A method for preparing a 6- or 10-oxidized modified steroid drug

Abstract

The application provides a preparation method of a 6-position or 10-position oxidatively modified steroid drug, and the method comprises the following steps: S1: irradiating a solution of 19-methyl steroid drug Ia or 19-demethyl steroid drug Ib and a catalyst with a light source under an oxygen or air atmosphere, and removing the solvent after the irradiation is completed; S2: treating the reaction product after the solvent removal in S1 with a reducing agent, so that 6-position oxidatively modified steroid drug IIa and IIIa or 10-position oxidatively modified steroid drug IIb is obtained. In the preparation method, no reagent with high danger and environmental pollution, such as metal, strong base or peroxide, is used, the yield is high, the method is green, environmentally friendly, simple and easy to implement, and the production applicability is strong.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for preparing a steroidal drug with 6- or 10-position oxidation modification. Background Technology

[0002] Steroid drugs are hormone-like drugs whose molecular structure contains steroidal components. They mainly include adrenocortical hormones, sex hormones, and anabolic steroids. Many important steroid drugs produce oxidation products at positions 6 or 10 after metabolism in vivo. These oxidation products play an important role in studying drug metabolism and exploring new drug targets.

[0003] Currently, methods for preparing steroid drugs with 6- or 10-position oxidation modifications are limited, leading to high costs. Eur. J. Org. Chem. 2013, 8307 reported the conversion of testosterone to 6β-hydroxytestosterone in an excess potassium tert-butoxide / Cu–Al Ox / oxygen system, but the yield was low and it only involved testosterone as a steroid drug. Patent EP1148061B1 reported the conversion of eplerenone to enol ether in a triethyl orthoformate / p-toluenesulfonic acid system, followed by oxidation of the enol ether with m-chloroperoxybenzoic acid to obtain 6β-hydroxyeplerenone. Most of these processes use metals, strong bases, or peroxides, resulting in poor safety and severe environmental pollution. For the 19-demethyl steroid drug Ib, there is currently no publicly reported method for 10-position oxidation modification.

[0004] In view of this, the present invention is hereby proposed. Summary of the Invention

[0005] The main objective of this invention is to provide a method for preparing a steroidal drug with 6- or 10-position oxidation modification, in order to at least partially solve at least one of the above-mentioned technical problems.

[0006] As one aspect of the present invention, the present invention provides a method for preparing a steroidal drug with 6- or 10-position oxidation modification.

[0007]

[0008] In the above reaction formula,

[0009] R1 is selected from H, -SC(=O)R8, CO2R9 and C1-C8 alkyl, wherein R8 and R9 are each independently C1-C8 alkyl;

[0010] R2 and R3 are each independently selected from H, OH, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, COR 10 and OCOR 11 , where R 10 and R 11Each independently represents either unreplaced or C6-C 10 Aryl-substituted C1-C 10 alkyl;

[0011] Alternatively, R2 and R3 together with the carbon atoms they are attached to form a 5-6 member oxygen-containing heterocycle;

[0012] R4 is H or OH; R5 is H or halogen, or R4 and R5 together with the carbon atom they are attached to form a 3-7 membered oxygen-containing heterocycle;

[0013] R6 is H or a C1-C8 alkyl group;

[0014] R7 is H or a C1-C8 alkyl group.

[0015] As shown in the reaction formula above, the method includes the following steps:

[0016] S1: In an oxygen or air atmosphere, irradiate a solution of 19-methylsteroid drug Ia or 19-demethylsteroid drug Ib and catalyst in a solvent with a light source, and remove the solvent after irradiation;

[0017] S2: The reactants after removing the solvent from S1 are treated with a reducing agent to obtain steroidal drugs IIIa and IIIa with 6-position oxidation modification, or steroidal drug IIIb with 10-position oxidation modification.

[0018] Preferably, in the above reaction formula,

[0019] R1 is selected from H, -SAc, CO2Me, and C1-C4 alkyl groups;

[0020] R2 and R3 are each independently selected from H, OH, C1-C4 alkyl, C2-C4 alkynyl, COR 10 and OCOR 11 , where R 10 It is a C1-C4 alkyl group, R 11 For those not replaced or replaced by C6-C 10 Aryl-substituted C1-C 10 alkyl;

[0021] Alternatively, R2 and R3 can connect to form a 5-6 member oxygen-containing heterocycle;

[0022] R4 is H or OH;

[0023] R5 is H or a halogen, or R4 and R5 together with the carbon atom they are attached to form a 3-7 membered oxygen-containing heterocycle;

[0024] R6 is H or methyl;

[0025] R7 is methyl or ethyl.

[0026] More preferably, in the above reaction formula,

[0027] R1 is selected from H, -SAc, and CO2Me;

[0028] R2 is selected from H, OH, methyl, ethyl, and COR. 10 , where R 10 The compounds are methyl, ethyl, propyl, isopropyl, and n-butyl.

[0029] R3 is selected from H, methyl, ethyl, ethynyl, propynyl, and OCOR. 11 , where R 11 It is a C1-C5 alkyl group that is substituted with or unsubstituted with phenyl; preferably, R 11 Selected from methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, phenethyl, and phenylpropyl;

[0030] Alternatively, R2 and R3 can be connected to form a 5-6 membered lactone ring, preferably a valproic acid ring or a caprolactone ring, more preferably a valproic acid ring.

