WO2016122325A1

WO2016122325A1 - Methods for providing intermediates in the synthesis of atorvastatin.

Info

Publication number: WO2016122325A1
Application number: PCT/NL2016/050070
Authority: WO
Inventors: Alexander Stephan Siegfried DÖMLING
Original assignee: Rijksuniversiteit Groningen
Priority date: 2015-01-30
Filing date: 2016-01-29
Publication date: 2016-08-04

Abstract

The invention relates to the field of medicinal chemistry, In particular, it relates to methods for providing intermediates in the synthesis of Atorvastatin, a competitive inhibitor of HMG-Co A reductase. Provided is a process for providing a compound having a Formula (I) or a pharmaceutically acceptable salt, ester, amide or stereoisomer thereof, comprising reacting in a 4 component Ugi-reaction in a single reaction mixture the compounds of formula A, formula B, formula C and formula D.

Description

Title: Methods for providing intermediates in the synthesis of Atorvastatin. The invention relates to the field of medicinal chemistry. In particular, it relates to methods for providing intermediates in the synthesis of Atorvastatin and to compounds for use therein.

Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. As such,

atorvastatin calcium is a potent lipid lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent, as well as in the treatment of osteoporosis, benign prostatic hyperplasia (BPH) and

Alzheimer's disease.

Atorvastatin (Lipitor) was first synthesized in 1985 by Bruce Roth of Parke-Davis Warner-Lambert Company (since acquired by Pfizer). The best selling drug in pharmaceutical history, sales of Lipitor since it was approved in 1996 exceed US$125 billion, and the drug has topped the list of best-selling branded pharmaceuticals in the world for nearly a decade.

When Pfizer's patent on Lipitor expired on November 30, 2011, generic atorvastatin became available in the United States, initially manufactured only by generic drugmakers Watson Pharmaceuticals and India's Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics— $10 or less for a month's supply— until other manufacturers were able to supply the drug in May 2012.

Many generic companies and groups are working on alternative syntheses for atorvastatin. The original process of Pfizer involved the multistep synthesis of the key intermediate (3R,5R)-7-(N-(carboxy(4- fluorophenyl)methyl)isobutyramido)-3,5-dihydroxyheptanoic acid which can then be converted via a [3+2] cycloaddition reaction involving a Miinchnone intermediate into the final compound atorvastatin. The common technical syntheses involve intermediate I shown below. Intermediate I

wherein PG means "protecting group" , i.e. functional groups known in the art of chemistry used during synthesis to protect parts of molecules that should not undergo a reaction. See for example the monography T. W.

Greene "Protective Groups in Organic Synthesis" (ISBN- 13: 978- 0471697541 ISBN-10: 0471697540 Edition: 4*^h). However, current technical syntheses of atorvastatin suffer from major practical, economical and environmental drawbacks. First, the synthesis protocols are lengthy and use expensive starting materials. Second, some of the reactions involve environmentally unfriendly steps, e.g. bromination, formation of acylchlorides, chlorinated solvents.

Therefore, there is a need for an improved method which avoids at least some of the above drawbacks and ideally involves only a few synthesis steps. The present inventors set out to develop a process for the

manufacture of the key atorvastatin intermediate in one or two steps from cheap and bulk starting materials.

It was surprisingly found that this goal could be met by the provision of a novel process which is based on a four component Ugi reaction involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide, followed by an (in situ) hydrolysis step to give the key intermediate I. This process for synthesis of key intermediate I is the shortest ever described synthesis and also commercially competitive to known technical syntheses. While the classical Pfizer rout uses 4-5 sequential steps for the preparation of I, our synthesis comprises only 1 or 2 steps. Thus, the length of the intermediate synthesis can be reduced by 50- 75%. The starting materials are commercial available or can be synthesized according to methods known in the art. Moreover, our procedure is environmentally benign as it typically employs an alcohol solvent system and does not involve dangerous halogenations steps or acylation steps.

Accordingly, the invention provides a process for providing a compound having a Formula (I)

Formula I

or a pharmaceutically acceptable salt or stereoisomer thereof, comprising reacting in a single reaction mixture, more specifically in a 4 component Ugi reaction, the compounds of formula A, formula B, formula C and formula D, either in a solvent or solventless, wherein the compounds are defined as follows: i) Formula A

ii) Formula B

„ CHO iii) Formula C

iv) Formula D

„ NC

and wherein

Rl is a linear or branched C 1-C5 alkyl, C3-C8 aroyl or C3-C8 heteroaroyl, optionally substituted;

