WO2009035407A1

WO2009035407A1 - Use of intermediates ((r ) -2,2, 4-trimethyl-l, 3-dioxolane-4-yl) methanol (a), 3-f luoro-4-nitro-phenol (b) and 1- (4-chloro- benzyl) -piperidin-4-ylamine (c)

Info

Publication number: WO2009035407A1
Application number: PCT/SE2008/051021
Authority: WO
Inventors: Debra Ainge; Frieder Gnad; Rhona Sinclair; Luis-Manuel Vaz; Andrew Wells
Original assignee: Astrazeneca Ab
Priority date: 2007-09-14
Filing date: 2008-09-12
Publication date: 2009-03-19

Abstract

The present invention relates to novel processes for the preparation of intermediate compounds which can be used to prepare therapeutic agents. The present invention also relates to novel intermediate compounds which can be used to prepare therapeutic agents. More specifically, the invention relates to the use of intermediates ((R) -2,2,4-trimethyl-l, 3- dioxolane-4 -yl) methanol (A), 3-f luoro-4-nitro-phenol (B) and 1- (4-chloro-benZyl) -piperidin-4-ylamine (C).

Description

Use of intermediates ( (R ) -2,2, 4-trimethyl-l, 3-dioxolane-4- yl) methanol (A) , 3-fluoro-4-nitro-phenol (B) and l-(4-chloro- benZyl) -piperidin-4-ylamine (C)

The present invention relates to novel processes for the preparation of intermediate compounds which can be used to prepare therapeutic agents. The present invention also relates to novel intermediate compounds which can be used to prepare therapeutic agents. More specifically, the present invention relates to the use of intermediates ((R)-2,2,4- trimethyl-l,3-dioxolan-4-yl)-methanol (A), 3-fluoro-4-nitro-phenol (B) and l-(4-chloro- benzyl)-piperidin-4-ylamine (C) in the preparation of 2-{2-chloro-5-{[(25)-3-(5-chloro- i 'H,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy}-4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid (Ia).

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Studies have demonstrated that the actions of chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CRl for the C-X₃- C family. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

WOO 1/98273 discloses a series of compounds having a structure (I) shown below, where R^a is a phenyl group (which may be substituted), where R^b represents a suitable substituent and n is typically 0, 1 or 2 and where R^c is hydrogen or a group such a C_halky!.

WO03/051839 discloses the CCRl antagonist iV-{2-[((25)-3-{[l-(4- chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4 hydroxyphenyl}acetamide. A related compound, N-{5-Chloro-2-[((25)-3-{[l-(4- chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl}acetamide has also been shown to antagonise CCRl activity.

Methods of synthesising compounds of the type described above typically involve alkylation of a protected acetamidophenol derivative (2) with an epoxide derivative e.g. [2- methyloxiranyl]methyl-3-nitrobenzene sulfonate (3) (also known as methylglycidyl nosylate) to give an epoxy ether derivative (4) e.g. as shown in step (i) of scheme 1 below. Reaction of the epoxide product (4) with a piperidine amine (5) as shown in step (ii) of the process shown below (and deprotection of any protected substituent groups) can give rise to the target pharmaceutical compound (1).

Scheme 1

Whilst acceptable as a method to prepare target compounds in quantities of up to five kilograms, such routes are not considered suitable for further scale-up. One reason for this is the safety issues surrounding the transport and handling of the glycidyl nosylate (3), which has been found to have potentially dangerous thermal properties. Furthermore, known methods for the synthesis and purification of the glycidyl nosylate (3) can give rise to variable yields and significant levels of by-products.

In view of the above, it would be advantageous to find new methods of synthesising compounds of formula (I). WO2007/129960 and WO2008/010764 disclose new advantageous methods of preparing compounds of formula (I), for example, the method described in scheme 2.

Scheme 2

The present invention relates to processes for the preparation of key intermediates A, B and C, as shown in scheme 2, whose utility in the preparation of compounds of formula (I) has been demonstrated.

One embodiment of the invention relates to the use of intermediates ((i?j-2,2,4-trimethyl- l,3-dioxolan-4-yl)-methanol (A), 3-fluoro-4-nitro-phenol (B) and l-(4-chloro-benzyl)- piperidin-4-ylamine (C) in the preparation of 2-{2-chloro-5-{[(25)-3-(5-chloro-i Η,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid (Ia).

Intermediate A: (( ,)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol

One embodiment of the present invention relates to the preparation of intermediate A, (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol and its (R)- and (S)- enantiomers according to the following processes. The preparation of A from methallyl alcohol has been described by B. Wirtz, R. Barner, J. Hϋbscher , J. Org. Chem., 1993, 55, 3980 as shown in scheme 3. Although suitable for making milligram quantities of ((i?j-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol, the chemistry described is not considered suitable for the preparation of multikilogram amounts. One reason for this is the problem associated with the handling and purification of small water soluble molecules. In addition, it seems that several of the intermediates described are unstable under the reaction and purification conditions resulting in low and variable yields of products containing significant levels of by-products.

Scheme 3

Reagents and Conditions: (i) H₂O₂, H₂WO₄; (ii) Acetone, p-TSA Q ; (iii) Amano AK lipase, vinyl acetate, n-hexane

In one embodiment of the process of the invention, methallyl alcohol (A.I) is oxidised to the desired triol A.2 using alternative oxidation systems to those previously described for these substrates. For example H2WO4/H2O2 can be replaced with Na₂WO₄ZH₂O₂ and/or 5 formic acid and H₂O₂. The use OfNa₂WOVH₂O₂ as an alternative oxidation system surprisingly results in increased stability of the racemic Acetonide A.3 during isolation and hence improved yields and chemical purity.