[0031] R4 is H or OH;

[0032] R5 is H or a halogen, or R4 and R5 form a 3-7 member oxygen-containing heterocycle; preferably, the 3-7 member oxygen-containing heterocycle is selected from ethylene oxide, oxetane, oxopentane, oxhexane and oxepane, more preferably ethylene oxide and oxetane, and more preferably ethylene oxide;

[0033] R6 is H or methyl;

[0034] R7 is methyl or ethyl.

[0035] Preferably, in step S1,

[0036] The light source is selected from blue light with a wavelength in the range of 400–480 nm; the irradiation intensity of the light source is 25-200 W, preferably 25-100 W; more preferably 50 W; the irradiation time of the light source is 10-40 h, preferably 10-30 h;

[0037] Preferably, the catalyst is selected from one or a combination of several of Na2-eosin Y, H2-eosin Y, K2-eosin Y, eosin B, phloxine B, dibromofluorescein, liquid bromine, N-bromosuccinimide, or dibromohydantoin; preferably, it is Na2-eosin Y;

[0038] Preferably, the molar ratio of the 19-methylsteroid drug Ia or the 19-demethylsteroid drug Ib to the catalyst is 1:0.03–0.08;

[0039] Preferably, the solvent in step S1 is selected from one or a combination of acetone, ethyl acetate, or acetonitrile.

[0040] Preferably, the reaction temperature in step S1 is room temperature.

[0041] Preferably, in step S1, the method for removing the solvent is selected from the following: rotary drying, freeze drying, supercritical carbon dioxide extraction; rotary drying is preferred.

[0042] Preferably, in step S2, an organic solvent is added along with the reducing agent, and preferably, the organic solvent is methanol.

[0043] Preferably, in step S2, the reducing agent is selected from one or a combination of several of triphenylphosphine, sodium sulfite, or thiourea; thiourea is preferred.

[0044] Preferably, in step S2, the molar ratio of 19-methylsteroid drug Ia or 19-demethylsteroid drug Ib to the reducing agent is 1:1.0–1.5.

[0045] Preferably, in step S2, the reaction is stirred simultaneously for 2-10 hours, more preferably 3-6 hours, and even more preferably 4 hours.

[0046] Preferably, after the reaction in S2 is completed, a separation and purification step is further included. The separation and purification step includes: evaporating the organic solvent, adding water, extracting with ethyl acetate, washing the organic phase with saturated sodium bicarbonate solution and saturated brine, drying with anhydrous sodium sulfate, evaporating again, and column chromatography to obtain steroidal drugs IIIa and IIIa with 6-position oxidation modification or steroidal drug IIb with 10-position oxidation modification.

[0047] In a second aspect, the present invention provides the application of the method for preparing the above-mentioned 6-position or 10-position oxidized steroidal drug in the preparation of oxidized steroidal drugs.

[0048] The active pharmaceutical ingredient of the steroidal drug with oxidative modification at the 6 or 10 position is selected from testosterone, methyltestosterone, testosterone propionate, testosterone undecanoate, progesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone acetate, norethindrone heptaate, spironolactone, eplerenone, nandrolone phenylpropionate, levonorgestrel, and medroxyprogesterone acetate.

[0049] Preferably, the active pharmaceutical ingredient of the steroidal drug with oxidative modification at the 6- or 10-position includes testosterone, methyltestosterone, hydroxyprogesterone caproate, spironolactone, eplerenone, nandrolone phenylpropionate, levonorgestrel, and medroxyprogesterone acetate.

[0050] The steroidal drugs with 6- or 10-position oxidation modification in this invention include, but are not limited to, the drugs described above.

[0051] Beneficial effects:

[0052] The present invention provides a green preparation method for steroidal drugs with 6- or 10-position oxidation modification. This method involves only two steps: irradiating the reactants with a light source under an oxygen or air atmosphere, and treating them with a reducing agent. The reaction does not use highly hazardous or environmentally polluting reagents such as metals, strong bases, or peroxides. This preparation method boasts high yield, is environmentally friendly, simple, and highly applicable to production. Detailed Implementation

[0053] The following embodiments further illustrate the above-described content of the present invention in detail. However, this should not be construed as limiting the scope of the present invention to the following embodiments; all technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the content and principles of the present invention should be included within the protection scope of the present invention.

[0054] the term

[0055] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0056] "Steroid" refers to a class of tetracyclic aliphatic hydrocarbon compounds with a cyclopentane-polyhydrophenanthrene core. Its basic skeleton and carbon atom numbering are shown in the following structural formula. In this invention, "oxidation modification at position 6 or 10" corresponds to position 6 or 10 in this structural formula:

[0057]

[0058] In this invention, "steroidal drugs" refers to hormones and their derivatives containing steroidal structures in their molecular structure, including but not limited to: testosterone, methyltestosterone, testosterone propionate, testosterone undecanoate, progesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone acetate, norethindrone heptaate, spironolactone, eplerenone, nandrolone phenylpropionate, levonorgestrel, and medroxyprogesterone acetate.

