198414-31-2

Telapristone acetate

[(8S,11R,13S,14S,17R)-11-[4-(Dimethylamino)phenyl]-17-(2-methoxyacetyl)-13-methyl-3-oxo-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate

 17-acetoxy- 11 β-[4-(dimethylamino)-ρhenyl]-21-methoxy-19-noφregna-4,9-dien-3,20-dione

17-Acetoxy-llβ-f4-(dimethylamino)-phenyl)1-21-methoxy-19-norpregna-4,9-dien-3,20- dione

17α-acetoxy-llβ-[4-(N,N-dimethylamino)phenyl]-21-methoxy- 19-norpregna-4, 9-diene-3,20-dione 

CDB-4124; 17α-Acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione)

Telapristone (proposed trade names Proellex and Progenta) is an investigational selective progesterone receptor modulator, tested for treatment of progesterone sensitive myomata.^[1] CDB-4124 was originally developed the National Institutes of Health, and as of 2012 is in Phase II clinical trials for uterine fibroids and endometriosis.^[2] It also has some antiglucocorticoidactivity

 17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione, (also known as CDB-4124)

17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) is a selective progesterone receptor modulator, it is being tested for treatment of progesterone sensitive myomata.

International patent application WO 97/41145 disclosed for the first time the preparation of 17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione). In example 9 it is characterized as light-yellow powder with a melting point of 116° C. (purity: 98.06%, characteristic FT-IR absorption bands at: 1124, 1235, 1370, 1446, 1518, 1612, 1663, 1734, 2940 cm⁻¹).

According to the published international patent applications of WO 01/47945 and WO 01/74840 the obtained 17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) was light-yellow powder as well having a melting point of 116° C. (purity: 98.87%, 98.06%, characteristic FT-IR absorption bands at: 1124, 1235, 1370, 1446, 1518, 1612, 1662, 1734, 2940 cm⁻¹)

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http://www.google.com/patents/WO2001047945A1?cl=en

Preparation of 17α-hydroxy-llβ-[4-(N,N-dimethylamino)phenyl]-21-methoxy- 19-norpregna-4,9-diene-3,20-dione (10) :

A suspension of 2-iodoxybenzoic acid (IBX, 599 mg, 2.14 mmol) in anhydrous dimethylsulfoxide (DMSO) (5.0 mL; Aldrich, Sure-Seal) was stirred magnetically under nitrogen and warmed in an oil bath at 55 – 60°C. After several minutes, all of the IBX was solubilized. To the IBX solution was added a solution of the 20-alcohol (18, 500 mg, 1.07 mmol) in DMSO (5 mL). Additional DMSO (3 mL) was used to rinse in residual 18. After a period V2 hr of reaction, approximately 70% of the 20-alcohol (18) had been converted to the 20-ketone (10), as evidenced by TLC (15% acetone in methylene chloride; aliquot was diluted in water and extracted by EtOAc). After 3 hr, there was no observable change in the conversion. The reaction mixture was transferred to a separatory funnel, diluted with water, and extracted by EtOAc (3x). The EtOAc extracts were washed with additional water (2x) and brine (lx). The combined extracts were dried by filtration through sodium sulfate, evaporated in vacuo, and dried overnight under high vacuum to recover 600 mg of a brown film. The film product was taken up in EtOAc and filtered through silica on a sintered glass funnel to remove residual DMSO and highly polar impurities. Evaporation of EtOAc afforded 450 mg of a yellow film. Repeated trituration with hexane, with scratching and sonicating, produced a solid. The solid was dried overnight under high vacuum to give 349 mg of 10 as a yellow powder in 70.1% yield. The product was carried directly to the next reaction without further purification. NMR (300 MHz, CDCI₃) : δ 0.408 (s, 3 H, C18-CH₃),2.906 (s, 6 H, -N(CH₃)₂), 3.454 (s, 3 H, C21-OCH₃), 4.245 and 4.388 (AB, 2 H, C21-CH₂, JAB = 17.41 Hz), 4.378 (d, 1 H, Cllβ-CH, J = 7.50), 5.758 (s, 1 H, C4-CH), 6.638 (d, 2 H, 3′,5′-aromatic CH, J = 8.55 Hz) and 6.975 (d, 2 H, 2′,6′-aromatic CH, J = 8.55 Hz).

