Process for the Manufacture of Organic Compounds

Field of the Invention

The present invention relates to a novel process for the preparation of (R)-3-Cycloalkyl-2-[4-(4- substitued amine-l-sulfonyl)-phenyl]-N-(5-substituent-yl-thiazolo[5,4-b ]pyridin-2-yl)-propionamide and a composition obtainable by said chiral process.

Summary of the Invention

(R)-3-Cycloalkyl-2-[4-(4-substitued amine-l-sulfonyl)-phenyl]-N-(5-substituent-yl-thiazolo[5,4- ό]pyridin-2-yl)-propionamide, represented by formula (I)

wherein X, Y and R are as defined below; in free form or in an appropriate acidic or basic salt form; are valuable glucokinase activators, which have been described in PCT Application No. PCT/US2006/038200, for example.

Detailed Description of the Invention

Therefore, an object of the instant invention is the process for the preparation of a (i?)-3-Cycloalkyl-2- [4-(4-substitued amine- 1 -sulfonyl)-phenyl]-N-(5-substituent-yl-thiazolo[5,4-Z)]pyrid in-2-yl)- propionamide, comprising:

(a) reacting an acid chloride of formula 1 with a chiral auxiliary of formula 2 to form a synthon of formula 3

Chiral Auxiliary

(b) reacting the synthon of formula 3 with a compound of formula 4 to form in situ a compound of formula 5, then with hydrolysis of the chiral auxiliary to form chiral compound 6

(c) taking a chiral compound of formula 6 and forming an acid chloride in situ

(d) reacting the acid chloride of step (c) with a compound of formula 6a in the presence of a base to form a compound of formula 7

(e) reacting the compound of formula 7 with chlorosulfonic acid in an aprotic solvent to form a compound of formula 8 in situ

(f) reacting the compound formed in step (e) with or without isolation with a secondary amine;

(g) recovering a compound of formula 10 in free form or in salt form,

wherein

R is a C _3-6 cycloalkyl;

Lg is a leaving group;

Chiral auxiliary is any suitable chiral molecule that induces chirality;

X is halogen, cyano, nitro, optionally substituted alkyl, alkoxy, alkylthio, alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino, aryl or heterocyclyl; and

R ₅ is hydrogen, (C ₃ _i ₂ )cycloalkyl, (C _6- io)aryl, (C _3- io)heterocyclyl or (d^alkyl optionally substituted by carboxy, (Ci _-6 )alkoxy, (C _]-2 )alkoxy, (C _]-4 )alkoxy, (Ci _-6 )alkylthio, (C _3-7 )cycloalkyl, (C _{3- 7} )cycloalkoxy, (C _3-7 )cycloalkylthio, (C ₆ -io)aryl, (C _6- io)aryloxy, (C _6- io)arylthio, (C _3- io)heterocyclyl or (C _{3- 1} o)heterocyclyloxy ;

R ₆ is either -(CR ₇ R ₈ ) _m -W-R ₉ in which

R ₇ and Rg are, independently from each other, hydrogen, optionally substituted alkyl or cycloalkyl; or

R ₇ and R ₈ combined are alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered ring; m is zero or an integer from 1 to 5; W is -NRio- in which

Rio is hydrogen, optionally substituted alkyl or heterocyclyl; or Rio is -C(O)Rn, -C(O)ORn, or -C(O)NRi ₂ Ri ₃ in which

Ri i and Rn are, independently from each other, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Ri ₃ is hydrogen or lower alkyl; or

Ri ₃ and R] ₂ combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; or W is absent;

R ₉ is hydrogen, optionally substituted Ci-C ₇ alkyl, cycloalkyl, aryl or heterocyclyl; or R ₉ and Ri ₀ combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; or

R ₆ and R ₅ combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring which may be optionally substituted, or may contain 1 to 3 other heteroatoms selected from oxygen, nitrogen and sulfur, or may be part of another ring, or

R ₆ is free or esterified carboxy, tetrazolyl, cyano or -C(O)NRnRi ₂ in which

Ri ₁ and R _i2 are, independently from each other, hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or

Ri ₁ and R ₁₂ combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring.

Specifically, an object of the instant invention is the synthetic scheme below Scheme 1

auxiliary

I) H ₂ SO ₄ / HOAc

2) (+)-α-Methylbenzylamine

3) HCI

Compound 1 may be reacted with (IR, 2R)-psuedoephedrine or any other suitable disposed chiral auxiliary (2) to form compound 3. Other suitable chiral auxiliaries are (4R,5S )-(+)-4-methyl-5- phenyl-2-oxazolidinone, R (+)-diphenyl methyl-2-oxazolidinone, R (+)-isopropyl-2-oxazolidinone, R (+)-tert butyl-2-oxazolidinone, R (+)-phenyl-2-oxazolidinone or R (+)-benzyl-2-oxazolidinone; however, this list is not exhaustive or limiting. This coupling to an amide bond may be performed as defined herein above, e.g., via conversion of the acid to the corresponding acid chloride or in the presence of a coupling agent such as EDCI, HOBt or PyBOP, or a mixture of coupling agent thereof.

A resulting compound of formula 3 may then be treated with a base, such as sodium hydride, lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl)amide (LHMDS), preferably LHMDS, followed by addition of an alkylating agent of the formula R-(CH ₂ )-Lg wherein R has a meaning as defined herein above, and Lg represents a leaving group, such as chloride, bromide, iodide, mesylate, tosylate or triflate, preferably iodide or triflate, to afford a compound of the formula 5 above. The alkylation step is preferably conducted in a polar organic solvent, such as THF, DMF, N-methylpyrrolidone (NMP), l,3-dimethyl-3,4,5,6-tetrahydro-2(7H)-pyridone (DMPU) or l,3-dimethyl-3,4,5,6-tetrahydro- 2(7H)-pyrimidinone (DMTP), or in a mixture of solvents thereof.

A resulting compound 5 may be readily hydro lyzed using a variety of aqueous acidic conditions such as glacial acetic acid, formic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof and preferably glacial acetic / 8 N sulfuric acid.