[0059] In this invention, the terms "C1-C8" refer to having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C1-C5" refers to having 1, 2, 3, 4, or 5 carbon atoms, "C1-C4" refers to having 1, 2, 3, or 4 carbon atoms, and "C6-C..." 12 "has a similar meaning."

[0060] In this invention, the term "4-8-element" refers to having 4-8 ring atoms, the term "3-7-element" refers to having 3-7 ring atoms, and so on.

[0061] In this invention, the term "alkyl" refers to a saturated straight-chain or branched linear hydrocarbon moiety. For example, the term "C1-C8 alkyl" refers to a straight-chain or branched alkyl group having 1 to 8 carbon atoms, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, etc.; preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; the term "C1-C4 alkyl" has a similar meaning.

[0062] In this invention, "alkenyl" refers to a hydrocarbon group containing an unsaturated carbon-carbon double bond. For example, the term "C2-C4 alkenyl" refers to an alkenyl group with 2-4 carbon atoms, and includes, without limitation, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl.

[0063] In this invention, "alkynyl" refers to a hydrocarbon group containing an unsaturated carbon-carbon triple bond. For example, the term "C2-C4 alkynyl" refers to an alkynyl group with 2-4 carbon atoms, and includes, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0064] In this invention, the term "heterocycle" refers to a ternary to fifteen-membered, preferably ternary to twelve-membered, saturated or partially unsaturated non-aromatic heterocycle containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur: a monocyclic, bicyclic, or tricyclic heterocycle containing one to three nitrogen atoms and / or one oxygen or sulfur atom, or one or two oxygen and / or sulfur atoms, in addition to a carbocyclic member. The term "oxygen-containing heterocycle" refers to a saturated or partially unsaturated non-aromatic heterocycle containing one to four oxygen atoms; preferably, the "oxygen-containing heterocycle" in this invention is a monocyclic heterocycle, such as (but not limited to) ethylene oxide, oxetane, oxetane, oxetane, oxetane pentane, oxetane hexane, butyrolactone ring, pentylactone ring, caprolactone ring, etc.

[0065] In this invention, "aryl" refers to a hydrocarbon moiety comprising one or more aromatic rings. For example, the term "C6-C..." 12 "Aryl" refers to an aromatic cyclic group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrene, anthracene, and phenanthrene.

[0066] Example 1

[0067]

[0068] Example 1-1

[0069] Compound Ia-1 (1 g, 2.40 mmol), Na2-eosin Y (83 mg, 0.12 mmol), and acetonitrile (70 mL) were added to a 200 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 29 hours, the acetonitrile was evaporated to dryness, and thiourea (219 mg, 2.88 mmol) and methanol (30 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give IIIa-1 (651 mg, 63% yield) and IIIa-1 (52 mg, 5% yield).

[0070] Examples 1-2

[0071] Compound Ia-1 (83 mg, 0.20 mmol), Na2-eosin Y (9.7 mg, 0.014 mmol), and acetonitrile (10 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 12 hours, the acetonitrile was evaporated to dryness, and thiourea (18 mg, 0.24 mmol) and methanol (10 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give IIIa-1 (74 mg, 86% yield) and IIIa-1 (4 mg, 4% yield).

[0072] Examples 1-3

[0073] In Examples 1-2, Na2-eosin Y was replaced with equimolar amounts of H2-eosin Y, K2-eosin Y, eosin B, phloxine B, dibromofluorescein, liquid bromine, N-bromosuccinimide, or dibromohydantoin, with all other conditions remaining unchanged. The yields of product IIIa-1 were 60%, 78%, 65%, 72%, 15%, 4%, 5%, and 5%, respectively; the yields of product IIIa-2 were 11%, 6%, 3%, 4%, 3%, 8%, 9%, and 6%, respectively.

[0074] Examples 1-4

[0075] In Examples 1-2, the acetonitrile was replaced with the same volume of acetone or ethyl acetate, while all other conditions remained unchanged. The yields of product IIIa-1 were 83% and 67%, respectively, and the yields of product IIIa-2 were 6% and 19%, respectively.

[0076] Examples 1-5

[0077] Compound Ia-1 (83 mg, 0.20 mmol), Na2-eosin Y (9.7 mg, 0.014 mmol), and acetonitrile (10 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 12 hours, the irradiation was stopped, and triphenylphosphine (68 mg, 0.26 mmol) was added to the system, which was stirred for 4 hours. The acetonitrile was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give IIIa-1 (55 mg, 64% yield) and IIIa-1 (3 mg, 3% yield).

[0078] Examples 1-6

[0079] Compound Ia-1 (83 mg, 0.20 mmol), Na2-eosin Y (9.7 mg, 0.014 mmol), and acetonitrile (10 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 12 hours, the irradiation was stopped, and sodium sulfite (38 mg, 0.30 mmol) was added to the system, which was stirred for 4 hours. The acetonitrile was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give IIIa-1 (4 mg, 5% yield) and IIIa-1 (less than 1% yield).