R2 is benzyl, naphthyl or cyclohexyl, optionally substituted; or phenyl optionally substituted with fluorine, chlorine, bromine, hydroxyl or trifluoromethyl; pyridinyl or pyridinyl substituted with fluorine, chlorine, bromine, hydroxyl or trifluoromethyl; or alkyl of from one to seven carbon atoms; or wherein R2 is being selected from the group consisting of I, Br, CI, trifluoromethanesulfonate, methanesulfonate, 4-methylphenylsulfonate, boronic acid, boronic acid esters, nitro, diazonium tetrachloroborate, diazonium tetrafluroborate, diethyltriazene, aryliodonium triflate, aryliodonium mesylate, aryliodonium tosylate, aryliodonium iodide, trimethylammonium chloride, trimethylammonium iodide and

trimethylammonium bromide;

R3 is a branched C3-C8 alkyl, a group selected from benzyl, diphenylmethyl, trityl, 4-nitrobenzyl, and 4-methoxybenzyl, preferably wherein R3 is -C(CH₃)3 R4 and R5 are each independently Ci-Cio alkyl, C(0)Ra, - SiRbRcRd, or R4 and R5 together form isopropyl; wherein Ra is H, Ci-Cio alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroalkyl, optionally substituted with aryl, heteroaryl, lower (C1-C6 ) alkyl, halogen, and wherein Rb, Rc and Rd are each independently C1-C6 alkyl;

R6 is C1-C10 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroalkyl, optionally substituted with aryl, heteroaryl, lower (C1-C6 ) alkyl, lower (C1-C6 ) alkoxy, halogen, or CN, -SiRbRcRd wherein Rb, Rc and Rd are each independently C1-C6 alkyl.

A process of the invention is not disclosed or suggested in the prior art. Park et al. (Bioorganic & Medicinal Chem. Letters 18 (2008) 1151- 1156) and WO2005/014539 both relate to HMG-CoA reductase inhibitors the synthesis but fail to disclose the compound of Formula I. Whereas they do relate to a compound of Formula II as depicted herein below, the compound is prepared by a different reaction path that does not involve an intermediate compound of Formula I. As used herein, a "cycloalkyl" relates to a saturated or partially saturated cyclic group, with one or several ring structures, preferentially 1 or 2, and 3 to 14 ring carbons, more preferably 3 to 10, most preferably 3 to 7 ring carbons. Moreover, cycloalkyl relates to cychc groups in which one or several hydrogen atoms are exchanges by fluoro-, chloro-, bromo- or iodo, or -OH, =O, -SH, =S, -NH2, =NH or -NO2, for example cyclic ketones such as cyclohexanone, 2-cyclohenxenone or cyclopentanone. Other examples of cycloalkyl groups are cyclopropyl-, cyclobutyl-, cyclopentyl-, spiro[4,5]- decanyl-, norbornyl-, cyclohexyl-, cyclopentenyl-, cyclohexadienyl-, decalinyl-, cubanyl-, bicyclo[4.3.0]nonyl-, tetralin-, cyclopentylcyclohexyl-, fhiorcyclohexyl- or the cyclohex-2-enyl group. "Aryl" refers to an aromatic group comprising of one or several rings and consisting of 6 to 14 ring carbon atoms, preferably 6 to 10, more preferably 6 ring carbon atoms. Moreover aryl refers to groups whereby one or several hydrogen atoms are replaced by fluoro-, chloro-, bromo- or iodo, or -OH, - SH, -NH2, or -NO2, Examples include phenyl-, naphthyl-, biphenyl-,

2- fluorphenyl-, anilinyl-, 3-nitrophenyl or 4-hydroxyphenyl groups.

"Aralkyl" relates to groups according to the above definition comprising of the aryl- and an alkyl-, alkenyl, alkinyl and/or cycloalkenyl- group.

Examples include toluole, xylen, mesitylene, styrene, benzylchloride, o- fluortoluene, lH-indene, tetralen, dihydronaphthalen, indenone,

phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane.

"Heteroaryl" relates to aromatic groups comprising of one or several rings and consisting of 6 to 14 ring carbon atoms, preferentially 5 to 10, most preferentially 5 to 6 ring atoms and one or more (preferentially 1, 2, 4, or 4) oxygen, nitrogen, phosphorous or sulfur atoms. Moreover heteroaryl refers to groups whereby one or several hydrogen atoms are replaced by fluoro-, chloro-, bromo- or iodo, or -OH, -SH, -NH2, or -NO2, Examples include 4-pyridyl-, 2-imidazolyl-, 3-phenylpyrrolyl-, thiazolyl-, oxazolyl-, triazolyl-, tetrazolyl-, isoxazolyl-, indazolyl-, indolyl-, benzimidazolyl-, pyridazinyl-, chinolinyl-, purinyl-, carbazolyl-, acridinyl-, pyrimidyl-, 2,3'-bifuryl-,

3- pyrazolyl- and isochinolinyl groups. "Heteroalkyl" relates to groups according to the above definition where one or several of the ring carbon atoms are replaced by oxygen, nitrogen, sulfur, or phosphorous. Examples include morpholino-, morpholino ethyl-, piperidine, piperazine, oxetane, pyrrolidine, 4,5-dihydro-lH-imidazole, imidazoline, pyrazoline, 1,4-diazepane, azepane and azetidine. The Ugi reaction is known in the field of organic chemistry, and involves a multi-component reaction involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide. According to the present invention, the carboxylic acid compound of

