KR20000064495A - Preparation of 9,11B-epoxide steroid - Google Patents

Abstract

The present invention relates to a method of preparing an epoxy steroid of formula 1.0. The process reacts the bromine or chlorinating agent with triene of formula 2.0 in DMF containing a catalytic amount of 70% HClO ₄ at a temperature of from about 0 to about + 40 ° C. to give the corresponding bromoformate (3.0) or chloro Preparing formate (3.0A). The bromoformate or chloroformate is then mixed with an organic solvent comprising (a) THF or CH ₂ Cl ₂ and (b) C ₁ to C ₆ alkanol or acetonitrile at a temperature of about -20 to about + 10 ° C. Epoxy steroid (1.0) is prepared by reacting with a strong base.

Formula 1.0

Formula 2.0

Formula 3.0

Formula 3.0A

In the above formula,

R ¹ is selected from H, -OH or Cl, R ² is selected from hydrogen or lower alkyl,

R ³ is Cl if R ¹ is in the case of H H and when R ¹ is -OH a suitably protected -OH group, and R ¹ is Cl.

Description

Method for preparing 9,11β-epoxide steroid

East German 268954 A1 describes a method for preparing a Pregnan family of steroids containing a 9α-halogen-11β-formyloxy group. Steroids with these substituents are precursors to 9α-halo and 11β-hydroxysteroids, respectively. In view of the importance of 9α-halo, 11β-hydroxysteroids, methods for producing high yield precursors with minimal byproducts are highly desired in the art. The claimed invention makes this very contribution.

Summary of the Invention

The claimed invention relates to a process for preparing 9,11β-epoxy steroids from their 9,11-double bond precursors. When the 9,11-double-binding precursor reacts with a suitable brominating or chlorinating agent, the corresponding 9α-halo-11β-formate steroid is formed while using minimal amounts of DMF and minimal amounts of 70% HClO ₄ to form minimal dihalo byproducts. It will be prepared. The 9α-bromo-11β-formate or 9α-chloro-11β-formate steroid intermediate at low temperature is then reacted with a suitable strong base in a suitable organic solvent mixture to afford the corresponding 9,11β-epoxy steroid.

The present invention claimed is (A) a brominating agent selected from DBH or NBS or a chlorine selected from N-chloroimide or N-chloroamide in DMF containing a catalytic amount of 70% HClO ₄ at a temperature of from about 0 to about + 40 ° C. Reacting an agent with a compound of Formula 2.0 to obtain bromoformate of Formula 3.0 from the brominating agent or to obtain chloroframate of Formula 3.0A from the halogenating agent;

(B) a bromine of formula 3.0 with a strong base in an organic solvent mixture comprising (a) THF or CH ₂ Cl ₂ and (b) C ₁ to C ₆ alkanol or acetonitrile at a temperature of about −20 to about + 10 ° C. A method for preparing an epoxy steroid of Formula 1.0, including reacting morphformate or chloroformate of Formula 3.0A to yield an epoxy steroid of Formula 1.0.

In the above formula,

R ¹ is selected from H, -OH, or Cl;

R ² is selected from hydrogen or lower alkyl;

And when R ¹ is H R ³ is H, and R ^1, R ³ is a suitably protected -OH group when the -OH, in the case where R ¹ is Cl R ³ is Cl.

The present invention also provides a bromoformate of Formula 3.0 comprising reacting a compound of Formula 2.0 with a brominating agent selected from DBH or NBS in DMF containing a catalytic amount of 70% HClO ₄ at a temperature of about 0 to about 40 ° C. It relates to a manufacturing method.

Formula 2.0

Formula 3.0

In the above formula,

R ² is selected from hydrogen or lower alkyl;

R ³ is selected from H, suitably protected -OH group or Cl.

The present invention also relates to a strong base and a formula 3.0 in an organic solvent mixture comprising (a) THF or CH ₂ Cl ₂ and (b) C ₁ to C ₆ alkanol or acetonitrile at a temperature of from about −20 ° C. to about + 10 ° C. A method for preparing an epoxy steroid of formula (1.0) comprising reacting a bromoformate of or chloroformate of formula (3.0A).

Formula 1.0

Formula 3.0

Formula 3.0A

In the above formula,

R ¹ is selected from H, -OH or Cl;

R ² is selected from hydrogen or lower alkyl;

R ³ is selected from H when R ¹ is H, -OH group suitably protected when R ¹ is -OH, or Cl when R ¹ is Cl.

As used herein, the following terms have the following meanings unless stated otherwise:

Alkyl is a straight and branched carbon chain having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms;

DBH is 1,3-dibromo-5,5-dimethylhydantoin;

DMF is dimethylformamide;

Lower alkyl is a straight or branched chain alkyl group having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary-butyl, n-pentyl, isopentyl, n-hexyl and 2 , 3-dimethyl-butyl;

Meq is molar equivalent;

NBS is N-bromosuccinimide;

THF is tetrahydrofuran.

