WO2014096018A1

WO2014096018A1 - Methods for the preparation of substituted acetophenones

Info

Publication number: WO2014096018A1
Application number: PCT/EP2013/077114
Authority: WO
Inventors: André FALDT; Jakob TORÄNG; Kim Troensegaard Nielsen; Lene Hoffmeyer Ringborg
Original assignee: Leo Pharma A/S
Priority date: 2012-12-19
Filing date: 2013-12-18
Publication date: 2014-06-26

Abstract

The present application discloses novel methods for the preparation of pyrid-4-yl substituted acetophenones, in particular 2-{6-[2-(3,5-dichloro-pyridin-4-yl)-acetyl]-2,3-dimethoxy-phenoxy}-N-propyl-acetamide. The application also discloses novel stable crystalline forms of 2-{6-[2-(3,5-dichloro-pyridin-4-yl)-acetyl]-2,3-dimethoxy-phenoxy}-N-propyl-acetamide.

Description

METHODS FOR THE PREPARATION OF SUBSTITUTED ACETOPHENONES

FIELD OF THE INVENTION

The present invention relates to novel methods for the preparation of pyrid-4-yl substituted acetophenones. BACKGROUND OF THE INVENTION

WO 2008/077404 Al discloses novel substituted acetophenones useful as PDE4 inhibitors as well as suitable methods for the preparation thereof.

In the development of new drug candidates, it is highly desirable to have access to a number of alternative methods for the preparation of target compounds in that some efficient small- scale synthesis may turn out to be difficult to up-scale to production scale quantities. Also, small-scale syntheses may involve reagents and solvents which are not feasible to utilize at a production scale level.

Hence, it is an object of the present invention to provide alternative methods for the preparation of substituted acetophenones of the type disclosed in WO 2008/077404 insofar that such alternative methods provide advantages with respect to one or more features like purity, yield, ease of purification, process economy, availability of starting materials and reagents, safety, predictability, etc.

SUMMARY OF THE INVENTION

It has been found by the present inventors that at least some of the above-mentioned features can be improved by utilizing the alternative methods disclosed herein.

Hence, the present invention provides three alternative methods for the preparation of pyrid- 4-yl substituted acetophenones, e.g. a compound of the formula I, cf. claims 1, 8 and 12.

The present invention also provides novel crystalline forms of 2-{6-[2-(3,5-dichloro-pyridin-4- yl)-acetyl]-2,3-dimethoxy-phenoxy}-N-propyl-acetamide. LEGEN DS TO TH E FIGURE

Figure 1 illustrates the first alternative method for the preparation of a compound of the formula I through the alkylation of a compound of the formula II with a compound of the formula III. Figure 2 illustrates the second alternative method for the preparation of a compound of the formula I through a nucleophilic substitution of a compound of the formula VII with an anion of the formula VIII.

Figure 3 illustrates the third alternative method for the preparation of a compound of the formula I through the al kylation of a pyridine of the formula V with an anion of the formula X. Figure 4 shows a X-ray powder diffraction pattern for crystalline Form A of compound (1) .

Figure 5 illustrates the single-crystal X-ray structure of crystalline Form A of compound ( 1) showi ng the configuration of the compound and the atomic labelling . The thermal ellipsoids are scaled to enclose 50% probability and the hydrogen atoms are drawn as fixed spheres.

Figure 6 illustrates the unit cell of crystalline Form A of compound ( 1) seen perpendicularly to the b axis. Notify that n (pi) stacking along the b axis occurs and that the unit cell contains 4 molecules.

Figure 7 shows a X-ray powder diffraction pattern for crystalline Form B of compound (1) .

Figure 8 illustrates the single-crystal X-ray structure of crystalline Form B of compound ( 1) showing the configuration of the compound and the atomic labelling . The thermal ellipsoids are scaled to enclose 50% probability and the hydrogen atoms are drawn as fixed spheres.

Figure 9 illustrates the unit cell of crystalline Form B of compound ( 1) seen perpendicularly to the b axis. Notify that n (pi) stacking along the b axis occurs and that the unit cell contains 8 molecules.

DETAILED DISCLOSURE OF TH E INVENTION The present invention relates to alternative methods for the preparation of compounds of the formula I

wherein

Ri and R₂ are independently selected from Ci-6-alkyl, C₃-₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈- cycloalkyl) and C₂-6-alkenyl;

R₃ is selected from hydrogen, Ci-₆-alkyl, C₃.₈-cycloalkyl, and Ci-₃-alkyl-(C₃.₈-cycloalkyl); R₄ is selected from Ci-6-alkyl, C₃.₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci-₃-alkyl-phenyl and Ci-₃-alkyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; or R₃ and R₄ together with the intervening nitrogen atom represent an N-heterocyclic ring optionally substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; and each Q is selected from chloro, bromo and fluoro.

