One-Step Process For The Synthesis Of Alkylated Metyrapone Analogs

Abstract

Process for preparing metyrapone type compounds are generally described herein. In particular, one step process for preparing metyrapone type compounds are described herein. Such processes generally include an alpha-carbon arylation coupling reaction between 3-isobutyrylpyridine and 3-halopyridine compounds in the presence of a palladium catalyst and a phosphine ligand to form the metyrapone-type compounds.

##STR00001##

Claims

1. A process for the preparation of a compound having the following formula ##STR00008## said process comprising the steps of 1) preparing a reaction mixture from at least: i) a halopyridine of the following structure: ##STR00009## ii) a substituted pyridine of the following structure, ##STR00010## iii) a palladium containing catalyst, if iv) does not comprise palladium; iv) a phosphine or carbene ligand; v) a Bronsted base; and vi) a solvent; 2) heating the reaction mixture to one or more temperatures in the range of about 30 to about 110° C. such that a the product compound is formed; wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each, independently, an alkyl group comprising in the range of one to four carbon atoms, R.sub.5 and R.sub.6 are each, independently, an alkyl group comprising in the range of from one to three carbon atoms, and X is selected from the group consisting of chlorine, bromine and iodine, sulfonate, triflate, nonaflate or a diazonium salt.

2. The process of claim 1, wherein said phosphine ligand is selected from the group consisting of a) a trialkyl/aryl phosphine comprising substituents independently selected from the group consisting of tert-butyl-, cyclohexyl, and adamantyl-, or a Buchwald ligand or precatalyst selected from the following: dialkylbiaryl monophosphenes such as, for example, dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos™). Other Buchwald-types include 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos™); (2-biphenyl)di-tert-butylphosphine (JohnPhos™); (2-biphenyl)dicyclohexylphosphine (CyJohnPhos™); 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (Sphos™); 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos™); 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (DavePhos™); 2-di-tert-butylphosphino-2′-methylbiphenyl (tBuMePhos™); 2-dicyclohexylphosphino-2′-methylbiphenyl (MePhos™); Preferred are tri-tert-butylphosphine and tricyclohexylphosphine; b) selected from the group consisting of, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 9,9-Dimethyl-4,5-bis (di-tert-butylphosphino) xanthene (t-Bu-Xantphos), 2,2′-bis (diphenylphosphino)-1,1′-binaphthalene (BINAP), and 1,1′-Bis(diphenylphosphino)ferrocene (dppf), 1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (QPhos); and c) N-heterocyclic carbene containing ligand or catalyst selected from the group consisting of: such as, for example, 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium tetrafluoroborate (SIPr—HBF.sub.4); 1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride; 1,3-dimesitylimidazolidinium chloride, 4,5-dihydro-1,3-bis(2,4,6-trimethylphenyl)-1H-imidazolium chloride; 1,3-bis(tricyclo[3.3.1.1.sup.3,7]dec-1-yl)-1H-imidazolium tetrafluoroborate; 1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride; (1,3-bis(2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium(II) dichloride; (PEPPSI™-SIPr catalyst); [1,3-bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl) palladium(II); and dichloride (PEPPSI™-IPr catalyst).

3. The process of claim 1, wherein said palladium catalyst is selected from the group consisting of palladium(II) acetate, bis(dibenzylideneacetone)palladium(0), tris (dibenzylideneacetone)dipalladium(0),tetrakis (triphenylphosphine)palladium(0), and [1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium(II).

4. The process of claim 1 wherein said base is selected from the group consisting of lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, lithium bis(trimethylsilyl) amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, lithium dicyclohexylamide, cesium carbonate, and potassium phosphate.