A person skilled in the art would recognise that solvents, bases and catalysts may be used0 in this process. Suitable solvents that may be used for the preparation of A.2 are, but not limited to, water or acetic acid. Suitable oxidising agents that may be used for the preparation of the A.2 are, but not limited to, hydrogen peroxide with acetic acid, tungstic acid or sodium tungstate. Suitable solvents for the preparation of A.3 are, but not limited to, acetone, 2,2-dimethoxypropane, tert-butyl methyl ether. Suitable reagents for the5 preparation of A.3 are, but not limited to, acetone and 2,2-dimethoxypropane. Scheme 4

A.R-5 A.R.S-3 ^{A R}-⁶

In a further embodiment of the process of the invention, racemic acetonide A.3 is resolved into its separate enantiomers using an enzymatic resolution reaction using alternative enzyme/acyl donor systems to those previously described. Replacement of vinyl acetate to vinyl laurate or succinic anhydride, as described in scheme 4, results in more facile and higher yielding isolation of the desired alcohol, either by distillation or aqueous work-up. Replacement of Amano AK lipase with alternative enzymes, such as, but not limited to, Amano PS-D (Pseudomonas cepacea lipase on celite) results in the selective acylation of A.S-3, leaving A.R-3 in high optical purity (greater than 99%). Using this method, as opposed to the literature method, allows a more facile separation of the products, A.R-5 and A.R-6 both having higher molecular weights than the acetate A.R-4. In addition, esters A.R-5 and A.R-6 can be separated from A.R-3 by aqueous work-up instead of distillation as described in the literature.

One embodiment of the invention relates to the process for the preparation of succinic acid mono-((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester by reacting (2,2,4-trimethyl- l,3-dioxolan-4-yl)-methanol with dihydro-furan-2.5-dione.

Scheme 5

A.R,S-3 A .R-5

A person skilled in the art would recognise that solvents and catalysts may be used in this process. Suitable solvents that may be used, but not limited to, are tøt-butylmethyl ether. Suitable catalysts are Pseudomonas cepacea lipase.

The reaction may be performed at a temperature range between ambient temperature and Another embodiment of the invention relates to the process for the preparation of dodecanoic acid ((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester by reacting (2,2,4- trimethyl-l,3-dioxolan-4-yl)-methanol with dodecanoic acid vinyl ester.

Scheme 6

A person skilled in the art would recognise that solvents and catalysts may be used in this process. Suitable solvents that may be used, but not limited to, are tøt-butylmethyl ether. Suitable catalysts are Pseudomonas cepacea lipase. The reaction may be performed at a temperature range between ambient temperature and

35°C.

A further embodiment of the invention relates to compounds succinic acid mono-((i?)- 2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (A.R-5) and dodecanoic acid ((i?)-2,2,4- trimethyl- 1 ,3-dioxolan-4-yl-methyl) ester (A.R-6).

Yet another embodiment relates to the use of (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol in the preparation of succinic acid mono-((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (A.R-5) and dodecanoic acid ((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (A.R-6).

Scheme 7

A.R,S-7 A.S-3 A.S-7

O^^OH

A.R-3 In a further embodiment of the process of the invention, racemic butyrate ester A.R,S-7 is resolved into its separate enantiomers by an enzymatic resolution reaction using alternative enzyme systems to those previously described. In this case, using literature methods, A.R-3 is obtained by hydrolysis of A.S-7 as shown in scheme 7. The use of the alternative enzymes, such as CAL-B (Candida antarctica lipase B), Novozyme 435, Chirazyme L-2 or CLEA CAL-B selectively produces AJ?-3 directly, thereby negating the need for hydrolysis of the butyrate ester A.S-7.

One embodiment of the invention relates to the process for the preparation of ((R)-2,2,4- trimethyl-l,3-dioxolan-4-yl)-methanol from butyric acid ((i?,5)-2,2,4-trimethyl-l,3- dioxolan-4-yl)-methyl ester through enzymatic resolution. In another embodiment the enzyme Candida antarctica lipase B is used for the enzymatic resolution. A person skilled in the art would recognise that solvents and catalysts may be used in this process. Suitable solvents that may be used, but not limited to, are tert-butanol/water (9/1) or nBuOH/ tert-butylmethyl ether. Suitable catalysts are Candida antarctica lipase B.

The reaction may be performed at a temperature range between 10 and 25°C.

A person skilled in the art would recognise that solvents, or combinations of solvents may be used in this process. Suitable solvents that may be used for this enzymatic resolution are, but not limited to, water, alcohols such as n-butanol, ethers such as TBME, and buffered solutions such as pH 7 phosphate buffer and mixtures thereof. Using these new methods, a commerically viable process for the preparation of ((i^-2,2,4- trimethyl-l,3-dioxolan-4-yl)-methanol has been developed.

KR 20040056592 describes a catalyzed resolution method of racemic cis-l,3-dioxolane derivatives using enzymatic resolution. These derivatives are different from the compounds used in the present process and so for example do not have a tetra substituted chiral center at the center to be resolved. The tetra substituted derivatives were not expected to perform under the reaction conditions as the chiral center to be resolved becomes more hindered.