In the compound of the formula I, Ri and R₂ are typically independently selected from Ci-₆- alkyl, C₃.₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈-cycloalkyl) and C₂-6-alkenyl . In some preferred embodiments, Ri and R₂ are independently selected from Ci-₆-alkyl, C₃.₈-cycloalkyl and Ci_₃- alkyl-(C₃.₈-cycloalkyl), e.g. from Ci-₆-alkyl, in particular from Ci_₃-alkyl, such as methyl, ethyl, prop-l-yl and prop-2-yl, especially methyl.

R₃ is typically selected from hydrogen, Ci-₆-alkyl, C₃.₈-cycloalkyl, and Ci-₃-alkyl-(C₃.₈-cyclo- alkyl). In some preferred embodiments, R₃ is selected from hydrogen and Ci-₆-alkyl, e.g. from hydrogen and Ci_₃-alkyl, in particular R₃ is hydrogen. R₄ is typically selected from Ci-6-al kyl, C₃-₈-cycloalkyl, Ci-₃-alkyl-(C₃-8-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci-3-al kyl-phenyl and Ci-₃-al kyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-6-alkyl, Ci-₆-alkoxy and halogen. In some embodiments, R₄ is selected from Ci-₆-al kyl, Ci-₃-alkyl-(C₃-₈-cycloalkyl), Ci_₃-alkyl-phenyl and Ci-₃-al kyl-pyridyl, wherein any phenyl and pyridyl may be substituted as mentioned above, e.g . from Ci-₆-alkyl and Ci-₃-alkyl-(C₃.₈-cycloalkyl), in particular from Ci_₃-al kyl (like prop-l-yl and) -CH₂-cyclohexyl .

Alternatively, R₃ and R₄ may together with the intervening nitrogen atom represent an N- heterocyclic ring optionally substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen. In some embodiments, the heterocyclic ring is selected from pyrrolidinyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,2- thiazolyl, 1,3-thiazolyl, piperidinyl, pyridazinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl and tetrazolyl, e.g . from piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl .

Q is typically selected from chloro, bromo and fluoro, preferably chloro, where the Q's preferably are the same. In one embodiment, both Q's are chloro.

One particularly interesting sub-class of compounds of the formula I are those where Ri and R₂ are independently selected from Ci_₃-alkyl ; R₃ is selected from hydrogen and Ci_₃-al kyl; R₄ is selected from Ci-₆-alkyl, C₃.₈-cycloalkyl, Ci-₃-al kyl-(C₃.₈-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci_-3- alkyl-phenyl and Ci-₃-alkyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-₆-alkyl, Ci-6-al koxy and halogen; and each Q is chloro.

Another particularly interesting sub-class of compounds of the formula I are those where Ri and R₂ are independently selected from Ci_₃-alkyl ; R₃ and R₄ together with the intervening nitrogen atom represent an N-heterocyclic ring optionally substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; and each Q is chloro. In one embodiment, R_x and R₂ are both methyl, R₃ is hydrogen, and R₄ is prop-l-yl .

In another embodiment, R_x and R₂ are both methyl, R₃ is hydrogen, and R₄ is -CH₂- cyclohexyl .

Definitions

The term "Ci-6-alkyl" is intended to mean a saturated, straight or branched hydrocarbon chain having from one to six carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. In some embodiments, "Ci-6-alkyl" is a Ci-₄-alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl. Correspondingly, "C_halky!" includes methyl, ethyl, propyl and isopropyl.

The term "C₃-₈-cycloalkyl" is intended to mean a cyclic alkyl group having from three to eight carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Furthermore, the term "cycloalkyl" as used herein may also include polycyclic groups such as for example bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptanyl . In some embodiments, "C₃-₈-cycloalkyl" is a C₃-6-cycloalkyl group, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "C₂-6-alkenyl" is intended to mean a straight or branched hydrocarbon chain or cyclic hydrocarbons comprising from two to six carbon atoms and containing one or more double bonds, including di-enes and tri-enes. Examples of alkenyl groups include ethenyl; 1- and 2- propenyl; 1-, 2- and 3-butenyl, and 1,3-but-dienyl; 1-, 2-, 3-, 4- and 5-hexenyl, and 1,3- hexa-dienyl, and 1,3,5-hexa-trienyl; and cyclohexenyl. The term "Ci-6-alkoxyl" is intended to mean Ci-₆-alkyl-0- wherein "Ci-6-alkyl" is as defined above.

The term "halogen" is intended to mean one of fluoro, chloro, bromo and iodo. Preferably, the term "halogen" designates fluoro or chloro.