Formula A has the structure

wherein Rl is a linear or branched C1-C5 alkyl, a C3-C8 aroyl or a C3-C8 heteroaroyl, which may optionally substituted. In one embodiment, Rl is a linear or branched C1-C5 alkyl optionally substituted with a halogen. For example, Rl is selected from isopropyl, ethyl, trifluorom ethyl and difluoromethyl. In a preferred aspect, Rl is isopropyl. Accordingly, in one embodiment a method of the invention uses isobutyric acid as carboxylic acid starting compound. According to the present invention, the aldehyde compound of Formula B has the structure

,CHO wherein R2 is a substituted C5- or C6-membered aryl or heteroaryl. For example, R2 is a phenyl or substituted phenyl. Preferably, R2 is a phenyl substituted with a halogen, more preferably wherein R2 is para- fluorophenyl. Accordingly, in one embodiment the method of the invention uses 4-fluorobenzaldehyde as aldehyde starting compound.

In a preferred embodiment, Rl is isopropyl and R2 is para-fluorophenyl.

In a specific aspect of the invention, there is provided a method to incorporate a "hot" fluorine ¹⁹F in the final compound, such that they used as radiotracers e.g. for positron emission tomography (PET) or magnetic resonance imaging (MRI). This is readily achieved by introducing a specific moiety via the aldehyde component of Formula B by choosing specific precursors to label the compound by a process known per se in the art, for instance by the copper-mediated nucleophilic fluorination according to by TredweUas et al. (Angew. Chem. Int. Ed. 2014, 53, 7751-7755) disclosing the production of ¹⁸F arenes from pinacol-derived aryl boronic esters (arylBPin) upon treatment with [18F]KF/K222 and [Cu(OTf)2(py)4] (OTf=trifluoromethanesulfonate, py=pyridine).

For example, R2 is a phenyl substituted at the para-position with (4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl). Alternatively hot ¹⁸F can be

introduced by other methods as summarized in: Tredwell, M. and

Gouverneur, V. (2012), ¹⁸F Labeling of Arenes. Angew. Chem. Int. Ed., 51: 11426-11437. doi: 10.1002/anie.201204687. According to the present invention, the amine compound of Formula C is of the structure

wherein R3 is a branched C3-C8 alkyl, a carboxy protecting group selected from benzyl, diphenylmethyl, trityl, 4-nitrobenzyl, and 4-methoxybenzyl;

R4 and R5 are each independently C1-C10 alkyl, C(0)Ra, - SiRbRcRd, or R4 and R5 together form isopropyl; wherein Ra is H, C1-C10 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroalkyl, optionally substituted with aryl, heteroaryl, lower alkyl, halogen, and wherein Rb, Rc and Rd are each independently Ci-Ce alkyl. The term "lower alkyl" as used herein refers to a subset of alkyl which means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, n-hexyl, and the like. Optionally, lower alkyl is referred to as "Ci-C₆ alkyl."

Preferably, R3 is a branched C3-C8 alkyl, more preferably R3 is -C(CH3)3 In one embodiment, R4 and R5 are each independently C1-C10 alkyl, C(O)Ra, or -SiRbRcRd. In another embodiment, R4 and R5 together form isopropyl.

In one embodiment, R3 is a branched C3-C8 alkyl and R4 and R5 together form isopropyl. Preferably, R3 is -C(CH3)3 and R4 and R5 together form isopropyl. Accordingly, in one embodiment the method of the invention uses feri-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate as amine starting compound.

According to the present invention, the isocyanide compound of Formula D has the structure R6-NC, wherein R6 preferably is selected from group consisting of tert-butyl-, l, l-dimethly-3,3-dimethyl-butyl-, benzyl-, p- methoxybenzyl-, diphenylmethyl-, di(p-methoxy-phenyl)methyl-, allyl-, 1- adamantyl-, 2-adamantyl-, 2-(dialkoxymethyl)phenyl-, trityl-, cyclohexene-1- yl-, 2-propane-2-methyl-3-olyl-, 2-cyanoethyl-, TMS-CN (TMS =

trimethylsilyl), AgCN, 2-propane-2-methyl-3-alkyloxycarbonyloxyl-, or a polymer bound form thereof, and 4-nitro-2-methoxyphenyl. Preferably, R6 is 2-nitro-4-methoxyphenyl. Accordingly, in one embodiment the method of the invention l-isocyano-4-methoxy-2 -nitrobenzene is used as isocyanide starting compound.

Preferred isocyanide components that are able to afford the acid functional group in Step 2 of the synthesis (see below) are described by A. Domling, and I. Ugi, (Multicomponent Reactions with Isocyanides. Angew. Chem. Int. Ed. 2000, 39, 3168-3210). These include tert-butyl isocyanide, (1, 1,3,3)- tetramethylbutyl isocyanide, adamantly isocyanide, isopropyl isocyanide and cyclohexenyl isocyanide.