Preferably R ¹ is -OH and R ² is lower alkyl and most preferably -CH ₃ .

R ³ is (a) H when R ¹ is H, (b) Cl when R ¹ is Cl, and (c) ROH is suitably protected when R ¹ is OH. Suitably protected -OH groups are obtained using suitable protecting groups known in the art. Suitable protecting groups are those which are readily hydrolyzed under the reaction conditions of epoxide formation to give an unprotected —OH group for R ¹ . Suitable protection groups are described in Green et al., Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons Inc., New York, 1991, which is incorporated herein by reference.

For example, where R ¹ is -OH, suitable R ³ groups include -OC (O) R ⁴ (ester) or -OC (O) OR ⁵ (carbonate). R ⁴ is selected from C ₁ to C ₆ alkyl, -CF ₃ , -CCl ₃ , aryl (eg phenyl, benzyl or naphthyl), vinyl (-CH = CH ₂ ) or allyl (CH ₂ = CHCH _2- ) do. R ⁵ is selected from C ₁ to C ₆ alkyl, aryl (eg phenyl or benzyl), vinyl (-CH = CH ₂ ) or allyl (CH ₂ = CHCH _2- ). Preferably R ³ is -OC (O) OR ⁵ , more preferably R ³ is -OC (O) OR ⁵ , wherein R ⁵ is C ₁ to C ₆ alkyl, most preferably R ³ is -OC (O) OR ⁵ , where R ⁵ is -C ₂ H ₅ .

R ³ is H, Cl or -OC (O) R ⁴ , wherein R ⁴ is C ₁ to C ₆ alkyl or -CF ₃ or R ³ is -OC (O) OR ⁵ , wherein R ⁵ is C Starting reactants of Formula 2.0, which are ₁ to C ₆ alkyl, are disclosed in International Application No. PCT / US95 / 06600, filed May 30, 1995, and US Application No. 08 / 252,302, filed June 1, 1994. It may be prepared according to the described methods, each of which is incorporated herein by reference.

R ³ is -CO (O) R ⁴ and R ⁴ is selected from -CCl ₃ , aryl (eg phenyl, benzyl or naphthyl), vinyl (-CH = CH ₂ ) or allyl (CH ₂ = CHCH _2- ) Or starting reactants of formula 2.0 wherein R ³ is -OC (O) OR ⁵ and R ⁵ is selected from aryl (e.g., phenyl, benzyl), vinyl or allyl, using appropriate reactants according to the methods described in the above-mentioned literature. Can be prepared by one skilled in the art.

For example, if R ⁴ is phenyl, benzyl, naphthyl, vinyl or allyl, the reactants ClC (O) C ₆ H ₅ , ClC (O) CH ₂ C ₆ H ₅ , CIC (O) C ₁₀ H ₇ , ClC (O) CH═CH ₂ or ClC (O) CH ₂ CH═CH ₂ may be used respectively to obtain the desired —OC (O) R ⁴ group. When R ⁵ is phenyl, benzyl, vinyl or allyl Reactant ClC (O) OC ₆ H ₅ , ClC (O) OCH ₂ C ₆ H _5, ClC (O) OCH = CH ₂ or ClC (O) OCH ₂ CH = Each CH ₂ can be used to obtain the desired -OC (O) OR ⁵ group. The solvent for these reactants is, for example, methylene chloride in the presence of triethyleneamine.

Those skilled in the art will combine It will be appreciated that this represents an α or β configuration. E.g, or Are each or or or Indicates.

The reaction of bromoformate (3.0) or chloroformate (3.0A) to prepare the epoxy steroid (1.0) is preferably carried out under an inert atmosphere such as nitrogen.

The compound of formula 2.0 is reacted with a suitable brominating or chlorinating agent.

Suitable brominating agents are DBH or NBS, with DBH being preferred. Suitable chlorinating agents are N-chloroimide or N-chloroamide. Examples of chlorinating agents include N-chloroacetamide, N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, or 1,3,5-trichloroisocyanuric acid. Preferably, 1,3-dichloro-5,5-dimethylhydantoin or 1,3,5-trichloroisocyanuric acid is used. Most preferably 1,3,5-trichloroisocyanuric acid, for example, Is used. Preferably bromination agents are used.

The compound of formula 2.0 is reacted with a brominating or chlorinating agent in DMF to which a catalytic amount of 70% HClO ₄ is added. A sufficient amount of the compound of formula 2.0 and the brominating or chlorinating agent are used to allow the reaction to proceed at a suitable rate to yield the desired bromoformate of formula 3.0 or the chloroformate of formula 3.0A.