The term "aryl" is intended to mean a carbocyclic aromatic ring system derived from an aromatic hydrocarbon by removal of a hydrogen atom. Aryl furthermore includes bi-, tri- and polycyclic ring systems. Examples of preferred aryl moieties include phenyl, naphthyl, indenyl, indanyl, fluorenyl, and biphenyl. Preferred "aryl" is phenyl, naphthyl or indanyl, in particular phenyl, unless otherwise stated.

The term "N-heterocyclic ring" is intended to mean a heterocyclic ring or a heteroaromatic ring having at least one nitrogen atom, and being bound via a nitrogen atom. Examples of such N-heterocyclic rings are pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, piperidinyl, pyridazinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl, etc.

Combined terms like "Ci-₃-alkyl-(C₃-₈-cycloalkyl)", "Ci-₃-alkyl-phenyl" and "Ci-₃-alkyl-pyridyl" are - unless otherwise indicated - understood a having the radical position (a bond) at the left-hand side, e.g. "Ci-₃-alkyl-(C₃.₈-cycloalkyl)" is read as -(Ci-₃-alkyl)-(C₃.₈-cycloalkyl), i.e. where the group is attached via the Ci_₃-alkyl group. First alternative method

It appears that the first alternative method provides advantages over the known methods by relying on cheap starting materials, and ease of the production method since intermediates are precipitated directly from the reaction mixtures. II + III -> I

The first alternative method for the preparation of a compound of the formula I includes the step of alkylating a compound of the formula II

wherein R_x, R₂ and Q are as defined above for the compound of the formula I, with an amide compound of the formula III

wherein X is selected from chloro and bromo, and R₃ and R₄ are as defined above for the compound of the formula I. Preferably both Q in the compound of the formula II are chloro.

The alkylation reaction is typically conducted in an aprotic polar solvent, e.g. selected from DMSO (dimethyl sulfoxide), DMF (Ν,Ν-dimethylformamide), DMI (l,3-dimethyl-2-imidazo- lidinone), NMP (N-methylpyrrolidone), EtOAc (ethyl acetate), MeCN (acetonitrile) and THF (tetrahydrofuran), and mixtures hereof, in the presence of a base, e.g. selected from K₂C0₃, Na₂C0₃, KHCO3, NaHCOs, tert-BuONa (sodium tert-butoxide), tert-BuOK (potassium tert- butoxide), Et₃N (triethylamine) and DIPEA (Ν,Ν-diisopropylethylamine). In one embodiment, the aprotic solvent is selected from DMSO, NMP and THF and mixtures thereof, in the presence of K₂C0₃ as the base. In another embodiment, the aprotic solvent is selected from a DMSO/THF mixture and a NMP/THF mixture, in the presence of K₂C0₃ as the base. In a particular embodiment, the aprotic solvent is DMSO and the base is K₂C0₃.

The ratio between the solvent and the compound of formula II may have an influence in relation to the impurities formed. Hence, it is typically preferred that the solvent to compound ratio (i.e. the solvent:formula II v/w ratio) is in the order of 1 : 1 to 5: 1, where a ratio of 1 : 1 to 2.1 : 1 appears to have positivie influence on the suppression of the formation of impurities, in particular when DMSO is selected as the solvent.

The compound of formula III is typically used in excess, e.g. such that the molar ratio (formula III)/(formula II) is from 1 : 1 to 3 : 1, in particular from 1 : 1 to 1.75: 1. The base is usually used in approximately stoichiometric amounts relative to the compound of the formula II, such as where the equivalent ratio (base)/(formula II) is from 0.3 : 1 to 3 : 1, in particular from 0.5: 1 to 2: 1.

The alkylation reaction is typically conducted at a temperature in the range of 20-100 °C, such as in the range of 40-80 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc. The reaction is typically allowed to proceed for 4-72 hours, such as 16-24 hours. The end-point for the reaction may alternatively be set as the presence of e.g. about 2 % of the compound of the formula II. The reaction is typically terminated by quenching under stirring with a solution of an acid, such as acetic acid (AcOH), trifluoro acetic acid (TFA), H₃P0₄, H₂S0₄, HCI, etc., in an polar organic solvent, such as DMSO, ethanol, 2-propanol, acetone, MeOH or MeCN. The amount of acid used should be so as to neutralise the base rather than markedly acidifying the solution.

After the quenching reaction is completed, the crude product (crude I) is typically obtained by precipitation upon addition of water. Alternatively, the product can be obtained by addition of an organic aqueous solvent, e.g. EtOAc and water or toluene and water, followed by extraction (organic phase), washing and evaporation/concentration prior to re-precipitation from either acetone/water or from DMSO/IPA/water. Washing with a mild (e.g. 5 %) aqueous solution of e.g. AcOH provides a product which is very clean and white in appearance.