Preparation of 17α-acetoxy-llβ-[4-(N,N-dimethylamino)phenyl]-21-methoxy- 19-norpregna-4, 9-diene-3,20-dione (11) :

A mixture of trifluoroacetic anhydride (47 mL) and glacial acetic acid (19.1 mL) in methylene chloride (300 mL) was allowed to stir at room temperature under nitrogen. After ¹/₂ hr of stirring, the mixture was cooled to 0°C in an ice water bath and tosic acid (2.85 g, 14.98 mmol) was added. A solution of the 17α-hydroxy compound (10, 6.18 g, 13.33 mmol) was added in 50 mL of methylene chloride and rinsed in with additional CH₂CI₂ (50 mL). After stirring for a period of 2 hr at 0°C, examination by TLC (silica; 10% acetone in methylene chloride; neutralized with NH₄OH before developing) indicated that the reaction was >95% complete. The reaction mixture was diluted with water (300 mL) and neutralized by careful addition of concentrated NH₄OH (75 mL).

More NH₄OH was added to a pH of 7 as indicated by a pH paper. The product obtained was extracted by CH₂CI₂ (3x) and the organic extracts were washed with water (2x) and brine (lx). The combined organic extracts were dried by filtration through Na₂SO₄ and evaporated in vacuo to give 7.13 g of the crude product (11). A pure material was obtained by flash column chromatography (silica; 10% acetone in methylene chloride). The impure fractions were combined and chromatographed a second time. The pure fractions from both chromatographic runs were combined and evaporated in vacuo, then evaporated from ether, and further dried under high vacuum to produce a pale yellow foam. Treatment with pentane followed by scratching and sonicating produced 4.13 g of 11 as a fine yellow powder in 61.3% yield; m.p. softens at 116°C.

Analysis by a reverse phase HPLC on a NOVAPAK™ Cι₈ column eluted with 70% CH₃OH in water with 0.03% Et₃N at a flow rate of 1 mL per min and at λ = 302 indicated 98.87 % purity of 11 with retention time t_R = 6.45 min.

FTIR (KBr, diffuse reflectance) : v_max 2940, 1734, 1662, 1612, 1518, 1446, 1370, 1235 and 1124 cm^“1.

NMR (300 MHZ, CDCI₃) : δ 0.38 (s, 3 H, C18-CH₃), 2.08 (s, 3H, C17α-0Ac), 2.90 (s, 6 H, -N(CH₃)₂), 3.42 (s, 3 H, C21-OCH₃), 4.07 and 4.33 (AB, 2 H, C21-CH₂, J_AB= 18 Hz), 4.37 (s, 1 H, Cllβ-CH), 5.80 (s, 1 H, C4-CH), 6.67 (d, 2 H, 3′,5′-aromatic CH, J = 9 Hz) and 7.0 (d, 2 H, 2′, 6′- aromatic CH, J = 9 Hz).

MS (El) m/z (relative intensity) : 505 (M⁺, 13.5), 445 (1.1), 372 (2.7), 134 (16.2) and 121 (100).

Anal. Calcd for C₃₁H₃₉NO₅: C, 73.64; H, 7.77; N, 2.77 Found : C, 73.34; H, 7.74; N, 2.70.

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synthesis

http://www.google.com/patents/WO2009001148A2?cl=en

According to the above mentioned facts, there is no such known process, which is suitable for the realization of the synthesis of CDB-4124 on industrial scale using simple reaction conditions. Our aim was to elaborate a process, which is easy to scale-up, the industrial realization of which is safe, economical and the purity of the active ingredient fulfils the requirements of the pharmacopoeia.