At least about 0.5 molar equivalents (Meq) of brominating agent (eg DBH) or chlorinating agent is used. Usually, about 0.5 to about 2.0 Meq, preferably about 0.65 to about 1.0 Meq, more preferably about 0.7 to about 0.8 Meq, most preferably about 0.75 Meq is used.

DMF is used in excess relative to the compound of formula 2.0. Sufficient DMF is used to act as solvent and reactant and preferably minimum requirements are used. The volume of DMF is used in excess of about 2 to 20 times, preferably about 2 to 5 times, more preferably about 3 to about 4 times, and most preferably about 3.5 times the amount of the compound of formula 2.0. . A catalytic amount of 70% HClO ₄ is used and preferably the minimum requirement is used. Suitable amounts of at least about 0.5 Meq of 70% HClO ₄ , from about 0.5 to about 3.0 Meq and preferably from about 0.5 to about 1.0 Meq and more preferably from about 0.5 to about 0.7 Meq and most preferably about 0.6 Meq are used. .

Brominated or chlorinating compounds of the compound of formula 2.0 at a temperature of about 0 to about 40 ° C, preferably about 5 to about 30 ° C and more preferably about 10 to about 25 ° C and most preferably about 10 to about 20 ° C React.

Those skilled in the art will appreciate that reactions that form bromoformates or chloroformates can be searched by known techniques to determine the time at which the reaction is terminated. For example, HPLC can be used to search the reaction to determine the time all starting materials are consumed.

Preferably bromoformate of formula 3.0 or chloroformate of formula 3.0A is separated from the reaction mixture by techniques known in the art before proceeding to the next reaction (epoxide formation). Bromopromate or chloroformate can be isolated as a wet cake by quenching the reaction in excess water to precipitate the bromoformate or chloroformate and then filtering the slurry obtained. Preferably, C ₁ to C ₆ alkanols (eg methanol, ethanol or isopropanol, preferably methanol) are added to the water to quench the reaction.

For example, to quench the reaction of a compound in which R ² is in the β-position, an alkanol (eg, methanol) is about 3.5 times (3.5X) or more, preferably 3.5X, more than the amount of the compound of Formula 2.0. Used as Preferably, the quench solution (water and alkanol mixture) is at least about 5%, preferably about 5 to 25% and more preferably about 10 to about 15% and more preferably about 12 to about 14% and most Preferably about 13% alkanols, preferably methanol.

Also, for example, to quench the reaction of a compound in which R ² is in the α-position, the alkanol (eg methanol) is about 13 times (13X) or more, preferably 13X, above the amount of the compound of Formula 2.0. Used. Preferably the quench solution (water and alkanol mixture) is from about 5% to about 30% alkanol (preferably methanol), preferably from about 10 to about 20% and more preferably from about 10 to about 15% and Most preferably about 14% is used.

Bromoformate of formula 3.0 or chloroformate of formula 3.0A to prepare an epoxy steroid of formula 1.0 comprises (a) THF or CH ₂ Cl ₂ and (b) C ₁ to C ₆ alkanols or acetonitrile React with a strong base in an organic solvent mixture.

Suitable strong bases are bases which provide -OH ions upon decomposition in aqueous solution. The strong base may be an inorganic salt such as NaOH or KOH or an organic salt such as sodium methoxide, potassium methoxide, sodium butoxide, potassium butoxide, sodium tert-butoxide or potassium tert-butoxide. . Preferably NaOH is used.

Sufficient water is used to dissolve the base and provide -OH ions in the solution. Base may be added to the reaction mixture as an aqueous solution or a sufficient amount of water may be added to dissolve the added base in the reaction mixture. Preferably, the base is added as a freshly prepared aqueous solution.

About 7.5 Meq or more, suitably about 7.5 to about 50 Meq, preferably about 7.5 to about 25 Meq and more preferably about 10 to about 20 Meq, more preferably about 14 to about 16 Meq and most preferably about 15 Meq. Water is used to provide an aqueous solution of the base.

The base is effectively used in an amount causing the formation of 9,11β-epoxide and the R ³ ester or carbonate protecting group is hydrolyzed to the R ¹ -OH group when the base is present.

When R ³ is selected from H or Cl a base (eg NaOH) of from about 1.0 to about 4.0 Meq, preferably from about 1.5 to about 2.0 Meq, is used.

When R ³ is an ester or carbonate protecting group such as -OC (O) R ⁴ or -OC (O) OR ⁵ ] the base (eg NaOH) is from about 2.0 to about 4.0 Meq, preferably from about 2.5 to about 3.5Meq and most preferably in an amount of about 3.0Meq.

For the organic solvent mixture used in the epoxide reaction, CH ₂ Cl ₂ is preferably used for compounds in which R ² is in the α or β position. More preferably when THF is used, R ² is used together with the compound in the α-position.