Alternatively, depending on the chiral auxiliary employed formula 5 may also be hydrolyzed, e.g., in the presence of an aqueous base such as sodium, lithium or potassium hydroxide and an organic solvent such as THF or lower alcohol, preferably, methanol or ethanol, to afford a carboxylic acid of formula 6 wherein R has meanings as defined herein above. Under certain circumstances the addition of a peroxide such as hydrogen peroxide may facilitate this hydrolysis.

In the coupling reaction cited herein above to form 7, an activated derivative of a carboxylic acid e.g., those corresponding to carboxylic acids of formula 6, include acid chlorides, bromides and fluorides, mixed anhydrides, lower alkyl esters and activated esters thereof, and adducts formed with coupling agents, such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1 -hydroxy benzotriazole (HOBt), O-(\ ,2-dihydro-2-oxo-l-pyridyl)-N ₎ N,N ',N '-tetramethyluronium tetrafluoroborate, benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) and the like. Mixed anhydrides are preferably such from pivalic acid, or lower alkyl hemiesters of carbonic acids, such as ethyl or isobutyl analogs. Activated esters include, for example, succinimido, phthalimido or 4-nitrophenyl esters.

The reaction of an activated derivative of a carboxylic acid, e.g., those corresponding to carboxylic acids of formula (6), with an amine, e.g., those of formula (6a) where X is defined herein, may be carried out in the presence of a base, such as pyridine, triethylamine (TEA), diisopropylethylamine (DIEA) or N-methylmorpholine (NMM) in an inert organic solvent, such as dichloromethane (DCM), N,N-dimethylformamide (DMF) or tetrahydrofuran (THF), or a mixture of solvents thereof. Carboxylic acids of formula 6 may be converted to their activated derivatives using methods described herein or according to methods generally known in the art, e.g., a carboxylic acid of formula 6 may be treated with a chlorinating agent, such as thionyl chloride or oxalyl chloride, to afford a corresponding acid chloride thereof, or by the treatment of a coupling agent such as EDCI or HOBt, or a mixture of coupling agents thereof.

Compound 7 containing R and X groups as defined herein may be treated with chlorosulfonic acid to afford the desired para substituted sulfonyl chloride along with minor amounts of regioisomers which

are carried through to the next step. A compound of formula 8 may be isolated as a stable compound or carried on without isolation.

A compound of formula 8 may then be treated with an amine of the formula , R ₆ -NH-R ₅ , or an acid addition salt thereof, wherein R ₅ and R ₆ have meanings as defined herein above, in the presence of a base, such as pyridine, TEA, DIEA or NMM, in an inert organic solvent, such as DCM, DMF or THF, or a mixture of solvents thereof, to afford a compound of the formula 10 wherein R, R ₅ , Re and X have meanings as defined herein above. Preferably, the reaction is conducted at a temperature ranging from about -4 ⁰ C to room temperature (RT), more preferably, the reaction temperature is about 0 ⁰ C. Amines of formula R ₆ -NH-R ₅ are known, or if they are novel they may be prepared using methods well known in the art or as described herein in the illustrative Examples. Regioisomers formed from the chlorosulfonylation reaction then lead to regioisomeric analogs of 10 are then readily separated at this stage by chromatography or recrystallization. Chromatography may be performed under normal or reverse phase conditions or in some instances by the use of chiral columns and conditions using solvents appropriate to the conditions and well known in the art. Recrystallization may be effected in any number of solvents including alcohol solvents e.g., methanol, ethanol, isopropanol and the like as well as aprotic solvents e.g., ethyl acetate, acetone, methylene chloride, toluene and the like depending on the respective polarity of the compound.

Compound 6a is synthesized by the following scheme.

Scheme 2

6a

The primary amino functionality of 6e may be protected as shown herein employing BOC anhydride or the like in the presence of a base, typically an amine base, e.g. DMAP, triethylamine or the like and in an aprotic organic solvent, e.g. tetrahydrofuran, dioxane or the like. Under these reaction conditions there is the possibility of forming a di-BOC material. Should this material be present the di-BOC compound may be converted to the desired mono BOC material using e.g. potassium carbonate in a suitable solvent. In addition to the BOC protecting group referred to herein, other amide, urethane and urea protecting agents as well as benzyl, imine acetal and others knowledgeable to those trained in the art would be acceptable.

Compound 6d may then be used in a coupling procedure using a substituted boronic acid or equivalent where X is defined herein, e.g. aryl, heteroaryl, optionally substituted alkyl and the like in addition to a palladium reagent affords 6b. In a similar manner using the appropriate catalyst, substitution of X with amino groups is possible using Buchwald conditions, carbonylation affords esters and amides; nucleophilic displacement with thiols affords alkylthiol derivatives, which can be further oxidized to alkyl sulfoxides and sulfones.

The protecting group can be readily removed using acidic conditions, e.g. TFA or HCl in a suitable solvent followed by neutralization using ammonium hydroxide to afford 6a.

The compounds of formula I can exist in free form or in acid addition salt form. Salt forms may be recovered from the free form in a known manner and vice-versa. Acid addition salts may e.g. be those of pharmaceutically acceptable organic or inorganic acids. The preferred acid addition salts are the hydrochlorides, salts of methanesulfonic, sulfuric, phosphoric, citric, lactic and acetic acid.

Listed below are definitions of various terms used to describe the compounds of the present invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group, , e.g., wherein an attachment point of a certain group is limited to a specific atom within that group, the point of attachment is defined by an arrow at the specific atom.

The term "optionally substituted alkyl" refers to unsubstituted or substituted alkyl groups, i.e., straight- or branched-chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-10 carbon

atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, «-butyl, t- butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halogen, hydroxy, alkanoyl, alkoxy, alkanoyloxy, thiol, alkylthio, alkylthiono, sulfonyl, sulfamoyl, carbamoyl, cyano, carboxy, acyl, aryl, alkenyl, alkynyl, aralkoxy, guanidino, optionally substituted amino, heterocyclyl including imidazolyl, fiiryl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

The term "lower alkyl' ¹ refers to those alkyl groups as described above having 1-7, preferably 2-4 carbon atoms.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

The term "alkenyl" refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon double bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.