5. The process of claim 1, wherein said solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, and toluene.

Description

DETAILED DESCRIPTION

[0022] The halopyridine reactant can be a chloro-, a bromo- or an iodopyridine, with a bromo- or iodopyridine preferred, and a bromopyridine most preferred. In other aspects, X is sulfonate, triflate, nonaflate or a diazonium salt. In some aspects of the invention, the sulfonate ester of 3-hydroxypyridine can be used. In some aspects of the invention, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each, independently, hydrogen, or an alkyl groups comprising in the range of one to four carbon atoms. In other aspects, the halopyridine is a chloropyridine, and in still further aspects the halopyridine is an unsubstituted halopyridine.

[0023] The substituted pyridine used in the process comprises a tertiary alpha carbon atom such that, upon arylation, a quaternary center is established at the alpha carbon. In one aspect of the invention R.sub.5 and R.sub.6 are each, independently, an alkyl groups having in the range of one to five, or in other aspects, one to three carbon atoms. In yet another aspect, R.sub.5 and R.sub.6 are each methyl. In one aspect of the invention, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are, each independently, hydrogen, or an alkyl groups comprising in the range of one to four carbon atoms. In yet another aspect, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each hydrogen, and in a further aspect, additionally, R.sub.5 and R.sub.6 are each methyl groups. In a preferred aspect, the halopyridine is a bromopyridine; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 of the halopyridine and R.sub.7, R.sub.8, R.sub.9 and R.sub.10 of the substituted pyridine are each hydrogen; and R.sub.5 and R.sub.6 are each methyl groups.

[0024] The structures for the halopyridine and the substituted pyridine depict the halogen and the acyl substituent, respectively, in the meta position with respect to the nitrogen. However, it is thought that an ortho or para relationship, particularly concerning the halopyridine, could give a viable reaction.

[0025] The phosphine ligand is selected from among one or more of the following groups:

a) Trialkyl/aryl phosphines comprising substituents independently selected from tert-butyl-, cyclohexyl-, adamantyl-, or other bulky substituents. By trialkyl/aryl, it is meant that the three ligands consist of any combination of alkyl and aryl groups. Also included in the trialkyl/aryl class are Buchwald-type ligands or pre-catalysts such as dialkylbiaryl monophosphenes such as, for example, dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos™). Other Buchwald-types include 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos™); (2-biphenyl)di-tert-butylphosphine (JohnPhos™); (2-biphenyl)dicyclohexylphosphine (CyJohnPhos™); 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (Sphos™); 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos)™; 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl (DavePhos™); 2-di-tert-butylphosphino-2′-methylbiphenyl (tBuMePhos™); 2-dicyclohexylphosphino-2′-methylbiphenyl (MePhos™); Preferred are tri-tert-butylphosphine and tricyclohexylphosphine;
b) Phosphine ligands selected from selected from the following group: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos™), 9,9-dimethyl-4,5-bis(di-tert-butylphosphino)xanthene (t-Bu-Xantphos™), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP), and 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (QPhos™);
c) an N-heterocyclic carbene containing ligand or catalyst selected from the group consisting of: such as, for example, 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium tetrafluoroborate (SIPr—HBF.sub.4); 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride; 1,3-dimesitylimidazolidinium chloride, 4,5-dihydro-1,3-bis(2,4,6-trimethylphenyl)-1H-imidazolium chloride; 1,3-bis (tricyclo[3.3.1.1.sup.3,7]dec-1-yl)-1H-imidazolium tetrafluoroborate; 1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride; (1,3-bis(2,6-diisopropylphenyl)imidazolidene) (3-chloropyridyl) palladium(II) dichloride; (PEPPSI™-SIPr catalyst); [1,3-bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); and dichloride (PEPPSI™-IPr catalyst).

[0026] It should be noted that some of the N-heterocyclic carbine ligands also contain palladium and are thus catalyst/ligand complexes as added. The foregoing can be the case for the Buchwald ligands as well. In such cases the palladium catalyst is already present, and a separate palladium catalyst, below, is not strictly necessary.

[0027] The palladium catalyst is selected from the group consisting of palladium(II) acetate, bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), tetrakis (triphenylphosphine)palladium(0), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II). In a preferred aspect, the catalyst is palladium(II) acetate. In other aspects, the catalyst can be a mixture of two or more of the above.