The 4-component Ugi reaction can be performed in any suitable solvent. Included are 2,2,2-trifluoroethanol (TFE), methanol, ethanol, butanol, propanol, iso-propanol, glycol, glycerine, water, mixtures of alcohol and water, biphasic solvent mixtures such as water mixed with DMF, HMPT, DCM, chloroform, toluene, benzene or chlorobenzene.

The reaction is preferably allowed to proceed until a desirable yield has been obtained. This will depend on the reactants, reaction conditions, solvent and the like. The reaction can be performed in the temperature ranges of -40 °C up to 100°C. Preferably, the reaction is performed between room

temperature and 50°C Most preferably the reaction is performed at about 20°C, since this does not require any coohng or heating efforts. Typically, the incubation is performed during at least 24 hours, preferably 1-4 days, at room temperature.

The relative amounts of the 4 starting compounds can vary. Good results can be obtained when using about equimolar amounts. For example, each of the components of Formula A, B and D is initially present in an amount of 0.9- 1.3 equivalents relative to the amount of the amine of Formula C.

Preferably, the components of Formula A, B and D are added in equal or small excess amounts (1.0-1.2 eq) of the amine. In a specific aspect, the method of the invention comprises a reaction according to the following scheme:

Alternatively, the reaction can be performed with the formamide precursor of the isocyanide with in situ formation of the isocyanide and subsequent addition of the other components, thus allowing for a "one-pot" process. This procedure avoids the isolation of the noxious isocyanide, is shorter and saves synthetic steps. In this embodiment the formamide is first converted in situ to the isocyanide using a suitable dehydrating agent and a base. Then, the other starting materials of the Ugi reaction (the acid, aldehyde and amine) in a suitable co-solvent, are added.

Accordingly, in one embodiment a method of the invention comprises reacting a formamide precursor of a compound of the formula D in the presence of a dehydrating agent and a base to produce in situ the compound of formula D, followed by adding the compounds of formula A, formula B and formula C in a suitable co-solvent to initiate the Ugi reaction.

Exemplary dehydrating agents are phosphorous oxychloride, thionyl chloride, tosylchloride, phosgene, diphosgene, triphosgene, or

cyanurchloride. Suitable bases include TEA, pyridine, Hiinig's, KOtBu base, NaOH, or KOH. Suitable solvents for the dehydration reaction are DCM, chloroform, toluene, xylene, benzene or 1,3- dimethyl benzene. Examples of suitable co-solvents for the Ugi reaction include methanol, ethanol, propanol, butanol, glycol, glycerine, trifluoroethanol or aqueous mixtures thereof. The reaction is allowed to proceed until a desirable yield has been obtained. This will depend on the reactants, reaction conditions, solvent and the like. The reaction can be performed in the temperature ranges of -40°C up to 100°C. Preferably, the reaction is performed between room temperature and 50°C. Most preferably the reaction is performed at 20°-40 °C, since this does not require any cooling or heating efforts. Typically, the incubation is performed during at least 24 hours, preferably 1-4 days, at room

temperature. The dehydration part of the reaction can be performed under cooling with an ice bath or any other suitable cooling mixture.

The relative amounts of the 4 starting compounds can vary. Good results can be obtained when using about equimolar amounts. For example, each of the components of Formula A, B and D is initially present in an amount of 0.9-1.3 equivalents relative to the amount of the amine of Formula C.

Preferably, the components of Formula A, B and D are added in equal or small excess amounts (1.0-1.2 eq) of the amine.

In a specific aspect, the method of the invention comprises a reaction according to the following scheme:

In a further embodiment, the invention provides a bisamide compound of the Formula I, or a pharmaceutically acceptable salt, ester, amide or stereoisomer thereof wherein each of R1-R6 including the preferred embodiments is defined as herein above.

In one embodiment, the invention provides (3R,5R)-7-(N-(carboxy(4- fluorophenyl)methyl)isobutyramido)-3,5-dihydroxyheptanoic acid. As is clear from the present application, a bisamide compound of the invention is advantageously used as intermediate in the synthesis of biologically active compounds, in particular statins such as atorvastatins and derivatives thereof.

Following formation of the bisamide compound according to the 4- component Ugi reaction of the invention, the Ugi product may be hydrolyzed under acid or alkaline or hydrogenolytic conditions to obtain a monoamide compound accordin to Formula II.

Wherein R1-R5 are as defined herein above and wherein R7 is H, alkyl, aroyl, or heteroaroyl. Preferably, R7 is methyl, ethyl, benzyl or H.

In one embodiment, the Ugi product is hydrolysed in a methanolic KOH solution. For example, hydrolysis is achieved at room temperature using a 2N methanolic KOH solution.