The term "alkynyl" refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon triple bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.

The term "alkylene" refers to a straight-chain bridge of 2-6 carbon atoms connected by single bonds, e.g., -(CH ₂ )χ-, wherein x is 2-6, which may be interrupted with one or more heteroatoms selected from O, OC(O)-, S, S(O), S(O) ₂ or NR, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl, acyl, carbamoyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl and the like. The alkylene may further be substituted with one or more substituents selected from optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, oxo, halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the like; and it may be part of another ring.

The term "cycloalkyl" refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may contain one or more carbon to carbon double bonds, or the cycloalkyl may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like.

Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.

Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6- dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

The term "alkoxy" refers to alkyl-O-.

The term "alkanoyl" refers to alkyl-C(O)-.

The term "alkanoyloxy" refers to alkyl-C(O)-O-.

The terms "alkylamino" and "dialkylamino" refer to alkyl-NH- and (alkyl) ₂ N-, respectively.

The term "alkanoylamino" refers to alkyl-C(O)-NH-.

The term "alkylthio" refers to alkyl-S-.

The term "trialkylsilyl" refers to (alkyl) ₃ Si-.

The term "trialkylsilyloxy" refers to (alkyl) ₃ Si0-.

The term "alkylthiono" refers to alkyl-S(O)-.

The term "alkylsulfonyl" refers to alkyl-S(O) ₂ -.

The term " alkoxy carbonyl" refers to alkyl-O-C(O)-.

The term "alkoxycarbonyloxy" refers to alkyl-O-C(O)O-.

The term "carbamoyl" refers to H ₂ NC(O)-, alkyl-NHC(O)-, (alkyl) ₂ NC(O)-, aryl-NHC(O)-, alkyl(aryl)-NC(O)-, heteroaryl-NHC(O)-, alkyl(heteroaryl)-NC(O)-, aralkyl-NHC(O)-, alkyl(aralkyl)- NC(O)- and the like.

The term "sulfamoyl" refers to H ₂ NS(O) ₂ -, alkyl-NHS(O) ₂ -, (alkyl) ₂ NS(O) ₂ -, aryl-NHS(O) ₂ -, alkyl(aryl)-NS(O) ₂ -, ^yI) ₂ NS(O) ₂ -, heteroaryl-NHS(O) ₂ -, aralkyl-NHS(O) ₂ -, heteroaralkyl-NHS(O) ₂ - and the like.

The term "sulfonamido" refers to alkyl-S(O) ₂ -NH-, aryl- S (O) ₂ -NH-, aralkyl-S(O) ₂ -NH-, heteroaryl- S(O) ₂ -NH-, heteroaralkyl-S(O) ₂ -NH-, alkyl-S(O) ₂ -N(alkyl)-, aryl-S(O) ₂ -N(alkyl)-, aralkyl-S(O) ₂ - N(alkyl)-, heteroaryl-S(O) ₂ -N(alkyl)-, heteroaralkyl-S(O) ₂ -N(alkyl)- and the like.

The term "sulfonyl" refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

The term "optionally substituted amino" refers to an amino group which may optionally be substituted by substituents such as optionally substituted alkyl, acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the like.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-12 carbon atoms in the ring portion, such as phenyl, biphenyl, naphthyl and tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as optionally substituted alkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio, arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamido, heterocyclyl and the like.

The term "monocyclic aryl" refers to optionally substituted phenyl as described under aryl.

The term "aralkyl" refers to an aryl group bonded directly through an alkyl group, such as benzyl.

The term "aralkanoyl" refers to aralkyl-C(O)-.

The term "aralkylthio" refers to aralkyl-S-.

The term "aralkoxy" refers to an aryl group bonded directly through an alkoxy group.

The term "arylsulfonyl" refers to aryl-S(O) ₂ -.

The term "arylthio" refers to aryl-S-.

The term "aroyl" refers to aryl-C(O)-.

The term "aroyloxy" refers to aryl-C(O)-O-.

The term "aroylamino" refers to aryl-C(O)-NH-.

The term "aryloxycarbonyl" refers to aryl-O-C(O)-.

The term "heterocyclyl" or "heterocyclo" refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or a carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, moφholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-l,l-dioxothienyl, l,l,4-trioxo-l,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl, benzothiazolyl, 4,5,6,7- tetrahydro-benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, thiazolo[5,4- b]pyridinyl, thiazolo[5,4-d]pyrimidinyl, oxazolo[5,4-b]pyridinyl, 6,7-dihydro-4H-thiopyrano[4,3- djthiazolyl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl, 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-pyrazolo[l,5-a]pyridinyl, 5,6,7,8-tetrahydro-triazolo[l,5-a]pyridinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo [3 ,2-b] -pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, l,3-dioxo-l,3- dihydroisoindol-2-yl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like.

The term "heterocyclyl" includes substituted heterocyclic groups. Substituted heterocyclic groups refer to heterocyclic groups substituted with 1, 2 or 3 substituents selected from the group consisting of the following:

(a) optionally substituted alkyl;

(b) hydroxyt (or protected hydroxyl);

(c) halo;

(d) oxo, i.e., =0;

(e) optionally substituted amino;

(f) alkoxy;

(g) cycloalkyl;

(h) free or esterified carboxy;

(i) heterocyclyl;

Q) alkylthio;

(k) alkylthiono;

(1) nitro;

(m) cyano;

(n) sulfamoyl;

(o) alkanoyloxy;

(p) aroyloxy;

(q) arylthio;

(r) aryloxy;

(s) sulfamoyl;

(t) sulfonyl;

(u) carbamoyl;

(v) aralkyl; and

(w) aryl optionally substituted with alkyl, cycloalkyl, alkoxy, hydroxyl, amino, acylamino, alkylamino, dialkylamino or halo.

The term "heterocyclooxy" denotes a heterocyclic group bonded through an oxygen bridge.

The term "heteroaryl" refers to an aromatic heterocycle, e.g., monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benziniidazolyl, benzofuryl and the like, optionally substituted by, e.g., lower alkyl, lower alkoxy or halo.