[0028] The base is selected from lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, lithium dicyclohexylamide, cesium carbonate, and potassium phosphate. Hydrides, such as sodium hydride and potassium hydride, and carbonates, such as, for example sodium carbonate, can be used as well. In a preferred aspect, the base is sodium t-butoxide. In other aspects, the base can be a mixture of two or more of the above.

[0029] The solvent is selected from tetrahydrofuran; 2-methyltetrahydrofuran; 1,4-dioxane, dimethoxyethane; and toluene. In a preferred aspect, the solvent is tetrahydrofuran. In other aspects, the solvent can be a mixture of two or more of the above.

[0030] The reactants and solvent can be combined in any order to make the reaction mixture. It can be convenient to combine the palladium catalyst, phosphine ligand and base to form a dry mixture in a reaction vessel, adding the halopyridine, the substituted pyridine and the solvent on top of the dry mixture.

[0031] The reaction generally will proceed to substantial completion if heated at appropriate temperatures for sufficient times. Thus, stoichiometric equivalents of the halopyridine and the substituted pyridine can be used. The palladium catalyst and phosphine ligand are preferably used in a molar ratio in the range of from about 1 to about 5 moles of ligand per mole of palladium catalyst, with a ratio in the range of about 1 to about 2 moles of ligand per mole of palladium catalyst preferred. In general the ligand and catalyst each comprise from about 0.05 to about 10 mol % based upon moles of substrate, with about 0.1 to about 5 mol % preferred. The amount of solvent used should be sufficient to solvate the dry ingredients, and other than that concern, the amount used is not deemed to be critical. In general, the payload (i.e., the amount of both reactants combined relative to the amount of solvent) is most conveniently in the range of about 1 to about 30 wt %.

[0032] The reaction mixture is then heated. It can be convenient to heat to the reflux temperature of the solvent for the duration of the reaction. In general, the reaction mixture is heated to one or more temperatures in the range of about 30 to about 110, for time in the range of about 0.5 to about 24 hours. In one aspect of the invention, the reaction mixture is heated to one or more temperatures in the range of about 45 to about 100 C. In another aspect of the invention, the heating time is in the range of about 1 to about 6 hours. In yet another aspect, the heating time is in the range of about 2 to about 4 hours. In a preferred aspect, the reaction mixture is heated to one or more temperatures in the range of about 80 to about 110 C for a time in the range of about 2 to about 4 hours.

[0033] After the reaction has reached completion, it can be quenched, such as with ammonium chloride, water or other reagent which removes or inactivates the base, preferably after cooling the reaction somewhat, such as to room temperature.

[0034] The product can be separated using extraction, such as with ethyl acetate. In general, yield can be in the range of from about 70% to about 90% based upon the weight of the halopyridine. Purity can be in the range of about 90% to greater than 99% GC area % after purification.

[0035] Example Ib, below, is a counterexample which reproduces a run from Briscoe & Buchwald, Organic Letters, 11, 1773 (2009), except for the use of 3-isobutyrylpyridine as a reactant, which would be expected to form metyrapone, rather than 3-acetylpyridine as used in the reference. Despite the fact that the reference reaction did form product, no product was observed. With the substitution, the reaction does not proceed at all, even with the same catalyst and under the same conditions as used in the reference. Thus, even in the absence of chelation, the difficulty in forming the quaternary center necessary for the formation of metyrapone can prevent the formation of product.