In the third reaction step, the monoamide product can then be cyclized to a substituted pyrrole ring system, characteristic of the atorvastatin and precursors thereof, according to methods known in the art, for example involving [3+2] cycloadditons. These have been described in literature, for example in: Roth, Bruce D. et al. Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(lH-pyrrol- l-yl)ethyl]-2H-pyran 2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. Journal of Medicinal Chemistry, 34(1), 357-66; 1991; Morin et al. Modular Mesoionics: Understanding and

Controlling Regioselectivity in 1,3-Dipolar Cycloadditions of Miinchnone Derivatives. J. Am. Chem. Soc, 2013, 135 (46), pp 17349-17358; Fisk et al., The diverse chemistry of oxazol-5-(4H)-ones. Chem. Soc. Rev., 2007,36, 1432-1440.

The [3+2] cycloaddition involves the in situ formation of the Muenchnone intermediate. Mesoionic azomethine ylide-type dipoles (Muenchnones) can be obtained from N-acylated amino acids with a dehydrating agent. The water-removing agent is acetic anhydride used simultaneously for the acylation of the amino acid, or Ν,Ν'-dicyclohexylcarbodiimide (DCC), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), Ν,Ν'- diisopropylcarbodiimide (DIC), Ν,Ν'-diethylcarbodiimide, acetic acid, acetic acid anhydride, a mixture of acetic acid, acetic acid anhydride, or

propylphosphonic anhydride (T3P) or under microwave conditions with and without dehydrating agents.

The stereospecificity of the [3+2] cycloaddition can be directed by the amount of dehydrating agent. The poor regio control of the cycloaddition with unsymmetrical substrates is a known problem of this reaction. For example, one equivalent of DCC in the cycloaddition leads to a 1: 1 mixture of the two regioisomers. Surprisingly, the present inventors found that augmenting the amount of dehydrating agent, e.g. DCC to 1.5 - 2

equivalents yields the right regioisomer in a ratio of 4: 1. Accordingly, in one embodiment a method of the invention comprises a [3+2] cycloaddition wherein the dehydrating agent is used in an amount of more than one equivalent, preferably at least 1.2 equivalent, more preferably at least 1.5 equivalent. For example, 1.5 to 3 equivalent is used. DCC is a preferred dehydrating agent.

In one embodiment, the monoamide is reacted with N,3- diphenylpropiolamide until the reaction mixture becomes transparent. Following addition of a suitable dehydrating (imide) agent such as Ν,Ν'- dicyclohexylcarbodiimide (DCC), the solution can be refluxed for 24h to obtain the desired pyrrole ring system.

1 eq DCC

1 .5 eq DCC

2 eq DCC

A method of the invention optionally further comprises conversion of R4 and R5 to hydrogens (resulting in hydroxyl groups) to yield the 3,5- dihydroxyheptanoic acid moiety characteristics of atorvastatin, precursors and derivatives thereof.

For example, in case the R4 and R5 groups together form an acetal (e.g. derived from an amine starting compound wherein R4 and R5 together form isopropyl), the acetal can be deprotected by methods known in the art. In one embodiment, the acetal compound is dissolved in suitable solvent and a strong (sulphonic) acid is added. For example, dichlorom ethane and camphorsulfonic are used. If desired, the resulting dihydroxyheptanoic acid moiety can be converted into a desirable pharmaceutically acceptable salt or stereoisomer thereof by methods generally known in the art. Pharmaceutically acceptable salts of the compound include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulph ate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,

hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 1 ,5- naphthalenedisulfonate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.

Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. In a specific embodiment, a calcium salt or sodium salt of the compound is formed. EXPERIMENTAL SECTION

The invention is exemplified by the examples herein below. General Synthetic Plan for the manufacture of atorvastatin

The synthesis typically comprises 5 main steps :

Step one is an Ugi 4 component reaction according to claim 1.

Alternative step one with in situ isocvanide formation and

subsequent one-pot Ugi reaction.

Step two is the hydrolysis of the isocvanide component and the -butyl ester.

Step three is the cyclization to the substituted pyrrole ring system 

Example 1: Ugi 4 component reaction

4-fluorobenzaldehyde (Compound A; 1.2 eq), tert-butyl 2-((4R,6R)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (Compound B; 1.0 eq), isobutyric acid (Compound C; 1.2 eq) and l-isocyano-4-methoxy-2- nitrobenzene (Compound D; 1.2 eq) were added together along with 2,2,2- trifluoroethanol (TFE) and stirred at room temperature for 72h. The solvent was evaporated under reduced pressure and the residue was purified using flash chromatography to obtain the desired bisamide product. Other reaction solvent used for this reaction include ethanol, methanol, propanol, isopropanol, water or mixtures thereof.