Examples of C ₁ to C ₆ alkanols include, but are not limited to, methanol, ethanol or isopropanol. Preferably methanol is used with THF or CH ₂ Cl ₂ .

CH ₂ Cl ₂ or THF, preferably CH ₂ Cl _2, is used as solvent in excess of the amount of the compound of formula 2.0. Typically the solvent is at least about 3 times (3X) or more, preferably about 3X to about 20X and preferably about 4X to about 10X and more preferably about 5X to about 8X and most preferably the amount of the compound of formula 2.0 Is used in an amount of about 6X to about 7X.

C ₁ to C ₆ alkanols or acetonitrile, preferably methanol, are used in excess relative to the amount of the compound of formula 2.0. Typically when the R ² is in the α-position the alkanol or acetonitrile is at least one fold greater than the amount of the compound of formula 2.0, suitably about 1X to about 20X and preferably about 1X to about 5X, more preferably Is used in amounts of about 1X to about 3X and most preferably about 2X.

When R ² is in the β position, the alkanol or acetonitrile is about 3 times (3X), suitably about 3X to about 20X and preferably about 3X to about 10X and more preferably greater than the amount of the compound of formula 2.0 Is used in excess of about 5X to about 7X and most preferably about 6X.

The reaction of bromoformate of formula 3.0 or chloroformate of formula 3.0A with a base to form an epoxide of formula 1.0 is carried out at a temperature low enough to reduce the formation of unwanted byproducts. It is generally used at a temperature of about +10 to about -20 ° C, preferably about 0 to about -10 ° C, more preferably about -2 to about -6 ° C and most preferably about -5 ° C.

Those skilled in the art can be searched by known techniques such as HPLC to determine the time at which the reaction to form the epoxide is completed and for example that no further starting material is present. It will be recognized. The reaction may then be quenched to pH about 3 to about 5 with an organic acid. Suitable organic acids include, but are not limited to, acetic acid, formic acid and tartaric acid, preferably acetic acid.

Epoxy steroids of Formula 1.0 may be isolated by known techniques. Since epoxy steroids are usually obtained as precipitates, they can be separated by filtration.

Epoxides can be purified by techniques known in the art. For example, in a preferred purification method, the epoxide of formula 1.0 is dissolved by heating in a mixture of a sufficient amount of CH ₂ Cl ₂ and methanol. The resulting mixture is then filtered, concentrated, cooled, filtered, washed (preferably methanol) and dried in vacuo to give a purified epoxide of formula 1.0.

The epoxy steroids obtained can be used to prepare another known steroid using known techniques. For example, betamethasone, beclomethasone, dexamethasone or mometasone furoate can be prepared using epoxy steroids.

The following examples are intended to illustrate the claimed invention and these examples should not be considered as limiting the invention.

The water used in the examples is deionized water.

Example 1

A. Bromoformate Formation

In the above formula,

R ³ is —OC (O) OC ₂ H ₅ .

16β-methyl-triene-21-catylate (50 g purity) (50 g) of Formula 2.1 is dissolved in DMF (175 ml) at room temperature. Cool the mixture to about 10 ° C. and then add 70% HClO ₄ (6.25 ml) to the mixture. The reaction is added for 5 minutes while maintaining the temperature below 20 ° C. The mixture is cooled to about 10 ° C. and DBH (25.1 g) is added to the mixture. Add for 15 minutes while maintaining the reaction temperature below 20 ℃.

After about 3 hours HPLC shows that some starting material is still present and additionally 0.5 g of DBH is added and stirred for about 1 hour. When HPLC indicates the reaction is complete, the reaction mixture is diluted with CH ₃ OH (175 ml) and stirred for about 10 minutes. Bromoformate of formula 3.1 is precipitated in 1500 ml of water at room temperature. The mixture is stirred at room temperature for about 40 minutes followed by the addition of ice (700 g) to reduce the temperature to below 10 ° C. The mixture is stirred at less than 10 ° C. for about 30 minutes, then filtered and the precipitate (wet cake) is washed with water (about 1000 ml). The wet cake is dried in vacuo overnight to yield about 114 g of wet cake.

Analytical samples of the wet cake are taken and vacuum dried for NMR analysis.

¹ H-NMR (400 MHz, CDCl ₃ ): 8.12 (s, 1H), 6.85 (d, J = 10 Hz, 1H), 6.34 (dd, J = 10, 1.7 Hz, 1H), 6.10 (d, 1.6 Hz, 1H), 5.90 (br s, 1H), 5.02 (d, J = 18 Hz, 1H), 4.86 (d, J = 18 Hz, 1H), 4.22 (q, J = 7Hz, 2H), 2.89 (dd, J = 14.8, 3.6 Hz, 1H), 2.60 (m, 1H), 2.40 (m, 2H), 2.15 (m, 3H), 1.95 (m, 1H), 1.75 (m, 2H), 1.58 (s, 3H) , 1.33 (t, J = 7 Hz, 3H), 1.25 (m, 1H), 1.19 (d, J = 7 Hz, 3H), and 1.00 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): 204.8, 186.3, 165.4, 159.6, 155.2, 151.5, 130.1, 125.6, 89.2, 82.2, 75.1, 72.0, 64.9, 49.8, 49.7, 49.5, 44.6, 35.9, 34.5, 33.8, 31.0, 29.1, 25.1, 20.1, 17.9, and 14.6

B. Epoxide Formation

In the above formula,

R ³ is OC (O) OC ₂ H ₅ .

