Synthesis of Δ9,11 steroids

Abstract

The present invention relates to a method for preparing Δ9,11 steroids by deoxygenation of 9,11-epoxy steroids using HI. The disclosed method selectively forms Δ9,11 steroids, such as vamorolone, and can also be used for steroid synthesis of pharmaceutical purity Δ9,11 steroids.

Description

[Technical Field]

[0001] We describe a method for preparing Δ9,11 steroids by deoxygenation of 9,11-epoxy steroids using HI. The disclosed method selectively forms Δ9,11 steroids, such as vamorolone, and can also be used for steroid synthesis of pharmaceutical-grade Δ9,11 steroids. [Background technology]

[0002] Background of the Invention Glucocorticoids are the standard treatment for many inflammatory conditions, but long-term use is associated with a wide range of side effects. Recently, Δ9,11 steroid analogs have shown promise as a source of safer drugs for treating chronic inflammatory diseases.

[0003] Typical glucocorticoids, such as cortisol, prednisone, and prednisolone, have Δ9,11 steroid counterparts, such as tirilazad, VBP1, and anecortave. De novo synthesis is required for such Δ9,11 steroids.

[0004] Furthermore, the synthesis of therapeutically useful corticosteroids, such as mometasone, metamethasone, and beclomethasone, requires functionalization of the C-9 and C-11 positions of the steroid molecule. Functionality is generally introduced via a Δ9,11 steroid intermediate. Therefore, the synthesis of therapeutically useful Δ9,11 steroids and the synthesis of Δ9,11 steroid intermediates is becoming increasingly important.

[0005] Methods for preparing Δ9,11 steroids, i.e., steroids with a 9,11-double bond, are known in the art. For example, 11-hydroxysteroids can be converted to the corresponding mesylates (by treating the steroids with mesyl chloride), which are then converted to the Δ9,11 steroids by an elimination reaction. However, each prior art method is not regiospecific when starting from 11-hydroxysteroids and typically results in a mixture of Δ9,11 steroids containing a large and undesirable amount of Δ11,12 steroids. Separation of these regioisomeric products is difficult and generally requires tedious physical separation procedures, resulting in increased costs and reduced yields.

[0006] Other synthetic strategies are also known: US 5,399,727 (Patent Document 1) discloses the synthesis of specific Δ9,11 steroids from 9-hydroxysteroids with chlorosulfonic acid in organic solvents. EP 0 969 012 (Patent Document 2) discloses processes for the regioselective dehydration of 11-hydroxysteroids using either PCl5, PCl3, POCl3, or SO2Cl2 with imidazole, or PPh3 with CCl4. These processes are very harsh, require toxic chemicals, and result in unintended by-products and impurities.

[0007] Vamorolone (17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione) is an active pharmaceutical ingredient (API) that is a clinical candidate for the treatment of DMD, for example. Thus, vamorolone is a novel Δ9,11 steroid of high therapeutic interest. TIFF0007783973000001.tif50128

[0008] Vamorolone is currently prepared from commercially available 3TR (tetraene acetate) - see Scheme 2. In step a, TMS imidazole, MeMgCl, and THF are added to 3TR, followed in step b by CuAc, HO, DMPU, MeMgCl, and THF. In step c, compound 2 from the intermediate under treatment with peracetic acid in toluene 3 After treatment with NaHSO and TFA (step d), EtOAc and heptane (step e), and acetonitrile trituration (step f), HBr in CHCl was added (step g) and MeOH (step h) was used for crystallization to give acetyl-vamorolone. 4 Acetyl-vamorolone is deacetylated with K2CO3 in MeOH followed by HCl to give vamorolone (step i). The synthesis is disclosed in Bioorganic & Medicinal Chemistry, Volume 21, Issue 8, 15 April 2013, Pages 2241-2249 (Non-Patent Document 1).

[0009] Scheme 2: Preparation of vamorolone in the prior art TIFF0007783973000002.tif83151

[0010] This process is difficult to control and requires the use of several toxic and hazardous chemicals, and therefore represents an unattractive synthesis of vamorolone.

[0011] Overall, there is a need for a more direct and safe method of producing vamorolone and other Δ9,11 steroids in high yield and with controlled pharmaceutical purity that eliminates the presence of numerous impurities and by-products (e.g., steroid by-products) in the final product. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] US 5,399,727 [Patent Document 2] EP 0 969 012 [Non-patent literature]

[0013] [Non-Patent Document 1] Bioorganic & Medicinal Chemistry, Volume 21, Issue 8, 15 April 2013, Pages 2241-2249 Summary of the Invention

[0014] The present invention fulfills this need by providing a convenient, non-toxic, and quantitative synthesis of vamorolone and other Δ9,11 steroids. The new synthesis is surprisingly simple and significantly reduces steroid by-products. For the synthesis of vamorolone and other Δ9,11 steroids, commercially available 8-DM, either protected, e.g., acetylated, or unprotected, commercially available 8-DM ((1S,2S,13R,14R,15S,17S)-14-hydroxy-14-(2-hydroxyacetyl)-2,13,15-trimethyl-18-oxapentacyclo[8.8.0.0], isopropyl alcohol. 1,17 .0 2,7 .0 11,15 HI is used to deoxygenate a 9,11 epoxide steroid precursor, such as 8-DM. Δ9,11 steroids, such as 8-DM, are commercially available, and a protecting group (attached to the 21-OH moiety) can be attached using conventional synthetic means available in the art.

[0015] Accordingly, the present invention provides a process for preparing a Δ9,11 steroid of formula I: TIFF0007783973000003.tif63128In formula, The dotted lines are single or double bonds; R 1 is H or OH; R 2 or R 3one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine, which throughout this specification can be part of a linear or cyclic moiety).