Surprisingly it was found, that the following process fulfils the above mentioned requirements: i) epoxide formation on the double bond in position 5(10) of 3,3-[l,2-ethandiyl- bis(oxy)]-oestr-5(10),9(l l)-dien-17-one of formula (II)

with hydrogen peroxide; ii) addition of hydrogen cyanide formed in situ on position 17 of the obtained 5,1 Oa- epoxy-3,3-[l,2-ethandiyl-bis(oxy)]-5α-oestr-9(l l)-en-17-one of formula (III)

iii) silylation of the hydroxyl group in position 17 of the formed 5,10α-epoxy-3,3-[l,2- ethandiyl-bis(oxy)]-17α-hydroxy-5α-oestr-9(l l)-en-17β-carbonitrile of formula (IV)

with trimethyl chlorosilane; iv) reacting the obtained 5,10α-epoxy-3,3-[l,2-ethandiyl-bis(oxy)]-17-[trimethyl-silyl- oxy]-5α-oestr-9(ll)-en-17β-carbonitrile of formula (V)

with 4-(dimethylamino)-phenyl magnesium bromide Grignard reagent in the presence of CuCl

(Teutsch reaction); v) silylation of the hydroxyl group in position 5 of the formed 1 lβ-[4-(dimethyl-amino)- phenyl]-3 ,3-[ 1 ,2-ethandiyl-bis(oxy)] -5-hydroxy- 17α-[trimethylsilyl-(oxy)] -5α-oestr-9-en- 17β- carbonitrile of formula (VI)

with trimethyl chlorosilane; vi) reacting the obtained llβ-[4-(dimethylamino)-phenyl]-3,3-[l,2-ethandiyl-bis(oxy)]- 5,17α-bis-[trimethyl-silyl-(oxy)]-5α-oestr-9-en-l 7β-carbonitrile of formula (VII)

with diisobutyl aluminum hydride and after addition of acid to the reaction mixture vii) methoxy-methylation of the obtained llβ-[4-(dimethylamino)-phenyl]-3,3-[l,2- ethandiyl-bis(oxy)]-5,17α-bis-[trimethyl-silyl-(oxy)]-5α-oestr-9-en-17β-carbaldehide of formula (VIII)

with methoxy-methyl Grignard reagent formed in situ, while hydrolyzing the trimethylsilyl protective groups; viii) oxidation of the hydroxy! group in position 20 of the obtained 17,20ξ-dihydroxy-

3-[4-(dimethylamino)-phenyl]-21 -methoxy- 19-norpregna-4,9-dien-3-one of formula (IX)

with dicyclohexyl carbodiimide in the presence of dimethyl sulfoxide and a strong organic acid (Swern oxidation), and in given case after purification by chromatography ix) acetylation of the hydroxyl group in position 17 of the obtained l lβ-[4- (dimethylamino)-phenyl]- 17-hydroxy-21 -methoxy- 19-norpregna-4,9-dien-3 ,20-dione of formula (X)

with acetic anhydride in the presence of perchloric acid, and in given case the obtained 7- acetoxy-11 β-[4-(dimethylamino)-phenyl)]-21-methoxy-19-norpregna-4,9-dien-3 ,20-dione of formula (I) is purified by chromatography.