Intermediate B : 3-fluoro-4-nitrophenol

A further embodiment of the present patent relates to processes for the preparation of intermediate B. The nitration of 3-fluorophenol has been described by H. H. Hodgson and J. Nixon, J. Chem. Soc, 1928, 1879. The procedure described therein is low yielding and mixtures of regioisomers and polynitrated derivatives is obtained. Furthermore, chromatography is required to isolate the desired regioisomer. The new processes described herein are contemplated to be suitable for the preparation of 3-fluoro-4- nitrophenol that are suitable for large scale manufacture.

One embodiment of the present invention relates to the improved preparation of 3-fluoro- 4-nitrophenol by direct nitration of 3-fiuorophenol as described in scheme 8.

Scheme 8

+ regioisomers

+ polynitrated derivatives

The process involves the treatment of 3-fluorophenol with nitric acid in acetic acid at room temperature. The reaction conditions implemented lead to a mixture of the three possible regioisomers of fluoro-nitro-phenol with much improved regioselectivity with respect to the desired regioisomer, intermediate B. After extraction of the undesired regioisomers using methylcyclohexane or cyclohexane and extraction of the desired regioisomer from the aqueous mixture using methy tert-butyl ether followed by solvent replacement with toluene, intermediate B, can be isolated directly from the reaction, avoiding the use of chromatography. This extraction technique can also be applied to other methods of preparing intermediate B such as the method described by JJ. Parlow, A.M. Stevens, R.A. Stegeman, W.C. Stallings, R.G. Kurumbail, M.S. South, J. Med. Chem., 2003, 46, 4297. One embodiment relates to the process of 3-fluoro-4-nitrophenol from 3-fluorophenol using a nitrating agent and cyclohexane or methylcyclohexane at room temperature. Another embodiment relates to the process for preparation of 3-fluoro-4-nitrophenol by direct nitration of 3-fluorophenol whereby the regioisomers are obtained in a ratio of 3- fluoro-4-nitrophenol : 5-fluoro-2-nitrophenol : 3-fluoro-2-nitro-phenol 5.3 : 3.6 : 1. One embodiment relates to the use of methylcyclohexane or cyclohexane in the preparation of 3-fluoro-4-nitrophenol by direct nitration of 3-fluorophenol. A further embodiment relates to the use of nitric acid as a nitrating agent. Another embodiment relates to the use of iron nitrate or bismuth nitrate as a nitrating agent.

Optionally, 3-fluoro-4-nitrophenol can be recrystallised from toluene. A person skilled in the art would recognise that solvents, acids and alternative nitration reagents may be used in this process.

One embodiment relates to the process in Scheme 8 using solvents selected from water, acids (acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, propionic acid, sulfuric acid, nitric acid), organic solvents (tetrahydrofuran, dichloromethane) and combinations thereof, nitric acid as the nitrating agent and cyclohexane or methylcyclohexane.

Intermediate C : l-(4-chloro-benzyl)-piperidin-4-ylamine

A further embodiment of the present patent relates to processes for the preparation of intermediate C. The preparation of C from isonipecotamide has been previously described by P.W.Shum, N.P. Peet, P.M. Weintraub, T.B. Le, Z. Zhao, F. Barbone, B. Cashman, J.

Tsay, S. Dwyer, P. C. Loos, E.A. Powers, K. Kropp, P. S. Wright, A. Bitonti, J. Dumont and D. R. Borcherding in Nucleosides, Nucleotides and Nucleic Acids, 2001, 20 (4), 1067. Although suitable for making kilogram quantities of l-(4-chloro-benzyl)-piperidin-4- ylamine, the chemistry described is not considered suitable for the preparation of multikilogram amounts. One reason for this is the use of phenyl iodo diacetate, a very expensive and thermally unstable reagent, used in the Hoffmann degradation of isonipecotamide leading to l-(4-chloro-benzyl)-piperidin-4-ylamine. The new processes described herein are contemplated to be suitable for the preparation of l-(4-chloro-benzyl)-piperidin-4-ylamine, based on the reduction of pyridin-4-ylamine, that are suitable for large scale manufacture. Another advantage of these new approaches is the use of a readily available starting material, pyridin-4-ylamine, and simple chemical transformations for the synthesis of l-(4-chloro-benzyl)-piperidin-4-ylamine.

One embodiment of the present invention relates to the preparation of l-(4-chloro-benzyl)- piperidin-4-ylamine according to scheme 9. Scheme 9

C.1 C.2

The formation of intermediate C can be achieved using the procedure described by G.N.

Walker, M.A. Moore, B.N. Weaver, J Org.Chem., 1961, 26, 2740, where intermediate C.2 is reduced to the desired compound C using sodium borohydride.

We have now demonstrated that compound C.2 can be reduced to the corresponding intermediate C or salt thereof using a rhodium on charcoal catalyst under hydrogenation conditions.

One advantage of this new approach is to negate the use of sodium borohydride, enabling an easier isolation of the desired intermediate C, without the need to dispose of boron contaminated wastes.

One embodiment of the invention relates to the process for the preparation of l-(4-chloro- benzyl)-piperidin-4-ylamine (C) by reducing l-(4-chloro-benzyl)-piperidin-4-ylamine

(C.2) using a rhodium on charcoal catalyst under hydrogenation conditions.

Scheme 10

C.2 ^c A person skilled in the art would recognise that solvents may be used in this process.

Suitable solvents that may be used, but not limited to, are alcoholic solvents such as, but not limited to, methanol, ethanol, isopropanol. The reaction may be performed at a temperature range between ambient temperature and reflux temperature of the chosen alcoholic solvent.

Another embodiment of the present invention relates to the preparation of l-(4-chloro- benzyl)-piperidin-4-ylamine according to scheme 11.