[0016] Preferred is a process for preparing a Δ9,11 steroid of formula Ia: TIFF0007783973000004.tif71128In formula, The dotted lines are single or double bonds; R 1 is H or OH; R 2 or R 3 one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, substituted aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0017] More preferred is a process for preparing a Δ9,11 steroid of formula Ib: TIFF0007783973000005.tif58128In formula, R 1 is H or OH; R 2 or R 3one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, substituted aryl, heteroaryl, or C1-C6 alkoxy), or NR II where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0018] Even more preferred is a process for preparing a Δ9,11 steroid of formula Ic: TIFF0007783973000006.tif61128In formula, The dotted lines are single or double bonds; R 2 or R 3 one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, substituted aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0019] Even more preferred is a process for preparing a Δ9,11 steroid of formula Id: TIFF0007783973000007.tif56128In formula, R 2 or R 3 one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) Iand R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, substituted aryl, heteroaryl, or C1-C6 alkoxy, or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0020] Even more preferred is a process for preparing a Δ9,11 steroid of formula Ie: TIFF0007783973000008.tif64128In formula, The dotted lines are single or double bonds; R 3 is CH3 or H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0021] Even more preferred is a process for preparing a Δ9,11 steroid of formula If: TIFF0007783973000009.tif56128In formula, R 3 is CH3 or H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR IIis a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0022] Particularly preferred is a process for preparing a Δ9,11 steroid of any of formulae Ia to If as defined above, wherein X is H, OH or OAc.

[0023] Most preferred is a method for preparing one of the following Δ9,11 steroids: TIFF0007783973000010.tif174140

[0024] The method of the present invention comprises treating a 9,11-epoxy-steroid of formula II with hydroiodic acid HI to form a compound of formula I: TIFF0007783973000011.tif49128In formula, The dotted lines are single or double bonds; R 1 is H or OH; R 2 or R 3 one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0025] Preferably, the method of the present invention comprises treating a 9,11-epoxy-steroid of formula IIa with hydroiodic acid HI to form a compound of formula Ia: TIFF0007783973000012.tif49128In formula, The dotted lines are single or double bonds; R1 is H or OH; R 2 or R 3 one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0026] More preferably, the method of the present invention comprises treating a 9,11-epoxy-steroid of formula IIb with hydroiodic acid HI to form a compound of formula Ib: TIFF0007783973000013.tif56128In formula, R 1 is H or OH; R 2 or R 3 one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0027] Even more preferably, the method of the present invention comprises treating a 9,11-epoxy-steroid of formula IIc with hydroiodic acid HI to form a compound of formula Ic: TIFF0007783973000014.tif50128In formula, The dotted lines are single or double bonds; R 2 or R 3 one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0028] Even more preferably, the method of the present invention comprises the step of treating a 9,11-epoxy-steroid of formula IId with hydroiodic acid HI to form a compound of formula Id: TIFF0007783973000015.tif50128In formula, R 2 or R 3 one of which is CH3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0029] Even more preferably, the method of the present invention comprises treating a 9,11-epoxy-steroid of formula IIe with hydroiodic acid HI to form a compound of formula Ie: TIFF0007783973000016.tif51128In formula, The dotted lines are single or double bonds; R3 is CH3 or H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0030] Even more preferably, the method of the present invention comprises the step of treating a 9,11-epoxy-steroid of formula IIf with hydroiodic acid HI to form a compound of formula If: TIFF0007783973000017.tif47128In formula, R 3 is CH3 or H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety).

[0031] More preferably, the method of the present invention comprises treating the 9,11-epoxy-steroid of VBP1, anecortave and tirilazad, respectively, with hydroiodic acid HI to form VBP1, anecortave and tirilazad, respectively.