In one interesting embodiment, the alkylation reaction is conducted in an aprotic polar solvent, e.g. from DMSO, in the presence of a base, e.g. K₂C0₃, using the compounds of the formulas II and III in a molar ratio (formula III)/(formula II) from 1 : 1 to 1.75: 1, and the base in approximately stoichiometric amounts relative to the compound of the formula II, such as an equivalent ratio (base)/(formula II) from 0.5: 1 to 2: 1. Within this embodiment, the alkylation is preferably conducted at a temperature in the range of 40-80 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc., and is allowed to proceed for 16-24 hours, or until an end-point set as the presence of e.g. about 2 % of the compound of the formula II is reached. The reaction is terminated by quenching under stirring with a weak acid, such as acetic acid (AcOH), used in equivalent amounts relative to the base. After the quenching reaction is completed, the crude product (crude I) is typically obtained by precipitation by addition of water. Purification of I

The resulting product (crude I) may advantageously be purified by precipitation,

chromatography or the like.

In one embodiment, the resulting product is re-precipitated by first suspending the crude I in acetone, e.g. from 1 : 1 to 5: 1 (w/w acetone:crude I), such as from 1 : 1 to 2 : 1; subsequently adjusting the temperature to about 40-60 °C, such as 45-55 °C; addition of water, e.g. from 1 : 1 to 10: 1 (w/w water:crude I), such as from 1 : 1 to 3 : 1; stirring at a temperature of about 40-60 °C, such as 45-55 °C, for about 5-48 hours, such as 15-24 hours; cooling of the mixture (solution or suspension) to about 0-30 °C, such as 20-30 °C under stirring for about 1-24 hours, such as 2-5 hours; and finally collection of the purified I as a precipitate. (In case of a solution being formed upon stirring, the solution is preferably cooled to 30-35 °c to induce crystal formation before the crystals are matured at 45-55 °C. This subsequent maturing/stirring is found to produce more a filterable suspension.) The collected solid is washed using a mixture of acetone and water followed by drying in vacuum at about 35-55 °C, such as 40-50 °C. The purification procedure is particularly suited when the amount of unreacted starting material (compound II) is below about 0.2 %.

In another embodiment, the resulting product is re-precipitated by first suspending the crude I in DMSO and 2-propanol (IPA), e.g. from 1 : 1 to 5: 1 (w/w DMSO:crude I), such as from 1 : 1 to 2: 1, and from 1 : 1 to 5: 1 (w/w IPA:crude I), such as from 1 : 1 to 2 : 1 ; subsequently adjusting the temperature to about 35-55 °C, such as 40-50 °C, until completed dissolution of the compound I; addition of water, e.g. from 1 : 1 to 10: 1 (w/w water:crude I), such as from 1 : 1 to 3 : 1; stirring at a temperature of about 35-55 °C, such as 40-50 °C, for about 5-48 hours, such as 15-24 hours; cooling of the mixture to about 0-30 °C, such as 20-30 °C under stirring for about 1-24 hours, such as 2-5 hours; and collection of the precipitate by filtration; washing of the filter cake 2-4 times with DMSO/IPA/water (e.g. in a ratio of about 3 :4:8, v/v/v) and 1-3 times with water; and finally drying in vacuo at about 35-55 °C, such as 40-50 °C. This purification procedure is particularly suited when the amount of unreacted starting material (compound II) is above about 0.2 %.

Other alternative purification methods (suspension/dissolution and re-precipitation) involve the use of mixtures of THF/heptane, EtOAc/heptane, toluene/MTBE, acetone/water,

EtOH/water, etc.

Also, the crude I may be dissolved, e.g. in toluene, THF/toluene (e.g. 1 :2 v/v) or

EtOAc/heptane (e.g. 1 :2 v/v), and may then be filtered through e.g. activated charcoal or a combination of activated charcoal and silica gel. In one embodiment, when the crude I is obtained by addition of a weak acid in a 2-propanol solution and the precipitation is effected by addition of water, possibly under simultaneous cooling, the addition of water is typically carried out at 40-50 °C to avoid crashing out of lumbs and/or oils. The mixture is typically stirred at 35-45 °C overnight to allow for the crystals to mature, and in this way an easier to filter solid is produced, and the procedure is also likely to remove some more colour from solid material. The suspension is then cooled to room temperature within 1-2 hours followed by further cooling to 0-5 °C for e.g. another 1 hour before collected the product by filtration.

IV ^ II

The compound of the formula II may be obtained as disclosed in WO 2008/077404. However, advantageously, it is prepared by dealkylation of a compound of the formula IV

wherein R_lr R₂ and Q are as defined above for the compound of the formula I, and R_x is selected from Ci_₃ alkoxy, in particular methoxy.