Scheme 11

The reduction of pyridin-4-ylamine Cl to the corresponding piperidin-4-ylamine C.3 is a known transformation using sodium in alcohol (E. Koenigs and L.Neumann, Chem. Ber.,

1915, 48, 956) or electrochemical techniques (E. Wedekind, Chem. Ber., 1915, 48, 691).

We have now demonstrated the reduction of Cl to intermediate C.3 using a rhodium on charcoal catalyst under hydrogenation conditions.

One advantage of this new approach is to negate the use very strong reducing conditions, employing metallic sodium in alcoholic solvent, and to use milder hydrogenation conditions using a rhodium catalyst.

The selective alkylation method leading to the formation of intermediate C.3 has been described for example by F. Laduron, V. Tamborowski, L. Moens, A. Horvath, D. de

Smaele and S. Leurs in Organic Process Research & Development, 2005, 9, 102.

Another embodiment of the invention relates to the process for the preparation of piperidin-4-ylamine (C.3) by reducing pyridin-4-ylamine (Cl) using rhodium on charcoal catalyst under hydrogenation conditions.

A further embodiment of the invention relates to the process for the preparation of l-(4- chloro-benzyl)-piperidin-4-ylamine (C) by reacting piperidin-4-ylamine (C.3) with 1- chloro-4-chloromethyl benzene.

Yet a further embodiment relates to the process for the preparation of piperidin-4-ylamine

(C.3) by reducing pyridin-4-ylamine (Cl) using rhodium on charcoal catalyst under hydrogenation conditions followed by the preparation of l-(4-chloro-benzyl)-piperidin-4- ylamine (C) by reacting piperidin-4-ylamine (C.3) with l-chloro-4-chloromethyl benzene.

A person skilled in the art would recognise that solvents and bases may be used in this process. Suitable solvents that may be used for the preparation of C from C.3, but not limited to, are methyl isobutyl ketone, acetone, 2-butanone, 3-pentanone and cyclohexanone.

Suitable solvents that may be used for the preparation of C are, but not limited to alcoholic solvents such as isopropanol. Suitable bases are but not limited to sodium hydroxide. The reaction may be performed at ambient temperature.

Examples

The invention will now be further explained with reference to the following illustrative examples.

Unless otherwise specified, all starting materials & reagents were purchased from standard suppliers (Sigma Aldrich, Apollo, Johnson Matthey and Fisher Scientific), and were used without further purification unless otherwise stated. The preparation and resolution of

(i?,5)-(2,2,4-trimethyl-l,3-dioxolane-4-yl)-methanol is known in the literature (B. Wirz, R. Barner and J. Huebscher, J. Org. Chem., 1993, 55, 3980). Reactions were carried out using standard glassware under a nitrogen atmosphere, unless otherwise stated.

NMR spectra were acquired on Varian Inova 300MHz or 400MHz or Bruker 300MHz and 200MHz spectrometers (as detailed) as solutions in suitably deuterated solvents. Nominal masses were determined either by GCMS or LCMS (as detailed). LCMS were ran on an Agilent binary 1100 HPLC with 80Hz DAD and Multimode ES+APC1 positive ion, Agilent LCMS DSL (negative ion) or a Waters 2790 HPLC equipped with 996 Photo Diode Array detector and Micromass ZMD (single quadropole mass spectrometer with Z- spray interface). GCMS data was acquired using an Agilent 6890 GC coupled to a 5973 MSD, equipped with either EI or CI source. For CI experiments, reagent grade methane from BOC gases was used as reagent gas. Chiral HPLC was ran on an Agilent HP-1100 VWD Detector. Each exemplified compound represents a particular and independent aspect of the invention.

The following abbreviations are used:

CDCl₃ Deuterated Chloroform

CI Chemical Ionisation

DMSO Dimethylsulfoxide

ESI Electron Spray Impact GC Gas Chromatography

GCMS Gas Chromatography / Mass Spectroscopy

HPLC High Performance Liquid Chromatography

LCMS Liquid Column Chromatography / Mass Spectroscopy

MIBK Methyl IsoButyl Ketone TBME tert-Butylmethyl Ether

THF Tetrahydrofuran

ReI vol relative volume

Ambient or room temperature a temperature between 15 and 26°C

Intermediate A Example 1 Preparation of racemic (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol

Method A:

A solution of methallyl alcohol (lmol equiv) and tungstic acid (O.Olmol equiv) in water (2rel vols) is heated to 50⁰C. Hydrogen peroxide 30% solution in water (1. lmol equiv) is slowly added to the reaction mixture at a rate that maintains the internal temperature in the range 75-85°C. Once the addition is complete, the reaction mixture is stirred for a further 2 hours at 75°C to destroy most of the remaining peroxides. Sodium sulfite is then added to finally destroy all the peroxides. The reaction mixture is concentrated in vacuo to afford 2- methyl- 1,2,3-propanetriol as a pale yellow, viscous, opaque oil. This oil is used in the next step without purification. ¹U NMR (299.94 MHz, DMSO) δ 0.97 (s, 3H), 3.21 (m, 4H), 4.02 (br s, IH), 4.37 (t, 2H). The crude 2-methyl-l,2,3-propanetriol (l.Omol equiv) is dissolved in acetone (lOmol equiv). Para-toluenesulphonic acid monohydrate (O.lOmol equiv) is added and the resulting mixture is stirred at ambient temperature for 2 hours. The pH of the reaction solution is then set to 7-8 by the addition of 10% sodium hydroxide solution, and the acetone is removed in vacuo. Fresh, dry acetone is added and the precipitate is removed by filtration. The filtercake is washed with more acetone. The combined filtrates are concentrated in vacuo to afford an oil. This is purified by vacuum distillation (120⁰C / 10-15mbar) to afford racemic acetonide as a clear, colourless oil. ¹H NMR (299.94 MHz, CDCl₃) δ 1.30 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.92 (t, IH, J= 6.6Hz), 3.49 (2H, m), 3.73 (IH, d, J = 8.7Hz), 3.98 (d, IH, J= 8.7Hz). m/z GCMS (CI) 147 (M+H), 131 (M-CH₃), 89 (M+H- C₂H₆O).