[0032] Most preferably, the method of the present invention involves the use of 8-DM or 8-DM-acetate to form vamorolone and vamorolone-acetate, respectively. The method includes treating a 9,11-epoxy-steroid, TIFF0007783973000018.tif52128, with hydroiodic acid (HI). [The present invention 1001] Use of hydroiodic acid to prepare Δ9,11 steroids from 9,11 epoxy steroids. [The present invention 1002] The Δ9,11 steroid is a steroid of formula I: TIFF0007783973000019.tif63128 During the ceremony, The dotted lines are single or double bonds; R 1 is H or OH; R 2 or R 3 One of them is CH 3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF 3 、C 1 ~C 6 Alkyl or C 1 ~C 6 Alkoxy, C 5 ~C 12 cycloalkyl, aryl, heteroaryl), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety), Use of the present invention 1001. [The present invention 1003] the Δ9,11 steroid is a steroid of the formula If: TIFF0007783973000020.tif62128 During the ceremony, R 3 is CH 3 or H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF 3 、C 1 ~C 6 Alkyl, C 5 ~C 12 Cycloalkyl, aryl, heteroaryl or C 1~C 6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety), Use of the present invention 1001 or 1002. [The present invention 1004] The Δ9,11 steroid is vamorolone or vamorolone acetate TIFF0007783973000021.tif48140 Use of any one of inventions 1001 to 1003. [The present invention 1005] 1. A process for preparing a Δ9,11 steroid of formula I: TIFF0007783973000022.tif50128 During the ceremony, The dotted lines are single or double bonds; R 1 is H or OH; R 2 or R 3 One of them is CH 3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF 3 、C 1 ~C 6 Alkyl, C 5 ~C 12 Cycloalkyl, aryl, heteroaryl or C 1 ~C 6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic substructure The method comprises treating a 9,11 epoxy steroid of formula II with hydroiodic acid, HI, to form a compound of formula I: TIFF0007783973000023.tif47128 During the ceremony, The dotted lines are single or double bonds; R 1 is H or OH; R 2 or R 3 One of them is CH 3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF 3 、C 1 ~C 6 Alkyl, C 5 ~C 12 Cycloalkyl, aryl, heteroaryl or C 1 ~C 6 alkoxy), or NR II (where NR II is a tertiary amine), The method. [The present invention 1006] The Δ9,11 steroid is a compound of formula Id: TIFF0007783973000024.tif49128 During the ceremony, R 2 or R 3 One of them is CH 3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF 3 、C 1 ~C 6 Alkyl, C 5 ~C 12 Cycloalkyl, aryl, heteroaryl or C 1 ~C 6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety; and, The 9,11 epoxy steroid is a compound of formula IId: TIFF0007783973000025.tif53128 During the ceremony, R 2 or R 3 One of them is CH 3 and the other is H, or both are H; and X is H, halo, OR (where R is H or C(O)R) I and R I CF 3 、C 1 ~C 6 Alkyl, C 5 ~C 12 Cycloalkyl, aryl, heteroaryl or C 1 ~C 6 alkoxy), or NR II (where NR II is a tertiary amine and the tertiary amine is part of a linear or cyclic moiety), Hydroiodic acid HI is used to form a compound of formula Id, The method of the present invention 1005. [The present invention 1007] The Δ9,11 steroid is vamorolone or vamorolone acetate TIFF0007783973000026.tif48128 and 9,11 epoxy steroids, 8-DM and 8-DM acetate, respectively TIFF0007783973000027.tif52128 is a compound of The method of the present invention 1005 or 1006. [The present invention 1008] Any of the methods of claims 1005 to 1007, wherein the Δ9,11 steroid is prepared in an organic solvent using an aqueous HI solution, with or without the addition of an organic acid, and the treatment is carried out at a temperature below 15°C. [The present invention 1009] The organic solvent is MeCN, CH 2 Cl 2 or toluene; or a mixture of two or all three thereof; and the organic acid is acetic acid; The method of the present invention 1008. [The present invention 1010] 1009. The method of any of claims 1005 to 1009, wherein the Δ9,11 steroid is prepared using an aqueous solution of HI in toluene at a concentration of 48 to 68 wt %. [The present invention 1011] The method of any of claims 1005 to 1010, wherein when X is OH, the 9,11 epoxy steroid is acetylated prior to treating the 9,11 epoxy steroid with HI. [The present invention 1012] The method of invention 1011, wherein the Δ9,11 steroid obtained in invention 1015 is deacetylated after treating the 9,11 epoxy steroid with HI. [The present invention 1013] A step of recrystallizing the crude Δ9,11 steroid obtained in any of the methods 1002 to 1015 of the present invention in iPrOH or a mixture of iPrOH and water. 10. The method of any of claims 1005 to 1012 for preparing a pharmaceutically pure Δ9,11 steroid, comprising: [The present invention 1014] recrystallizing the crude vamorolone in isopropanol or a mixture of water and isopropanol to form purified vamorolone of 99.5 wt% purity or greater. A method for purifying vamorolone, comprising: [The present invention 1015] A compound produced by any of the methods of the present invention 1005 to 1014. [The present invention 1016] A compound produced by the method of the present invention 1013 or 1014. [The present invention 1017] A pharmaceutical composition comprising a compound of the present invention 1015 or 1016. DETAILED DESCRIPTION OF THE INVENTION

[0033] Details of the invention As used herein, the term "alkyl" refers to a straight or branched unsaturated hydrocarbon chain; preferred is C1-C6 alkyl having 1 to 6 carbon atoms. The definition of alkyl and C1-C6-alkyl includes, for example, methyl, ethyl, n-, isopropyl, n-, iso-, sec- and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, and 3,3-dimethylbutyl.

[0034] The term "alkoxy" refers to an alkyl (carbon and hydrogen chain) group, RO, single-bonded to oxygen; preferred are C1-C6 alkoxy groups having 1 to 6 carbon atoms.

[0035] The term "halo" preferably means bromo, chloro or iodo.

[0036] A "cycloalkyl" group in the context of the present invention is, unless otherwise defined, a cyclic saturated hydrocarbon group. Preferred are C5-C 12 It is cycloalkyl.

[0037] In the context of the present invention, "aryl" refers to an aromatic hydrocarbon unless otherwise defined. Preferred is phenyl or substituted phenyl. The term "heteroaryl" defines an aryl that may have one, two or more heteroatoms selected from O, N, P and S, and may optionally be substituted with additional groups. Aryl may be substituted or unsubstituted. "Substituted aryl" refers to an aryl as defined above, but containing one or more substituents. Preferred is a substituted aryl containing one or more alkoxy substituents, such as methoxy groups, and / or one or more halogens, such as Cl. Heteroaryl may be substituted or unsubstituted. "Substituted heteroaryl" refers to a heteroaryl as defined above, but containing one or more substituents. Preferred is a substituted heteroaryl containing one or more alkoxy substituents, such as methoxy groups, and / or one or more halogens, such as Cl.

[0038] The term "tertiary amine" refers to an amino group in which the nitrogen atom is bonded to three organic radicals, two of which may also be part of a ring together. II is a tertiary amine, where the tertiary amine is part of a linear or cyclic moiety. Preferred tertiary amines are substituted or unsubstituted piperazine moieties, e.g., TIFF0007783973000028.tif39128.

[0039] The phrase "organic phase" is abbreviated herein as "OP" and "aqueous phase" as "AP."

[0040] The term "pharmaceutical purity" defines a compound of the present invention, e.g., a Δ9,11 steroid, that is at least 99 wt% pure, as determined by HPLC or other conventional methods. More preferably, the compound of the present invention, e.g., a Δ9,11 steroid, is at least 99.5 wt% pure, as determined by HPLC or other conventional methods. Most preferably, the compound of the present invention, e.g., a Δ9,11 steroid, is at least 99.9 wt% pure, as determined by HPLC or other conventional methods.

[0041] The following solvents and reagents used in the method of the present invention are identified by the abbreviations shown: ethyl acetate (EtOAc); acetic acid (HOAc); tetrahydrofuran (THF); dimethyl sulfoxide (DMSO); triethylamine (EtN); diisopropylethylamine (Hunig's base); methanol (MeOH); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); triphenylphosphine (PPh); diisopropyl ether (iPrO); dimethoxyethane (DME); t-butyl methyl ether (t-BuOMe); N,N-dimethylaminopyridine (DMAP); dimethylformamide (DMF); p-toluenesulfonyl chloride (TsCl); BuSnO (TBTO) polymethylhydrosiloxane (PMHS).