The term "heteroarylsulfonyl" refers to heteroaryl-S(O) ₂ -.

The term "heteroaroyl" refers to heteroaryl-C(O)-.

The term "heteroaryloxycarbonyl" refers to heteroaryl-O-C(O)-.

The term "heteroaroylamino" refers to heteroaryl-C(O)NH-.

The term "heteroaralkyl" refers to a heteroaryl group bonded through an alkyl group.

The term "heteroaralkanoyl" refers to heteroaralkyl-C(O)-.

The term "heteroaralkanoylamino" refers to heteroaralkyl-C(O)NH-.

The term "acyl" refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl and the like.

The term "acylamino" refers to alkanoylamino, aroylamino, heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.

The term "esterified carboxy" refers to optionally substituted alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclooxycarbonyl and the like.

Preferred is process that manufactures compounds of formula (I)

wherein

X is halogen, cyano, nitro, optionally substituted alkyl, alkoxy, alkylthio, alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino, aryl or heterocyclyl; and

Y is NR ₅ R ₆

R ₅ is hydrogen, (C ₃ .i ₂ )cycloalkyl, (C ₆ -io)aryl, (C _3- io)heterocyclyl or (Ci _-6 )alkyl optionally substituted by carboxy, (Ci _-6 )alkoxy, (Ci _-2 )alkoxy-(Ci _-4 )alkoxy, (Ci ^alkylthio, (C _3-7 )cycloalkyl, (C _{3- 7} )cycloalkoxy, (C _3-7 )cycloalkylthio, (C ₆ -io)aryl, (C _6- io)aryloxy, (C _6- io)arylthio, (C ₃ _io)heterocyclyl or (C ₃ . ₁ o)heterocyclyloxy;

R ₆ is either -(CR ₇ Rg) _1n -W-R ₉ in which

R ₇ and R ₈ are, independently from each other, hydrogen, optionally substituted alkyl or cycloalkyl; or R ₇ and R ₈ combined are alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered ring; m is zero or an integer from 1 to 5; W is -NRio- in which

Rio is hydrogen, optionally substituted alkyl or heterocyclyl; or Rio is -C(O)Rn, -C(O)OR _n , or -C(O)NR ₁₂ Ri ₃ in which

Rn and Ri ₂ are, independently from each other, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Rn is hydrogen or lower alkyl; or

Rn and Ri ₂ combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; or W is absent;

R ₉ is hydrogen, optionally substituted Ci-C ₇ alkyl, cycloalkyl, aryl or heterocyclyl; or R ₉ and Rio combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; or

R ₆ and R ₅ combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring which may be optionally substituted, or may contain 1 to 3 other hetero atoms selected from oxygen, nitrogen and sulfur, or may be part of another ring, or

R ₆ is free or esterified carboxy, tetrazolyl, cyano or -C(O)NRnRi ₂ in which

Ri 1 and Ri ₂ are, independently from each other, hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or

Rn and Ri ₂ combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; in free form or in acid addition salt form.

Another group is one of above compounds of formula (I) wherein the substituent on the adamantyl is bonded on a bridgehead.

The compounds of formula (I) exist in the form of optically active R isomer and the process of the present invention is capable of yielding compounds of formula (I) with a high (at least 95%) enantiomeric purity of the (R)-3-Cycloalkyl-2-[4-(4-substitued amine- l-sulfonyl)-phenyl]-N-(5- substituent-yl-thiazolo[5,4-έ]pyridin-2-yl)-propionamide.

Therefore, a further object of the instant invention is a composition of (R)-3-Cycloalkyl-2-[4-(4- substitued amine- l-sulfonyl)-phenyl]-N-(5-substituent-yl-thiazolo[5,4-ό]pyri din-2-yl)-propionamide of formula (I), obtainable according to the process of claim 1, whereby 95% to 99,9% is (R)-3- Cycloalkyl-2- [4-(4-substitued amine- 1 -sulfonyl)-phenyl] -N-(5-substituent-yl-thiazolo [5,4-&]pyridin- 2-yl)-propionamide.

Preferred (R)-3-Cycloalkyl-2-[4-(4-substitued amine- 1 -sulfonyl)-phenyl]-N-(5-substituent-yl- thiazolo[5,4-&]pyridin-2-yl)-propionamides are those described as preferred compounds in the above process.

Examples

Representative Example 1

iV-[(/l?,2R)-2-hydroxy-l -methyl-l-phenylethylJ-N-methyl benzeneacetamide (A2)

Reaction Scheme:

A1 A2

Procedure

250 g (1.513 mol, 1.0 equiv) of (IR, 2R)-psuedoephedrine, 4 L of tetrahydrofuran and 241 mL (1.73 mol, 1.14 equiv) of triethyl amine were charged to a nitrogen-flushed 12-L round bottom flask and the mixture stirred at ambient temperature until a clear solution is obtained. The solution was cooled to 0-5 ⁰ C and 258.0 g, (1.675 mol, 1.1 equiv) of phenylacetyl chloride was added over 2 h maintaining the internal temperature < 5 °C (exothermic reaction). Stirring was continued at 0-5 ⁰ C for 30 min. HPLC showed completion of the reaction. To this mixture, 1 L of 10% potassium bicarbonate solution, 500 mL of de-ionized water and 1 L of ethyl acetate were added and the mixture was stirred for 5 min. The organic phase was separated and an additional 500 mL of ethyl acetate was added to the aqueous phase, stirred for 5 min and separated from the aqueous phase. The combined organic phase was washed successively with 2000 mL of brine solution, 1600 mL of 2 N HCl solution and 1600 mL of 10% solution of NaCl in water. The organic phase was evaporated on the rotary evaporator and 1500 mL of ethyl acetate was added to the resulting solid residue. The mixture was heated to reflux to give a clear light solution which was filtered through a glass fiber filter. The filtrate was heated to reflux using a Dean-Stark apparatus to distill off 300 mL of solvent (70 mL of water + 230 mL of ethyl acetate). Heating was stopped and the solution was allowed to cool to ambient temperature. The product started crystallizing out at 67-70 ⁰ C. The batch was cooled to 0-5 ⁰ C and held at 0-5 ⁰ C for 30 min. The white solids were filtered through a filter paper and the cake was washed with 2x250 mL of cold (0-5 ⁰ C) ethyl acetate. The product was dried at 45 ⁰ CM.5 mbar forl8 h to afford 338.5 g ofN-[(lR,2R)-2-hydroxy-l-methyl-2-phenylethyl]-N-methyl benzeneacetamide A2 as a white crystalline solid in 79% yield.