Method B:

A solution of methallyl alcohol (lmol equiv) and sodium tungstate dihydrate (O.Olmol equiv) in water (2 rel vols) is heated to 60⁰C. Hydrogen peroxide 35% solution in water (1.3mol equiv) is slowly added to the reaction mixture at a rate that maintains the internal temperature in the range 60-85⁰C. Once the addition is complete, the reaction mixture is stirred for a further 30 min at 70⁰C to destroy most of the remaining peroxides. The reaction mixture is then stirred for a minimum of 2h30min at 100⁰C to finally destroy all the peroxides. The reaction mixture is cooled to 50⁰C and water is distilled off under reduced pressure. The reaction mixture is concentrated in vacuo to afford 2 -methyl- 1,2,3- propanetriol as a pale yellow, viscous, opaque oil. This oil is used in the next step without purification. ¹U NMR (299.94 MHz, DMSO) δ 0.97 (s, 3H), 3.21 (m, 4H), 4.02 (br s, IH), 4.37 (t, 2H).

The crude 2-methyl-l,2,3-propanetriol (l.Omol equiv) is dissolved in acetone (lOmol equiv). Para-toluenesulphonic acid monohydrate (O.lOmol equiv) is added and the resulting mixture is stirred at ambient temperature for 2 hours. The pH of the reaction solution is then set to 7-8 by the addition of a solution of 0.6M aqueous NaHCO₃, and the acetone is removed under reduced pressure. The aqueous mixture is extracted 5 times with TBME (1.5 rel vol). The combined organic layers are dried by azeotropic distillation at atmospheric pressure. (Racemic (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol can be isolated as an oil by further concentration). IH NMR (299.94 MHz, CDCl₃) δ 1.30 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.92 (t, IH, J = 6.6Hz), 3.49 (2H, m), 3.73 (IH, d, J = 8.7Hz), 3.98 (d, IH, J = 8.7Hz). m/z GCMS (CI) 147 (M+H), 131 (M-CH3), 89 (M+H-C2H6O).

Example 2 Resolution of racemic (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol

(Method Al : using dihvdro-furan-2.5-dione)

Racemic (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol (477.6g, 3.27mol, l.Oequiv) is dissolved in TBME (2.39L). To this solution is added succinic anhydride (163.5g, 1.63mol, 0.5equiv) and the mixture is stirred at ambient temperature. The catalyst, Amano PS-D (23.9g, 5wt%) is added to the reaction mixture in one portion. The resulting mixture is then stirred at ambient temperature (21⁰C) for 2-6 hours, and the progress of the reaction is monitored by chiral GC analysis, checking for the complete disappearance of ((S)-2,2,4- trimethyl-l,3-dioxolan-4-yl)-methanol. The catalyst is removed by filtration and the filtercake is washed with TBME (478mL). The combined filtrates are treated with half- saturated sodium carbonate solution until the pH of the mixture is about 7-8 (about 1.2L in total is required for the neutralisation). The layers are separated and the aqueous layer is re- extracted with TBME (1.2L). The layers are separated and the combined organic layers are washed with brine (50OmL). The organic layer is collected and the solvent is removed to as low a volume as possible by distillation. The remaining solvent residues are removed using a rotavapour. The crude ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol is isolated as a pale yellow oil (197g, 1.35mol). This is purified by vacuum distillation (5mbar, 120⁰C jacket temperature) to give ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol as a clear, colourless oil (177g, 1.21mol). IH NMR (299.94 MHz, CDC13) δ 1.30 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.92 (t, IH, J = 6.6Hz), 3.49 (2H, m), 3.73 (IH, d, J = 8.7Hz), 3.98 (d, IH, J = 8.7Hz). m/z GCMS (CI) 147 (M+H), 131 (M-CH3), 89 (M+H-C2H6O).

(Method A2 : using dihydro-furan-2.5-dione)

To this solution of racemic (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol in TBME (1 mol equiv) is added succinic anhydride (0.41 mol equiv) and the mixture is stirred at ambient temperature. The catalyst, Lipase PS Amano IM (0.0309 rel weight) is added to the reaction mixture in one portion. The resulting mixture is then stirred at ambient temperature for 2-6 hours. The catalyst is removed by filtration. The filtrates are treated with a solution of 10%w/w aqueous sodium carbonate (0.25 mol equiv). The biphasic mixture is separated and the aqueous layer is re-extracted with TBME (2.3 rel vols). The biphasic mixture is separated and the combined organic layers are washed with a solution of 5%w/w aqueous sodium carbonate (0.02 mol equiv), until the pH of the mixture is 7.5- 8.0. TBME is removed by reduced pressure distillation to afford an oil. The crude ((R)- 2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol is isolated as a pale yellow oil. This is purified by distillation under reduced pressure to give ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl)- methanol as a clear, colourless oil in 27% yield (with respect to isobutenol) and 95% purity by GC. ¹H NMR (299.94 MHz, CDCl₃) δ 1.30 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.92 (t, IH, J= 6.6Hz), 3.49 (2H, m), 3.73 (IH, d, J= 8.7Hz), 3.98 (d, IH, J= 8.7Hz). m/z GCMS (CI) 147 (M+H), 131 (M-CH₃), 89 (M+H-C₂H₆O).

