WO2005079337A2

WO2005079337A2 - Process for making ep4 agonists and intermediates thereof

Info

Publication number: WO2005079337A2
Application number: PCT/US2005/004529
Authority: WO
Inventors: Shannon Condon; Paul Devine; Donald R. Gauthier, Jr.; John Limanto; Ronald H. Szumigala, Jr.
Original assignee: Merck & Co., Inc.
Priority date: 2004-02-17
Filing date: 2005-02-14
Publication date: 2005-09-01
Also published as: WO2005079337A3; EP1718298A2

Abstract

This invention relates to a process for making a series of 1,6-disubstituted piperidin-2-one, 3,4-disubstituted 1,3-oxazinan-2-one, 3,4-disubstituted 1,3-thiazinan-2-one, and 4,5-disubstituted morpholin-3-one derivatives, which are agonists of the EP4 subtype of prostaglandin E2 receptors. The compounds are useful in the treatment of glaucoma and other conditions that are related to elevated intraocular pressure in the eye of a patient. The compounds are also useful for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.

Description

TITLE OF THE INVENTION

PROCESS FOR MAKING EP4 AGONISTS AND INTERMEDIATES THEREOF

This Application claims the benefit of US provisional application 60/545,109, filed February 17, 2004.

BACKGROUND OF THE INVENTION Prostaglandin and prostaglandin derivatives are known to lower intraocular pressure by increasing uveoscleral outflow. This is true for both the F type and A type of prostaglandins. This invention is particularly interested in processes for making those compounds that lower IOP via the uveoscleral outflow pathway and other mechanisms by which the E series prostaglandins (PGE2) may facilitate IOP reduction. Of particular interest to this invention is a process for making compounds that are agonist of the EP4 subtype receptor. Said compounds are useful for lowering IOP, treating glaucoma and stimulating bone formation and increasing bone mass in mammals, including man. In light of the above, an objective of the present invention is to provide a process for making stable EP4 agonist for use as a glaucoma and/or bone formation stimulating agent. This and other aspects of the invention can be realized upon review of the specification as a whole.

SUMMARY OF THE INVENTION This invention relates to a process for making a series of 1,6-disubstituted piperidin-2- one, 3,4-disubstituted l,3-oxazinan-2-one, 3,4-disubstituted l,3-thiazinan-2-one, and 4,5-disubstituted morpholin-3-one derivatives, which are agonists of the EP4 subtype of prostaglandin E2 receptors. The compounds are useful in the treatment of glaucoma and other conditions that are related to elevated intraocular pressure in the eye of a patient. The compounds are also useful for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts. There is disclosed a process for making compounds of the structural formula I:

FORMULA I or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug or mixture thereof, wherein,

Q is (CH₂)_m, (CH2)_mC6-10aryl, (CH2)_mC5-i o heterocyclyl, (CH2)_mC3-10 heterocycloalkyl, (CH2)_mC3_8 cycloalkyl, C(halo)2 said cycloalkyl, heterocycloalkyl, aryl or heterocyclyl unsubstituted or substituted with 1-3 groups of Ra.

X and Y independently represent CH₂, O, NR⁹ or S, provided however, that X and Y are not O, NR⁹ or S at the same time;

U represents H, Cl-3 alkyl or is not present when W is =0;

W represents OH or =0, provided that U is not present when W is =0;

Rl represents (CH2)_phydroxy, (CH₂)_pCN, (CH₂)_pCO₂Rl0, (CH₂)_nSθ3R6, -(CH2)pCF₂S02NH₂, - (CH2)_pS0₂NH2, -(CH₂)_pCONHS0₂R²,

-(CH2)pS0₂NHCOR2 -(CH₂)pPO(OH)₂, (CH2)_pCONHP0₂R6,

(CH2)_PCONHR8, (CH₂)_pCi-4alkoxy, -(CH2)_pcycloalkyl,

(CH2)p-hydroxymethylketone or (CH2)nheterocyclyl, said heterocyclyl unsubstituted or substituted with

1 to 3 groups of R^a and optionally containing an acidic hydroxyl group;

R² independently represents Ci-io alkyl, (CH2)_mC6-10aryl,

(CH2)_mC5-ioheterocyclyl, (CH2)_mC3-10 heterocycloalkyl, (CH2)_mC3-8 cycloalkyl, O-Ci-ioalkyl, O-

C6-10aryl, 0-C3-l()cycloalkyl, O-C3.10 heterocycloalkyl, O-C3-10 heterocycloalkyl, provided that when

R² i_s 0-Cι_ιoalkyl, O-C6-10aryl, 0-C3_ιocycloalkyl, O-C3.10 heterocycloalkyl, or O-C3.10 heterocycloalkyl, R3 and R4 are not halogen, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclyl unsubstituted or substituted with 1-3 groups of R^a;

R3 and R4 independently represents hydrogen, halogen, or Cχ-6 alkyl, or R3 and R4 may be taken together to form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, and NR9_;

R6 and R independently represents hydrogen, or Cl-4 alkyl;

R8 represents hydrogen, acyl, or sulfonyl; R9 represents hydrogen, C_l-6 alkyl, said alkyl optionally substituted with 1-3 halogen, CN, OH, C,.₆ alkoxy, Cι_6 acyloxy or amino;