[0080] Spectral data of ΙΙa-1

[0081] 1 H NMR (500MHz, CDCl3): δ5.80(s,1H),4.17(d,J=2.9Hz,1H),3.87(t,J=3.1Hz,1H),2.59–2.45(m,4H),2.41–2. 36(m,2H),2.34(s,3H),2.25(ddd,J=15.1,11.5,3.9Hz,1H),2.04(ddt,J=7.4,4.9,2.7Hz,1H),1.93(ddd,J=1 2.9,9.2,7.2Hz,1H),1.82(ddd,J=14.2,9.2,4.7Hz,1H),1.72(dd,J=14.1,4.4Hz,1H),1.66–1.59(m,1H),1. 59–1.51(m,2H),1.49–1.42(m,2H),1.38(s,3H),1.34–1.21(m,2H),1.01(s,3H),0.97(dd,J=11.8,4.6Hz,1H)

[0082] 13 C NMR (126MHz, CDCl3): δ199.84,194.34,176.78,164.62,129.17,95.84,76.86,49.31,49.28,45.69, 45.48,38.11,37.27,35.35,34.32,32.48,31.42,31.40,31.30,29.36,22.42,20.70,20.48,14.75.

[0083] Spectral data of ⅢⅢa-1

[0084] 1 H NMR (600MHz, CDCl3): δ6.12(d,J=1.0Hz,1H),4.39(d,J=3.8Hz,1H),2.61–2.38(m ,5H),2.37(s,3H),2.33(dd,J=11.1,3.9Hz,1H),2.24(ddd,J=14.3,12.2,3.8Hz, 1H),2.15(ddd,J=13.3,5.1,2.7Hz,1H),2.00–1.80(m,3H),1.75–1.68(m,1H),1. 67–1.59(m,2H),1.57–1.48(m,2H),1.45–1.29(m,3H),1.19(s,3H),0.98(s,3H).

[0085] 13 C NMR (151MHz, CDCl3): δ198.50,197.08,190.76,176.48,159.46,128.02,95.31,52.50,47.53,45.46 ,44.64,40.40,37.33,35.72,35.12,33.93,31.19,31.16,30.94,29.22,22.31,20.55,18.19,14.68.

[0086] Example 2

[0087]

[0088] Compound Ia-2 (1 g, 2.41 mmol), Na2-eosin Y (83 mg, 0.12 mmol), and acetonitrile (70 mL) were added to a 200 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 20 hours, the acetonitrile was evaporated to dryness, and thiourea (220 mg, 2.89 mmol) and methanol (30 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give Ia-2 (634 mg, 61% yield) and IIIa-2 (126 mg, 12% yield).

[0089] Spectral data of ΙΙa-2

[0090] 1 H NMR (500MHz, CDCl3): δ5.92 (s, 1H), 4.57 (d, J = 2.3Hz, 1H), 3.62 (s, 3H), 3.08 (d, J = 5.3Hz, 1H), 3.00 (dd, J=11.2,4.6Hz,1H),2.91(dd,J=4.6,2.2Hz,1H),2.59(ddd,J=18.0,9.5,6.5Hz,1H),2.53–2.36(m,3H), 2.28(ddd,J=13.2,9.4,6.6Hz,1H),2.23–2.09(m,2H),2.00–1.83(m,4H),1.81(d,J=14.2Hz,1H),1.68( dd,J=14.6,5.4Hz,1H),1.59(s,3H),1.58–1.48(m,1H),1.33(ddd,J=13.3,5.2,2.4Hz,1H),1.02(s,3H).

[0091] 13 C NMR (126MHz, CDCl3): δ199.71,176.58,171.51,165.16,128.86,94.96,72.48,65.55,51.87,51.78, 47.90,44.17,39.36,36.96,35.12,33.39,32.95,31.29,31.07,29.13,28.20,24.59,22.00,16.38.

[0092] Spectral data of ⅢΙΙa-2

[0093] 1H NMR (600MHz, CDCl3): δ6.34(d,J=0.8Hz,1H),3.68(s,3H),3.53(d,J=5.1Hz,1H),3.24 (d,J=5.4Hz,1H),2.69(dd,J=10.4,5.1Hz,1H),2.66–2.57(m,2H),2.55–2.46(m,2H),2 .37–2.26(m,2H),2.25–2.17(m,1H),2.09–2.01(m,2H),1.99–1.95(m,1H),1.93–1.87( m,2H),1.79–1.73(m,1H),1.58–1.52(m,2H),1.48–1.44(m,3H),1.02(d,J=1.2Hz,3H).

[0094] 13 C NMR (151MHz, CDCl3): δ198.51,195.89,176.28,167.85,157.68,129.19,94.42,64.22,56.07,52.75 ,52.53,44.28,40.72,38.13,37.17,35.03,33.40,31.08,31.05,29.09,27.98,24.21,21.99,16.35.

[0095] Example 3

[0096]

[0097] Example 3-1

[0098] Compound Ia-3 (1 g, 2.59 mmol), Na2-eosin Y (72 mg, 0.10 mmol), and acetonitrile (75 mL) were added to a 200 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 18 hours, the acetonitrile was evaporated to dryness, and thiourea (237 mg, 3.11 mmol) and methanol (30 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give IIIa-3-1 (551 mg, 53% yield) and IIIa-3-2 (295 mg, 28% yield).