Preferably, both Q in the compound of the formula IV are chloro. The dealkylation may be conducted using one of various possible reagents, such as various Lewis acids, e.g . BCI₃ (e.g . BCI₃ in an apolar solvent like toluene or BCI₃ as a gas), AICI₃ (e.g . AICI₃ in Et₃N), LiCI (e.g . LiCI in DMF). In one preferred embodiment, the dealkylation reaction is conducted using BCI₃ in an apolar solvent, e.g. toluene, or using BCI₃ as a gas.

Typically, the compound of the formula IV is suspended or dissolved in an aprotic apolar solvent, such as toluene, heptane or dichloromethane. The reagent is added - typically gradually - in excess. Typically, the reagent is used such that the equivalent ratio

(reagent)/(formula IV) is from 1 : 1 to 2.5 : 1, in particular from 1.3 : 1 to 2 : 1.

The dealkylation reaction is typically conducted at a temperature in the range of 10-50 °C, such as in the range of 25-45 °C. The reaction is typically allowed to proceed for 5-24 hours, such as 16-24 hours. The end-point for the reaction may alternatively be set as the presence of e.g . about 5 % of the compound of the formula IV. The reaction is typically terminated by quenching under stirring by slow addition of a solution of a base, such as NaOH, in a water/EtOH mixture. After the quenching reaction is completed, the product (crude II) is typically obtained by precipitation after pH adjustment to around 6 to 7 and cooling . In one preferred embodiment, the compound of the formula IV is suspended or dissolved in an aprotic apolar solvent, such as toluene, and the dealkylation is conducted using BCI₃ in an aprotic apolar solvent, preferably toluene, such that the equivalent ratio (reagent)/(formula IV) is from 1.3 : 1 to 2.1 : 1, and at a temperature in the range of 10-45 °C. The reaction is allowed to proceed for 3-24 hours, or to an end-point set as the presence of e.g. about 5 % of the compound of the formula IV. The reaction is terminated by quenching under stirring with aqueous solution of a base, such as NaOH, KOH, NH₃ etc. After the quenching reaction is completed, the product (II) is obtained by precipitation after pH adjustment to around 6 to 7 and cooling.

In another preferred embodiment, the compound of the formula IV is suspended or dissolved in an aprotic apolar solvent, such as toluene, and the dealkylation is conducted adding BCI₃ gas such that the equivalent ratio (reagent)/(formula IV) is from 1.3 : 1 to 2.1 : 1, and at a temperature in the range of 10-45 °C. The reaction is allowed to proceed for 3-24 hours, or to an end-point set as the presence of e.g. about 5 % of the compound of the formula IV. The reaction is terminated by quenching under stirring with solution of a base, such as NaOH, KOH, NH₃ etc., in water. After the quenching reaction is completed, the product (II) is obtained by precipitation after pH adjustment to around 6 to 7 and cooling.

The compound of formula II may suitably be purified by recrystallization from suitable solvents like EtOH, MeOH, EtOAc, MeCN. It can also be used in the alkylation step without further purification.

V + VI ^ IV

The compound of the formula IV may be obtained as disclosed in WO 2008/077404. However, advantageously, it is prepared by alkylating a pyridine of the formula V

wherein Q is as defined above for the compound of the formula I, in particular chloro, and Q_x is selected from fluoro, chloro, bromo and iodo, preferably chloro, with an anion of the formula VI

wherein R_lr R₂ and R_x are as defined above for the compound of the formula I. Preferably, the compound of the formula V is 3,4,5-trichloro-pyridine.

The anion of the formula VI is typically prepared in-situ by deprotonation of the corresponding acetophenone in an aprotic polar solvent, e.g. selected from THF, methyl-THF, DMF, DMSO, NMP and MeCN, in the presence of a strong non-nucleophilic base, e.g. selected from lithium bis(trimethylsilyl)amide (LHMDS), potassium bis(trimethylsilyl)amide (KHMDS), tert-BuONa, tert-BuOK, tert-BuOLi, K₂C0₃ and KHC0₃. In one embodiment, the aprotic solvent is selected from DMF, DMSO and NMP, and mixtures thereof, in the presence of tert-BuONa as the base. In a particular embodiment, the aprotic solvent is DMF and the base is tert-BuONa.

The compound of formula V is typically used in excess, e.g. such that the molar ratio (formula V)/(formula VI) is from 1 : 1 to 2: 1, in particular from 1 : 1 to 1.5: 1. The base is usually used in approximately stoichiometric amounts relative to the compound of the formula V, such as where the equivalent ratio (base)/(formula V) is from 1 : 1 to 3 : 1, in particular from 1.8: 1 to 2.5: 1.