^(IR-hydroxy-liϊ-methyl^-phenylethy^-TV-methyl S-cyclopentyl-lR-phenyl-propionamide

(A4)

Procedure:

176.9 g (0.629 mol, 1.0 equiv) ofN-[(lR,2R)-2-hydroxy-l-methyl-2-phenylethyl]-N-methyl benzeneacetamide A2 was charged to a dry 5 -L reactor under a nitrogen blanket with 1 L of anhydrous peroxide-free THF. The suspension was cooled to -10 ± 3 °C and 1500 mL (1.5 mol, 2.4 equiv) of lithium bis(trimethylsilyl)amide (1 M in THF) was added slowly maintaining the batch temperature at -10 ± 3 ⁰ C . To this was added 140 mL of DMPU (l,3-dimethyl-3,4,5,6-tetrahydro- 2(lH)-pyrimidinone) followed by 157.36 g (0.75 mol, 1.2 equiv) of iodomethylcyclopentane A3 followed 2 h later by an additional 65.32 g (0.31 mol, 0.5 equiv) of iodomethylcyclopentane A3. The batch was slowly warmed to 0 °C and maintained at 0 °C for 18 h. Workup entailed addition of 500 mL of tert-butyl methyl ether followed by 1100 mL of 2.4N HCl slowly while maintaining the batch temperature < 15 ⁰ C. The pH of the resulting reaction mixture was 2-3. The organic layer was separated and washed with 500 mL of saturated solution OfNaHCO ₃ in water, and then with 2x500 mL of water. The organic phase was dried over anhydrous MgSO ₄ , filtered and concentrated under vacuum to a minimum volume. 250 mL of ethyl acetate was added twice and removed by distilling the solvent under low vacuum at 60 ⁰ C. 245g of N-(2R-hydroxy-lR-methyl-2-phenylethyl)-N-methyl 3-cyclopentyl-2R-phenyl-propionamide A4 was obtained as an amber colored oil in 93% yield, (chemical purity: 96.4% / chiral purity: R:S 99.4:0.6

2-(lξ)-pheiiyl-3-cyclopentyl propionic acid (A5)

Procedure:

A nitrogen-flushed 3-L round bottomed flask was charged with 228 g (625.4 mmol, 1.0 equiv) of A4, 610 mL of glacial acetic acid and 610 niL of 8 N sulfuric acid and stirred. The mixture was heated to reflux (105 ⁰ C). The batch was maintained at 105 ⁰ C until completion of reaction (7.5 h). The reaction mixture was cooled to 15 ⁰ C over a period of 1 h. The resulting black solid was filtered through a polypropylene filter paper and the cake washed with 2x500 mL of deionized water. The cake was pulled dry under house-vacuum for 30 min. The black solid was transferred to a 2-L, 4-necked round bottomed flask and 8 g of charcoal and 750 mL of tert-butyl methyl ether was added. The mixture was stirred and heated to reflux (-65 ⁰ C) for 20 min. The batch was cooled to 30-35 ⁰ C and filtered through a pad of Celite ^® over a filter paper. The cake was washed with 2x100 mL of tert-butyl methyl ether. The solvent was removed on a rotary evaporator under vacuum to afford 109 g of 2-(i?)- phenyl-3-cyclopentyl propionic acid A5 as an off-white solid in 80% yield (>99% chemical purity / 96.0:4.0 R:S). The optical purity of the product was further improved by resolution (described in the next step).

2-(J?J-PhenyI-3-cycIopentyl propionic acid (AT)

Procedure:

A nitrogen-flushed 5-L Round bottomed flask was charged with 109 g (0.50 mol, 1.0 equiv) of A5 and 1000 mL of absolute ethanol and 1300 niL of deionized water was added. The mixture was stirred at ambient temperature and a solution of 60.6 g (0.50 mol) of (R)-α-methylbenzylamine dissolved in 300 mL of absolute ethanol was added over a period of 30 min. The mixture was heated to reflux (84 ⁰ C) and then the clear colorless solution was allowed to cool to 20-23 °C over 4-6 h. The white solid was filtered using house-vacuum and the cake washed with 2x150 mL of ethanol-water (1 :1). The cake was dried under vacuum until no more solvent came off the cake. The solids were then transferred to a 1-L round bottom flask and 500 mL of 2 N HCl solution was added. The mixture was stirred for 5 min and transferred to a 2-L separating funnel. The mixture was extracted with 500 mL of tert-butyl methyl ether. The aqueous phase was reextracted with 250 mL of tert-butyl methyl ether. The combined organic phase was washed with 250 mL of deionized water and dried over anhydrous MgSO ₄ . The solution was filtered and the solvent removed on a rotary evaporator under vacuum, to afford 95.8 g 2-(i?)-Phenyl-3-cyclopentyl propionic acid A7 as a white solid in 87.5% yield (chemical purity >99.5%; chiral purity 99.4:0.6 R:S).

(R)-N-(5-ChIoro-thiazolo[5,4-A]pyridin-2-yl)-3-cyclopenty I-2-phenyI-propionamide (A9)

Procedure:

A 2-L, 4-necked flask was charged with 95 g (0.436 mol, 1 equiv) of (R)-3-cyclopentyl-2- phenylpropionic acid A7, 0.15 g of N,N-dimethylformamide, 1.254 kg of methylene chloride, and 151 g of thionyl chloride. The reaction mixture was stirred at 17 ± 5 ⁰ C for 15 min to give a homogenous mixture, and then heated slowly to 33 ⁰ C over 1 h and subsequently refluxed gently at 33-37 ⁰ C for 1 h. The reaction mixture was concentrated at 35 ± 5 ⁰ C (20 mbar.) to afford a yellow oil which was diluted with 269 g of hexane and flushed twice at 35 ± 5 ⁰ C (20 mbar) to give a straw- yellow oil (-104.5 g).

