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CN107188922B - Salt of abiraterone derivative and preparation method and medical application thereof - Google Patents

Salt of abiraterone derivative and preparation method and medical application thereof Download PDF

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Publication number
CN107188922B
CN107188922B CN201710095036.6A CN201710095036A CN107188922B CN 107188922 B CN107188922 B CN 107188922B CN 201710095036 A CN201710095036 A CN 201710095036A CN 107188922 B CN107188922 B CN 107188922B
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dimethyl
decahydro
methylpiperidine
cyclopenta
phenanthren
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CN107188922A (en
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张晨
黄龙彬
黄安邦
莫毅
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a salt of a compound shown as a formula (I), a preparation method and application thereof, a pharmaceutical composition containing the salt of the compound shown as the formula (I), and application thereof in preparing medicaments for preventing and treating cancers.

Description

Salt of abiraterone derivative and preparation method and medical application thereof
Technical Field
The invention relates to a salt of an abiraterone derivative and application thereof in preparing a medicament for preventing and treating cancers.
Background
Prostate cancer is a common malignant lethal cancer, the incidence of the disease in our country is on the rise in recent years, and the market demand thereof is continuously and rapidly increasing.
Androgens are key factors in prostate carcinogenesis. Androgen biosynthesis first converts pregnenolone and progesterone to 17 α -hydroxy derivatives via 17 α -hydroxylase activation, and then forms dehydroepiandrosterone and androstenedione, both precursors of testosterone, via C17, 20-lyase activation. In this process, cytochrome P450 is a key enzyme in the synthetic pathway. CYP17 is a cytochrome P450 enzyme that catalyzes the enzymatic activity of two independently regulated steroids, 17 α -hydroxylase and C17, 20-lyase, thereby regulating the in vivo synthesis of sex steroid precursors in the testis and other parts of the body.
Abiraterone acetate is an abiraterone prodrug, is a CYP17 enzyme inhibitor, is approved for sale in the United states in 2011, is suitable for treatment of prostate cancer (CRPC) patients, and recommends a dose of combining 1 oral administration of 1000mg per day with 2 oral administrations of prednisone 5mg per day.
PCT/CN2015/095776 discloses an abiraterone prodrug, i.e. a compound of formula (I), which has better pharmacokinetic profile than abiraterone acetate, but which has poor solubility of the free base, and a process for its preparation. In order to solve the problem of poor solubility of the free base, it is necessary to find a related salt with good solubility and good stability. The compounds of formula (I) have the following structure:
disclosure of Invention
The invention aims to provide a stable salt of abiraterone derivative with good solubility.
The invention also aims to provide a preparation method of the abiraterone derivative salt.
It is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a salt of an abiraterone derivative.
The invention also aims to provide application of the salt of the abiraterone derivative in preparing a medicament for treating cancer-related diseases.
The purpose of the invention is realized by the following scheme:
the invention relates to a salt of a compound shown as a formula (I), which is characterized in that the salt is selected from one or a plurality of compositions of inorganic acid salts or organic acid salts except hydrochloride,
in a preferred embodiment of the invention, the salt of the compound represented by the formula (I) is characterized in that the ratio of the compound represented by the formula (I) to each acid is selected from 0.5-2.
In a preferred embodiment of the invention, the salt of the compound represented by the formula (I) is selected from the group consisting of benzenesulfonate, salicylate, benzoate, acetate, S- (+) -mandelate, propionate, crotonate, furoate, cinnamate, ethanesulfonate, glycolate, lactate, methanesulfonate, fumarate, formate, sulfate, hydrobromide, phosphate, trifluoroacetate, tartrate, citrate, p-toluenesulfonate, maleate, succinate, oxalate, methanesulfonate, malonate, and 2-hydroxybutylate; preferably one or more of formate, di-p-toluenesulfonate, maleate or succinate; further preferred is formate or di-p-toluenesulfonate.
The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a salt according to the invention, together with pharmaceutically acceptable carriers and excipients.
The invention also relates to application of the salt or the pharmaceutical composition thereof in preparing a medicament for treating diseases related to cancer.
A preferred embodiment of the invention wherein said cancer is prostate cancer.
The invention provides a preparation method of a salt of a compound shown as a formula (I), which comprises the following steps:
1) dissolving a compound of formula (I) in a suitable solvent;
2) adding corresponding acid or its solution in proper solvent, separating solid after reaction, drying,
3) if no solid is precipitated after the reaction, an anti-solvent can be added to precipitate the solid, and then the solid is separated and dried.