The alkylation reaction is typically conducted at a temperature in the range of -10-30 °C, such as in the range of 0-25 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc. The reaction is typically allowed to proceed for 5-24 hours, such as 16-24 hours. The end-point for the reaction may alternatively be set as the presence of e.g. about 5 % of the compound of the formula VI. The reaction is typically terminated by quenching under stirring with an alcohol, e.g. ethanol, followed by the addition of water. The crude product (crude IV) is typically obtained by precipitation by addition of water.

The crude IV may suitably be purified by recrystalisation in suitable solvents like EtOH, MeOH, EtOAc, MeCN, heptane, toluene, but can also be used without further purification. Second alternative method

It appears that the second alternative method provides advantages over the known methods with respect to the use of less reactive and less toxic reagents, i .e. LHMDS is the most reactive reagent used compared to the tert-BuONa and BCI₃ used in the first alternative method . Both reagents needs to be handled carefully and with caution.

VII + VIII I

The second alternative method for the preparation of a compound of the formula I includes the step of nucleophilic substitution of a compound of the formula VII

wherein R_lr R₂, R3 and R₄ are as defined above for the compound of the formula I, and wherein R_y is selected from Ci-6-alkyl, aryl and Ci-₃-alkyl-aryl, wherein any aryl may be optionally substituted with Ci-6-alkyl, Ci-₆-alkoxy and halogen, using an anion of the formula VIII

wherein Q is as defined above for the compound of the formula I.

Preferably, the anion of the formula VIII is the anion of 3,5-dichloro-4-methyl-pyridine. The anion of the formula VIII is typically prepared in-situ by deprotonation of the corresponding pyridine in an aprotic polar solvent, e.g. selected from THF, methyl-THF, dioxane, diethyl ether, and methyl tert-butyl ether (MTBE), in the presence of a strong non- nucleophilic base, e.g. selected from lithium bis(trimethylsilyl)amide (LHMDS), LDA (lithium diisopropyl amide), potassium bis(trimethylsilyl)amide (KHMDS), MeLi, sec-BuLi, tert-BuLi, MeMgCI, EtMgCI, PhLi, LiNH₂ and KNH₂. In one embodiment, the aprotic polar solvent is selected from THF, 2-methyl-THF and MTBE and mixtures thereof, in the presence of LHMDS as the base. In another embodiment, the aprotic solvent is selected from THF, 2-methyl-THF and MTBE and mixtures thereof, in the presence of LDA as the base. In a particular embodiment, the aprotic solvent is THF and the base is LHMDS.

The compound of formula VIII is typically used in excess, e.g. such that the molar ratio (formula VIII)/(formula VII) is from 1 : 1 to 2: 1, in particular from 1.3 : 1 to 1.7: 1. The base is usually used in approximately stoichiometric amounts relative to the compound of the formula VIII, such as where the equivalent ratio (base)/(formula V) is from 1 : 1 to 2: 1, in particular from 1.3 : 1 to 1.7: 1.

The alkylation reaction is typically conducted at a temperature in the range of -20-25 °C, such as in the range of -5-25 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc. The reaction is typically allowed to proceed for 3-24 hours, such as 14-20 hours. The end-point for the reaction may also be set as the presence of e.g. about 5 % of the compound of the formula VIII. The reaction is typically terminated by quenching under stirring with an aqueous solution of an acid, e.g. an aqueous solution of NH₄CI or dilute hydrochloric acid, etc. The crude product (crude I) is typically obtained by concentration of the organic phase.

In one preferred embodiment, the anion of the formula VIII is prepared in-situ by

deprotonation of the corresponding pyridine in an aprotic polar solvent, e.g. THF, in the presence of lithium bis(trimethylsilyl)amide (LHMDS). The compound of formula VIII is used in excess, e.g. such that the molar ratio (formula VIII)/(formula VII) is from 1.3 : 1 to 1.7: 1. The base is used in approximately stoichiometric amounts relative to the compound of the formula VIII, such as where the equivalent ratio (base)/(formula VIII) is from 1.3 : 1 to 1.7: 1. The alkylation reaction is conducted at a temperature in the range of -5-25 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc. The reaction is typically allowed to proceed for 15-20 hours, or to an end-point set as the presence of e.g. about 5 % of the compound of the formula VIII, and the reaction is terminated by quenching under stirring with an aqueous solution of an acid, e.g. an aqueous solution of NH₄CI or dilute hydrochloric acid etc.

Purification of crude I may be effected as described above under the first alternative method. Typically, however, higher amounts of acetone and water are used. In one embodiment, the product I is collected after extraction, washing, concentration of the organic phase by evaporation and re-precipitating the concentrated residue. The residue is dissolved in acetone, e.g. from 1 : 1 to 20: 1 (v/w acetone:VII), such as from 10 : 1 to 15 : 1; subsequently adjusting the temperature to about 40-65 °C, such as 50-65 °C; addition of water, e.g. from 1 : 1 to 40: 1 (v/w water: VII), such as from 25: 1 to 35: 1 ; stirring at a temperature of about 25-45 °C, such as 30-35 °C, for about 5-48 hours, such as 15-24 hours; cooling of the suspension to about 0-25 °C, such as 5-15 °C under stirring for about 1- 72 hours, such as 4-12 hours; and finally collection of the purified I as a precipitate. The collected solid is washed using water followed by drying in vacuum at about 35-55 °C, such as 40-50 °C.