[0099] Example 3-2

[0100] Compound Ia-3 (500 mg, 1.29 mmol), Na2-eosin Y (36 mg, 0.052 mmol), and acetonitrile (37 mL) were added to a 100 mL beaker at room temperature. The reaction system was irradiated with a 50 W blue LED in air. After 22 hours, the acetonitrile was evaporated to dryness, and thiourea (118 mg, 1.55 mmol) and methanol (20 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give IIIa-3-1 (226 mg, 44% yield) and IIIa-3-2 (137 mg, 26% yield).

[0101] Spectral data of ΙΙa-3-1

[0102] 1 H NMR (500MHz, CDCl3): δ6.06 (s, 1H), 3.23–2.76 (m, 1H), 2.54 (ddd, J = 17.3, 15.0, 4.9Hz, 1H), 2.4 2(ddd,J=17.6,4.5,2.5Hz,1H),2.13(s,3H),2.12–2.07(m,2H),2.08(s,3H),2.05–1.93(m,2H), 1.89–1.67(m,6H),1.62(dt,J=12.6,3.2Hz,1H),1.52(qd,J=13.2,4.2Hz,1H),1.46(s,3H),1.43 (s,3H),1.41–1.35(m,1H),1.31–1.19(m,1H),1.04(ddd,J=12.2,10.9,4.1Hz,1H),0.74(s,3H).

[0103] 13 C NMR (126MHz, CDCl3): δ204.17,200.87,170.78,170.26,123.12,96.84,71.40,52.98,51.01,46.94, 45.45,38.63,37.71,33.90,31.12,30.86,30.49,29.35,26.53,23.85,21.32,20.81,20.09,14.57.

[0104] Spectral data of ΙΙa-3-2

[0105] 1H NMR (500MHz, CDCl3): δ6.37 (d, J=0.9Hz, 1H), 3.06–2.79 (m, 1H), 2.47 (ddd, J=17.5, 14.8, 4.9Hz, 1H ),2.36(dddd,J=17.6,4.7,2.5,1.0Hz,1H),2.23–2.13(m,1H),2.12–2.08(m,1H),2.09(s,3H),2.0 3(s,3H),2.00–1.91(m,2H),1.83–1.60(m,6H),1.57(ddd,J=12.7,4.2,2.9Hz,1H),1.45–1.36(m,1 H),1.40(s,3H),1.35–1.26(m,2H),1.24(s,3H),1.03(ddd,J=12.4,10.7,4.1Hz,1H),0.67(s,3H).

[0106] 13 C NMR (126MHz, CDCl3): δ204.06,200.25,175.64,170.79,122.38,96.73,71.91,52.50,50.96,47.14, 46.77,38.69,38.47,33.77,33.33,30.97,30.40,30.35,26.49,23.99,21.34,20.81,20.61,14.53.

[0107] Example 4

[0108]

[0109] Compound Ia-4 (86 mg, 0.20 mmol), Na2-eosin Y (9.7 mg, 0.014 mmol), and acetonitrile (10 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 12 hours, the acetonitrile was evaporated to dryness, and thiourea (18 mg, 0.24 mmol) and methanol (10 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give Ia-4 (25 mg, 28% yield) and IIIa-4 (48 mg, 54% yield).

[0110] Spectral data of ΙΙa-4

[0111] 11H NMR (600 MHz, CDCl3): δ 5.82 (s, 1H), 4.36 (t, J = 2.9 Hz, 1H), 2.93 (dd, J = 13.3, 11.3 Hz, 1H), 2.52 (ddd, J = 17.1, 15.0, 4.9 Hz, 1H), 2.39 (dt, J = 17.7, 3.7 Hz, 1H), 2.34 (t, J = 7.5 Hz, 2H), 2.08–2.05 (m, 1H), 2.03 (s, 3H), 2.03–1.99 (m, 1H), 1.95 (td, J = 13.1, 4.4 Hz, 1H), 1.79–1.69 (m, 4H), 1.67–1.55 (m, 4H), 1.54–1.45 (m, 1H), 1.37 (s, 3H), 1.34–1.27 (m, 6H), 1.03–0.95 (m, 1H), 0.88 (t, J = 6.8 Hz, 3H), 0.87–0.85 (m, 1H), 0.69 (s, 3H).

[0112] 13 13C NMR (151 MHz, CDCl3): δ 204.38, 200.63, 173.55, 168.28, 126.48, 96.55, 72.97, 53.13, 51.29, 47.06, 38.56, 38.09, 37.20, 34.59, 34.32, 31.39, 31.13, 30.51, 29.92, 26.60, 24.64, 23.91, 22.43, 20.72, 19.64, 14.57, 14.05.

[0113] Spectral data of ΙΙΙa-4

[0114] 1 1H NMR (600 MHz, CDCl3): δ 6.17 (s, 1H), 3.00–2.86 (m, 1H), 2.70 (dd, J = 16.1, 4.1 Hz, 1H), 2.59–2.43 (m, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.18–2.07 (m, 2H), 2.04 (s, 3H), 1.96–1.86 (m, 2H), 1.81–1.70 (m, 4H), 1.66–1.60 (m, 3H), 1.54–1.44 (m, 2H), 1.35–1.28 (m, 6H), 1.16 (s, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.67 (s, 3H).