The "suitable solvent" means a solvent having a certain solubility for the compound of formula (I) and the acid and capable of forming a salt thereof.
The "antisolvent" refers to a solvent which is not well soluble in the formed salt of the compound of formula (I) at ordinary temperature and is miscible with a suitable solvent in which the compound of formula (I) and an acid are dissolved.
In a preferred embodiment of the present invention, a process for the preparation of a salt of a compound of formula (I), wherein
1) The solvent is selected from one or more of methyl tert-butyl ether, ethyl acetate, dichloromethane, methanol, ethanol, isopropanol, trifluoroethanol, acetone, 1, 4-dioxane, tetrahydrofuran, chloroform, methylcyclohexane, diethyl ether, toluene, xylene, isopropyl acetate and the like;
2) wherein the molar ratio of the compound of formula (I) to the corresponding acid is 1: 0.5-1: 3, preferably 1: 0.5-1: 2.0; if the reaction is incomplete, adding corresponding acid according to the condition; suitable solvents are selected from one or more of methyl tert-butyl ether, ethyl acetate, dichloromethane, methanol, ethanol, isopropanol, trifluoroethanol, acetone, 1, 4-dioxane, tetrahydrofuran, chloroform, methylcyclohexane, diethyl ether, toluene, xylene, isopropyl acetate, and the like.
3) The anti-solvent is selected from one or more of methyl tert-butyl ether, ethyl acetate, dichloromethane, methanol, ethanol, isopropanol, trifluoroethanol, acetone, 1, 4-dioxane, tetrahydrofuran, chloroform, methylcyclohexane, diethyl ether, toluene, xylene, isopropyl acetate, petroleum ether and the like;
in a preferred embodiment of the invention, the preparation method of the salt of the compound shown in the formula (I) is characterized in that the reaction temperature is selected from 10 ℃ to the boiling point temperature of a relevant solvent, preferably 10 ℃ to 60 ℃.
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), deuterated acetonitrile (CD)3CN), internal standard Tetramethylsilane (TMS).
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Anniji chemistry, Shanghai Demer, Chengdong chemical, Shaoshou chemical technology, Bailingwei technology, and the like.
Example 1
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate 1.5(2R,3R) -2, 3-dihydroxybutanedioate (Compound 1)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-
2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate.sesqui(2R,3R)-2,3-dihydroxybutanedioate
To a reaction flask were added [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (2.37g, 5mmol) and methylene chloride (150mL), a methanol solution (3mL) of tartaric acid (0.75g, 5mmol) was added dropwise at room temperature, the system was suspended and reacted at room temperature for 30 minutes, the system was clarified, a methanol solution (3mL) of tartaric acid (0.75g, 5mmol) was added thereto, the system was suspended and filtered, and the filter cake was washed with methylene chloride (5 mL. times.2) to obtain [ (3S,8R, 9S) as a white solid, 10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate 1.5(2R,3R) -2, 3-dihydroxysuccinate (Compound 1) (0.7g, 20% yield).
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.38(dd,1H),7.88–7.79(m,1H), 7.38(dd,1H),6.09(dd,1H),5.45(d,1H),4.60(td,1H),4.45(s,3H),3.43(br,2H), 3.10(br,2H),2.84(s,3H),2.66(br,1H),2.43–2.24(m,3H),2.22–2.03(m,5H), 2.03–1.57(m,10H),1.50(td,1H),1.23-1.13(m,2H),1.12(s,3H),1.09(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 2
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate, dicitrate (Compound 2)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate.dicitrate
To a reaction flask were added [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (2.74g, 5.77mmol) and methylene chloride (120mL), a methanol solution (6mL) of citric acid (2.3g, 11.54mmol) was added dropwise at room temperature, reaction was carried out at room temperature for 30 minutes, precipitation occurred gradually in the system, suction filtration was carried out, the filter cake was washed with methyl tert-butyl ether (10 mL. times.2) to give [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2 as a white solid, 3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate dicitrate (Compound 2) (4.88g, 98% yield).