Ή NMR (500 MHz, CDC1₃) δ 10.21 (d, J = 9.8 Hz, 1H), 8.69 (dd, J = 9.3, 3.7 Hz, 1H), 7.64 (d, J = 2.8 Hz, 1H), 7.46 (td, J = 9.0, 5.5 Hz, 2H), 7.23 (dd, J = 9.3, 2.8 Hz, 1H), 7.14 (td, J = 9.0, 4.6 Hz, 2H), 5.59 (d, J = 4.9 Hz, 1H), 4.27- 4.16 (m, 1H), 3.86 (s, 3H), 3.78 (m, 1H), 3.69-3.61 (m, 1H), 3.61-3.49 (m, 1H), 3.45-3.31 (m, 1H), 3.01-2.90 (m, 1H), 2.46-2.36 (m, 2H), 2.34-2.21 (m, 2H), 1.46 (s, 12H), 1.41 (s, 4H), 1.38-1.32 (m, 4H), 1.24-1.17 (m, 9H).

MS (ESI) m/z calculated for C33H44FN3O9: [M]⁺: 645,31; found [M-H]⁺:

644.27.

For this step the inventors also tested different isocyanide components (Compound D) that are also able to afford the acid functional group in Step 2 of the synthesis. Such isocyanides are described by A. Domling, and I. Ugi, in their paper (Multicomponent Reactions with Isocyanides. Angew. Chem. Int. Ed. 2000, 39, 3168-3210). Specifically the following isocyanides were tested in the Ugi reaction with 4-fluorobenzaldehyde, tert -butyl 2-((4R,6R)- 6-(2-aminoethyl)-2,2-dimethyl- l,3-dioxan-4-yl)acetate, isobutyrcarboxylic acid to yield the corresponding Ugi products: tert-butylisocyanide (87% yield), 1, 1,3,3-tetramethyl-butylisocyanide, benzylisocyanide,

diphenylmethyhsocyanide, tritylisocyanide, 2-cyanoethylisocyanide, phenylisocyanide, cyclopropylisocyanide, cyclopropylmethylisocyanide, 2- isocyanoethyl methyl carbonate, tosylmethylisocyanide, allylisocyanide, homoallyhsocy anide, 1 -(2 ,2 -dimethoxyethyl)-2 -isocy anobenzene, 1 -(2 ,2 - diethoxyethyl)-2 -isocy anobenzene, o-nitrophenylisocy anide, o-nitro-p- chlorophenylisocyanide, l-isocyano-4-methoxy-2,6-dinitrobenzene and 1- isocyano-2-methoxy-4-nitrobenzene.

Furthermore the inventors aimed at the introduction of "hot" fluorine ¹⁹F in the end product. For this reason they choose to introduce this moiety via the aldehyde group in the Ugi reaction by choosing specific precursors (Angew. Chem. Int. Ed. 2014, 53, 7751-7755).

These precursors are the following:

Example 2: Hydrolysis of the Ugi product

The Ugi product obtained from Example 1 was added to a 2N methanolic KOH solution and stirred at room temperature for 24h. The solvent was evaporated under reduced pressure and the residue was extracted with ether and water. The water layer was separated and acidified to pH 4 with concentrated HCl. The mixture was further extracted with ethyl acetate and water. The ethyl acetate layer was dried with MgS0₄ concentrated under reduced pressure to give the desired product as a mixture of

diastereoisomers with ratio (5:4). (Yield: 90 %)

Ή NMR (500 MHz, CDC1₃) δ 7.33 (dt, J = 8.3, 5.4 Hz, 4H), 7.05 (td, J = 8.5, 3.3 Hz, 4H), 5.63 (s, 1H), 5.52 (s, 1H), 4.29-4.16 (m, 2H), 3.73 (dt, J = 19.5, 10.8 Hz, 2H), 3.58-3.41 (m, 2H), 3.38-3.17 (m, 2H), 2.88 (dq, J = 13.0, 6.5 Hz, 2H), 2.64-2.49 (m, 2H), 2.47-2.34 (m, 2H), 1.38 (d, J = 4.7 Hz, 7H), 1.34 (s, 5H), 1.20 (d, J = 7.0 Hz, 5H), 1.17-1.12 (m, 12H). MS (ESI) m/z calculated for C22H30FNO7: [M]⁺: 440,20; found [M-H]⁺: 440.30. Example 3: Cyclization to the pyrrole ring system

2-(N-(2-((4R,6R)-6-(carboxymethyl)-2,2-dimethyl-l,3-dioxan-4- yl)ethyl)isobutyramido)-2-(4-fluorophenyl)acetic acid (1.0 eq) of Example 2 was dissolved along with N,3-diphenylpropiolamide (1.0 eq) in toluene.