A 5-L 4-necked flask was charged with 81.6 g (0.44 mol, 1.01 equiv) of 5-chloro-thiazolo[5,4- &]pyridin-2yl-amine (A8), 0.8 g of N,N-dimethylaminopyridine, and 582 g of pyridine. The mixture was stirred at 22 ± 5 ⁰ C for 15 min to give a homogenous mixture, and then the solution was cooled to 15 ± 5 ⁰ C. To this was added a solution of 104.5 g of the crude acid chloride acid in 533 g of tetrahydrofuran at 18 ± 5 ⁰ C over 30 min and the suspension was stirred at 22 ± 5 ⁰ C overnight. The straw-yellow hazy contents were cooled to 10 ± 5 ⁰ C and 2.0 kg of 4 N hydrochloric acid solution were added slowly at 15 ± 5 ⁰ C over 30 min (pH >1) to give a straw- yellow suspension. 1.628 kg of t- butyl methyl ether was then added and the mixture stirred at 20 ± 5 ⁰ C for 10 min. The top organic layer was washed with 500 g of 2 N hydrochloric acid solution, 500 g of saturated sodium chloride solution, 500 g of saturated sodium bicarbonate solution followed by 500 g of saturated sodium

chloride solution. The organic phase was dried over 200 g of magnesium sulfate (anhydrous), filtered and the filter cake washed once with 148 g of methyl t-butyl ether.

The filtrate was concentrated at 35 ± 5 ⁰ C (20 mbar) to a gummy solid, then dried overnight at 35 ± 5 ⁰ C (10 mbar) to give 156 g (91% yield) of (R)-N-(5-chloro-thiazolo[5,4-b]pyridin-2-yl)-3- cyclopentyl-2-phenyl-propionamide A9 as a yellow solid. (Chemical Purity (by HPLC): 97.5% )

4-[(R)-l-(5-Chloro-thiazolo[5,4-A]pyridin-2-ylcarbamoyl)- 2-cyclopentyl-ethyl]-benzenesulfonyI chloride (AlO):

AlO

Procedure:

A 5-L 4-necked flask was charged with 1.98 kg of methylene chloride, and

156 g (0.405 mol, 1 equiv) of (R)-N-(5-chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2 -phenyl- propionamide A9. The contents were stirred at 22 ± 5 ⁰ C for 15 min, and the homogenous solution was cooled to -15 ⁰ C . To this was added a solution of 2.188 kg of chlorosulfonic acid in 2.37 kg of methylene chloride at -5 ± 5 ⁰ C over 30 min to give a homogenous mixture. The contents were warmed slowly to 22 ± 5 ⁰ C over 2 h and stirred at room temperature overnight. The homogenous mixture was cooled to 5 ± 5 ⁰ C and added dropwise via a 1 -L addition funnel to a stirring mixture of

1.32 kg of methylene chloride, 3.0 kg of crushed ice, and 2.0 kg of water in a 12-L 4-necked flask Cool to 5 ± 5 ⁰ C over 1 h. The 5-L flask and addition funnel were rinsed once with 396 g of methylene chloride.

The hazy mixture was warmed to 22 ± 5 ⁰ C to obtain two clear separated layers. The organic layer was washed once with 1.5 kg of saturated sodium chloride solution and then dried with 200 g of sodium sulfate (anhydrous), the solids were filtered and washed Ix with 264 g of methylene chloride. The filtrate was concentrated at 35 ± 5 ⁰ C (20 mbar) to a gummy solid, diluted at 30 ± 5 ⁰ C with 300 niL of t-butyl methyl ether and re-evaporated. The yellow solid was dried at 35 ± 5 ⁰ C (20 mbar) overnight to give 216 g of crude AlO (para / meta = 85 /15). ⁴ A 3-L 4-necked flask with the above solid was charged with 1.567 kg of acetonitrile, and 216 g of water. The contents were heated to 40 ± 5 ⁰ C over 30 min, and then the suspension cooled to 22 ± 5 ⁰ C over 15 min. The solids were filtered and the filter cake washed twice with a total amount of 142 g of acetonitrile and 20 g of water. The wet cake was dried at 40 ± 5 ⁰ C (20 mbar) for 16 h to give 156 g (97% yield) of 4-[(R)-l-(5-Chloro- thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-2-cyclopentyl-ethyl]- benzenesulfonyl chloride AlO, para/meta = 88 / 12) as an off-white solid. (Chemical purity 98.0%, chiral purity 99.0% R isomer).

3-[{4-[l-(5-Chloro-thiazolo[5,4-6]pyridin-2-yIcarbamoyl)- 2-cyclopentyI-ethyI]-benzenesulfonyl}- (2-methoxy-ethyl)-amino]-propionic acid tert-butyl ester (All)

Procedure:

In a N ₂ purged, 3 neck, 1 L flask 52.3 g (0.108 mol, 1 equiv) of 4-[(R)-l-(5-Chloro-thiazolo[5,4- b]pyridin-2-ylcarbamoyl)-2-cyclopentyl-ethyl]-benzenesulfony l chloride AlO and 230.0 g of acetonitrile were added to give a slurry. The mixture was cooled to -10 °C ± 3 ⁰ C and 22.9 g (0.1 13 mol, 1.05 equiv) of 3-(2-Methoxy-ethylamino)-propionic acid tert-butyl ester ZlOa was added such that the temperature did not exceed 0 ⁰ C. Subsequently, 17.05 g of triethylamine was added maintaining the temperature < 0 °C. The resulting solution was warmed to 18 ⁰ C over a period of 0.5 h and then stirred at 18 ⁰ C ± 3 °C forl h. Upon completion, the mixture was concentrated to remove acetonitrile to afford an oil. To this was added 450 g of ethyl acetate to give a solution. The solution was washed with 2 x 175 mL of water and then 175 mL of 10% citric acid solution and finally with 2 X 175 mL of water. The combined organic layer was concentrated to an oil. The oil was treated with MTBE to chase residual ethyl acetate to obtain 69.0 g of crude product as a white solid foam. This material was chromatographed over silicagel. Elution with 25-50% ethyl acetate/heptane to afford 2.6 g of the meta isomer, 14 g of mixed fractions and 29 g of 3-[{4-[l-(5-Chloro-thiazolo[5,4-b]pyridin-2- ylcarbamoyl)-2-cyclopentyl-ethyl]-benzenesulfonyl}-(2-methox y-ethyl)-amino]-propionic acid tert- butyl ester