In step A the bromoformate wet cake (113 g) is dissolved in a mixture of CH ₂ Cl ₂ (350 ml) and methanol (325 ml). The resulting mixture is cooled to about −5 ° C. and degassed by vacuum three times under nitrogen and maintained under nitrogen. The NaOH solution is prepared by dissolving NaOH (15 g) in water (15 ml) and the resulting NaOH solution is cooled to about 5 ° C. Freshly prepared NaOH solution is added to the bromoformate CH ₂ Cl ₂ / CH ₃ OH mixture. The NaOH solution is slowly added (0.3 ml / min) for about 1 hour while maintaining the temperature of the reaction mixture at about -5 to about -3 ° C.

The resulting reaction mixture is stirred at about −3 to about −5 ° C. for about 2 hours. After confirming that the reaction is complete by HPLC, the reaction mixture is quenched with acetic acid (40 ml). The reaction mixture is concentrated to 250 ml by distilling CH ₂ Cl ₂ and vacuum distillation of CH ₃ OH. Water (175 ml) is then added to the mixture and the mixture is concentrated to 250 ml. Water (500 ml) is then added and the resulting slurry is cooled to about 1 ° C. The slurry is stirred at about 1 ° C. for about 3 minutes, then filtered and the resulting wet cake is washed with water. The wet cake is dried in vacuo at about 50 ° C. for about 16 hours to give 41.2 g of crude epoxide (Formula 1.1) (purity 90.0% relative to standard). This yields 97% molar yield from triene-21-cartylate (Formula 2.1).

The crude epoxide (Formula 1.1) (41.1 g) is heated until dissolved in a mixture of CH ₂ Cl ₂ (697 ml) and methanol (205 ml). The resulting solution is filtered and concentrated to a volume of about 164 ml. The resulting slurry is cooled to about 1 ° C., stirred at about 1 ° C. for about 30 minutes, filtered and washed with cooled methanol (2 × 25 ml). The wet cake obtained is vacuum dried at about 50 ° C. to give 36.0 g of epoxide (Formula 1.1) having a purity of 99% relative to the standard. This represents a recovery of 96% and a total molar yield of 93% from triene-21-cartylate (Formula 2.1).

HPLC retention time and ¹ H-NMR of the epoxide are the same as the standard compound.

¹ H-NMR (400 MHz), DMSO: 6.62 (d, J = 10 Hz, 1H), 6.10 (br s, 1H), 6.09 (dd, J = 10, 1.8 Hz, 1H), 5.26 (s, 1H) , 4.52 (t, J = 5.8 Hz, 1 H). 4.37 (dd, J = 19.4, 5.9 Hz, 1H), 4.10 (dd, J = 19.3, 5.8 Hz, 1H), 3.19 (br s, 1H), 2.67 (m, 1H), 2.45 (m, 2H), 2.36 (m, 2H), 2.21 (m, 2H), 2.05 (m, 2H), 1.59 (m, 1H), 1.52 (m, 1H), 1.37 (s, 3H), 1.33 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H), 0.86 (s, 3H).

Example 2

A. Bromoformate Formation

In the above formula,

R ³ is —OC (O) OC ₂ H ₅ .

16α-methyl-triene-21-catylate (10% purity) (10 g) of formula 2.2 is dissolved in DMF (50 ml) at room temperature. 70% HClO ₄ (1.25 ml) is then added to the mixture. DBH (4.5 g) is then added at room temperature for about 15 minutes. The resulting mixture is stirred at room temperature for about 1 hour and searched by HPLC. If HPLC indicates that the reaction is not complete, add about 0.2 g of DBH and continue stirring for about 30 minutes. If HPLC indicates the reaction is complete, CH ₃ OH (100 ml) is added to the mixture. Bromoformate of Formula 3.2 is precipitated in water (1000 ml) containing CH ₃ OH (100 ml). The mixture is filtered and the wet cake of bromoformate is washed with water.

B. Epoxide Formation

In the above formula,

R ³ is —OC (O) OC ₂ H ₅ .