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.39(dd,1H),7.84(d,1H),7.38 (dd,1H),6.09(dd,1H),5.45(d,1H),4.66–4.53(m,1H),3.44(br,2H),3.08(br, 2H),2.86(d,4H),2.84(s,3H),2.76(d,4H),2.67(d,1H),2.44–2.23(m,3H),2.23– 1.43(m,16H),1.13(m,2H),1.11(s,3H),1.08(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 3
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate citrate (Compound 3)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate citrate
To a reaction flask were added [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (0.95g, 2.0mmol) and methylene chloride (15mL), a methanol solution (1.8mL) of citric acid (0.38g, 2.0mmol) was added dropwise at room temperature, reaction was carried out at room temperature for 60 minutes, precipitation was gradually generated in the system, suction filtration was carried out, the filter cake was washed with methyl tert-butyl ether (10 mL. times.2) to give [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2 as a white solid, 3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate citrate (compound 3) (1.07g, yield 80%).
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.38(dd,1H),8.00–7.73(m,1H), 7.37(dd,1H),6.08(dd,1H),5.45(d,1H),4.67–4.47(m,1H),3.41(br,2H),3.06(br, 2H),2.83(t,5H),2.74(d,2H),2.70-2.60(m,1H),2.44–2.23(m,3H),2.22–1.44 (m,16H),1.23-1.15(m,2H),1.12(s,3H),1.08(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 4
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate di-p-toluenesulfonate (Compound 4)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate·di(4-methylbenzenesulfonate)
To a reaction flask were added [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (7.6g, 16.0mmol) and methylene chloride (152mL), p-toluenesulfonic acid (6.09 g, 32.0mmol) was added in portions at room temperature, reaction was carried out for 10 minutes at room temperature, precipitation was gradually generated in the system, suction filtration was carried out, the filter cake was washed with methyl t-butyl ether (20 mL. times.2) to give [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2 as a white solid, 3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate di-p-toluenesulfonate (Compound 4) (9.2g, 67% yield).
1H NMR(400MHz,CD3OD)δ8.83(d,1H),8.68(d,1H),8.65–8.53(m,1H), 8.02(dd,1H),7.79–7.64(m,4H),7.32–7.13(m,4H),6.47(dd,1H),5.45(d,1H), 4.71–4.52(m,1H),3.48(dd,2H),3.04(ddd,2H),2.86(s,3H),2.69-2.55(m,1H), 2.45–2.28(m,9H),2.28–1.98(m,5H),1.98–1.42(m,11H),1.22–1.14(m,2H), 1.13(s,3H),1.12(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 5
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate p-toluenesulfonate (Compound 5)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate·4-methyl 4-methylbenzenesulfonate
Charging [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (0.95g, 2.0mmol) and dichloromethane (5mL) into a reaction flask, adding p-toluenesulfonic acid (0.38g, 2.0mmol) in portions at room temperature, reacting at room temperature for 30 minutes without precipitation, adding methyl t-butyl ether (50mL) dropwise into the system to precipitate a solid, filtering with suction, washing the filter cake with methyl t-butyl ether (20 mL. times.2) to obtain [ (3S,8R,9S,10R,13S,14S) -10 as a white solid, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate p-toluenesulfonate (Compound 5) (1.22g, 91.7% yield).
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.38(dd,1H),7.84(dt,1H),7.71 (d,2H),7.38(dd,1H),7.23(d,2H),6.09(dd,1H),5.45(d,1H),4.65-4.53(m,1H), 3.48(br,2H),3.04(br,2H),2.86(s,3H),2.66(br,1H),2.44–2.25(m,6H),2.25– 2.01(m,5H),1.99-1.44(m,11H)1.23-1.13(m,2H),1.12(s,3H),1.09(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 6
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate maleate (Compound 6)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate·maleate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a) (0.95g, 2.0mmol) and ethanol (5mL) into a reaction flask, adding a maleic acid solid (0.23g, 2.0mmol) in portions at 50 ℃, gradually clarifying the system, reacting at room temperature for 30 minutes without precipitation, dropwise adding methyl tert-butyl ether (30mL) into the system, separating out the solid, performing suction filtration, washing a filter cake with methyl tert-butyl ether (20mL multiplied by 2) to obtain white solid [ (3S,8R,9S, 10R), 13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate maleate (compound 6) (1.22g, 91.7% yield).