3-[{4-[l-(5-Chloro-thiazolo[5,4-A]pyridin-2-ylcarbamoyl)- 2-cyclopentyl-ethyl]-benzenesulfonyl}- (2-methoxy-ethyl)-amino]-propionic acid (A12)

Procedure: To a N ₂ purged, 3-neck, 1 L flask was added 181 g (0.278 mol, 1 equiv) of 3-[{4-[l-(5- Chloro-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-2-cyclopentyl-e thyl]-benzenesulfonyl}-(2-methoxy- ethyl)-amino] -propionic acid tert-butyl ester and 254.0 g of trifluoroacetic acid to gradually form a solution. The solution was stirred for 3.5 h and then 1.5 L of methylene chloride was added, the layers were separated. The organic layer was washed two times with 1.0 L of water, dried with

magnesium sulfate and concentrated to a foam. The product was placed under high vacuum for 12 h to give 155 g of product in 92% yield (chem. Chemical purity 98% /chiral purity >99%).

S-CZ-Methoxy-ethylaminoVpropionie acid tert-butyl ester

Z10c Z10b Z10a

Procedure:

To a N ₂ purged 1-L 3-necked flask with an overhead stirrer was added 37.6 g (0.50 mol, 1 equiv) of 2-methoxyethyl amine, 632 g of ethanol and 67.0 g (0.522 mol, 1.04 equiv) of tert-butyl acrylate. The solution was stirred at 20 ± 3 ⁰ C for 18 h and then concentrated under reduced pressure to afford 94 g of an oil which was used without further purification (yield 92.5%).

Representative Example 2

(5-Bromo-thiazoIo[5,4-b]-2-carbamic tert-butyl ester (A2c)

50 ⁰ C Acetone DMAP

A2c

Procedure:

A flask was charged with 80.0 g (0.348 mol) of 5-Bromo-thiazolo[5,4-b]pyridin-2-ylAmine A2d, 1027 g of acetone, 50.8 g of triethylamine, 2.0 g of DMAP, and 100.4 g (0.46mol, 1.3 equiv) of di- tert-bxxty\ di carbonate. The mixture was stirred and heated to 50 ⁰ C for 3 h. The reaction mixture was cooled to 10 ⁰ C, and 2000 g of water was added slowly while maintaining the reaction temperature at 10 ± 5 ⁰ C. The reaction mixture was stirred for 1 h and subsequently the solids were filtered off and the filter cake washed with 200 g of water. The solids were dried at 45 ⁰ C for 16 h to give 90.4 g of (5-Bromo-thiazolo[5,4-έ]-2-carbamic tert-butyl ester A2c in 80% yield.

([5-Pyridin-4-yl]-thiazolo[5,4-Z>]pyridine-2-yl)-Carba mic acid tert-buty\ ester (A2a):

116 ⁰ C DMF H ₂ O

Procedure: A flask was charged with 20 g of (5-Bromo-thiazolo[5,4-b]-2-carbarnic tør/-butyl ester A2c, 9.7 g of 4-pyridine boronic acid A2b, 171.8 g of DMF, 61 g of water, 60 g of cesium carbonate, and 2.14 g of PdCl ₂ (dbpf). The stirred suspension was heated to 116 ⁰ C and maintained at this temperature for 1 h. When A2c was consumed, the reaction mixture was cooled to room temperature and passed through a short column packed with Celite and activated carbon. 360 g of water was added to the filtrate and the solids were filtered and washed with 50 g of water. The solids were dried under vacuum at 45 ⁰ C for 24 h to give 16 g (80% yield) of A2a.

([5-Pyridin-4-yl]-thiazoIo[5,4-A]pyridine-2-ylamine (A2)

Procedure:

To a N ₂ purged 1-L, 3-necked flask, 35 g (0.107mol) of crude A2a, 150 niL of isopropyl acetate, and 230 mL of 5-6 N HCl in isopropanol were heated at 45 ⁰ C for 4 h and then at 60 °C for 2 h. Upon completion, the solution was concentrated under vacuum to dryness and 200 mL of isopropyl acetate were added. The resulting slurry is filtered and the cake washed with 50 mL of isopropyl acetate. The solid HCl salt was dissolved in 400 g of water and the insoluble residue filtered to give a clear solution. The aqueous solution was placed in a N ₂ purged 1 L, 3-necked flask fitted with overhead stirring and the pH adjusted to 9.0 by adding 5.O g of ammonium hydroxide. The addition of base coincides with precipitation of solids. The resulting mixture was stirred for 15 min and the solids filtered and washed with two portions of 50 g of water. Air was pulled through the cake for 0.5 h and then the solids were placed in a vacuum oven with N ₂ purge for 12 h at 50 ⁰ C ±3 ⁰ C to give 23.6 g (93.2%) of 5-[pridin-4-yl]-thazolo[5,4-ό] pyridine-2-ylamine A2.

(R)-3-CyclopentyI-2-phenyl-N-(5-pyridin-4-yl-thiazolo[5,4 -b]pyridin-2-yl)- propionamide (A3).