When the mixture became transparent N,N'-dicyclohexylcarbodiimide (DCC) (1.5 eq) was added and the solution was refluxed for 24h. The volatiles were evaporated under reduced pressure and the crude mixture was extracted with dichlorom ethane (DCM) and water. The organic layer was dried with MgS0₄ concentrated under reduced pressure and purified by column chromatography to give the desired product. Ή NMR (500 MHz, CDC1₃) δ 7.22-7.12 (m, 8H), 7.07 (d, J = 7.6 Hz, 2H), 6.99 (dd, = 10.7, 6.5 Hz, 3H), 6.88 (d, J = 6.7 Hz, 1H), 4.20 (dt, J = 13.0, 4.1 Hz, 1H), 4.14-4.03 (m, 1H), 3.89-3.79 (m, 1H), 3.70 (dd, = 6.7, 4.9 Hz, 1H), 3.62-3.51 (m, 1H), 2.53 (dd, J = 15.9, 6.8 Hz, 1H), 2.37 (dd, J = 15.9, 6.0 Hz, 1H), 1.74-1.61 (m, 2H), 1.53 (d, J = 7.1 Hz, 6H), 1.37 (s, 4H), 1.31 (s, 3H). MS (ESI) m/z calculated for C36H39FN2O5: [M]⁺: 599.28; found [M-H]⁺: 599.36. Example 4: Deprotection of the acetal group

2-((4S,6S)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- (phenylcarbamoyl)-lH-pyrrol-l-yl)ethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid (1.0 eq) of Example 3 was dissolved in dichloromethane (DCM) and camphorsulfonic acid (1.0 eq.) was added.

The reaction mixture was stirred at room temperature until the complete consumption of the starting material. The crude material was purified by column chromatography to provide the desired product. (Yield 90%)

Ή NMR (500 MHz, CDC1₃) δ 7.17 (m, 8H), 7.06 (m, 2H), 6.97 (m, 4H), 4.08 (d, J = 9.6 Hz, 2H), 3.98-3.84 (m, 1H), 3.70 (d, J = 17.2 Hz, 2H), 3.63-3.48 (m, 1H), 2.56 (s, 1H), 2.24 (s, 1H), 1.85 (d, J = 8.6 Hz, OH), 1.69 (d, J = 13.1 Hz, OH), 1.64-1.57 (m, OH), 1.51 (d, J = 6.9 Hz, 6H). MS (ESI) m/z calculated for C33H35FN2O5: [M]⁺: 559.25; found [M-H]⁺: 559.20.

Example 5: Salt formation

(3S,5S)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH- pyrrol- l-yl)-3,5-dihydroxyheptanoic acid of Example 4 was dissolved in methanol (MeOH) and sodium hydroxide was added and stirred for lh at 20 to 25°C. Methanol was distilled by reduced pressure.

The solid sodium salt was filtered and subsequently dissolved again in methanol and treated with calcium chloride at 20 to 25°C. Water was added after the calcium salt precipitated out. The precipitate was filtered and dried to give the desired product.

Ή NMR (500 MHz, DMSO) δ 7.70 (d, = 7.8 Hz, 1H), 7.51 (d, = 8.0 Hz, 2H), 7.29-7.14 (m, 6H), 7.07 (d, J = 5.5 Hz, 4H), 6.99 (dd, J = 15.2, 6.9 Hz,

2H), 4.75 (d, = 4.6 Hz, 1H), 4.65 (d, = 4.6 Hz, 1H), 3.97-3.88 (m, 1H), 3.76 (dd, J = 27.9, 17.1, 2H), 3.52 (s, 2H), 3.28-3.14 (m, 1H), 2.12 (d, J = 4.6 Hz, 2H), 1.67 (m, 5H), 1.52 (m, 2H), 1.37 (d, J = 6.9, 6H). MS (HRMS FAB-) m/z calculated for C₆6H₆7CaF2N4Oio: [M]-: 1153.4451.; found [M-H]-: 1153.4453.

Example 6: In situ one-pot procedure

To a stirred solution of the 4-methoxy-2-nitrophenyl formamide (1.0 mmol) in dichloromethane (1 ml), triethylamine (2.4 mmol) was added at 0 °C. After 10 min, triphosgene (0.4 mmol) was added dropwise over 30 min. The reaction mixture was stirred at 0 °C for an additional 20 min and then 4- fluorobenzaldehyde (Compound A; 1.2 eq), tert-butyl 2-((4R,6R)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (Compound B; 1.0 eq), isobutyric acid (Compound C; 1.2 eq) and methanol (2 ml) were added. The solution was stirred for 48 h and the solvent partially removed and the product precipitated. The solid was filtered, washed with cold MeOH, affording the compound pure as white solid. The analytical data is equivalent to Example 1.