Example 11

17-Acetoxy-llβ-f4-(dimethylamino)-phenyl)1-21-methoxy-19-norpregna-4,9-dien-3,20- dione [compound of formula (Dl 70 % Perchloric acid (6 ml) was added to stirred and cooled ((-20) – (-25) ⁰C) acetic anhydride (45 ml) at such a rate to keep the temperature below (-15) °C. Then a solution of l lβ-[4-(dimethylamino)-phenyl)]-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione (15.5 g) in dichloromethane (60 ml) was added at (-20) – (-25) ⁰C. After completion of the reaction – followed by thin layer chromatography – the reaction mixture was diluted with dichloromethane (50 ml), cooled to (-10) ⁰C and ion exchanged water (52 ml) was added to decompose the acetic anhydride. After stirring for 10 min 25 % ammonium hydroxide solution (77 ml) was added at such rate to keep the temperature below 25 ⁰C (pH=7-8). Then the precipitated carbamide by-product was filtered off, the aqueous phase was separated, extracted with dichloromethane (2×30 ml) and the combined organic layers were concentrated to yield 16.2 g (95.8 %) of the title compound, which was purified by HPLC according to method described in the next example. NMR: ¹H NMR C500 MHz. CDCl₁ (TMS), δ (ppmT): 0.40 (3H, s, 18-CH₃); 2.10 (3H₅ s, O-CO- CH₃); 2.90 (6H, s, N-CH₃); 3.41 (3H, s, 0-CH₃); 4.09 (IH, d, H_x-21); 4.38 (IH, m, H-Il); 4.29 (IH, d, H_y-21); 5.77 (IH, br, H-4); 6.62 (2H₅ m, H-3′ & H-5′); 6.96 (2H, m, H-2′ & H-6′) 1³C NMR (125 MHz. CDCU (TMS), δ fppmϊ): 15.6 (C-18); 21.1 (0-CO-CH₃); (39.3 (C-Il); 40.6 (N-CH₃); 59.4 (0-CH₃); 76.0 (C-21); 93.9 (C-17); 112.8 (C-3′ & C-5′); 123.0 (C-4); 127.3 (C-2′ & C-6′); 129.4 (C-IO); 131.3 (C-I’); 145.5 (C-9); 148.7 (C-4′); 156.4 (C-5); 170.7 (0-CO-CH₃); 199.4 (C-3); 202.7 (C-20)

Example 12 Purification of crude CDB-4124 by HPLC (eluent: cyclohexanermethyl-tert-butyl- ether;acetone = 60:30:10) (laboratory scale) [compound of formula (DI

Silicagel (51O g, ZEOPREP C-GEL C-490L, 15-35 μm of particle size; bed length about 60 cm) was filled to an axial bed compression HPLC column of 5 cm of diameter with slurry packing method and the column was equilibrated with a 60:30:10 mixture of cyclohexane – methyl-tert-butyl ether – acetone eluent. 5.1 g of the crude compound of formula (I) (CDB-4124) obtained in the previous example (content of impurities: less than 4 %) was dissolved in the eluent (100 ml), filtered and injected on the column. The product was eluted with 85 ml/min flow rate and UV detection was used. The first fraction was about 40 ml, the main fraction containing the pure CDB-4124 was about 560 ml. The solid title compound was obtained by concentration of the eluted main fraction. Yield: 4.25 g (83.33 %), content of impurities: less than 0.5 %. Melting point: 118⁰C.

[a^ = +127.2 ° (c=l %, chloroform)

NMR: ¹H NMR (500 MHz. CDCh (TMS). δ fppmV): 0.40 (3H, s, 18-CH₃); 2.10 (3H, s, O-CO-

CH₃); 2.90 (6H, s, N-CH₃); 3.41 (3H, s, 0-CH₃); 4.09 (IH, d, H_x-21); 4.38 (IH, m, H-I l); 4.29 (IH, d, H_y-21); 5.77 (IH, br, H-4); 6.62 (2H, m, H-3′ & H-5′); 6.96 (2H, m, H-2′ & H-6′)

¹³C NMR (125 MHz. CDCh (TMS), δ (ppm)): 15.6 (C-18); 21.1 (0-CO-CH₃); (39.3 (C-Il);

40.6 (N-CH₃); 59.4 (0-CH₃); 76.0 (C-21); 93.9 (C-17); 112.8 (C-3′ & C-5′); 123.0 (C-4);

127.3 (C-2′ & C-6′); 129.4 (C-IO); 131.3 (C-I’); 145.5 (C-9); 148.7 (C-4′); 156.4 (C-5); 170.7

(0-CO-CH₃); 199.4 (C-3); 202.7 (C-20)

References