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.38(dd,1H),7.91–7.70(m,1H), 7.38(ddd,1H),6.25(s,2H),6.09(dd,1H),5.45(d,1H),4.71–4.51(m,1H),3.48(br, 2H),3.11(br,2H),2.86(s,3H),2.68(br,1H),2.49–2.26(m,3H),2.22–2.02(m, 5H),2.02–1.44(m,11H),1.18–1.13(m,2H),1.12(s,3H),1.09(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 7
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate 1.5 maleate (Compound 7)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate.1.5maleate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a) (0.95g, 2.0mmol) and ethanol (5mL) into a reaction flask, adding a maleic acid solid (0.46g, 4.0 mmol) in portions at 50 ℃, gradually clarifying the system, reacting at room temperature for 30 minutes without precipitation, dropwise adding methyl tert-butyl ether (30mL) into the system, separating out the solid, performing suction filtration, washing the filter cake with methyl tert-butyl ether (20mL multiplied by 2) to obtain white solid [ (3S,8R,9S, 10R), 13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate 1.5 maleate (compound 7) (1.2g, 82% yield).
1H NMR(400MHz,CD3OD)δ8.58(s,1H),8.43(d,1H),7.95(s,1H),7.57– 7.26(m,1H),6.27(s,3H),6.14(s,1H),5.45(d,1H),4.59(s,1H),3.59(br,2H),3.04 (br,2H),2.87(s,3H),2.66(br,1H),2.43–2.27(m,3H),2.26–2.01(m,5H),2.01– 1.44(m,11H),1.23-1.15(m,2H),1.12(s,3H),1.09(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 8
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate succinate (Compound 8)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate succinate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a) (0.95g, 2.0mmol) and ethanol (5mL) into a reaction bottle, adding succinic acid solid (0.47g, 4.0 mmol) in portions at 50 ℃, gradually clarifying the system, reacting at room temperature for 30 minutes without precipitation, dropwise adding methyl tert-butyl ether (30mL) into the system, separating out the solid, performing suction filtration, washing the filter cake with methyl tert-butyl ether (20mL multiplied by 2) to obtain white solid [ (3S,8R,9S, 10R), 13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate butandioate (compound 8) (0.33g, 28% yield).
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.38(dd,1H),7.89–7.78(m,1H), 7.41-7.32(m,1H),6.08(dd,1H),5.45(d,1H),4.68–4.49(m,1H),3.26(br,2H), 2.84(t,2H),2.69(s,3H),2.62-2.54(m,1H),2.53(s,4H),2.43–2.23(m,3H),2.16– 1.43(m,16H),1.22–1.13(m,2H),1.12(s,3H),1.09(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 9
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate oxalate (Compound 9)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate oxalate
Charging [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (0.95g, 2.0mmol) and ethanol (5mL) into a reaction flask, adding oxalic acid solid (0.18g, 2.0mmol) in portions at 50 ℃, precipitating the system, suction-filtering, washing the filter cake with methyl tert-butyl ether (20 mL. times.2) to obtain [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2 as a white solid, 3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate oxalate (Compound 9) (0.36g, yield 32%).
1H NMR(400MHz,CD3OD)δ8.57(d,1H),8.43(dd,1H),8.01–7.85(m,1H), 7.46(dd,1H),6.14(dd,1H),5.45(d,1H),4.58(s,1H),3.57–3.49(br,2H),3.01(br, 2H),2.85(s,3H),2.63(br,1H),2.46–2.26(m,3H),2.25–2.01(m,5H),1.98–1.45 (m,11H),1.23–1.13(m,2H),1.12(s,3H),1.09(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 10
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate-di-oxalate (compound 10)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate dioxalate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (0.95g, 2.0mmol) and ethanol (5mL) into a reaction flask, adding oxalic acid solid (0.36g, 2.0mmol) in portions at 50 ℃, clarifying the system, gradually generating precipitate, filtering, washing the filter cake with methyl tert-butyl ether (20mL multiplied by 2) to obtain white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate-di-oxalate (compound 10) (1.3g, 100% yield).
1H NMR(400MHz,CD3OD)δ8.62(d,1H),8.47(dd,1H),8.05(d,1H),7.55 (dd,1H),6.19(dd,1H),5.45(d,1H),4.58(s,1H),3.58(br,2H),3.02(t,2H),2.86(s, 3H),2.62(br,1H),2.44–1.46(m,19H),1.15(d,2H),1.12(s,3H),1.10(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 11
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate-malonate (compound 11)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate malonate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (0.95g, 2.0mmol) and ethanol (5mL) into a reaction flask, adding oxalic acid solid (0.21g, 2.0mmol) in portions at 50 ℃, clarifying the system, reacting at room temperature for 30 minutes without precipitation, dropwise adding methyl tert-butyl ether (50mL) into the system, precipitating the solid, performing suction filtration, washing the filter cake with methyl tert-butyl ether (20 mL. times.2) to obtain white solid [ (3S,8R,9S,10R, 13S), 14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate malonate (compound 11) (0.84g, 73% yield).