[0115] 13C NMR (151MHz, CDCl3): δ203.87,201.46,199.37,173.38,160.44,125.84,96.09,51.90,50.36,46.94,46.56,39 .72,35.62,34.52,34.17,34.02,31.36,30.73,30.40,26.60,24.59,23.72,22.40,20.55,17.65,14.42,14.03.

[0116] Example 5

[0117]

[0118] Compound Ia-5 (58 mg, 0.20 mmol), Na2-eosin Y (9.7 mg, 0.014 mmol), and acetonitrile (10 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 12 hours, the acetonitrile was evaporated to dryness, and thiourea (18 mg, 0.24 mmol) and methanol (10 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give Ia-5 (19 mg, 31% yield) and IIIa-5 (28 mg, 46% yield).

[0119] Spectral data of ΙΙa-5

[0120] 1 H NMR (600MHz, CDCl3): δ5.81(d,J=1.0Hz,1H),4.34(t,J=2.9Hz,1H),3.65(t,J=8.6Hz,1H),2.51(ddd,J=17.3,15.1,5 .0Hz,1H),2.38(dddd,J=17.3,4.2,2.7,1.1Hz,1H),2.13–1.95(m,4H),1.87(dddd,J=12.5,4.1,2.8Hz,1H),1.70(ddd ,J=14.9,13.4,4.5Hz,1H),1.68–1.56(m,2H),1.54–1.48(m,1H),1.50–1.42(m,1H),1.38(s,3H),1.39–1.34(m,1H), 1.27–1.19(m,1H),1.09(td,J=12.9,4.3Hz,1H),0.97(ddd,J=12.2,10.8,7.3Hz,1H),0.94–0.87(m,1H),0.81(s,3H).

[0121] 13 C NMR (126MHz, CDCl3): δ200.56,168.47,126.50,81.83,73.17,53.88,50.63,43.0 6,38.21,38.19,37.27,36.56,34.37,30.62,29.93,23.44,20.75,19.69,11.24.

[0122] Spectral data of ⅢΙΙa-5

[0123] 1 H NMR (600MHz, CDCl3): δ6.15(d,J=1.0Hz,1H),3.68(t,J=8.6Hz,1H),2.66(dd,J=15.7,3.8Hz,1H),2. 52(ddd,J=17.5,14.7,5.2Hz,1H),2.48–2.40(m,1H),2.17–2.12(m,1H),2.12–2.06(m,1H),2.01(dd ,J=15.7,12.4Hz,1H),1.97–1.86(m,3H),1.79–1.66(m,2H),1.65–1.57(m,1H),1.55–1.44(m,2H),1 .41–1.33(m,1H),1.33–1.27(m,1H),1.20–1.17(m,1H),1.16(s,3H),1.15–1.08(m,1H),0.79(s,3H).

[0124] 13 C NMR (151MHz, CDCl3): δ201.98,199.55,160.90,125.69,81.36,51.33,51.13,46. 37,43.08,39.91,36.10,35.64,34.34,34.05,30.37,23.24,20.66,17.67,11.12.

[0125] Example 6

[0126]

[0127] Compound Ia-6 (60 mg, 0.20 mmol), Na2-eosin Y (9.7 mg, 0.014 mmol), and acetonitrile (10 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 12 hours, the acetonitrile was evaporated to dryness, and thiourea (18 mg, 0.24 mmol) and methanol (10 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give Ia-6 (14 mg, 22% yield) and I1a-6 (38 mg, 60% yield).

[0128] Spectral data of ΙΙa-6

[0129] 1 H NMR (500MHz, CD3OD): δ5.82 (d, J=0.9Hz, 1H), 4.30 (t, J=2.9Hz, 1H), 2.61 (ddd, J=17.2, 15.0, 5. 1Hz,1H),2.41–2.29(m,1H),2.17–2.03(m,2H),2.06–1.98(m,1H),1.97–1.87(m,1H),1.81–1.73 (m,1H),1.76–1.70(m,1H),1.72–1.65(m,1H),1.68–1.59(m,2H),1.56(td,J=12.6,3.7Hz,1H), 1.44(s,3H),1.44–1.37(m,1H),1.40–1.33(m,2H),1.33–1.24(m,2H),1.23(s,3H),0.96(s,3H).

[0130] 13 C NMR (126MHz, CD3OD): δ203.13,171.59,126.71,82.17,73.64,55.22,51.48,46.77,3 9.55,39.39,39.20,38.36,35.06,32.66,31.88,26.05,24.17,21.77,19.70,14.62.

[0131] Spectral data of ⅢΙΙa-6

[0132] 1H NMR (500MHz, CDCl3): δ6.15(d,J=1.0Hz,1H),2.71–2.59(m,1H),2.57–2.39(m,2H),2.15(ddd,J=13.4,5.2,2.6Hz,1H),2.05–1.93(m,2H),1.9 3–1.82(m,2H),1.80–1.68(m,2H),1.64–1.56(m,2H),1.49(td,J=12.8 ,3.8Hz,1H),1.42–1.28(m,4H),1.22(s,3H),1.17(s,3H),0.90(s,3H).

[0133] 13 C NMR (126MHz, CDCl3): δ201.99,199.57,160.95,125.67,81.41,51.09,51.04,46.55, 45.61,39.90,38.76,35.67,35.10,34.06,31.16,25.93,23.12,20.69,17.67,13.97.

