of Production and Research Project of Jiangsu Province (no. BY20221083).

ORCID iD

Mingguang Zhang

Supplemental material

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