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.39(dd,1H),7.92–7.78(m,1H), 7.38(dd,1H),6.09(dd,1H),5.45(d,1H),4.68–4.50(m,1H),3.45(br,2H),3.06(br, 2H),2.86(s,3H),2.68(s,1H),2.45–2.24(m,3H),2.24–2.02(m,5H),2.02–1.42 (m,11H),1.23-1.15(m,2H),1.12(s,3H),1.09(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 12
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate malate (Compound 12)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate·malate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (0.95g, 2.0mmol) and ethanol (5mL) into a reaction flask, adding malic acid solid (0.27g, 2.0mmol) in portions at 50 ℃, clarifying the system, reacting at room temperature for 30 minutes without precipitation, dropwise adding methyl tert-butyl ether (50mL) into the system, precipitating the solid, performing suction filtration, washing the filter cake with methyl tert-butyl ether (20 mL. times.2) to obtain white solid [ (3S,8R,9S,10R, 13S), 14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate malate (compound 12) (0.89g, 73% yield).
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.38(dd,1H),7.87–7.80(m,1H), 7.37(dd,1H),6.09(dd,1H),5.45(d,1H),4.57-4.50(m,1H),4.30(dd,1H),3.34(br, 2H),2.96(br,2H),2.83–2.75(m,4H),2.62(br,1H),2.53(dd,1H),2.42–2.24(m, 3H),2.22–2.02(m,5H),2.02–1.44(m,11H),1.18–1.13(m,2H),1.12(s,3H), 1.09(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 13
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate 2 benzenesulfonate (compound 13)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate·dibenzenesulfonate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (2.37g, 5.0mmol) and dichloromethane (25mL) into a reaction flask, adding benzenesulfonic acid (1.85g, 10.0mmol) in portions at room temperature, reacting at room temperature for 10 minutes, gradually generating precipitates in the system, filtering, washing the filter cake with methyl tert-butyl ether (20 mL. times.2) to obtain white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate 2 benzenesulfonate (compound 13) (3.2g, 76% yield).
1H NMR(400MHz,CD3OD)δ8.84(d,1H),8.69(d,1H),8.64(dd,1H),8.02 (dd,1H),7.87–7.78(m,4H),7.46–7.37(m,6H),6.47(dd,1H),5.45(d,1H),4.66- 4.51(m,1H),3.59-3.37(m,2H),3.14–2.96(m,2H),2.86(s,3H),2.68–2.58(m, 1H),2.45–2.28(m,3H),2.27–2.07(m,5H),2.05–1.47(m,11H),1.23-1.15(m, 2H),1.14(s,3H),1.12(s,3H).
MS m/z(ESI):475.4[M+1]。
Example 14
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate p-toluenesulfonate (Compound 14)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate benzenesulfonate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a) (4.74g, 10.0mmol) and dichloromethane (30mL) into a reaction flask, adding benzenesulfonic acid (1.85g, 10.0mmol) in portions at room temperature, reacting at room temperature for 30 minutes without precipitation, adding methyl tert-butyl ether (100 mL) dropwise into the system to precipitate a solid, performing suction filtration, washing the filter cake with methyl tert-butyl ether (30 mL. times.2) to obtain white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate benzenesulfonate (compound 14) (4.15g, 66% yield).
1H NMR(400MHz,CD3OD)δ8.54(d,1H),8.39(dd,1H),7.93–7.78(m,3H), 7.53–7.31(m,4H),6.17–6.05(m,1H),5.45(d,1H),4.58(s,1H),3.53(br,2H), 3.08(br,2H),2.86(s,3H),2.64(br,1H),2.43–1.43(m,19H),1.23-1.15(m,2H), 1.11(d,3H),1.08(d,3H).