[0042] The present invention relates to a Δ 9,11 The process includes deoxygenating a steroid of formula II to form a steroid, referred to as Process A.

[0043] Reaction Scheme A TIFF0007783973000029.tif43143

[0044] In Reaction Scheme A, a compound of Formula II is treated with HI to form a compound of Formula I. The present invention further includes the process of Reaction Scheme A as shown above, using a compound of Formula IIa, II, IIc, IId, or IIe in place of a compound of Formula II.

[0045] As an example, Reaction Scheme A' is shown: In Reaction Scheme A', a compound of Formula IId is treated with HI to form a compound of Formula Id.

[0046] Reaction Scheme A' TIFF0007783973000030.tif42153

[0047] Most preferred is the synthesis of vamorolone and vamorolone acetate, respectively (see Reaction Schemes B and B').

[0048] Reaction Scheme B: Synthesis of vamololone acetate TIFF0007783973000031.tif46143

[0049] In Reaction Scheme B, 8-DM acetate is treated with HI to form vamorolone acetate.

[0050] Reaction Scheme B': Synthesis of vamorolone TIFF0007783973000032.tif44146

[0051] In Reaction Scheme B', 8-DM is treated with HI to form vamorolone. Surprisingly, the primary alcohol (21-hydroxy in 8-DM) does not undergo conversion to the corresponding alkyl iodide (21-I).

[0052] According to the present invention, the deoxygenation reaction of the present invention with HI can be carried out in any organic solvent. However, the solvent choice is limited insofar as the solvent must be stable to the strong acid (HI) and potentially formed I2, and must not interfere with any of the reaction intermediates (e.g., iodohydrins). This reduces the number of solvent options.

[0053] Any aromatic solvent, any chlorinated solvent (CHCl, chloroform, 1,2-DCE, etc.), and any nitrile solvent, or a mixture of any of these solvents, can be used. Preferred aromatic solvents are toluene, xylene, benzene, and PhCF. Preferred chlorinated solvents are CHCl, chloroform, and 1,2-DCE. Preferred nitrile solvents are MeCN, propionitrile, and butyronitrile.

[0054] According to the present invention, three solvents are most preferred: toluene, MeCN and CH2Cl2. These solvents can be used alone or in a mixture of any of the three or a mixture of all three solvents.

[0055] Alcohol solvents that are stable in the presence of HI can be used as well, for example, CF3CH2OH and HFIP (hexafluoroisopropanol).

[0056] Ether solvents that are stable in the presence of HI can be used as well, for example, DIPE (diisopropyl ether).

[0057] The reaction can also be carried out directly in an organic acid without using any other solvent, for example, in formic acid, acetic acid (i.e., AcOH), TFA, etc. Examples of organic acids according to the present invention are acetic acid, TFA, formic acid, and propionic acid.

[0058] More preferably, the organic acid is AcOH. The organic acid, preferably AcOH, is a good solvent for the reaction because it promotes the removal of the hydroxy group at C11. However, in this embodiment, it is preferable to add an organic solvent (e.g., toluene, MeCN, and CHCl) before quenching the formed iodine with aqueous NaSO to avoid the formation of an insoluble residue by-product.

[0059] Another solvent according to the present invention is HO, where the reaction works similarly. Preferably, HO is used in admixture with one of the organic acids mentioned above. However, in HO without an organic acid, I will form and precipitate from the HO. This creates the need to quantitatively remove the precipitated I.

[0060] The reagent hydroiodic acid, HI, is preferably used in the form of a highly concentrated aqueous solution, more preferably at a concentration of 1% to 70%, preferably 5% to 70%, more preferably 10% to 70%, even more preferably 30% to 70% HI aqueous solution by mass, and most preferably 48% to 57% HI aqueous solution or 64% to 68% HI aqueous solution by mass.

[0061] The deoxygenation reaction with hydroiodic acid is carried out at a temperature below room temperature RT (ie 25°C), preferably below 15°C, more preferably below 10°C, most preferably below 5°C, for example 1-5°C.

[0062] To purify the compound of Formula II, the final compound is recrystallized. Recrystallization can be carried out from polar solvents such as water or alcohols and mixtures thereof, or alternatively from acetonitrile, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIK), and mixtures thereof. Preferably, recrystallization is carried out from isopropanol (iPr-OH) or a mixture of iPr-OH and water. More preferably, recrystallization is carried out in a mixture of iPr-OH:water ranging from 60:40 wt% to 100:0 wt%, preferably from 80:20 wt% to 100:0 wt%.

[0063] Typically, final crystallization of crude vamololone from isopropanol or an isopropanol-water mixture can provide a purity improvement of over 1 wt%, e.g., from 98.5 wt% to 99.6 wt%-99.9 wt%, while still providing good yields of 90% or more. This final polishing step by crystallization allows for excellent control of the impurity profile of the final API.

[0064] In a further aspect of the invention, a protecting group for the primary hydroxy group on C-21 can be added in place of moiety X prior to deoxygenation of Formula II, IIa, IIb, IIc, IId, IIe or IIf, respectively.

[0065] An alternative protecting group for X is OR, where R is C(O)R I and R I CF3, C1-C6 alkyl, C5-C 12 It is cycloalkyl, aryl, heteroaryl or C1-C6 alkoxy.

[0066] After the addition of the protecting group, deoxygenation according to the invention is carried out, followed by a deprotection step, i.e., a step of removing the protecting group.

[0067] In this step, the moiety X which is OR is converted to X which is OH, where R is C(O)R. I and R I CF3, C1-C6 alkyl, C5-C 12 cycloalkyl, aryl, heteroaryl, or C1-C6 alkoxy. OH can be further protected with methoxymethyl ether, tetrahydropyranyl ether, t-butyl ether, benzyl ether, dimethoxybenzyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, acetate, pivalate, benzoate, acetonide, or benzylidene acetal, or any other conventional protecting group.