Example Ia

[0036] Preparation of Metyrapone with a Pd(OAc).sub.2 Catalyst

[0037] Pd(OAc).sub.2 (15 mg, 0.067 mmol); P(t-Bu).sub.3 (15 mg, 0.074 mmol); and NaO-t-Bu (199 mg, 2.07 mmol) were weighed into a round bottom flask in a nitrogen purge box. The flask was removed from the purge box and THF (10 mL), 3-bromopyridine (0.17 mL, 279 mg, 1.76 mmol) and 3-isobutyrylpyridine (251 mg, 1.68 mmol) were added. The reaction was heated under reflux for 3.5 h. The reaction was cooled to room temperature and quenched with saturated aqueous NH.sub.4Cl (10 mL). The mixture was extracted with EtOAc (2×10 mL). The organic phases were combined and washed with saturated aqueous NaCl (10 mL), dried (MgSO.sub.4), filtered, and concentrated under reduced to give the crude metyrapone that was 80% pure by GC-MS.

Example Ib

[0038] XPhos precatalyst (32 mg, 0.043 mmol) and KOt-Bu (348 mg, 3.10 mmol) were weighed into a round bottom flask in a nitrogen purge box. The flask was removed from the purge box and 3-chloropyridine (0.17 mL, 202 mg, 1.79 mmol), 3-isobutyrylpyridine (255 mg, 1.71 mmol) and toluene (7 mL), were added. The reaction was heated to 60° C. for 3 h. A 0.15 mL aliquot was removed and the reaction progressed checked by GC-MS. GC-MS showed only unreacted starting material. The reaction was heated to 80° C. and maintained there for 3 hours, and then heated to 90° C. maintained there for 16 hours. The reaction was cooled to room temperature and quenched with saturated aqueous NH.sub.4Cl (10 mL). The mixture was extracted with EtOAc (2×10 mL). The organic phases were combined and washed with saturated aqueous NaCl (10 mL), dried (MgSO.sub.4), filtered, and concentrated. Analysis of the crude reaction mixture (365 mg) by GC-MS showed that no metyrapone was produced during the reaction and that the mixture was predominately recovered starting material.

##STR00007##

[0039] Components referred to by chemical name or formula anywhere in the specification or aspects hereof, whether referred to in the singular or plural, are identified as they exist prior to coming into contact with another substance referred to by chemical name or chemical type (e.g., another component, a solvent, or etc.). It matters not what chemical changes, transformations and/or reactions, if any, take place in the resulting mixture or solution as such changes, transformations, and/or reactions are the natural result of bringing the specified components together under the conditions called for pursuant to this disclosure. Thus the components are identified as ingredients to be brought together in connection with performing a desired operation or in forming a desired composition. Also, even though the aspects hereinafter may refer to substances, components and/or ingredients in the present tense (“comprises”, “is”, etc.), the reference is to the substance, component or ingredient as it existed at the time just before it was first contacted, blended or mixed with one or more other substances, components and/or ingredients in accordance with the present disclosure. The fact that a substance, component or ingredient may have lost its original identity through a chemical reaction or transformation during the course of contacting, blending or mixing operations, if conducted in accordance with this disclosure and with ordinary skill of a chemist, is thus of no practical concern.

[0040] The invention may comprise, consist, or consist essentially of the materials and/or procedures recited herein.

[0041] As used herein, the term “about” modifying the quantity of an ingredient in the compositions of the invention or employed in the methods of the invention refers to variation in the numerical quantity that can occur, for example, through typical measuring and liquid handling procedures used for making concentrates or use solutions in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make the compositions or carry out the methods; and the like. The term about also encompasses amounts that differ due to different equilibrium conditions for a composition resulting from a particular initial mixture. Whether or not modified by the term “about”, the aspects include equivalents to the quantities.

[0042] Except as may be expressly otherwise indicated, the article “a” or “an” if and as used herein is not intended to limit, and should not be construed as limiting, the description or an aspect to a single element to which the article refers. Rather, the article “a” or “an” if and as used herein is intended to cover one or more such elements, unless the text expressly indicates otherwise.

[0043] Each and every patent or other publication or published document referred to in any portion of this specification is incorporated in tow into this disclosure by reference, as if fully set forth herein.

[0044] This invention is susceptible to considerable variation in its practice. Therefore the foregoing description is not intended to limit, and should not be construed as limiting, the invention to the particular exemplifications presented hereinabove.