MS m/z(ESI):475.4[M+1]。
Example 15
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate methanesulfonate (Compound 15)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate methanesulfonate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a, 0.95g, 0.002mol) and ethanol (5ml) into a 25ml single-neck bottle, and stirring to obtain a white suspension; and (3) dripping solution of methanesulfonic acid (0.192g, 0.002mol) in ethanol (1ml) under stirring, quickly dissolving out, and quickly precipitating a large amount of solid and caking after dissolving out. Heating at 50 deg.C, gradually dissolving and clearing under stirring, cooling in water bath, stirring and crystallizing for 30 min, suction filtering, vacuum drying filter cake at room temperature for 1 hr to obtain white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthrene-3-yl ] 1-methylpiperidine-4-formate methanesulfonate (compound 15) (0.6g, yield: 52.63%).
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.39(dd,1H),7.90–7.78(m,1H), 7.39(dd,1H),6.09(dd,1H),5.44(d,1H),4.68–4.50(m,1H),3.58–3.38(m,2H), 3.08(d,2H),2.88(s,3H),2.71(s,4H),2.40–2.24(m,3H),2.24–2.03(m,5H),1.99 –1.55(m,10H),1.49(td,1H),1.16–1.02(m,8H).
Example 16
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate 2 methanesulfonate (Compound 16)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate dimethanesulfonate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a, 0.95g, 0.002mol) and ethanol (5ml) into a 25ml single-neck bottle, and stirring at 50 ℃ to obtain a white suspension; while stirring, a solution of methanesulfonic acid (0.384g, 0.004mol) in ethanol (1ml) was added dropwise thereto, and the mixture was quickly dissolved. Cooling at room temperature, stirring, crystallizing, and precipitating a large amount of solid and blocks; then, 6ml of ethanol was added thereto, and the mixture was stirred at room temperature for 1 hour, followed by suction filtration and cake filtration, and then dried under vacuum at room temperature for 1 hour to give a white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate, 2-methanesulfonate (Compound 16) (0.9g, yield: 67.66%).
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.86(d,1H),8.71(d,1H),8.70–8.60(m,1H), 8.05(dd,1H),6.50(dd,1H),5.47(s,1H),4.67–4.50(m,1H),3.57(d,2H),3.04(d, 2H),2.88(d,3H),2.71(s,6H),2.63(ddd,1H),2.37(dd,3H),2.26–2.07(m,5H), 1.99–1.60(m,10H),1.55(td,1H),1.22-1.12(m,8H).
Example 17
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate fumarate (Compound 17)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate fumarate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a, 0.95g, 0.002mol) and ethanol (5ml) into a 25ml single-neck bottle, and stirring at 50 ℃ to obtain a white suspension; fumaric acid (0.232g, 0.002mol) was added with stirring, and gradually dissolved off with stirring, and 15ml of t-butyl methyl ether was added. Ice water is cooled, stirred and crystallized for 1 hour, and then filtered, and the filter cake is dried in vacuum for 1 hour at room temperature to obtain white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate fumarate (compound 17) (0.7g, yield: 59.3%).
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.38(dd,1H),7.89–7.77(m,1H), 7.38(ddd,1H),6.71(d,2H),6.09(dd,1H),5.45(d,1H),4.59(ddd,1H),3.42(d,2H), 3.04(t,2H),2.82(s,3H),2.72–2.59(m,1H),2.40–2.24(m,3H),2.10(tdd,5H), 2.02–1.58(m,10H),1.50(td,1H),1.17–1.04(m,8H).
Example 18
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate formate (compound 18)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate formate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a, 0.95g, 0.002mol) and ethanol (5ml) into a 50ml single-neck bottle, and stirring at 50 ℃ to obtain a white suspension; 2ml of an ethanol solution of formic acid (0.184g, 0.004mol) was added thereto with stirring, and gradually dissolved out with stirring, and 21ml of t-butyl methyl ether was added thereto. Ice water is cooled, stirred and crystallized for 1 hour, and then filtered, and the filter cake is dried in vacuum for 1 hour at room temperature to obtain white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate formate (compound 18) (0.85g, yield: 81.73%).
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.53(d,1H),8.49(s,1H),8.38(dd,1H),7.87– 7.77(m,1H),7.37(ddd,1H),6.09(dd,1H),5.45(d,1H),4.59(tdd,1H),3.36(d,2H), 2.96(t,2H),2.77(s,3H),2.63(ddd,1H),2.39–2.23(m,3H),2.20–2.02(m,5H), 2.01–1.56(m,10H),1.50(td,1H),1.24–1.04(m,8H).