(Method B : using dodecanoic acid vinyl ester)

Racemic (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol (2Og, 117.7mmol, l.Oequiv) is dissolved in TBME (10OmL). To this solution is added dodecanoic acid vinyl ester (15.6mL, 58.8mmol, 0.5equiv) and the mixture is stirred at ambient temperature. The catalyst, Amano PS-D (1.0 g, 5wt%) is added to the reaction mixture in one portion. The resulting mixture is then stirred at ambient temperature (21⁰C) for 7-9 hours, and the progress of the reaction is monitored by chiral GC analysis, checking for the complete disappearance of ((S)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol. The catalyst is removed by filtration and the filtercake is washed with TBME (2x2 OmL). The combined filtrates are concentrated in vacuo to afford a clear, colourless oil. This crude product mixture is purified by vacuum distillation (140⁰C / 40-50mbar) using the wiped film evaporator to give ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol as a clear, colourless oil (6g, 41. lmmol).1H NMR (299.94 MHz, CDCl₃) δ 1.30 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.92 (t, IH, J= 6.6Hz), 3.49 (2H, m), 3.73 (IH, d, J= 8.7Hz), 3.98 (d, IH, J = 8.7Hz). m/z GCMS (CI) 147 (M+H), 131 (M-CH₃), 89 (M+H-C₂H₆O).

Example 3

Preparation of succinic acid mono-((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester Racemic (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol (6Og, 41 l.Ommol, l.Oequiv) is dissolved in TBME (30OmL). To this solution is added succinic anhydride (20.54g, 205.5mmol, 0.5equiv) and the mixture is stirred at ambient temperature. The catalyst, Amano PS-D (3g, 5wt%) is added to the reaction mixture in one portion. The resulting mixture is then stirred at ambient temperature (21°C) for 5-7 hours, and the progress of the reaction is monitored by chiral GC analysis, checking for the complete disappearance of ((S)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol. The catalyst is removed by filtration and the filtercake is washed with TBME (2x3 OmL). The combined filtrates are concentrated in vacuo. The products are separated by vacuum distillation (120⁰C, 5mbar) using the wiped film evaporator. ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol is isolated as a clear, colourless oil (26.7g, 182.9mmol) and succinic acid mono- {(R)-2,2,4-trimethyl- 1,3- dioxolan-4-yl-methyl} ester is isolated as a clear, colourless oil (45.6 g, 185.1 mmoles). ¹H NMR (299.94 MHz, CDCl₃) δ 1.32 (s, 3H), 1.41 (s, 6H), 2.69 (m, 4H), 3.72 (d, IH, J = 8.7Hz), 3.95 (IH, d, J= 8.7Hz), 4.02 (d, 1H, J= 11.2Hz), 4.07 (d, 1H, J= 11.2Hz).

Example 4

Preparation of dodecanoic acid ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester

Racemic (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol (5g, 34.25mmol, l.Oequiv) is dissolved in TBME (25mL). To this solution is added dodecanoic acid vinyl ester (3.9mL, 14.7mmol, 0.5equiv) and the mixture is stirred at ambient temperature. The catalyst, Amano PS-D (0.25g, 5wt%) is added to the reaction mixture in one portion. The resulting mixture is then stirred at ambient temperature (21⁰C) for 7-9 hours, and the progress of the reaction is monitored by chiral GC analysis, checking for the complete disappearance of ((S)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol. The catalyst is removed by filtration and the filtercake is washed with TBME (2x5mL). The combined filtrates are concentrated in vacuo to afford a clear, colourless oil. This crude product mixture is purified by vacuum distillation (130-150 ⁰C / 30-50 mbar) to give ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl)- methanol as a clear, colourless oil (2.48g, 17.0mmol) and dodecanoic acid {(i?)-2,2,4- trimethyl-l,3-dioxolan-4-yl-methyl} ester (5.6 Ig, 17.1mmol) as a pale yellow oil. ¹H NMR (399.82 MHz, CDCl₃) δ 0.88 (t, 3H, J= 7.2Hz), 1.35 (s, 3H), 1.41 (s, 6H), 1.29 (m, 16H), 1.63 (t, 2H, J= 7.2Hz), 2.34 (t, 2H, J= 7.6Hz), 3.73 (d, IH, J= 8.8Hz), 3.96 (IH, d, J = 8.8Hz), 3.99 (d, IH, J= 11.2Hz), 4.03 (d, IH, J= 10.8Hz). m/z GCMS (CI) 329 (M+H), 313 (M-CH₃), 271 (M+H-C₂H₆O). Example 5

Preparation of ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol by enzymatic resolution of butyric acid ((R,S)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester

Racemic butyric acid (2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (5g, 23.12mmol, 1.Oequiv) is dissolved in tert-buyl alcohol (45mL) and water (5mL). The catalyst, Amano PS-D (0.25g, 5wt%), is added to the reaction solution. The resulting mixture is stirred moderately and heated at 30⁰C for no more than 20 hours. The progress of the reaction is monitored by chiral GC analysis, checking for the complete disappearance of butyric acid ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester. The reaction mixture is cooled to ambient temperature and filtered to remove the catalyst. The solvent is removed in vacuo and the residual oil is dissolved in TBME (5OmL). This organic solution is washed with half-saturated sodium carbonate solution (2OmL) to remove the butyric acid by-product. The organic phase is collected, dried (over MgSO₄), filtered and concentrated in vacuo to afford a clear, colourless oil. This oil is purified by column chromatography (silica; 3% ethyl acetate in z^'sø-hexane elution) to afford butyric acid ((S)-2,2,4-trimethyl-l,3-dioxolan- 4-yl-methyl) ester as a clear, colourless oil (2.Og, 9.33mmol). ¹H NMR (399.82 MHz, CDCl₃) δ 0.96 (t, 3H, J= 7.6Hz), 1.32 (s, 3H), 1.41 (s, 6H), 1.66 (sextet, 2H, J= 7.6Hz), 2.33 (t, 2H, J= 7.6Hz), 3.72 (d, IH, J= 8.8Hz), 3.95 (d, IH, J= 8.8Hz), 3.99 (d, IH, J = 11.2Hz), 4.03 (d, IH, J= 11.2Hz). m/z GCMS (CI) 217 (M+H), 201 (M-CH₃), 159 (M+H- C₂H₆O).

Butyric acid ((S)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (1.Og, 4.62mmol, 1 equiv) is dissolved in TBME (5mL). 1 M Sodium hydroxide solution (5mL) is added and the resulting mixture is stirred at ambient temperature for 22 hours. Sodium chloride is added to saturate the aqueous phase and TBME (1OmL) is added. The mixture is stirred before separating the layers. The organic layer is collected, dried (over MgSO₄), filtered and concentrated in vacuo to afford ((R)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol as a clear, colourless oil (0.6g, 4.1 lmmol). ¹R NMR (299.94 MHz, CDCl₃) δ 1.30 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.92 (t, IH, J= 6.6Hz), 3.49 (2H, m), 3.73 (IH, d, J=8.7 Hz), 3.98 (d, IH, J=8.7 Hz). m/z GCMS (CI) 147 (M+H), 131 (M-CH₃), 89 (M+H-C₂H₆O).

Intermediate B Example 6

Preparation of 3-fluoro-4-nitrophenol by nitration of 3-fluorophenol

Method A

3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99% (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-25⁰C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10% solution of sodium carbonate (4* 10OmL) to remove any acetic acid.

TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29% yield and 97.9% purity by HPLC. ¹H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). ¹⁹F-NMR (376.209MHz, DMSO) δ - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H)

Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid

99% (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-25⁰C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3% aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-80⁰C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-5⁰C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27% yield and 97.4% purity by HPLC.

Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-100⁰C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-5⁰C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77% yield (recrystallisation only) and 99.2% purity by HPLC. ¹H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). ¹⁹F-NMR (376.209MHz, DMSO) δ -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)

Intermediate C Example 7 Preparation of 4-Amino-l-(4-chloro-benzyl)-pyridinium chloride

A solution of l-chloro-4-chloromethyl benzene (18.8g, 117mmol, l.lequiv) in toluene (5OmL) was added to a mixture of pyridin-4-ylamine (1Og, 106mmol, leq) in toluene (10OmL). The reaction was heated at 7O⁰C overnight. After cooling to ambient temperature, the solid product was collected by filtration, washed with toluene (2 x 5OmL) then dried in a vacuum oven at 45⁰C overnight to give the title compound as a white solid in 86% yield. ¹H-NMR (399.825 MHz, D₂O) δ 8.00 (d, J= 7.4Hz, 2H), 7.44 (d, J= 8.2Hz, 2H), 7.30 (d, J= 8.5Hz, 2H), 6.83 (d, J= 7.2Hz, 2H), 5.28 (s, 2H). m/z LCMS (ESI -ve) 219/221 (M+H)

Example 8

Preparation of l-(4-chloro-benzyl)-piperidin-4-ylamine

(Method A : using sodium borohydride)

Sodium borohydride (0.17g, 4.5mmol, 2.6equiv) was added to a suspension of 4-amino-l- (4-chlorobenzyl)-pyridinium chloride (0.45g, 1.76mmol, lequiv) in THF (4.5mL) at ambient temperature. After one hour at this temperature, no reaction had taken place, so methanol (4.5mL) was slowly added causing hydrogen evolution and a slight exotherm. After stirring at ambient temperature for 22 hours, further sodium borohydride (0.17g, 4.5mmol, 2.6equiv) was added and stirring continued at ambient temperature overnight. An additional portion of sodium borohydride (0.17g, 4.5mmol, 2.6equiv) was added and stirring continued for a further 2 days. Aqueous sodium hydroxide (1OmL) was added followed by ethyl acetate and the mixture was stirred vigorously. The layers were allowed to separate. The organic layer was washed with water (1OmL), 20% aqueous sodium chloride solution (1OmL) then evaporated to dryness in vacuo to leave an opaque oil. Analysis of this crude product by HPLC and GC showed 74 area% and 84 area% respectively of the title compound in 59% yield. ¹H-NMR (399.822 MHz, DMSO) δ 7.38- 7.28 (m, 4H), 5.80 (b, 2H), 3.41 (s, 2H), 2.73-2.64 (m, 3H), 1.97 (dt, J=2.2, 11.5Hz, 2H), 1.78 (s, 3H), 1.73-1.72 (m, 2H), 1.35 (dq, J=3.9, 11.5Hz, 2H). m/z LCMS (ESI +ve) 225/227 (M+H) (Method B : by hydrogenation in the presence of a rhodium on charcoal)