[0068] In a preferred embodiment, 8-DM is acetylated before deoxygenation with HI. The resulting 8-DM acetate is deoxygenated with HI to form vamorolone acetate, which is subsequently deacetylated to form vamorolone. If vamorolone acetate is partially deacetylated during the HI reaction, it is optional to reacetylate the partially deacetylated vamorolone. Quantitative acetylation may be contemplated to quantitatively isolate vamorolone acetate, or to obtain a quantitative total synthesis of vamorolone if the synthesis involves the formation of vamorolone acetate by adding HI to 8-DM acetate.

[0069] The acetylation procedure can be carried out using known reaction conditions as specified in the experimental section of this patent or conditions known to those skilled in the art. However, particularly preferred is the reaction using AcO in an organic solvent, preferably acetonitrile. Most preferably, AcO in acetonitrile is used with a catalytic amount of DMAP. 8-DM-acetate can be obtained as a crystalline product after aqueous quenching. Acetylation can be carried out at room temperature. The preferred temperature range is 20-30°C, more preferably 22-25°C.

[0070] The deacetylation hydrolysis procedure can be carried out using reactions known in the art. However, deacetylation with K2CO3 in alcohol or alcohol / water mixture is particularly preferred. Most preferred is K2CO3 in MeOH / H2O. In a further embodiment, vamololone acetate is deacetylated with KOH in alcohol or alcohol / water mixture. Most preferred is KOH in MeOH.

[0071] The temperature of the deacetylation reaction is below RT, preferably below 15°C, more preferably below 10°C, and most preferably between 0°C and 5°C.

[0072] In a preferred embodiment of the present invention, the Δ9,11 steroids are prepared by deoxygenation of the respective 9,11-epoxy steroids using HI, wherein the Δ9,11 steroids are prepared using an aqueous solution of HI at a concentration of 48-68 wt % in MeCN, CHCl, or toluene; or a mixture of two or all three thereof, in the presence or absence of an organic acid, wherein the treatment with HI is carried out at a temperature below 15°C.

[0073] In a more preferred embodiment of the present invention, the Δ9,11 steroids are prepared by deoxygenation of the respective 9,11-epoxy steroids using HI, wherein the Δ9,11 steroids are prepared using an aqueous solution of HI at a concentration of 48-68 wt % in MeCN, CHCl, or toluene; or a mixture of two or all three thereof, in the presence or absence of an organic acid which is acetic acid, wherein the treatment with HI is carried out at a temperature below 15°C.

[0074] In an even more preferred embodiment of the present invention, the Δ9,11 steroids are prepared by deoxygenation of the respective 9,11-epoxy steroids using HI, wherein the Δ9,11 steroids are prepared using an aqueous solution of HI at a concentration of 48-68 wt % in toluene in the presence or absence of an organic acid, which is acetic acid, wherein the treatment with HI is carried out at a temperature below 15°C.

[0075] In an even more preferred embodiment of the present invention, the Δ9,11 steroids are prepared by deoxygenating the respective 9,11-epoxy steroids with HI, wherein the Δ9,11 steroids are prepared using an aqueous HI solution at a concentration of 48-68 wt % in toluene in the presence or absence of an organic acid, which is acetic acid, wherein the treatment with HI is carried out at a temperature below 15° C., and wherein, when X is OH, the 9,11 epoxy steroid is acetylated before treating the 9,11 epoxy steroid with HI. In this embodiment, the Δ9,11 steroid obtained after treating the 9,11 epoxy steroid with HI is preferably deacetylated.

[0076] Most preferably, the method of the present invention produces vamorolone or vamorolone acetate from 8-DM, which is more preferably commercially available.

[0077] The Δ9,11 steroids obtained by the methods of the present invention are ideally pharmaceutically pure Δ9,11 steroids. Purification can be achieved by recrystallizing any of the Δ9,11 steroids obtained by any of the methods of the present invention, which are typically obtained as crude Δ9,11 steroids, in iPrOH or a mixture of iPrOH and water. [Example]

[0078] Example 1: Unsuccessful Attempts 1.1 Unsuccessful Conditions Deoxygenation attempts were found to be unsuccessful in the following reactions: a) A combination of a rhenium catalyst (CH3ReO3, Re2O7 or perrhenic acid) with triphenyl phosphite P(OPh)3 in toluene under reflux. b) Electrochemical reduction with NH4Br / THF aqueous solution with a Zn electrode. Constant current, 30 mA, and c) PPh3 and I2 in MeCN.

[0079] None of these reactions known from the literature proved to be successful.

[0080] 1.2 Useful but complex and toxic reactions with HBr Alternative deoxygenation conditions using HBr followed by tin-mediated PMHS reduction and subsequent water desorption involve large amounts of tin reagent and liquid sulfur dioxide as the solvent for the desorption step. The use of tin and toxic gases as solvents and reagents is undesirable for downstream manufacturing of APIs if it can be avoided.

[0081] Therefore, there is a need for new processes to avoid the use of dangerous and toxic chemicals towards the end of the chemical sequence to vamorolone.

[0082] Furthermore, the HBr route to vamorolone has the potential to form PMIs (potentially mutagenic impurities), such as allylic bromide of vamorolone, which may represent a patient risk. These impurities are difficult to track and must be strictly controlled to very low contamination levels.

[0083] Scheme II: TIFF0007783973000033.tif46166

[0084] The process in Scheme 2 has proven possible but was not intended for several reasons: debromination with Bu2Sn2O involves the in situ generation of Bu3SnH, which is toxic; Bu3Sn2O (TBTO) is used as a biocide in marine paints to reduce biofouling; TBT itself is highly toxic to non-target organisms; toxic effects occur already at 1 nanogram per liter of water; SO2 is toxic and poses a safety hazard in manufacturing plants, requiring specific safety equipment, controls, and waste disposal facilities.

[0085] 1.3 Useful but incomplete response from "TMSI" Deoxygenation was attempted using NaI (3.0 equiv.) and TMSCl (1.5 equiv.) in MeCN but proved unsuccessful. Deoxygenation occurred after in situ formation of TMS-iodohydrin and subsequent elimination.