In step A the wet cake of bromoformate is dissolved in a mixture of THF (80 ml) and CH ₃ OH (80 ml). The resulting solution is vacuum degassed under nitrogen, kept under nitrogen atmosphere and cooled to about −3 ° C. A NaOH solution is prepared by dissolving NaOH (1.75 g) in water (7.5 ml) and cooling the resulting NaOH solution to about 0 to about 5 ° C. The NaOH solution is added as bromoformate -THF / CH ₃ OH solution while maintaining the temperature of the reaction mixture at about -4.0 to -2.0 ° C. If HPLC indicated that the reaction was not complete after stirring at about −3 ° C. for about 2 hours (approximately 17% of starting material remained), react with additional NaOH solution (0.6 g NaOH in 3 ml of water) for about 15 minutes. Add to the mixture.

If HPLC indicates the reaction is complete (about 30 minutes), the reaction is quenched with acetic acid (4 ml) solution in water (4 ml). The solvent is distilled off to concentrate the mixture and water is added during distillation to remove residual solvent. Use water to make the volume about 150 ml. The mixture is cooled to about 0 ° C to about 5 ° C and stirred for about 30 minutes. The mixture is filtered and the wet cake is washed with water. The wet cake is dried in vacuo at about 60 ° C. to yield 8.06 g of crude epoxide (Formula 1.2) with a purity of 86.7%.

Crude epoxide (8.05 g) is dissolved by refluxing in a solution of CH ₃ OH (60 ml) and CH ₂ Cl ₂ (40 ml). The mixture is stirred for about 30 minutes and then concentrated to about 40 ml (45 ml of solvent is collected). The solution is slowly cooled to room temperature and then cooled to about 0 ° C to 5 ° C. The mixture is filtered and the precipitate is washed with cold CH ₃ OH (2 × 6 ml) and dried in vacuo. The epoxide of formula 1.2 is obtained as white crystals having a purity of 99% and an overall molar yield of 87% (based on the starting triene-21-catylate of formula 2.2).

¹ H-NMR (400 MHz, DMSO): 6.47 (d, J = 10 Hz, 1H), 5.96 (br s, 1H), 5.93 (dd, J = 10, 1.7 Hz, 1H), 4.89 (s, 1H) , 4.54 (t, J = 5.9 Hz, 1H), 4.31 (dd, J = 19.3, 6.4 Hz, 1H), 3.88 (dd, J = 19.3, 6.4 Hz, 1H), 3.05 (br s, 1H), 2.74 (m, 1H), 2.51 (m, 1H), 2.32 (m, 1H), 2.10 (m, 3H), 1.61 (m, 1H), 1.47 (m, 1H), 1.34 (m, 1H), 1.22 ( s, 3H), 1.14 (m, 1H), 1.05 (m, 1H), 0.60 (d, J = 6.8 Hz, 3H), 0.59 (s, 3H).

Example 3

A. Bromoformate Formation

In the above formula,

R ³ is —OC (O) OC ₂ H ₅ .

16α-methyltriene-21-catylate (purity 86.9%) (50 g) of formula 2.2 is suspended in DMF (175 ml) at room temperature. 70% of HClO ₄ (6.5 ml) is then added to the mixture at room temperature. DBH (25 g) is then added at room temperature for about 10 minutes. The resulting mixture is stirred at room temperature until HPLC indicates the reaction is complete (about 1 hour).

The reaction mixture is then diluted with CH ₃ OH (150 ml). Bromoformate of formula 3.2 is precipitated in water (4000 ml) containing CH ₃ OH (500 ml) and Na ₂ SO ₃ (6 g) for about 40 minutes. The resulting mixture is stirred at room temperature for about 30 minutes, then cooled to about 4 ° C. and stirred at this temperature for about 30 minutes. The bromoformate is filtered off and collected as a wet cake and the wet cake is washed with water (2000 ml).

B. Epoxide Formation

In the above formula,

R ³ is —OC (O) OC ₂ H ₅ .

In step A bromoformate is dissolved in a mixture of CH ₂ Cl ₂ (300 ml) and CH ₃ OH (25 ml). The aqueous layer is separated from the organic layer and the aqueous layer is extracted with CH ₂ Cl ₂ (100 ml). The organic layers are mixed and CH ₃ OH (100 ml) is added to the organic solution obtained. The resulting solution is cooled to about −4 ° C., vacuum degassed under nitrogen for 4 hours and kept under nitrogen.

A NaOH solution is prepared by dissolving NaOH (15 g) in water (30 ml). The NaOH solution is cooled and added to the bromoformate-CH ₂ Cl ₂ / CH ₃ OH solution for 1 hour while maintaining the temperature of the reaction mixture below -2 ° C. The reaction mixture is stirred at about −4 ° C. until HPLC indicates the reaction is complete (about 1 hour).