Rl° represents hydrogen, Ci-i o alkyl, C3-10 cyclcoalkyl, (CH2)ρC_f5-10 aryl, (CH2)ρC5-io heterocyclyl, CR6R7θC(0)0 C3-10 cycloalkyl or CR6R70C(0)0 Ci-io alkyl;

Z represents a triple bond, O, S, (C(Rb)2)_n, or Ch=CH_;

R^b represents hydrogen, Cl-6 alkyl or halogen;

R^a represents C\-_ alkoxy, Cl-6 alkyl, CF3_; nitro, amino, cyano, Cj-6 alkylamino, or halogen, orRa further represents for aryls and heterocyclyl SCι_6alkyl, SC6-l0aryl, SC5-ioheterocyclyl, OC6-10aryl, OC5_ιoheterocyclyl, CH2OC1 -6 alkyl, CH2SC1-6 alkyl, CH2θaryl, CH2Saryl;

— represents a double or single bond;

p represents 0-3;

n represents 0-4; and

m represents 0-8 comprising reducing a solution containing a compound of formula la:

la a solvent, a hydrogen source, and a ruthenium, iridium, rhodium, or vanadium metal catalyst, to produce a compound of formula I, wherein W, U, X, Y, Z, Q, Rl, R2, R3 and R4 are as described herein. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a scaleable route for preparing an EP4 agonist. The claimed process minimizes the formation of undesired impurities while allowing for a highly selective and economical means for making the compounds of formula I. In particular, the present invention is directed to a process for making a compound of formula lb

lb

or pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug or mixture thereof wherein R3 and R4 are halogen, u represents H, Cl-3 alkyl or is not present when W is =0; W represents OH or =0, provided that U is not present when W is =0, R² represents (CH2)_mC6-10aryl, and m represents 0 to 8; comprising the steps of: (1) contacting a solution containing a compound of formula II:

II and a solvent with a metal salt in the presence of an oxidizing agent to produce a compound of

formula lib, wherein Rd represents hydrogen or an amine protecting group:

alkyl

lib (2) deprotecting the amine protecting group using an acid to produce a compound of the formula DM:

alkyl

DM (3) reducing the compound of formula D using a reductant to produce a compound of formula IIb2:

IIb2

(4) protecting the compound of formula IIb2 using a hydroxyl protecting group, in the presence of a solvent to produce a compound of formula IIb3:

IIb3 where R^p is a hydroxyl protecting group; (5) alkylating the compound of formula Hb3 using a leaving group containing a Q.₁₅ saturate or unsaturated alkyl or alkyl ester group, to produce a compound of formula lie:

He

(6) oxidizing the compound of formula lie with oxidizing agent in the presence of a base and a solvent to produce a compound of formula lid

lid (7) adding a compound of formula lie:

wherein R^g represents a phosphonate ester, enolate, SiR^x ₃, or hydrogen wherein R^x is a C_1-3 alkyl, in the presence of a metal halide at a temperature of about 25°C to about 60°C, to produce a compound of formula πf : and

Hf (8) reducing the compound of formula ϋf by adding to a solution of formula Hf a hydrogen source and a ruthenium, iridium, rhodium, or vanadium metal catalyst to produce the compound of formula lb. Still another aspect of the invention is a process for making a compound of formula Hb:

lib wherein R^d is an amine protecting group; comprising the steps of contacting a solution of the compound of formula II:

π with metal salt in the presence of an oxidizing agent to produce a compound of formula lib. Another aspect of the process as recited above is where the reduction step is carried out using a ruthenium catalyst of the structural formula III:

in at a mole ratio of ruthenium catalyst to the compound of formula la or Ilf of about 0.5% to about 5%, preferably about 1 to about 3 mole%, at a temperature of about 20°C to about 25°C The hydrogen source is selected from the group consisting of cyclohexane, isopropanol, NaHCθ2, HCO2H, H2, a combination thereof, and the like. The reaction can be conducted using solvents such as dichloromethane (DCM), toluene, ethylacetate, acetonitrile, isopropyl acetate, DMF, MeOH, THF or a combination thereof. The reduction step uniquely provides >95% chemical selectivity between the double bond to ketone. It is also unique in that it affords >98% selectivity in terms of the relative stereochemistry between the two stereogenic centers in the molecule and provides the desired diastereomer (desired product) in 100% enantiomeric excess. Another aspect of the process as recited above is where the metal salt in step (1) is selected from the group consisting of ruthenium halide, iridium halide, rhodium halide, ruthenium oxide, iridium oxide, rhodium oxide, and the like and the oxidizing agent in is selected from the group consisting of sodium periodate, bleach, peroxide, sodium bromate and the like. The metal salt is generally present in an amount relative to the amount of active ingredient, wherein a mole ration of the metal salt source to the active ingredient is about 0.5 mol% to about 4 mol%, preferably about 1.5 mol% to about 2 mol%. The reaction can be conducted using solvents such as acetonitrile, water, THF, ethylacetate, isopropyl acetate or a combination thereof. Another aspect of the process recited above is where the compound of formula lib is alkylated (step 5) by adding a reagent such as KHMDS (potassium bis [trimethylsilyl] amide, LiHMDS (lithium bis[trimethylsilyl]amide), NaHMDS (sodium bis[trimethylsilyl]amide), nBuLi, KotBu, at a temperature of about 5° C to about 20° C and a leaving group containing a C1.1₅ saturate or unsaturated alkyl or alkyl ester group, wherein the leaving group selected from the group consisting of mesylate, tosylate, halide, triflate, phosphate and the like, preferably mesylate and the Cι.]₅ saturate or unsaturated alkyl or alkyl ester group is selected from ethyl, methyl, hexyl, butyl, propyl, cyclohexyl, phthalic acid, ethyl ethanoate, isopropyl benzoate, phenyl butanoate, alkyl esters, . The reaction is then heated to and aged at a temperature of about 45° C to about 60° C to produce a compound of formula πc. Solvents such as an alcohol, dichloromethane, toluene, tert-butyl methyl ether, tetrahydrofuran, or a combination thereof are typically employed. The alkylation step can be performed in several ways using methods generally known in the art. For example, in the case where R^d is a protecting group in the compound of formula lib R^d can be deprotected to provide the free amide using deprotection means known to those of ordinary skill in the art. For example, deprotection (step 2) of formula lib where R^d is BOC can be achieved by contacting the compound with an acid (e.g., hydrochloric acid, nitric acid, phosphoric acid, triflic acid and the like) in the presence of an alcohol such as isopropyl alcohol, ethanol, butanol and the like. The resulting free amide can then be reacted (step 3) with a reducing agent (reductant) in the presence of a solvent to provide an alcohol, which can be subsequently protected. It is preferable that the alcohol is protected. The reductant is selected from the group consisting of sodium borohydride, lithium borohydride, zinc borohydride and the like and the solvent is selected from the group consisting of isopropyl alcohol, methanol, ethanol, butyl alcohol and the like. The alcohol is then protected (step 4) using a hydroxyl protecting group (R^p) selected from the group consisting of silyl containing protecting groups such as triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl and the like. The protection reaction is typically carried out with the addition of about 1.5 to about 2.5 equivalents of imidazole at a temperature of about -5°Cto about 5°C under pressure (eg. N₂) to a solution cotaining the alcohol. Solvents such as dichloromethane, acetonitrile, THF, DMF and the like are generally used. Once the alcohol is protected it can then be alkylated using conditions described herein. Alternatively, the alkylation step can be achieved by alkylating the free amine without deprotection of the R^h group. Formula lie is then deprotected using TBAF, HF-Pyridine, or HC1. Typically, the reaction is run at a temperature of about -5 C to about 5 C under pressure (eg. N₂) in a solvent such as CH₂C1₂, MTBE, THF, MeCN, DMF and the like. Another aspect of the process recited above is where the base in step (6) is selected from the group consisting of Hunig base, alkyl amine such as methylamine, ethylamine, isopropylamine, triethylamine, trimethylamine, sodium hydroxide, and the like and the oxidizing agent is selected from the group consisting of S03- pyridine, rhuthenium chloride, TEMPO(2,2,6,6-tetramethyl-l- piperidinyloxy)-NMO(methylmorpholine N-oxide), oxylyl chloride-DMSO,

TPAP(tetrapropylammonium perruthenate)-NMO, Dess-Martin periodinane, TEMPO- trichloroisocyanuric acid and the like, preferably Sθ3- pyridine. The reaction can be conducted at a temperature of about -5° C to about 5° C, preferably 0° C using solvents such as dichloromethane, methyl sulfoxide, THF, dichloroethane or a combination thereof. Another aspect of the process recited above is where the metal halide is selected from the group consisting of ZnCl2, AICI3, AII3, TiCLj., TiBr T1F4, Zn(OTf)2, AlBr3, zirconium halides such as ZrCl4, L1CI3 and the like. Still another aspect of the process as recited above is where in Step (7) the metal halide is reacted with a solution containing the compound of formula He at a temperature range of about - 3°C to about 5°C, the compound of formula Ild is added to said solution at a temperature of about 20°C to about 25°C and the resulting solution heated to a temperature of about 40°C to about 60°C, preferably

45°C to 55°C. Examples of the amine protecting group include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p-methoxybenzyl, nitrobenzyl, triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl (eg benzyloxycarbonyl), p-methoxybenzyloxycarbonyl, trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl)alkylidene (eg methylidene; benzylidene and substituted benzylidene groups. It is understood that the substituents recited above would include the definitions recited below, and unless otherwise stated or indicated, the definitions shall apply throughout the specification and claims. The term "therapeutically effective amount", as used herein, means that amount of the EP4 receptor subtype agonist of formula I, or other actives of the present invention, that will elicit the desired therapeutic effect or response or provide the desired benefit when administered in accordance with the desired treatment regimen. A preferred therapeutically effective amount relating to the treatment of abnormal bone resorption is a bone formation, stimulating amount. Likewise, a preferred therapeutically effective amount relating to the treatment of ocular hypertension or glaucoma is an amount effective for reducing intraocular pressure and/or treating ocular hypertension and/or glaucoma. "Pharmaceutically acceptable" as used herein, means generally suitable for administration to a mammal, including humans, from a toxicity or safety standpoint. The term "prodrug" refers to compounds which are drug precursors which, following administration and absorption, release the claimed drug in vivo via some metabolic process. A non- limiting example of a prodrug of the compounds of this invention would be an acid of the pyrrolidinone group, where the acid functionality has a structure that makes it easily hydrolyzed after administration to a patient. Exemplary prodrugs include acetic acid derivatives that are non-narcotic, analgesics/non- steroidal, anti-inflammatory drugs having a free CH2COOH group (which can optionally be in the form of a pharmaceutically acceptable salt, e.g. -CH2COO-Na+), typically attached to a ring system, preferably to an aromatic or heteroaromatic ring system. The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group". Cycloalkyl is a species of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings, which are fused.

Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Alkoxy refers to C1 -Cg alkyl-O-, with the alkyl group optionally substituted as described herein. Examples of alkoxy groups are methoxy, ethoxy, propoxy, butoxy and isomeric groups thereof. Halogen (halo) refers to chlorine, fluorine, iodine or bromine. Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl. The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic) having 3 to 10 carbon atoms in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms. The term "cycloalkyl" refers to a cyclic alkyl group (nonaromatic) having 3 to 10 carbon atoms. The term "heteroatom" means O, S or N, selected on an independent basis. The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole, tetrazole, and oxazine. For purposes of this invention the tetrazole includes all tautomeric forms. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole.

The term heterocyclyl or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. The term heterocycle or heterocyclic includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, and triazolyl. For purposes of this invention, heterocyclyls containing acidic hydroxyl groups are those heterocyclyl groups that have an acidic hydroxy atom and can have a pKa in the range

of 3 to 10. Non-limiting examples of heterocyclyls containing acidic hydroxyl groups are:

O G is -C(R^C)₃ _{i-^0Rd , -N(R^e)_2> O, or S and ^OR^d each R^c independently is H, fluorine, cyano or Cι_₄ alkyl; each R^d independently is H, Cι_₄ alkyl, or a pharmaceutically acceptable cation; each R^e independently is H, -C(=O)-R^f, or -SO₂R^e, wherein R^f is C_1-4 linear alkyl or phenyl

The term "agonist" as used herein means EP4 subtype compounds of formula I interact with the EP4 receptor to produce maximal, super maximal or submaximal effects compared to the natural agonist, PGE2. See Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9^th edition, 1996, chapter 2. The term "active drug," as used herein, is defined as the actual amount of EP4 agonist, unstabilized and stabilized EP4 agonist, and alkali metal salt-containing EP4 agonist. The term "quantum sufficif ("q.s."), as used herein, is defined as the amount of a reagent necessary to increase the batch weight or volume to a specified total. As an example, a q.s. of 95% by wt% means the amount of reagent required to bring the weight percent up to 95% by weight based on 100% total weight. The batch-wise process of the present invention is carried using several reagents and processing units to prepare compounds of this invention. All reagents used during the present processes meet United States Pharmacopeia and National Formulary standards unless otherwise stated. The reaction parameters and conditions such as the mole ratio of carbon dioxide source and active ingredient, mole ratio of base and active ingredient (active bulkEP4 agonist), reaction temperatures, pH of the solution, and proper mixing are disclosed herein for illustrative purposes and are not meant to be limitative.

Methods of preparing the compound of the present invention are illustrated in the following process and examples. They are provided for illustrative purposes and should not be construed as limiting the invention disclosed herein.

Preparative Example 1

(R)-pipecolinic acid 1

To a slurry of (+/-)-pipecolinic acid (395 g, 3.06 moles) in MeOH (1.8L) at 60 °C was added L-tartaric acid (459 g, 3.06 moles). The slurry was warmed to reflux and aged lh (hour). The slurry was cooled to 23 °C, filtered, and the desired (R)-pipecolinic acid/L-tartaric acid filtercake was washed with MeOH (200 mL). The filtercake was air dried a white solid was isolated. The pipecolinic acid tartrate salt typically assayed at 85-89 %ee.

A slurry of salt (383g) in 2:1 H₂0/acetone (380 mL/190 mL) was warmed to reflux (60-65 °C) until all solids had dissolved. Acetone (1330 mL) was added over 2h while maintaining a reflux. The slurry was allowed to cool to 15-20 °C over lh and then filtered, washed with 4: 1 acetone/H₂0 (380 mL) and then air dried under vacuum. Isolated 313g of pipecolinic acid tartrate salt (>99 %ee).

To a slurry of (R)-pipecolinic acid tartrate salt (312g) in MeOH (3.0 L) was added 28% NE OH (83 mL, 1. leq) over 0.5h. The white slurry was aged 0.5h at ambient temperature and then the ammonium tartrate precipitate was filtered off. The filtercake was rinsed with MeOH (300 mL). The combined filtrate and rinse was concentrated to a white solid of (1). Preparative Example 2

To a slurry of pipecolinic acid (109.7 g) and BOC₂0 (222.4 g) in 1:1 tetrahydrofuran (THF) H₂0 (550/550 mL) was added 50% NaOH (45 mL). The slurry was warmed to reflux and aged 5h at reflux. The solution was cooled to 23 °C and then washed with heptane (550 mL) to remove unreacted BOC₂0. The aqueous (aq.) layer was then acidified with 5N HC1 (170 mL) to pH 4-5. The resulting slurry was extracted with 550 mL of tert-butyl methyl ether (MTBE). The organic layer was dried over Na₂S0 and then concentrated to a white solid of (2).