[0086] However, due to the incomplete conversion of 8-DM-acetate and the unsatisfactory impurity profile, a new solution was needed. Therefore, we sought to provide a new, yet simpler, more direct, and scalable synthesis.

[0087] Example 2: Synthesis of the present invention Scheme C: Synthetic route to vamorolone from 8-DM TIFF0007783973000034.tif57143

[0088] Vamorolone was synthesized from commercially available 8-DM in three synthetic steps.

[0089] The synthetic route began with the acetylation of 8-DM using acetic anhydride and catalytic DMAP in THF, followed by crystallization of 8-DM acetate after an aqueous quench. 8-DM acetate was then directly converted to vamorolone acetate via a deoxygenation reaction. This deoxygenation proceeded via the initial formation of the iodohydrin using excess aqueous HI, followed by simultaneous I2 and HO elimination, yielding vamorolone acetate. Partial deacetylation (20-25%) occurred during the reaction, thus necessitating reacetylation with acetic anhydride. After reacetylation was complete, vamorolone acetate was directly crystallized by the addition of HO. Finally, the acetate group was cleaved under basic conditions to yield crude vamorolone, which was recrystallized from iPrOH to yield the pure product.

[0090] 2.1 Acetylation TIFF0007783973000035.tif39144

[0091] A 10 L glass double-jacketed reactor was charged with 8-DM (490 g, 1.32 mol, 1.0 equiv) and DMAP (16.1 g, 0.132 mmol, 0.10 equiv). THF (1.25 L, 2.5 vol) was added at an IT of 20-25 °C. AcO (201 g, 187 mL, 1.97 mol, 1.5 equiv) was then added dropwise over 20-40 min, maintaining an IT below 30 °C during the addition. After the addition was complete, the reaction mixture was stirred for 30 min at an IT of 20-25 °C. IPC control by LC / MS indicated >99% conversion of 8-DM to 8-DM acetate.

[0092] The reaction mixture was quenched by the dropwise addition of HO (4.9 L, 10 vol) over 30-45 min, maintaining an IT below 25 °C. The resulting aqueous suspension was aged for 1 h at IT = 20-25 °C. The product was filtered, washed with HO (3 x 0.5 L), and dried on a rotary evaporator (900-10 mbar, 65 °C bath temperature) to give 8-DM acetate (539 g, 1.30 mol, 99% yield, >99% a / a, 98% w / w) as a white solid (Crystal 1#1).

[0093] Analysis data: LC / MS column: Zorbax RRHD SB-Aq, 2.1x50mm, 1.8μm Program: G_005%B_TFA_0,800ml_2,00min Eluent A: water / TFA 100:0.04, Eluent B: acetonitrile IPC preparation for LC / MS 10 microliters in 1 mL H2O:MeCN 1:1 Conversion was determined in terms of consumption of 8-DM to the formation of 8-DM acetate. Detected masses: [M+1] = 373.19 for 8-DM and [M+1] = 415.19 for 8-DM acetate.

[0094] 2.2 Deoxygenation by HI TIFF0007783973000036.tif33135

[0095] A 10 L glass dj reactor was charged with 8-DM acetate (500 g, 1.21 mol, 1.0 equiv). Toluene (2.5 L, 5 vol) was added. The suspension was cooled to IT = 0-5 °C, and then a solution of 57% aqueous HI (1.08 kg, 637 mL, 4.83 mol, 4.0 equiv) in AcOH (1.25 L, 2.5 vol) was added over 45-60 min via a peristaltic pump, maintaining an IT below 5 °C during the addition. The resulting dark purple to brown solution was stirred for 24 h at IT = 3-5 °C. IPC control by LC / MS indicated >98% conversion of 8-DM acetate / intermediate iodohydrin to vamorolone acetate / vamorolone.

[0096] The reaction mixture was quenched by the dropwise addition of 25% aqueous NaSO (2.0 L, 4 vol) over 10-20 min, maintaining an IT below 15 °C. After the addition was complete, EtOAc (1.0 L, 2 vol) was added, and the biphasic mixture was warmed to an IT of 15-20 °C. Stirring was stopped, and the phases were separated (organic phase 1 and aqueous phase 1; target pH of aqueous phase 1: 2; aqueous phase 1 was discarded). 25% aqueous NaSO (1.25 L, 2.5 vol) was added to organic phase 1, and the biphasic mixture was stirred at an IT of 15-20 °C for 5 min, stirring was stopped, and the phases were separated (organic phase 1 and aqueous phase 2; target pH of aqueous phase 2: 4-5; aqueous phase 2 was discarded). 25% aqueous NaSO (1.25 L, 2.5 vol) was added to organic phase 1, the biphasic mixture was stirred for 5 min at IT = 15-20 °C, stirring was stopped, and the phases were separated (organic phase 1 and aqueous phase 3; target pH aqueous phase 3:5-6; aqueous phase 3 was discarded). HO (0.5 L, 1.0 vol) was added to organic phase 1, the biphasic mixture was stirred for 5 min at IT = 15-20 °C, stirring was stopped, and the phases were separated (organic phase 1 and aqueous phase 4; target pH aqueous phase 4:5-6; aqueous phase 4 was discarded).

[0097] A slight vacuum was applied to the double-jacketed reactor (100-150 mbar) containing the organic phase 1, and toluene was distilled off from the reaction mixture at a jacket temperature (ET) of 70 °C while continuously adding MeCN. The distillation was continued until the target residual toluene value was achieved (target: less than 5% toluene by H-NMR of the reaction mixture). Final volume in the reactor after distillation: approximately 3.5 L (7.5 vol).

[0098] Once the toluene was removed, the vacuum was broken with N2, and the resulting fine suspension was cooled to IT = 20-25 °C. At this point, the amount of vamorolone was estimated by IPC (typical ratio: vamorolone acetate to vamorolone: ​​75:25; x = 25% a / a). DMAP (3.7 g, 0.0302 mol, 0.025 equiv) was added, followed by the slow addition of Ac2O (61.6 g, 57 mL, 0.603 mol, 0.5 equiv) over 5-10 min at IT = 20-25 °C. After complete addition of Ac2O, the reaction mixture was stirred for 30 min at IT = 20-25 °C. IPC control by LC / MS indicated ≤2% a / a of vamorolone (ratio: vamorolone acetate to vamorolone: ​​98.5:1.5).