The reaction is then quenched with a mixture of acetic acid (10 ml) and water (10 ml). Water (125 ml) is added and the mixture is stirred for about 5 minutes. The aqueous and organic layers are separated and the aqueous layer is extracted twice with CH ₂ Cl ₂ (125 ml). The organic layers are mixed and CH ₃ OH (200 ml) is added. The mixture is distilled off to remove 250 ml of solvent. The mixture is then filtered and the residue is washed with CH ₂ Cl ₂ (about 50 ml) added to the concentrated mixture. The obtained organic solution is concentrated to 150 ml volume. The resulting slurry was cooled to about −2 ° C., stirred at this temperature for about 30 minutes, filtered and washed with cold CH ₃ OH (30 ml) followed by a mixture of CH ₃ OH and water (1: 1) (30 ml). Wash. The precipitate is dried in vacuo at about 60 ° C. to give 35.5 g of epoxide (formula 1.2) having a purity of 99.2% and a total molar yield of 93.3% from triene of formula 2.2.

HPLC retention time and ¹ H-NMR spectrum are the same as the standard compound.

Example 4

A. Bromoformate Formation

Triene chloride of formula 2.3 (1 g) is dissolved in DMF (3.5 ml) and the resulting solution is cooled to about 13 ° C. 70% (0.13 ml) of perchloric acid is added to the solution followed by DBH (0.7 g). The mixture is stirred at room temperature until HPLC indicates the reaction is complete (about 2 hours).

CH ₃ OH (3.5 ml) is then added to the reaction mixture and the resulting mixture is stirred for about 5 minutes. This gives a bromoformate of formula 3.3 which crystallizes out of solution. Then water (70 ml) containing CH ₃ OH (7 ml) is added and the resulting mixture is stirred for about 30 minutes. The compound is then filtered and the precipitate (wet cake) is washed with water. The wet cake is dried to yield 1.26 g of bromoformate of formula 3.3 having a purity of about 97% (HPLC).

¹ H-NMR (400 MHz, CDCl ₃ ): 8.13 (s, 1H), 6.80 (d, J = 10 Hz, 1H), 6.36 (dd, J = 10, 1.8 Hz, 1H), 6.11 (br s, 1H ), 5.92 (br s, 1H), 4.59 (d, J = 16 Hz, 1H), 4.23 (d, J = 16 Hz 1H), 3.20 (m, 1H), 2.51 (m, 4H), 2.17 (m, 1H) ), 1.85 (m, 2H), 1.72 (m, 2H), 1.58 (s, 3H), 1.30 (m, 1H), 0.98 (d, J = 7 Hz, 3H), 0.96 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): 202.9. 185.9, 164.6, 159.3, 150.8, 130.0, 125.5, 91.2, 81.7, 74.7, 49.5, 48.8, 48.2, 44.9, 36.1, 36.0, 33.4, 31.8, 30.7, 28.6, 24.9, 17.8 and 14.8.

B. Epoxide Formation

In step A bromoformate (1 g) is dissolved in a mixture of CH ₂ Cl ₂ (10 ml) and CH ₃ OH (5 ml). The solution is cooled to about −5 ° C., degassed four times in vacuo and kept under nitrogen. A NaOH solution is prepared by dissolving NaOH (0.2 g) in water (1 ml). The NaOH solution is added to the bromoformate CH ₂ Cl ₂ / CH ₃ OH solution while maintaining the temperature at about −5 to about −3 ° C. for about 30 minutes. Search for the end of the reaction (about 1 hour) by HPLC. The reaction is quenched with acetic acid (0.5 ml).

CH ₂ Cl ₂ (5 ml) and water (5 ml) are then added to the mixture and the organic and aqueous layers are separated. The aqueous layer is extracted with CH ₂ Cl ₂ (5 ml) and the organic layers are mixed and washed with water (10 ml). The organic layer was concentrated to dryness to afford the epoxide (0.70 g) of formula 1.3. Epoxide is 97% pure (HPLC area) and total molar yield from triene chloride (Formula 2.3) is about 93%.

¹ H-NMR (400 MHz, CDCl ₃ ): 6.61 (d, J = 10 Hz, 1H), 6.22 (dd, J = 10, 1.8 Hz, 1H), 6.17 (br s, 1H), 4.58 (d, J = 16 Hz, 1H), 4.21 (d, J = 16 Hz, 1H), 3.05 (m, 1H), 2.60 (m, 1H), 2.45 (m, 1H), 2.28 (m, 2H), 2.19 (m, 1H ), 1.60 (m, 4H), 1.37 (s, 3H), 1.28 (m, 1H), 0.86 (s, 3H), 0.92 (d, J = 7 Hz, 3H).

HPLC retention time and ¹ H-NMR spectrum of the epoxide are the same as the standard compound.

While the present invention has been described in connection with the specific embodiments described, many alternatives, modifications, and variations thereof will be apparent to those skilled in the art. All such alternative methods, modifications, and variations thereof fall within the spirit and scope of the present invention.