Preparative Example 3

To a solution of N-BOC-pipecolinic acid (166.5 g, 726 mmoles) in 500 mL dimethylformamide (DMF) was added Mel (123.7 g, 871 mmoles) and K₂C0₃ (100.4 g, 726 moles). The reaction mixture slowly exothermed to 40 °C after 0.5h during a 4h age period at ambient temperature. Added MTBE (830 mL) and then washed with H₂0 (2 x 830mL) and 20% brine (300 mL). The organic layer was dried over Na₂S0 and concentrated to an oil (3).

Preparative Example 4

Preparation of Sodium Phosphonate 14 Ste l

To a neat solution of methyl benzoylformate (PhCOC0₂Me, 25 g, 0.15 mol, 1 equiv) at 15 °C under N₂ atmosphere was added neat diethylaminosulfur trifluoride (DAST, 34.4 g, 0.21 mol, 1.4 equiv) at a rate such that the internal temperature was maintained below 45 °C. At the end of the addition, the resulting brown solution was allowed to cool to RT and aged for 3 more hours, at which time a complete consumption of starting material was observed by high performance liquid chromatography (HPLC) and gas chromatography/mass spectroscopy (GC/MS). The reaction mixture was then poured slowly into a mixture of ice/H₂0 (NOTE: exothermic!) and the product was extracted with MTBE (3x). The combined organic layer was then neutralized slowly to a pH of 7 with a cold solution of 20% aqueous Na C0₃ (NOTE: gas evolution), washed with brine, dried over MgS0₄, filtered and concentrated in vacuo. The crude product was purified by vacuum distillation (bp= 103-105 °C at 24-25 torr) to give the desired product (13) as slightly yellow oil .

Step 2

To a solution of dimethyl methylphosphonate (28g, 0.23 mol, 1.05 equiv) in dry THF (400 mL, KF= 30 ppm) under N₂ atm at -78 °C was slowly added a 2M solution of sodium bis(trimethylsilyl)amide in THF (115 mL, 0.23 mol, 1.05 equiv) over 15 min. The resulting solution was aged for 30 min and then treated with neat methyl difluoroester (PhCF₂C0₂Me, 40g, 0.22 mol, 1.0 equiv) over 15 min. The reaction mixture was aged at -78 °C for lh, slowly warmed to RT and concentrated to about a quarter of its original volume and added MTBE (400mL) over 0.5h. The resulting suspension was further aged at RT for 0.5h and filtered. The wet cake was washed with MTBE (lOOmL) and dried in vacuo under a stream of N₂. The product was isolated as white solid (14). Example 1

To a solution of butoxycarbonyl (Boc)-Me ester (152.6 g, 627 mmol) in MeCN (305 mL) was added RuCl₃ (2.6 g, 12.5 mmol). A solution of NaBr0₃ (142.0 g, 941 mmol) in H₂0 (760 mL) was added over 2h. The solution was aged 12h at ambient temperature. Added EtOAc (760 mL) and cut the aqueous layer. The dark organic layer was washed with 10% Na₂S0₃ (305 mL) while the organic layer turned clear and the aqueous layer turned cloudy grey. The organic layer was washed with saturated brine (150 mL) and then dried over Na₂S0₄ to give oil (4).

Example 2 isopropyl 7-{(2i?)-2-[(l£)-4,4-difluoro-3-oxo-4-phenylbut-l-en-l-yl]-6-oxopiperidin-l-yl}heptanoate

Ste l

To a solution of BOC-Lactam (135.4 g, 526 mmol) in 135 mL of isopropyl alcohol (IPA) was added 5N HC1 in 263 mL/1316 mmol isopropyl alcohol (IPA) over 15min. Vigorous gas evolution occurred for 15min and then the solution was aged 2.5h at ambient temperature. Added EtOAc (800 mL) and washed with 15% Na₂C0₃ (350 mL). The aqueous layer was extracted with EtOAc (400 mL). The combined organic layers were dried over Na₂S0₄ and concentrated to oil (5). The enantiomeric purity was assayed at >99 %ee.

Step 3

To a solution of lactam ester (8.10 g, 51.7 mmol) in anhydrous ethanol (500 mL) was added sodium borohydride (2.5 g, 1.2 eq) in 0.5 g increments over 30 minutes. The solution was stirred for 3.5 hours at room temperature. The mixture was then treated with glacial acetic acid (2.8 equiv) and the precipitate removed by filtering through a plug of celite. The filtrate was then concentrated in vacuo and the resulting oil solidified upon standing under vacuum. The crude product was dissolved in CH₂C1₂ (50 mL), treated with KHC0₃ (1.5 equiv), aged for lh, filtered through a plug of Celite and the resulting filtrate was concentrated in vacuo to give the title compound 6, which was used directly in the next step without Ifurther purification. Step 4

To a solution of the lactam alcohol (lOg, 77.5 mmol, 1.0 equiv) in anhydrous CH₂C1₂ (50 mL) at 0 °C under N₂ atmosphere was added imidazole (6.9 g, 100.8 mmol, 1.3 equiv, ( the amount of imidazole was adjusted to neutralize any AcOH from the previous step) and 14 g/93.0 mmol/1.2 equiv of tert- butyldimethylsilyl chloride (TBSCI). The resulting mixture was warmed to room temperature (RT) and aged for 4 hours. Once the reaction was judged complete, CH₂C1₂ (100 mL) was added, followed by IN HC1 solution (30 mL). The organic layer was separated and the aqueous layer was back-extracted with CH₂C1₂ (2x50 mL). The combined organic layer was washed with 20% NaHC0₃ solution (40 mL), brine, dried over MgS0₄, filtered and concentrated in vacuo to give the desired compound as white solid. The silicon-containing byproducts can be removed by washing the solid with cold heptane (3mL/g) at -78 °C to give the titled compound 7.