[0099] The reaction mixture was quenched by the slow addition of HO (4.9 L, 10 vol) over 15-30 min, maintaining an IT below 25 °C. The resulting aqueous suspension was cooled to an IT of 0-5 °C and aged at this temperature for 2 h. The product was filtered, washed with HO / MeCN 4:1 (2 x 0.5 L), and dried on a rotary evaporator (900-10 mbar, 65 °C bath temperature) to give vamololone acetate (301 g, 0.76 mol, 63% yield, 98% a / a, 98% w / w) as an off-white solid (Crystal 1#1).

[0100] During the course of the reaction, partial deacetylation of vamorolone acetate to vamorolone was observed (20-25% a / a). Therefore, after aqueous workup and a solvent switch to MeCN, the ratio of vamorolone acetate to vamorolone was assessed by LC / MS (in % a / a), and the following amounts of DMAP and AcO were added: x = amount of vamorolone in % a / a (e.g., x = 20% a / a) DMAP equivalents = (0.1 x) / 100 (e.g., 0.02 equivalents) Ac2O equivalents = (2.0 x) / 100 (e.g., 0.40 equivalents)

[0101] Analysis Data LC / MS column: Zorbax RRHD SB-Aq, 2.1x50mm, 1.8μm Program: G_005%B_TFA_0,800ml_2,00min Eluent A: water / TFA 100:0.04, Eluent B: acetonitrile IPC preparation for LC / MS 10 microliters in 1 mL H2O:MeCN 1:1 Conversion was determined in terms of the total consumption of (8-DM acetate + intermediate iodohydrin) relative to the total of (vamorolone acetate + vamorolone). Detected masses: [M+1] = 415,19 for 8-DM acetate, [M+1] = 357,28 for vamorolone, 399,20 for vamorolone acetate, and 543,12 for the intermediate iodohydrin.

[0102] 2.3 Deacetylation TIFF0007783973000037.tif39146

[0103] A 10 L glass dj reactor was charged with vamorolone acetate (280 g, 0.703 mol, 1.0 equiv). MeOH (1.54 L, 5.5 vol) was added. The suspension was cooled to IT = 0-5 °C, and then a solution of K2CO3 (107 g, 0.773 mol, 1.1 equiv) in HO (0.7 L, 2.5 vol) was added dropwise via a peristaltic pump over 20-40 min, maintaining an IT below 10 °C during the addition. After the addition was complete, the reaction mixture was warmed to IT = 20-25 °C and stirred for 5 h. IPC control by LC / MS indicated 99.3% conversion of vamorolone acetate to vamorolone.

[0104] The reaction mixture was cooled to IT = 15-17 °C and quenched by the dropwise addition of 1 M aqueous HCl (950 mL, 0.95 mol, 1.35 equiv) over 20-40 min, maintaining the IT below 20 °C during the addition (target pH: 5-6). The resulting aqueous suspension was aged for 12 h at IT = 15-20 °C. The product was filtered, washed with HO / MeOH 2:1 (3 x 0.3 L), and dried on a rotary evaporator (900-10 mbar, 65 °C bath temperature) to give vamololone (241.5 g, 0.68 mol, 96% yield, >99% a / a, 98% w / w) as a pale yellow solid (crude 1#1).

[0105] Analysis Data LC / MS column: Zorbax RRHD SB-Aq, 2.1x50mm, 1.8μm Program: G_005%B_TFA_0,800ml_2,00min Eluent A: water / TFA 100:0.04, Eluent B: acetonitrile IPC preparation for LC / MS 10 microliters in 1 mL H2O:MeCN 1:1 Conversion was determined in terms of consumption of vamorolone acetate to the formation of vamorolone.

[0106] 2.4 Recrystallization TIFF0007783973000038.tif36143

[0107] A 10 L glass dj reactor was charged with vamorolone (230 g, 0.645 mol, 1.0 equiv). iPrOH (5 L, 22 vol) was added. The suspension was heated to reflux (jacket temperature ET = 97 °C) and stirred until complete dissolution of vamorolone occurred (10-15 min at this scale).

[0108] After complete dissolution, the clear yellow solution was gradually cooled to IT = 0–5°C over 12 h, followed by aging at IT = 0–5°C for 1 h. The recrystallized product was filtered, washed with cold iPrOH (2 x 250 mL), and dried on a rotary evaporator (900–10 mbar, 65°C bath temperature) to give vamorolone (201 g, 87% recovery, >99% a / a, 99% w / w) as an off-white glossy solid (Crystal 1#1).

[0109] Although high dilution is required to completely dissolve crude vamorolone at reflux temperature, isopropanol (iPrOH) has been found to be the solvent of choice for recrystallization, with excellent purity-enhancing properties (through impurity removal). Higher concentrations for satisfactory recrystallization can be obtained using mixtures of isopropanol and water. The maximum solubility of vamorolone was determined to be at reflux in an 80:20 (isopropanol:water) mixture.

[0110] 2.5 Purity improvement by charcoal treatment To improve the purity of vamorolone acetate, charcoal treatment was envisaged. Two options were found to be useful.

[0111] Option 1: Charcoal treatment of isolated vamorolone acetate Vamorolone acetate (10 g) from step HI (ELN293-1469.1) was suspended in MeCN (100 mL, 10 vol) and HO (10 mL, 1 vol). The suspension was heated to IT = 60-65 °C and stirred until vamorolone acetate was completely dissolved. Charcoal (1.0 g, 10% w / w) was then added and stirred at IT = 60-65 °C for 1 h. The mixture was hot filtered through a Whatman glass microfiber filter into a 500 mL round-bottom flask. Additional HO (90 mL, 9 vol) was slowly added to induce crystallization of vamorolone acetate. The suspension was gradually cooled to 0 °C and aged for 1 h. The white solid was filtered, washed with additional MeCN:H2O 1:4 (2 x 10 mL), and dried extensively on a rotavap (65 °C) under reduced pressure (9.0 g, 90% recovery).