IX + III ^ VII

The compound of the formula VII may be prepared by alkylating a compound of the formula IX

wherein R_x, R₂ and R_y are as defined above for the compound of the formula VII, with a compound of the formula III

wherein X is selected from chloro and bromo, and R₃ and R₄ are as defined above for the compound of the formula I. The alkylation of the compound of the formula IX is typically conducted in an aprotic polar solvent, e.g. selected from DMSO, DMF, DMI, NMP, EtOAc, MeCN and THF, in the presence of a base, e.g. selected from K₂C0₃, Na₂C0₃, KHC0₃, NaHC0₃, tert-BuONa, tert-BuOK, Et₃N and DIPEA (Ν,Ν-diisopropylethylamine). In one embodiment, the aprotic solvent is selected from DMF, DMSO and NMP and mixtures thereof, in the presence of K₂C0₃ as the base. In another embodiment, the aprotic solvent is selected from DMF, DMSO and NMP, and mixtures thereof, in the presence of DIPEA as the base. In a particular embodiment, the aprotic solvent is DMF and the base is K₂C0₃.

The compound of formula III is typically used in excess, e.g. such that the molar ratio (formula III)/(formula IX) is from 1 : 1 to 2: 1, in particular from 1.0: 1 to 1.4: 1. The base is usually used in approximately stoichiometric amounts relative to the compound of the formula IX, such as where the equivalent ratio (base)/(formula IX) is from 1 : 1 to 2: 1, in particular from 1.3 : 1 to 1.8: 1.

The alkylation reaction is typically conducted at a temperature in the range of 40-80 °C, such as in the range of 50-60 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc. The reaction is typically allowed to proceed for 5-24 hours, such as 12-24 hours. The end-point for the reaction may also be set as the presence of e.g. about 8 % of the compound of the formula IX. The reaction is typically terminated by quenching under stirring with water. After the quenching reaction is completed, the crude product (crude VII) is typically obtained by precipitation.

The crude VII may suitably be purified by recrystallization from e.g. MeOH, EtOH, IPA or can preferably be used without further purification.

XII ^ IX

The compound of the formula IX may be prepared by esterification of a compound of the formula XII

wherein R_x and R₂ are as defined above for the compound of the formula IX.

The esterification of the compound of the formula XII is typically conducted using an alcohol corresponding to the desired ester group in the compound of formula IX, i .e. an alcohol of the formula Ry-OH, wherein Ry is selected from Ci-6-alkyl, aryl and Ci-₃-alkyl-aryl, wherein any aryl may be optionally substituted with Ci-6-alkyl, Ci-₆-al koxy and halogen. Preferred alcohols are methanol, ethanol, 1-propanol, 2-propanol, and benzyl alcohol . Alternatively, isobutene may be used to obtain the tert-butyl ester.

Liquid alcohols may be also used as such, because no solvent is necessary. Otherwise, a polar aprotic solvent, e.g. selected from THF, 2-methyl-THF or methyl ethyl ketone (MEK), may be used .

The esterification is typically conducted in the presence of a catalytic amount of an acid, e.g. sulphuric acid, SOCI₂, HCI, oxalic acid, H₃P0₄.

In one embodiment, sulphuric acid is used as the catalyst. In another embodiment, the alcohol is methanol and sulphuric acid is used as the catalyst.

The acid is typically used in substochiometric amounts, e.g. such that the molar ratio

(acid)/(formula XII) is from 0.05 : 1 to 0.8 : 1, in particular from 0.4 : 1 to 0.8 : 1.

The esterification reaction is typically conducted at a temperature in the range of 40-120 °C, such as in the range of 50-80 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc. The reaction is typically allowed to proceed for 5-48 hours, such as 12-24 hours. The end-point for the reaction may also be set as the presence of e.g . about 8 % of the compound of the formula XII. The reaction is typically terminated by concentration of the reaction mixture and cooling which causes the product to precipitate. After completion of the precipitation, the crude product (crude IX) is typically obtained by filtration and washing with water or cold alcohol.

The crude XI may suitably be purified by recrystallization from e.g. MeOH, EtOH, IPA or can preferably be used without further purification.

Third alternative method

It appears that the third alternative method provides advantages over the known methods by involving low costs and only two steps.