A solution of 4-amino-l-(4-chlorobenzyl)-pyridinium chloride (lOOmg, 0.39mmol, lequiv) in ethanol (2.5mL) was hydrogenated in the presence of 5% rhodium on charcoal paste (lOOmg, 41% w/w) at 4.5bar hydrogen pressure at ambient temperature for 16 hours. Analysis of the reaction mixture at this point by GC and HPLC indicated presence of the title compound as the major component of the reaction mixture by comparison with an authentic sample. ¹H-NMR (399.822 MHz, DMSO) δ 7.38-7.28 (m, 4H), 5.80 (b, 2H), 3.41 (s, 2H), 2.73-2.64 (m, 3H), 1.97 (dt, J=2.2, 11.5Hz, 2H), 1.78 (s, 3H), 1.73-1.72 (m, 2H), 1.35 (dq, J=3.9, 11.5Hz, 2H). m/z LCMS (ESI +ve) 225.00 (M+H)

(Method C : by selective alkylation of piperidin-4-ylamine)

Piperidin-4-ylamine 94.9% (24.7kg, 234mol, lequiv) and MIBK (194L) were heated up at reflux for 4-24h. The mixture was cooled to below 30⁰C and a solution of NaOH 20% (71.5kg, 355.3mol, 1.52equiv) was added, followed by a solution of l-chloro-4- chloromethyl benzene (37.4kg, 232.2mol, 0.99equiv) in MIBK (39L). The mixture was allowed to stir at room temperature for 6-24h. The reaction mixture was quenched by addition of water (100L). The biphasic mixture was separated and acetic acid (21.2kg, 353.5mol, 1.5 lequiv) was added to the organic layer resulting in the precipitation of acetate 4-amino-l-(4-chloro-benzyl)-piperidinium. The solid was collected by filtration and further dried in a vacuum oven at 50⁰C overnight. Yield :65%, Purity by HPLC: 99.5%area. ¹H-NMR (399.822 MHz, DMSO) δ 7.38-7.28 (m, 4H), 5.80 (b, 2H), 3.41 (s, 2H), 2.73-2.64 (m, 3H), 1.97 (dt, J=2.2, 11.5Hz, 2H), 1.78 (s, 3H), 1.73-1.72 (m, 2H), 1.35 (dq, J=3.9, 11.5Hz, 2H). m/z LCMS (ESI +ve) 225/227 (M+H) Example 9

Preparation of piperidin-4-ylamine

A solution of pyridin-4-ylamine (lOOmg, l.Oόmmol, equiv) in a mixture of isopropanol (2.5mL) and aqueous hydrochloric acid (5 M, 0.3mL) was hydrogenated in the presence of 5% rhodium on charcoal paste (50 mg, 41% w/w) at 4.5bar hydrogen pressure at ambient temperature for 16 hours. Analysis of the reaction mixture at this point by GC indicated a mixture of piperidin-4-ylamine and pyridin-4-ylamine in approximately a 3:2 ratio by area.

Claims

1. A process for the preparation of succinic acid mono-((i?)-2,2,4-trimethyl-l,3-dioxolan-4- yl-methyl) ester by reacting (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol with dihydro- furan-2.5-dione.

2. A process for the preparation of dodecanoic acid ((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl- methyl) ester by reacting (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol with dodecanoic acid vinyl ester.

3. The process according to claims 1 or 2 using solvents selected from tert-butylmethyl ether.

4. The process according to any one of claims 1 to 3 using catalyst is Pseudomonas cepacea lipase.

5. The compounds succinic acid mono-((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (A.R-5) and dodecanoic acid ((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (A.R-6).

6. The use of (2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol in the preparation of succinic acid mono-((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (A.R-5) and dodecanoic acid ((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl-methyl) ester (A.R-6).

7. A process for the preparation of ((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol from butyric acid ((i?,5)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methyl ester through enzymatic resolution.

8. The process according to claim 7 wherein the enzyme Candida antarctica lipase B is used for the enzymatic resolution.

9. The process according to claims 7 or 8 using solvents selected from tert-butano I/water (9/1) or nBuOH/ tert-Butylmethyl ether.

10. A process for preparation of 3-fluoro-4-nitrophenol from 3-fluorophenol using a nitrating agent and cyclohexane or methylcyclohexane.

11. The process according to claim 10 using nitric acid as a nitrating agent.

12. The process according to claims 10 or 11 using solvents selected from water, acids (acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, propionic acid, sulfuric acid, nitric acid), organic solvents (tetrahydrofuran, dichloromethane) and combinations thereof, nitric acid as the nitrating agent and cyclohexane or methylcyclohexane.

13. The process according to claim 10 using iron nitrate or bismuth nitrate as a nitrating agent.

14. A process for the preparation of l-(4-chloro-benzyl)-piperidin-4-ylamine (C) by reducing l-(4-chloro-benzyl)-piperidin-4-ylamine (C.2) using a rhodium on charcoal catalyst under hydrogenation conditions.

15. The process according to claim 14 using solvents selected from alcoholic solvents.

16. A process for the preparation of piperidin-4-ylamine (C.3) by reducing pyridin-4- ylamine (Cl) using rhodium on charcoal catalyst under hydrogenation conditions.

17. The use of intermediates ((i?)-2,2,4-trimethyl-l,3-dioxolan-4-yl)-methanol (A), 3- fluoro-4-nitro-phenol (B) and l-(4-chloro-benzyl)-piperidin-4-ylamine (C) in the preparation of 2-{2-chloro-5-{[(25)-3-(5-chloro-lΗ,3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid (Ia).