Example 19
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate sulfate (Compound 19)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate sulfate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a, 0.95g, 0.002mol) and ethyl acetate (15ml) into a 50ml single-neck bottle, and stirring at room temperature to obtain a white suspension; 6ml of an ethyl acetate solution of sulfuric acid (0.196g, 0.002mol) was added thereto with stirring to conduct a reaction for 1 hour, followed by suction filtration and vacuum drying of the filter cake at room temperature for 1 hour to give [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate sulfate (Compound 19) (1g, yield: 87.34%) as a white solid.
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.76(s,1H),8.64(d,1H),8.41(d,1H),7.89(dd, 1H),6.40(s,1H),5.44(d,1H),4.66–4.46(m,1H),3.54(dd,2H),3.03(dd,2H), 2.89(d,3H),2.76–2.60(m,1H),2.44–2.29(m,3H),2.25–2.06(m,5H),2.00– 1.57(m,10H),1.49(td,1H),1.10(d,8H).
Example 20
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate 2 hydrobromide salt (Compound 20)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate dihydrobromide
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a, 0.95g, 0.002mol) and ethanol (15ml) into a 50ml single-neck bottle, and stirring at room temperature to obtain a white suspension; hydrobromic acid (40%, 0.85g, 0.0042mol) was added with stirring to rapidly dissolve and clear, then a white solid precipitated rapidly, which was crystallized with stirring at room temperature for 2 hours, filtered and the filter cake was dried under vacuum at 40 ℃ for 1 hour to give a white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate, 2-hydrobromide (compound 20) (0.85g, yield: 81.73%).
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.85(s,1H),8.68(dd,2H),8.04(dd,1H),6.49 (dd,1H),5.46(d,1H),4.68–4.49(m,1H),3.59–3.40(m,2H),3.06(d,2H),2.88(d, 3H),2.71–2.60(m,1H),2.46–2.30(m,3H),2.29–2.03(m,5H),1.99–1.60(m, 10H),1.59–1.48(m,1H),1.17–1.10(m,8H).
Example 21
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate hydrobromide (Compound 21)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate hydrobromide
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a, 0.95g, 0.002mol) and ethanol (10ml) into a 50ml single-neck bottle, and stirring at 50 ℃ to obtain a white suspension; hydrobromic acid (40%, 0.40g, 0.002mol) was added with stirring to rapidly dissolve and clear, then white solid was rapidly precipitated, crystallized with stirring at room temperature for 2 hours, filtered, and the filter cake was dried under vacuum at 40 ℃ for 1 hour to give white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate hydrobromide (compound 21) (0.95g, yield: 85.58%).
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.52(d,1H),8.39(dd,1H),7.90–7.77(m,1H), 7.40(dd,1H),6.09(dd,1H),5.45(d,1H),4.62–4.51(m,1H),3.48(s,2H),3.11(s, 2H),2.87(s,3H),2.70(d,1H),2.41–2.25(m,3H),2.25–2.03(m,5H),1.97–1.55 (m,10H),1.47(td,1H),1.09(d,8H).
Example 22
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate phosphate (compound 22)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate phosphate
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate (1a, 0.95g, 0.002mol) and dichloromethane (20ml) into a 50ml single-neck bottle, and gradually dissolving the mixture to be clear under stirring at room temperature; a solution of phosphoric acid (0.196g, 0.002mol) in methylene chloride (5ml) was added with stirring, and a colloidal solid was gradually precipitated with stirring, which was crystallized with stirring at room temperature for 2 hours, filtered, and the filter cake was dried under vacuum at 40 ℃ for 1 hour to give [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate phosphate (compound 22) (0.90g, yield: 78.95%) as a white solid.
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.50(d,1H),8.39(dd,1H),7.81(d,1H),7.39 (dd,1H),6.08(s,1H),5.41(d,1H),4.60–4.41(m,1H),3.54(s,2H),3.03(s,2H), 2.86(s,3H),2.68(s,1H),2.40–2.13(m,5H),2.05(dd,3H),1.98–1.48(m,10H), 1.47–1.35(m,1H),1.04(d,J＝15.3Hz,8H).