Step 5

7 8

To a 15 °C solution of lactam 7 (2.0 g, 8.22 mmoles) in THF (KF < 200 ppm) was added 1.90 g/ 9.04 mmoles of solid potassium bis [trirnethylsilyl] amide (KHMDS) in 20 mL of tetrahydrofuran (THF) and aged for 10 min at room temperature (rt). Freshly prepared mesylate (0.93 g, 8.22 mmoles, KF < 800 ppm) was added to the solution as a neat oil and the reaction was heated to 50 °C and aged for 2.5-3.5 h. The reaction was cooled to rt and diluted with MTBE (20 mL) and water (20 mL). The aqueous (aq.) layer was cut and the organics were washed with sat'd. brine (10 mL). Upon drying over Na S0₄, the solvent was removed to yield crude yellow oil 8. Step 6

To a solution of the tert-butyldimethylsilyl (TBS)-protected lactam (lOg, 24.2 mmol, 1 equiv) in dry MTBE (40 mL) at 0 °C under N₂ atmosphere was added a 70% solution of HF'Pyridine (4.84g, 169 mmol, 7 equiv) over 15 min. The resulting mixture was allowed to warm to RT and aged for 12h, at which the reaction was judged complete by HPLC and ¹HNMR analysis. The mixture was then diluted with MTBE (100 mL) and washed with cold H 0 (30 mL). The organic layer was then treated with saturated Na₂C0₃ (25 mL), brine, dried over MgS0₄, filtered and concentrated in vacuo. The resulting crude oil (9) is used directly in the next step. If desired, the alcohol can be purified by Si0₂ gel flash column chromatography (40: 1 CH₂Cl₂:MeOH).

Step 7

To a cold solution (0 °C) of alcohol 9 (9.46 g, 31.6 mmol), DMSO (237.3 mmol, 16.9 mL, 7.5 equiv), and Hunig base (16.5 mL, 94.9 mmol, 3 equiv) in dichloromethane (95 mL) was added Sθ₃ ^#Pyridine (15 g, 94.9 mmol, 3 equiv) as a solid over 15 minutes. The resulting solution was aged at 0 °C for 1.5 h, at which complete consumption of the starting material was observed. The reaction mixture was then diluted with EtOAc (150 mL) and washed with cold 4N aqueous HC1 (35 mL). The organic layer was separated and treated successively with saturated NaHC0₃ solution and brine. The solution then dried over MgS0₄ filtered and concentrated in vacuo to give the corresponding aldehyde, which was used in the next step without further purification.

To a solution of sodium phosphonate 14 (13.7 g, 45.7 mmol, 1.4 equiv) in THF (130 mL) at 0 °C under nitrogen was added ZnCl₂ (3.33g, 24.5 mmol, 0.75 equiv). The resulting mixture was stirred at rt for 15 minutes and then treated with a solution of aldehyde 10 (9.7g, 32.66 mmol, 1 equiv) in THF (10 mL). The resulting suspension was then heated to 55 °C for 48h, at which a 94-97% conversion was observed. The mixture was then concentrated to about a third of its volume, diluted with EtOAc (130 mL), washed with H₂0 (30 mL) and brine. The organic layer was then dried over MgS0₄, filtered and concentrated to give yellow oil (11), which can be purified by Si0₂ gel flash chromatography (19:1 - 9:1 toluene:acetone).

Example 3

7-{(2R)-2-[(lE,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-l-en-lyl]-6-oxopiperidin-l-yl}heptanoate (12)

To a solution of the enone (450 mg, 1 mmol, 1.0 equiv) in 0.5 M7~4.5mL/g anhydrous PhCH₃ or dichloromethane (DCM) under N₂ atmosphere was added Et₃N (0.14 mL, 1 mmol, 1.0 equiv) and HC0₂H (0.05 mL, 1.2 mmol, 1.2 equiv) at room temperature (RT). The resulting solution was stirred for 10 min and then treated with solid (R,R)-(-)-Ru-TsDPEN-cymene complex (19 mg, 0.03 mmol, 0.03 equiv) all at once. The reaction mixture was then aged at RT for 2h, at which a complete consumption of starting material was observed. Tert-butyl methyl ether - MTBE (5 mL) was added followed by IN HC1 (2mL). The organic layer was separated, washed with saturated Na₂C0₃, brine, dried over MgS0₄, filtered and concentrated in vacuo to give the final compound as viscous oil. (40-60:1 diastereomeric ratio, 83-85% assay yield). The catalyst can also be generated in situ by mixing 0.02 mol equiv of [RuCl₂(p-cymene)₂] and 0.04 mol equiv of the (RR)-N-Tosyl-l,2-diphenylethylene-l,2-diamine in DCM (dichloromethane) or PhCH₃, in the presence of 0.04 mol equiv of IM solution KOtBu in THF(tetrahydrofuran). After aging for 10 min at RT, Et₃N was added followed by HC0₂H and a solution of the enone in DCM).