Al

i SOCI ₂₁ CH ₂ CIJ ₁ D MF

Procedure:

A 250-mL 4-necked flask was charged with 11.8 g (0.054 mol.) of (R)-3-cyclopenty-2- phenylpropionic acid Al, 0.05 g of N,N-dimethylformamide, 152 g of methylene chloride, and 18.6 g of thionyl chloride. The reaction mixture was stirred at 17 ± 5 ⁰ C for 15 min to give a homogenous mixture and the solution was warmed slowly to 33 ⁰ C over 1 h and refluxed gently at 33-37 ⁰ C for 1 h. The reaction mixture was concentrated at 30 ± 5 ⁰ C (20 mbar.) to a yellow oil and the residue flushed twice at 30 ± 5 ⁰ C (20 mbar) with a total amount of 34 g of hexane and reconcentrated to a straw- yellow oil (-13.1 g weight) of acid chloride.

A 1-L 4-necked flask was charged with 11.7 g (0.054 mol) of 5-pyridin-4-yl-thiazolo[5,4-b]pyridin- 2yl-amine A2, 0.2 g of N,N-dimeyhylaminopyridine, 8.2 g of triethylamine, and 168 g of N ₅ N- dimethylformamide. The mixture was heated at 45 ± 5 ⁰ C for 15 min to give a homogenous mixture and then cooled to 7 ± 5 ⁰ C. A solution of 13.1 g of crude acid chloride in 33 g OfN ₅ N- dimethylformamide (anh.) was stirred at 7 ± 5 ⁰ C over 30 min and the suspension warmed to 22 ± 5 ⁰ C

over 1 h and then stirred at 22 ± 5 ⁰ C overnight. The straw-yellow hazy contents were cooled to 10 ± 5 ⁰ C and 624 g of water were added. The suspension was stirred at 22 ± 5 ⁰ C for 30 min and the solid was filtered off and the filter cake washed once with 400 g of water. The filter cake was air-dried at 22 ± 5 ⁰ C (house vaccum) for 2 h, then dried at 40 ± 5 ⁰ C(IO mbar) overnight to give 21.O g of (R)-3- Cyclopentyl-2-phenyl-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridi n-2-yl)- propionamide (A3) as a light tan solid (yield 92%).

[(λ)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-l-sulfonyl) -phenyl]-N-(5-pyridin-4-yl-thiazoIo[5,4- b]pyridin-2-yl)-propionamide (A6)

Reaction Scheme:

isomer

Procedure:

A 5-L 4-necked flask was charged with 130 g (0.30 mol, 1 equiv.)of (R)-3-Cyclopentyl-2-phenyl- N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)- propionamide (A3) and 2.15 kg of methylene chloride. The contents were stirred at 22 ± 5 ⁰ C for 15 min and then the suspension was cooled to -10 ⁰ C . A solution of 853 g of chlorosulfonic acid in 645 g of methylene chloride was added at -5 ± 5 ⁰ C over 30 min and the contents were then warmed slowly to 22 ± 5 ⁰ C over 2 h. The reaction was stirred at 22 ± 5 ⁰ C for 3 h to give a hazy mixture (two layers). The homogenous mixture was then cooled to 10 ± 5 ⁰ C.

A 12-L 4-necked flask was charged with 2.83 kg of methylene chloride and 2.198 kg (21.7 mol) of 1-methylpiperazine.

The homogenous solution was cooled to -5 ± 5 ⁰ C, then the sulfonyl chloride from above was added portionwise at 10 ± 5 ⁰ C through a 1-L addition funnel at 5 ± 5 ⁰ C over 1 h. The 5-L flask and addition funnel were rinsed once with 395 g of methylene chloride. The contents were subsequently warmed to 22 ± 5 ⁰ C and stirred for 2 h. Workup entailed addition of 4.333 kg of water into the mixture at 22 ± 5 ⁰ C to dissolve all 1-methylpiperazine salts. The mixture was concentrated at 25 ± 5 ⁰ C (20 mbar) to a light tan suspension. The solids were filtered off and the cake washed with a total of 1.2 kg of water. The filter cake was dried at 22 ± 5 ⁰ C (20 mbar) under the house vacuum overnight to give 33O g of crude A6 as a beige solid.

Purification

A N ₂ purged 5-L 4-necked flask was charged with 320 g of crude LCZ960 A6, 4.0 kg of water and 2.64 kg of methylene chloride. The mixture was stirred with overhead mechanical stirrer for 5 min at 17 ⁰ C ± 3 °C. The pH was adjusted to 1.0 by addition of 60 g of 6 N HCl in water to give two homogeneous layers. The methylene chloride layer was separated and discarded. The aqueous layer containing the drug substance was extracted twice with a total of 2.64 kg of

methylene chloride. The pH of the solution was adjusted to 9 by adding 10 g of a 1 :1 solution of ammonium hydroxide and water to give a precipitate. The suspended solids were stirred for 1 h at 17 °C ± 3 ⁰ C. and then the solids were filtered and the cake washed with 0.5 kg of water and air was pulled through the cake for at least 8 h. The solid was then placed in a vacuum oven (50 mbar, 40 ⁰ C) for 12 h with a N ₂ purge to give 130 g of [(R)-3-cyclopentyl-2-[4-(4-methyl- piperazine-l-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5, 4-b]pyridin-2-yl)-propionamide A6 as a beige solid in 75% yield.

Removal of Regioisomer :

A flask was charged with 7.2 g of the crude drug substance,60 mL of methanol and the mixture was heated to 50 ⁰ C and maintained at this temperature for 4 h. The reaction mixture was cooled to 20 ⁰ C and the solids were filtered (filtration rate was slow) and washed with 20 mL of methanol. The solids were dried at 45 ⁰ C for 16 h to give 5.8 g of drug substance in 81% yield, (chemical purity >98%).

For analysis of chiral purity, 2 mg of sample is dissolved in 1 mL of THF and 2 mL of ethanol. 2 uL of this solution is injected on a Rainin Dynamax Detector Model UV-I using a Chiralcel OD-H, 250 X 4.6 mm column at ambient temperature eluting with a mixture of hexane: ethanol (80:20) over 25 minutes (UV@350 nm, Flow rate: 1 mL / min). The retention time for the desired R-enantiomer was 16.8 min.

The above examples are representative processes to make chiral glucokinase activators herein described. The above illustrated processes do not limit the scope of the present invention.