Claims

A process for providing a compound having a Formula (I)

or a pharmaceutically acceptable salt or stereoisomer thereof, comprising reacting in a single reaction mixture the compounds of formula A, formula B, formula C and formula D, wherein the compounds are defined as follows: i) Formula A

ii) Formula B

,CHO

iii) Formula C

iv) Formula D

wherein

Rl is a linear or branched C1-C5 alkyl, C3-C8 aroyl or C3-C8 heteroaroyl, optionally substituted; R2 is benzyl, naphthyl or cyclohexyl, optionally substituted; or phenyl optionally substituted with fluorine, chlorine, bromine, hydroxy! or trifluoromethyl; pyridinyl or pyridinyl substituted with fluorine, chlorine, bromine, hydroxy! or trifluoromethyl; or alkyl of from one to seven carbon atoms; or wherein R2 is selected from the group consisting of I, Br, CI, trifluoromethanesulfonate, methanesulfonate, 4-methylphenylsulfonate, boronic acid, boronic acid esters, nitro, diazonium tetrachloroborate, diazonium tetrafluroborate, diethyltriazene, aryliodonium triflate, aryliodonium mesylate, aryliodonium tosylate, aryliodonium iodide, trimethylammonium chloride, trimethylammonium iodide and

trimethylammonium bromide

R3 is a branched C3-C8 alkyl, a carboxy protecting group selected from benzyl, diphenylmethyl, trityl, 4-nitrobenzyl, and 4-methoxybenzyl, preferably wherein R3 is -C(CH3)3;

R4 and R5 are each independently C 1-C 10 alkyl, C(0)Ra, - SiRbRcRd, or R4 and R5 together form isopropyl; wherein Ra is H, C 1-C 10 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroalkyl, optionally substituted with aryl, heteroaryl, C 1-C6 alkyl, halogen, and wherein Rb, Rc and Rd are each independently C1-C6 alkyl; R6 is Ci-Cio alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl or heteroalkyl, optionally substituted with aryl, heteroaryl, Ci-Ce alkyl, d-Ce alkoxy, halogen, or CN, -SiRbRcRd wherein Rb, Rc and Rd are each independently Ci-Ce alkyl.

2. Process according to claim 1, wherein Rl is a linear or branched C1-C5 alkyl, optionally substituted with a halogen,

3. Process according to claim 2, wherein Rl is selected from isopropyl, ethyl, trifluoromethyl and difluoromethyl, preferably isopropyl.

4. Process according to any one of claims 1-3, wherein R2 is a substituted C5- or C6-membered aryl or heteroaryl

5. Process according to any one of claims 1-4, wherein R2 is a phenyl or substituted phenyl, preferably a phenyl substituted with a halogen, more preferably wherein R2 is para-fluorophenyl.

6. Process according to claim 5, wherein Rl is isopropyl and R2 is para-fluorophenyl.

7. Process according to any one of the preceding claims, wherein R3 is a branched C3-C8 alkyl, preferably wherein R3 is -C(CH3)3

8. Process according to any one of the preceding claims, wherein R4 and R5 are each independently C1-C10 alkyl, C(0)Ra, or -SiRbRcRd.

9. Process according to any one of claims 1-7, wherein R4 and R5 together form isopropyl.

10. Process according to any one of the preceding claims, wherein R6 is selected from the group consisting of tert-butyl-, l, l-dimethyl-3,3- dimethyl-butyl-, benzyl-, p-methoxybenzyl-, diphenylmethyl-, di(p-methoxy- phenyl)methyl-, allyl-, 1-adamantyl-, 2-adamantyl-, 2- (dialkoxymethyl)phenyl-, trityl-, cyclohexene-l-yl-, 2-propane-2-methyl-3- olyl-, 2-cyanoethyl-, TMS-CN (TMS = trimethylsilyl), AgCN, 2-propane-2- methyl-3-alkyloxycarbonyloxyl-, or a polymer bound form thereof, and 4- nitr o - 2 -m ethoxyphenyl .

11. Process according to claim 10, wherein R6 is 2-nitro-4- methoxyphenyl.

12. Process according to claim 1, for providing (3R,5R)-7-(N-

(carboxy(4-fluorophenyl)methyl)isobutyramido)-3,5-dihydroxyheptanoic acid.

13. Process according to any one of the preceding claims, further comprising hydrolyzing the bisamide compound according to formula I under acid, alkaline or hydrogenolytic conditions to obtain a monoamide compound according to Formula II

wherein R1-R5 are as defined in any one of claims 1-9, and wherein R7 is H, alkyl, aroyl, or heteroaroyl, preferably wherein R7 is methyl, ethyl, benzyl or H.

14. Process according to claim 13, further comprising cyclization of the monoamide compound to a substituted pyrrole ring system, preferably comprising a [3+2] cycloaddition.

15. Process according to claim 14, further comprising converting and R5 to hydrogens.

Bisamide compound of the formula I

Formula I or a pharmaceutically acceptable salt, ester, amide or

stereoisomer thereof, wherein each of Rl to R6 is as defined as in any one of claims 1 to 11.

17. Bisamide compound obtainable by a method according to claim

15, being (3R,5R)-7-(N-(carboxy(4-fluorophenyl)methyl)isobutyramido)-3,5- dihydroxyheptanoic acid.

18. Use of a method according to any one of claims 1-15, or a bisamide compound according to claim 16 or 17, in the manufacture of atorvastatin or a derivative thereof.