The (R,R)-(-)-Ru-TsDPEN-cymene complex was prepared by mixing lmol equiv of [RuCl₂(p-cymene)₂], 2mol equiv (R,R)-N-Tosyl-l,2-diphenylethylene-l,2-diamine and 4.2 mol equiv of Et₃Ν in iPrOH at 80 °C for lh(hour). After solvent removal, the solid was washed with cold H₂0 and the recrystallized from MeOH to give the catalyst as orange solid.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a compound of formula I,

FORMULA I

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug or mixture thereof, wherein,

Q i_s (CH₂)_m, (CH2)_mC6-10aryl, (CH2)_mC5-io heterocyclyl, (CH2)_mC3_ιo heterocycloalkyl,

(CH2)mC3-8 cycloalkyl, C(halo)2 said cycloalkyl, heterocycloalkyl, aryl or heterocyclyl unsubstituted or substituted with 1-3 groups of R^a _;

U represents H, Cl-3 alkyl or is not present when W is =0;

W represents OH or =0, provided that U is not present when W is =0;

Rl represents (CH₂)_phydroxy, (CH₂)_pCN, (CH2)_pCO₂Rl0, (CH₂)_nS0₃R6, -(CH2)_pCF₂Sθ2NH2, -

(CH₂)pS0₂NH2, -(CH₂)pCONHS0₂R2,

-(CH₂)pS0₂NHCOR2, -(CH₂)pPO(OH)₂, (CH2)pCONHP0₂R6,

(CH2)pCONHRS, (CH₂)_pCι_4alkoxy, -(CH2)_pcycloalkyl, (CH2)p-hydroxymethylketone or (CH2)nheterocyclyl, _Said heterocyclyl unsubstituted or substituted with

1 to 3 groups of R and optionally containing an acidic hydroxyl group;

R² independently represents Ci-io alkyl, (CH2)_mC6-ioaryl, (CH2)mC5-ioheterocyclyl, (CH2)_mC3-10 heterocycloalkyl, (CH2)_mC3-8 cycloalkyl, 0-Cι_ιoalkyl, O- C6-10aryl, 0-C3-K)cycloalkyl, O-C3.10 heterocycloalkyl, O-C3-10 heterocycloalkyl, provided that when R2 _is O-Ci-ioalkyl, 0-C6-lθaryl, 0-C3_ιocycloalkyl, O-C3-10 heterocycloalkyl, or O-C3-10 heterocycloalkyl, R3 and R are not halogen, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclyl unsubstituted or substituted with 1-3 groups of R^a;

R3 and R independently represents hydrogen, halogen, or Cι_6 alkyl, or R3 and R may be taken together to form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, and NR9.

R6 and independently represents hydrogen, or C _4 alkyl;

R°> represents hydrogen, acyl, or sulfonyl;

R9 represents hydrogen, C,.₆ alkyl, said alkyl optionally substituted with 1-3 halogen, CN, OH, .₆ alkoxy, Ci-6 acyloxy or amino;

RlO represents hydrogen, Ci-io alkyl, C3. 0 cyclcoalkyl, (CH2)ρC6-lO aryl, (CH2)pC5_ιo heterocyclyl, CR6R70C(0)0 C3-10 cycloalkyl or CR6R70C(0)0 CMO alkyl;

Z represents a triple bond, O, S, (C(Rb)2)_n, or Ch=CH_;

R^b represents hydrogen, Cl-6 alkyl or halogen;

R^a represents Cι_β alkoxy, Cι_6 alkyl, CF3, nitro, amino, cyano, Cι_6 alkylamino, or halogen, or Ra further represents for aryls and heterocyclyl

SCi-6alkyl, SCβ-inaryl, SC5-ioheterocyclyl, OC -10aryl,

OC5_ιoheterocyclyl, CH2OC1.6 alkyl, CH2SC1-6 alkyl, CH2θaιyl, CH2Saryl;

__ represents a double or single bondi

p represents 0-3;

n represents 0-4; and m represents 0-8 comprising reducing a solution containing a compound of formula la:

la a solvent, a hydrogen source, and a ruthenium, iridium, rhodium, or vanadium metal catalyst, to produce a compound of formula I, wherein W, U, X, Y, Z, Q, Rl, R2, R3 and R are as described herein.

2. The process of Claim 1, wherein the metal catalyst is ruthenium having the structural formula ID:

III and is present at a mole ratio of ruthenium catalyst to the compound of formula la of about 0.5% to about 3% and the hydrogen source is selected from the group consisting of cyclohexane, isopropanol, NaHCθ2, HCO2H, and H2.