[0134] Example 7

[0135]

[0136] Compound Ib-1 (81 mg, 0.20 mmol), Na2-eosin Y (5.5 mg, 0.008 mmol), and acetonitrile (10 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 12 hours, the acetonitrile was evaporated to dryness, and thiourea (18 mg, 0.24 mmol) and methanol (10 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give Ib-1 (46 mg, 55% yield).

[0137] Spectral data of ΙΙb-1

[0138] 1H NMR (600MHz, CDCl3): δ7.28–7.21(m,2H),7.20–7.13(m,3H),5.73(d,J=1.9Hz,1H),4.57(dd,J=9.2,7.8Hz ,1H),2.92(t,J=7.8Hz,2H),2.60(t,J=7.8Hz,3H),2.59–2.48(m,1H),2.35–2.24(m,2H),2.21–2.07(m,2H) ,1.92(ddd,J=14.0,12.3,4.5Hz,1H),1.85–1.78(m,1H),1.75(dd,J=11.2,3.3Hz,1H),1.72–1.67(m,1H),1 .66–1.52(m,3H),1.48–1.38(m,1H),1.36–1.25(m,1H),1.19–1.11(m,1H),1.10–0.94(m,3H),0.77(s,3H).

[0139] 13 C NMR (151MHz, CDCl3): δ199.39,173.10,164.53,140.55,128.56,128.38,126.34,124.82,82.57,70.34,5 2.57,49.93,42.65,36.37,36.12,35.11,33.79,33.72,32.03,31.32,31.17,27.54,23.62,20.00,12.04.

[0140] Example 8

[0141]

[0142] Example 8-1

[0143] Compound Ib-2 (62 mg, 0.20 mmol), Na2-eosin Y (5.5 mg, 0.008 mmol), and acetone (10 mL) were added to a 100 mL round-bottom flask at room temperature. The reaction system was irradiated with a 50 W blue LED under an oxygen atmosphere. After 12 hours, the acetonitrile was evaporated to dryness, and thiourea (18 mg, 0.24 mmol) and methanol (10 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give Ib-2 (37 mg, 56% yield).

[0144] Example 8-2

[0145] Compound Ib-2 (500 mg, 1.60 mmol), Na2-eosin Y (66 mg, 0.096 mmol), and acetonitrile (80 mL) were added to a 100 mL beaker at room temperature. The reaction system was irradiated with a 50 W blue LED in air. After 22 hours, the acetonitrile was evaporated to dryness, and thiourea (146 mg, 1.92 mmol) and methanol (20 mL) were added. The mixture was stirred for 4 hours. The methanol was evaporated to dryness, and 30 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to give Ib-2 (240 mg, 46% yield).

[0146] Spectral data of ΙΙb-2

[0147] 1 H NMR (500MHz, CD3OD): δ5.78(d,J=1.8Hz,1H),2.91(s,1H),2.72(tdd,J=13.9,5.4,2.0Hz,1H),2.64(ddd,J=16.4,12.5,4.9H z,1H),2.41–2.22(m,4H),2.16–2.07(m,2H),2.01–1.87(m,3H),1.80–1.49(m,8H),1.45–1.30(m,2H),1.05(t,J=7.4Hz,3H).

[0148] 13 C NMR (126MHz, CD3OD): δ202.28,168.40,124.87,89.10,81.79,74.78,70.81,54.17,52. 37,49.07,40.34,36.77,34.58,34.49,33.20,32.74,29.51,23.50,21.44,19.89,9.97.

[0149] The above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. It is neither necessary nor possible to exhaustively list all possible implementations. However, obvious variations or modifications derived therefrom are still within the scope of protection of the claims of this patent application.

Claims

1. A method for preparing a steroidal drug with 6- or 10-position oxidation modification, characterized in that, The reaction formula for the preparation method is as follows: In the above reaction formula, R1 is selected from H, -SC(=O)R8, CO2R9 and C1-C8 alkyl, wherein R8 and R9 are each independently C1-C8 alkyl; R2 and R3 are each independently selected from H, OH, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, COR 10 and OCOR 11 , where R 10 and R 11 Each independently represents either unreplaced or C6-C 10 aryl-substituted C1-C 10 alkyl; Alternatively, R2 and R3, together with the carbon atoms they are attached to, form a 5-6 member oxygen-containing heterocycle; R4 is H or OH; R5 is H or halogen, or R4 and R5 together with the carbon atom they are attached to form a 3-7 membered oxygen-containing heterocycle; R6 is H; R7 is H or a C1-C8 alkyl group; The preparation method includes the following steps: S1: In an oxygen or air atmosphere, irradiate a solution of 19-methylsteroid drug Ia or 19-demethylsteroid drug Ib and catalyst in a solvent with a light source, and remove the solvent after irradiation; S2: The reactants after removing the solvent from S1 are treated with a reducing agent to obtain steroidal drugs IIIa and IIIa with 6-position oxidation modification, or steroidal drug IIIb with 10-position oxidation modification. In step S1, the catalyst is selected from one or a combination of several of Na2-eosin Y, H2-eosin Y, K2-eosin Y, eosin B or phloxine B; In step S2, the reducing agent is selected from one or a combination of triphenylphosphine or thiourea.

2. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 1, characterized in that, In the reaction formula, R1 is selected from H, -SAc, CO2Me, and C1-C4 alkyl groups; R2 and R3 are each independently selected from H, OH, C1-C4 alkyl, C2-C4 alkynyl, COR 10 and OCOR 11 , where R 10 It is a C1-C4 alkyl group, R 11 For those not replaced or replaced by C6-C 10 aryl-substituted C1-C 10 alkyl; Alternatively, R2 and R3 can connect to form a 5-6 member oxygen-containing heterocycle; R4 is H or OH; R5 is H or a halogen, or R4 and R5 together with the carbon atom they are attached to form a 3-7 membered oxygen-containing heterocycle; R6 is H; R7 is methyl or ethyl.

3. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 2, characterized in that, In the reaction formula, R1 is selected from H, -SAc, and CO2Me; R2 is selected from H, OH, methyl, ethyl, and COR. 10 , where R 10 The compounds are methyl, ethyl, propyl, and n-butyl. R3 is selected from H, methyl, ethyl, ethynyl, propynyl, and OCOR. 11 , where R 11 It is a C1-C5 alkyl group that is substituted with or unsubstituted with phenyl; Alternatively, R2 and R3 may connect to form a valproic acid ring or a caprolactone ring. R4 is H or OH; R5 is H or a halogen, or R4 and R5 form a 3-7 membered oxygen-containing heterocycle; wherein the 3-7 membered oxygen-containing heterocycle is selected from ethylene oxide, oxetane, oxepane, oxhexane, and oxepane. R6 is H; R7 is methyl or ethyl.

4. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 3, characterized in that, In the reaction formula, R 11 Selected from methyl, ethyl, propyl, n-butyl, n-pentyl, phenylethyl, and phenylpropyl.

5. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 3, characterized in that, In the reaction formula, R2 and R3 are connected to form a valproic acid ring.

6. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 3, characterized in that, In the reaction formula, R4 and R5 form ethylene oxide or oxobutane.

7. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 1, characterized in that, In step S1, the light source is selected from blue light with a wavelength in the range of 400–480 nm; the irradiation intensity of the light source is 25–200 W; and the irradiation time of the light source is 10–40 h. The catalyst is Na2-eosin Y; The molar ratio of the 19-methylsteroid drug Ia or 19-demethylsteroid drug Ib to the catalyst is 1:0.03–0.08; The solvent in step S1 is selected from one or a combination of acetone, ethyl acetate, or acetonitrile; The reaction temperature in step S1 is room temperature.

8. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 7, characterized in that, In step S1, the illumination intensity of the light source is 25-100 W.

9. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 7, characterized in that, In step S1, the illumination intensity of the light source is 50 W.

10. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 7, characterized in that, In step S1, the illumination time of the light source is 10-30 hours.

11. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 1, characterized in that, In step S1, the solvent removal method is selected from the following: rotary drying, freeze drying, and supercritical carbon dioxide extraction.

12. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 11, characterized in that, The method for removing the solvent is by rotary drying.

13. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 1, characterized in that, In step S2, an organic solvent is added along with the reducing agent; In step S2, the reducing agent is thiourea; In step S2, the molar ratio of 19-methylsteroid drug Ia or 19-demethylsteroid drug Ib to the reducing agent is 1:1.0–1.5; In step S2, the reaction is stirred simultaneously for 2-10 hours.

14. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 13, characterized in that, In step S2, an organic solvent is added along with the reducing agent, and the organic solvent is methanol.

15. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 13, characterized in that, In step S2, the reaction is stirred simultaneously for 3-6 hours.

16. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 13, characterized in that, In step S2, the reaction is stirred simultaneously for 4 hours.

17. The method for preparing a steroidal drug with 6- or 10-position oxidation modification according to claim 1, characterized in that, After the reaction in S2 is completed, a separation and purification step is also included. The separation and purification step includes: evaporating the organic solvent, adding water, extracting with ethyl acetate, washing the organic phase with saturated sodium bicarbonate solution and saturated brine, drying with anhydrous sodium sulfate, evaporating again, and column chromatography to obtain steroidal drugs IIIa and IIIa with 6-position oxidation modification or steroidal drug IIb with 10-position oxidation modification.

18. The application of the method for preparing the 6- or 10-position oxidized steroidal drug according to any one of claims 1-17 in the preparation of oxidized steroidal drugs.

19. The application according to claim 18, characterized in that, The active pharmaceutical ingredient of the steroidal drug with oxidative modification at the 6 or 10 position is selected from testosterone, methyltestosterone, testosterone propionate, testosterone undecanoate, progesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone acetate, norethindrone heptaate, spironolactone, eplerenone, nandrolone phenylpropionate, levonorgestrel, and medroxyprogesterone acetate.

20. The application according to claim 19, characterized in that, The active pharmaceutical ingredient of the steroidal drug with oxidative modification at the 6 or 10 position is selected from testosterone, methyltestosterone, hydroxyprogesterone caproate, spironolactone, eplerenone, nandrolone phenylpropionate, levonorgestrel, and medroxyprogesterone acetate.

Images