[0112] Option 2: Charcoal treatment during the HI process A 1 L glass dj reactor was charged with 8-DM acetate (30.0 g, 72.4 mmol, 1.0 equiv). Toluene (150 mL, 5 vol) was added. The suspension was cooled to IT = 0-5 °C, and then a solution of 57% aqueous HI (65.0 g, 38.2 mL, 290 mmol, 4.0 equiv) in AcOH (75 mL, 2.5 vol) was added via a peristaltic pump over 45-60 min, maintaining an IT below 5 °C during the addition. The resulting dark purple to brown solution was stirred at IT = 3-5 °C for 24 h. IPC control by LC / MS indicated >98% conversion of 8-DM acetate / intermediate iodohydrin to vamorolone acetate / vamorolone.

[0113] The reaction mixture was quenched by the dropwise addition of 25% aqueous NaSO (120 mL, 4 vol) over 10-20 min, maintaining an IT below 15 °C. After the addition was complete, EtOAc (60 mL, 2 vol) was added, and the biphasic mixture was warmed to an IT of 15-20 °C. Stirring was stopped, and the phases were separated (organic phase 1, i.e., OP1, and aqueous phase 1, i.e., AP1; target pH AP1: 2; AP1 was discarded). 25% aqueous NaSO (75 mL, 2.5 vol) was added to OP1, and the biphasic mixture was stirred at an IT of 15-20 °C for 5 min, stirring was stopped, and the phases were separated (OP1 and AP2; target pH AP2: 4-5; AP2 was discarded). A 25% aqueous solution of NaSO (75 mL, 2.5 vol) was added to OP1, and the biphasic mixture was stirred for 5 min at IT = 15-20 °C, stirring was stopped, and the phases were separated (OP1 and AP3; target pH AP3: 5-6; AP3 was discarded). HO (30 mL, 1.0 vol) was added to OP1, and the biphasic mixture was stirred for 5 min at IT = 15-20 °C, stirring was stopped, and the phases were separated (OP1 and AP4; target pH AP4: 5-6; AP4 was discarded).

[0114] A slight vacuum was applied to the double-jacketed reactor (100-150 mbar) containing OP1, and toluene was distilled off from the reaction mixture at a jacket temperature (ET) of 70 °C while MeCN was continuously added; distillation was continued until the target residual toluene value was achieved (target: less than 5% toluene by H-NMR of the reaction mixture. Final volume in the reactor after distillation: approximately 225 mL (7.5 vol)).

[0115] Once the toluene was removed, the vacuum was broken with N2, and the resulting fine suspension was cooled to IT = 20-25 °C. At this point, the amount of vamorolone was estimated by IPC (ratio: vamorolone acetate to vamorolone: ​​75:25; x = 25% a / a). DMAP (221 mg, 1.81 mmol, 0.025 equiv) was added, followed by the slow addition of Ac2O (3.7 g, 3.4 mL, 36.2 mmol, 0.5 equiv) over 2-3 min at IT = 20-25 °C. After complete addition of Ac2O, the reaction mixture was stirred for 30 min at IT = 20-25 °C. IPC control by LC / MS showed less than 1% a / a of vamorolone.

[0116] The reaction mixture was quenched by the slow addition of HO (30 mL, 1 vol) over 5-10 min. The suspension was heated to IT = 60-65 °C and stirred until complete dissolution occurred. Charcoal (3.0 g, 10% w / w) was then added and stirred at IT = 60-65 °C for 1 h. The mixture was hot filtered through a Whatman glass microfiber filter into a 1 L round-bottom flask. Additional HO (195 mL, 6.5 vol) was slowly added to induce crystallization of vamololone acetate. The suspension was slowly cooled to 0 °C and aged for 1 h. The white solid was filtered, washed with additional MeCN:HO 1:4 (2 x 40 mL), and dried extensively on a rotavap (65 °C) under reduced pressure (18.7 g, 46.9 mmol, 65% yield, >99% a / a).

Claims

1. Use of hydroiodic acid to prepare a Δ9,11 steroid from a 9,11 epoxy steroid, The Δ9,11 steroids are vamorolone or vamorolone acetate, respectively. and and the 9,11 epoxy steroid is 8-DM or 8-DM acetate, respectively. and 8-DM or 8-DM acetate, respectively, is treated with hydroiodic acid, HI, to give vamorolone or vamorolone acetate, respectively; use.

2. Vamorolone or Vamorolone Acetate , 8-DM and 8-DM acetate, respectively.

1. A method for preparing a compound comprising the steps of:

1. A method comprising treating 8-DM or 8-DM acetate, respectively, with hydroiodic acid, HI, to obtain vamorolone or vamorolone acetate, respectively.

3. 3. The method of claim 2, wherein vamorolone or vamorolone acetate is prepared using an aqueous HI solution in an organic solvent with or without the addition of an organic acid, respectively, and the treatment is carried out at a temperature below 15°C.

4. The organic solvent is MeCN, CH 2 Cl 2 or toluene; or a mixture of two or all three thereof; and the organic acid is acetic acid; 4. The method of claim 3.

5. 3. The method of claim 2, wherein vamorolone or vamorolone acetate is prepared using an aqueous solution of HI in toluene at a concentration of 48 to 68 wt %, respectively.

6. The method of claim 2, further comprising the step of acetylating 8-DM to obtain 8-DM acetate prior to treating the 8-DM acetate with HI.

7. The method of claim 6, further comprising the step of deacetylating vamorolone acetate to obtain vamorolone.

8. 3. The method of claim 2, further comprising recrystallizing vamorolone or vamorolone acetate in iPrOH or a mixture of iPrOH and water, respectively, to obtain pharmaceutically pure vamorolone or vamorolone acetate, respectively.

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