Example 23
[ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridinyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate, 2 (trifluoroacetic acid) salt (Compound 23)
[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)- 2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]1- methylpiperidine-4-carboxylate di(2,2,2-trifluoroacetate)
Adding [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-formate (1a, 0.95g, 0.002mol) and ethanol (6ml) into a 50ml single-neck bottle, and stirring at 50 ℃ to obtain a white suspension; trifluoroacetic acid (40%, 0.46g, 0.004mol) was added thereto with stirring, gradually dissolved and cleared with stirring, 30ml of t-butyl methyl ether was added thereto, and the mixture was stirred at room temperature for 3 hours, concentrating under reduced pressure to dry, adding tert-butyl methyl ether 20ml into residue, stirring to gradually precipitate solid, stirring to crystallize for 4 hr, suction filtration and vacuum drying of the filter cake at 40 ℃ for 1 hour gave white solid [ (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (3-pyridyl) -2,3,4,7,8,9,11,12,14,15 decahydro-1H-cyclopenta [ a ] phenanthren-3-yl ] 1-methylpiperidine-4-carboxylate, 2 (trifluoroacetic acid) salt (compound 23) (0.95g, yield: 80.71%).
MS m/z(ESI):475.4.
1H NMR(400MHz,CD3OD)δ8.68(d,1H),8.53(dd,1H),8.25–8.13(m,1H), 7.68(dd,1H),6.27(dd,1H),5.46(d,1H),4.59(d,1H),3.56(d,2H),3.04(dd,2H), 2.87(s,3H),2.65(dd,1H),2.34(ddd,3H),2.27–2.06(m,5H),1.98–1.59(m,10H), 1.52(td,1H),1.12(d,8H).
Test example
1. Solubility test
Respectively adding 2mL of physiological saline and 2mL of 0.5% CMC-Na solution into a BD centrifuge tube, adding samples one by one, heating in a water bath at 37 ℃ after adding the samples each time, and strongly shaking or ultrasonically treating. After a certain amount of sample was added, the solution became turbid, and the turbidity did not disappear by heating in a 37 ℃ water bath for 30 minutes and shaking vigorously or ultrasonically. The results are shown in Table 1.
Table 1 solubility test results
And (4) conclusion: the compounds of the invention all have good solubility, which is much improved compared to the free base (I) compounds.
2. Stability test
Samples were tested at elevated temperature (40 ℃ and 60 ℃ C., 10 days), elevated humidity (RH 75% and RH 92.50%, 10 days) and light (5500 + -500 lx, 10 days) for purity (in percent) by HPLC, and the results are shown in Table 2.
The purity conditions of HPLC detection are as follows: a chromatographic column: xselect CSH C18(4.6 × 150mm,3.5 um); column temperature: 35 ℃; detection wavelength: 275 nm; mobile phase: performing gradient elution; the flow rate was 1.0 mL/min.
Table 2 stability test results
And (4) conclusion: the compounds of the invention all have good stability.

Claims (6)

1. A salt of a compound of formula (I), wherein the salt is selected from the group consisting of benzenesulfonate, salicylate, benzoate, acetate, S- (+) -mandelate, propionate, crotonate, furoate, cinnamate, ethanesulfonate, glycolate, lactate, fumarate, formate, sulfate, hydrobromide, phosphate, trifluoroacetate, tartrate, citrate, p-toluenesulfonate, maleate, succinate, oxalate, methanesulfonate, malonate, or 2-hydroxysuccinate, and wherein the ratio of the compound of formula (I) to each acid is selected from 0.5 to 2;
2. the salt according to claim 1, characterized in that the salt is selected from the group consisting of one or more of formate, di-p-toluenesulfonate, maleate or succinate.
3. The salt according to claim 2, characterized in that said salt is selected from formate or di-p-toluenesulfonate.
4. A pharmaceutical composition comprising a therapeutically effective amount of a salt according to any one of claims 1 to 3, together with pharmaceutically acceptable carriers and excipients.
5. Use of a salt according to any one of claims 1 to 3 or a composition according to claim 4 in the manufacture of a medicament for the treatment of a disease associated with cancer.
6. The use according to claim 5, wherein the cancer is prostate cancer.
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Citations (3)

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CN102686600A (en) * 2009-02-05 2012-09-19 托凯药业股份有限公司 Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens
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CN102686600A (en) * 2009-02-05 2012-09-19 托凯药业股份有限公司 Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens
CN102477061A (en) * 2010-11-23 2012-05-30 苏州波锐生物医药科技有限公司 Pyridine androstane derivative and application thereof in preparation of drugs for preventing and/or treating prostate cancer
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