3. A process for making a compound of formula I

lb

or pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug or mixture thereof wherein R3 and R are halogen, u represents H, Cl-3 alkyl or is not present when W is =0; W represents OH or =0, provided that U is not present when W is =0, R² represents (CH2)_mC6-10aryl, and m represents 0 to 8; comprising the steps of: (1) contacting a solution containing a compound of formula D:

alkyl

π and a solvent with a metal salt in the presence of an oxidizing agent to produce a compound of formula Hb, wherein R represents hydrogen or an amine protecting group:

alkyl

lib (2) deprotecting the amine protecting group using an acid to produce a compound of the formula lib 1:

DM (3) reducing the compound of formula DM using a reductant to produce a compound of formula Hb2:

Db2

(4) protecting the compound of formula Hb2 using a hydroxyl protecting group, in the presence of a solvent to produce a compound of formula IIb3:

Hb3 where R^p is a hydroxyl protecting group;

(5) alkylating the compound of formula IIb3 using a leaving group containing a C_MS saturate or unsaturated alkyl or alkyl ester group, to produce a compound of formula lie:

lie

lid (7) adding a compound of formula De:

He wherein R represents a phosphonate ester, enolate, SiR >X ₃, or h.y.djrogen . w..ιhere :i„n n R is a C_1-3 alkyl, in the presence of a metal halide at a temperature of about 25°C to about 60°C, to produce a compound of formula Df: and

Iff (8) reducing the compound of formula Df by adding to a solution of formula Iff a hydrogen source and a ruthenium, iridium, rhodium, or vanadium metal catalyst to produce the compound of formula lb.

4. The process of Claim 3, wherein the metal salt in step (1) is selected from the group consisting of ruthenium halide, iridium halide, rhodium halide, ruthenium oxide, iridium oxide, rhodium oxide, the oxidizing agent is selected from the group consisting of sodium periodate, bleach, peroxide, sodium bromate, and the solvent is selected from the group consisting acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, and water, said metal salt present in an amount relative to the amount of active ingredient, wherein a mole ratio of the metal salt source to the active ingredient is about 0.5 mol% to about 4 mol%.

5. The process according to claim 3, wherein the acid in step (2) is selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid and triflic acid, the reductant in step (3) is selected from the group consisting of sodium borohydride, lithium borohydride, and zinc borohydride, and the hydroxyl protecting group and solvent in step (4) is selected from the group consisting of triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl and dichloromethane, acetonitrile, tetrahydrofuran, DMF or a combination thereof, respectively.

6. The process according to claim 3 wherein the oxidizing agent in step (6) is selected from the group consisting of Sθ3- pyridine, rhuthenium chloride, TEMPO(2,2,6,6-tetramethyl-l- piperidinyloxy)-NMO(methylmorpholine N-oxide), oxylyl chloride-DMSO, TPAP(tetrapropylammonium perruthenate)-NMO, Dess-Martin periodinane, TEMPO- trichloroisocyanuric acid and the base is selected from the group consisting of Hunig base, methylamine, ethylamine, isopropylamine, triethylamine, trimethylamine, and sodium hydroxide.

7. The process according to claim 3 wherein the compound of formula Hb is reacted with adding a reagent belonging to the group consisting of KHMDS (potassium bis [trimethylsilyl] amide, LiHMDS (lithium bis[trimethylsilyl]amide), NaHMDS (sodium bis[trimethylsilyl]amide), nBuLi, and KotBu at a temperature of about 5° C to about 20° C and a leaving group selected from the group consisting of mesylate, tosylate, halide, triflate, phosphate, heating to a temperature of about 45° C to about 60° C.

8. The process according to claim 3 where in step (7) R^ε is a phosphonate ester, the metal halide is selected from the group consisting of ZnCl2, AICI3, AII3, TiC i, TiBr4, TiF4_; Zn(OTf)2, zirconium halides (e.g., ZrCLi), InCl3 and the temperature is about 25°C to about 60°C.

9. The process according to claim 7 where in Step (7) the metal halide is ZnCl2, which is reacted with a solution containing the compound of formula He at a temperature range of about - 3°C to about 5°C, the compound of formula Ild is added to said solution at a temperature of about 20°C to about 25°C and the resulting solution heated to a temperature of about 40°C to about 60°C.

10. The process according to claim 3 where in Step (8) the compound of formula Ilf is contacted with a hydrogen source and then treated with the metal catalyst at a temperature of about 20°C to about 25°C, said metal catalyst being ruthenium having the structural formula HI:

HI and present at a mole ratio of ruthenium catalyst to the compound of formula la of about 0.5% to about 5% and the hydrogen source selected from the group consisting of cyclohexane, isopropanol, NaHCθ2, HCθ2H, andH2-

11. A process for making a compound of formula Hb:

Hb wherein R^d is hydrogen or an amine protecting group; comprising the steps of contacting a solution of the compound of formula II:

II and a solvent with a metal salt in the presence of an oxidizing agent to produce a compound of formula Hb.

12. The process of Claim 11, wherein the metal salt is selected from the group consisting of ruthenium halide, iridium halide, rhodium halide, ruthenium oxide, iridium oxide, rhodium oxide, and the oxidate is selected from the group consisting of sodium periodate, bleach, peroxide, sodium bromate, said metal salt present in an amount relative to the amount of active ingredient, wherein a mole ratio of the metal salt source to the active ingredient is about 0.5 mol% to about 4 mol%.

13. The process according to claim 3, wherein alternatively, the compound of formula DM is alkylated as in step (5) prior to performing steps (3), and (4).