Claims (20)

(A) a brominating agent selected from DBH or NBS or a chlorinating agent selected from N-chloroimide or N-chloroamide in DMF containing a compound of formula 2.0 at a temperature of about 0 to about + 40 ° C. containing a catalytic amount of 70% HClO ₄ Reacting with to give bromoformate of formula 3.0 from said brominating agent or to chloroformate of formula 3.0A from said chlorinating agent; (B) bromoformate of formula 3.0 or chloroformate of formula 3.0A is reacted at (a) THF or CH ₂ Cl ₂ and (b) C ₁ to C ₆ alkanols at a temperature of about -20 to about + 10 ° C. Or reacting with a strong base in an organic solvent mixture comprising acetonitrile to obtain an epoxy steroid of formula 1.0. Formula 1.0 Formula 2.0 Formula 3.0 Formula 3.0A In the above formula, R ¹ is selected from H, -OH, or Cl; R ² is selected from hydrogen or lower alkyl; R ³ is H when R ¹ is H, -OH group suitably protected when R ¹ is -OH, and Cl when R ¹ is Cl. The method of claim 1, wherein when R ¹ is —OH, R ³ is —OC (O) OR ⁵ , wherein R ⁵ is a C ₁ to C ₆ alkyl group. The method of claim 1, wherein R ³ is —OC (O) OC ₂ H ₅ . The process of claim 1 wherein the brominating agent is used and the brominating agent is DBH and the reaction to form bromoformate is carried out at a temperature of about +10 to about + 20 ° C. The method of claim 1 wherein the strong base is selected from NaOH or KOH. The method of claim 1 wherein the strong base is NaOH. The process of claim 1, wherein the organic solvent mixture of step (B) is a mixture of CH ₂ Cl ₂ and CH ₃ OH. The process of claim 1, wherein the reaction of Step B is carried out at a temperature of about 0 to about −10 ° C. 7. The method of claim 1, wherein R ³ is Cl. The compound of claim 1, wherein (1) when R ¹ is —OH, R ³ is —OC (O) OR ⁵ , wherein R ⁵ is a C ₁ to C ₆ alkyl group; (2) the bromination agent is used in step (A) and the bromination agent is DBH and the bromoformate is formed at a temperature of about + 10 ° C to about + 25 ° C; (3) The process wherein in step (B) the strong base is selected from NaOH or KOH and the organic solvent mixture is a mixture of CH ₂ Cl ₂ and methanol and the epoxide is formed at a temperature of about 0 to about −10 ° C. The method of claim 10, wherein when R ¹ is —OH, R ³ is —OC (O) OC ₂ H ₅ and the base of step (B) is NaOH. The method of claim 11, wherein R ² is methyl. The bromine agent of claim 12 wherein the brominating agent is used in an amount of about 0.5 to about 2.0 Meq (molar equivalents), 70% of HClO ₄ is used in an amount of about 0.5 to about 3.0 Meq, and the base is R ³ of H or Cl And used in an amount from about 2.5 to about 3.5 Meq when R ³ is -OC (O) OC ₂ H ₅ . The method of claim 13, wherein R ¹ is —OH or —Cl. The method of claim 14, wherein the reaction of Step A is carried out at a temperature of about +10 to about + 20 ° C. and the reaction of Step B is carried out at a temperature of about −2 to about −6 ° C. The method of claim 15, wherein R ¹ is —OH. A bromoformate of Formula 3.0 is prepared, comprising reacting a compound of Formula 2.0 with a brominating agent selected from DBH or NBS in DMF containing a catalytic amount of 70% HClO ₄ at a temperature of from about 0 to about + 40 ° C. How to. Formula 2.0 Formula 3.0 In the above formula, R ² is selected from hydrogen or lower alkyl, R ³ is selected from H, —OH protecting group or Cl. The method of claim 17, wherein the brominating agent is DBH and the reaction is carried out at a temperature of about +10 to about + 20 ° C. and R ² is methyl and R ³ is —OC (O) OC ₂ H ₅ or Cl. (A) THF or CH ₂ Cl ₂ and (b) C ₁ to C ₆ alkanol or acetonitrile at a temperature of about -20 to about + 10 ° C. A method for preparing an epoxide of Formula 1.0, including reacting with a strong base in an organic solvent mixture. Formula 1.0 Formula 3.0 Formula 3.0A In the above formula, R ¹ is selected from H, -OH, or Cl; R ² is selected from hydrogen or lower alkyl; R ³ is selected from H when R ¹ is H, suitably protected -OH group when R ¹ is -OH, or Cl when R ¹ is Cl. The process of claim 19, wherein the base is NaOH and the organic solvent mixture is a mixture of CH ₂ Cl ₂ and methanol, the reaction is carried out at about −2 to about −6 ° C., and R ³ is —OC (O) OC ₂ H _5. Or Cl.