V + X ^ I

The third alternative method for the preparation of a compound of the formula I includes the step of alkylating a pyridine of the formula V

wherein Q is as defined hereinabove for the compound of the formula I, in particular chloro, and Q_x is selected from fluoro, chloro, bromo and iodo, in particular chloro, with an anion of the formula X

wherein R_lr R₂, R3 and R₄ are as defined above for the compound of the formula I. Preferably, the compound of the formula V is 3,4,5-trichloro-pyridine.

The anion of the formula X is typically prepared in-situ by deprotonation of the corresponding acetophenone in an aprotic polar solvent, e.g. selected from THF, methyl-THF, DMF, DMSO, NMP and MeCN, in the presence of a non-nucleophilic base, e.g. selected from lithium bis(trimethylsilyl)amide (LHMDS), potassium bis(trimethylsilyl)amide (KHMDS), tert-BuONa, tert-BuOK, tert-BuOLi, K₂C0₃ and KHC0₃. In one embodiment, the aprotic solvent is selected from DMF, DMSO and NMP, and mixtures thereof, in the presence of tert-BuONa as the base. In a particular embodiment, the aprotic solvent is DMF and the base is tert-BuONa. The compound of formula V is typically used in excess, e.g. such that the molar ratio (formula V)/(formula X) is from 1 : 1 to 2: 1, in particular from 1 : 1 to 1.5: 1. The base is usually used in approximately stoichiometric amounts relative to the compound of the formula V, such as where the equivalent ratio (base)/(formula V) is from 1 : 1 to 3 : 1, in particular from 1.8: 1 to 2.5: 1. The alkylation reaction is typically conducted at a temperature in the range of -10-30 °C, such as in the range of 0-25 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc. The reaction is typically allowed to proceed for 5-24 hours, such as 16-24 hours. The end-point for the reaction may alternatively be set as the presence of e.g. about 5 % of the compound of the formula VI. The reaction is typically terminated by quenching under stirring with an alcohol, e.g. ethanol, followed by the addition of water. The crude product (crude X) is typically obtained by precipitation by addition of water.

In one preferred embodiment, the anion of the formula X is prepared in-situ by deprotonation of the corresponding acetophenone in an aprotic polar solvent, e.g. DMF, in the presence of a strong non-nucleophilic base, e.g. tert-BuONa. The compound of formula V is used in excess, e.g. such that the molar ratio (formula V)/(formula X) is from 1.2: 1 to 1.5: 1. The base is used in approximately stoichiometric amounts relative to the compound of the formula X, such as where the equivalent ratio (base)/(formula X) is from 1 : 1 to 2: 1. The alkylation reaction is conducted at a temperature in the range of 0-20 °C, in a dry atmosphere, e.g. under argon, nitrogen, etc., and the reaction is allowed to proceed for 3-24 hours, and is terminated by quenching under stirring with water so as to obtain the crude product (crude I).

Purification of crude I may be effected as described above under the first alternative method. XI + III -> X

The acetophenone corresponding to the compound of the formula X is typically prepared by alkylating a compound of the formula XI

wherein R_x and R₂ are as defined above for the compound of the formula I, with a compound of the formula III

wherein X is selected from chloro and bromo, and R₃ and R₄ are as defined above for the compound of the formula I. The alkylation of the compound of the formula XI is typically conducted in an aprotic polar solvent, e.g. selected from DMSO, DMF, DMI, NMP, EtOAc, MeCN and THF, in the presence of a base, e.g. selected from K₂C0₃, Na₂C0₃, KHC0₃, NaHC0₃, tert-BuONa, tert-BuOK, Et₃N and DIPEA (Ν,Ν-diisopropylethylamine). In one embodiment, the aprotic solvent is selected from DMSO, NMP and THF, and mixtures thereof, in the presence of K₂C0₃ as the base. In another embodiment, the aprotic solvent is selected from a DMSO/THF mixture and a NMP/THF mixture, in the presence of K₂C0₃ as the base. In a particular embodiment, the aprotic solvent is DMF and the base is K₂C0₃. In another particular embodiment, the aprotic solvent is NMP and the base is K₂C0₃. The compound of formula III is typically used in excess, e.g . such that the equivalent ratio (formula III)/(formula XI) is from 1 : 1 to 3 : 1, in particular from 1 : 1 to 1.5 : 1. The base is usually used in approximately stoichiometric amounts relative to the compound of the formula XI, such as where the equivalent ratio (base)/(formula XI) is from 0.5 : 1 to 3 : 1, in particular from 0.5 : 1 to 2 : 1.

The al kylation reaction is typically conducted at a temperature in the range of 20- 100 °C, such as in the range of 40-80 °C, in a dry atmosphere, e.g . under argon, nitrogen, etc. The reaction is typically allowed to proceed for 4-72 hours, such as 16-24 hours. The reaction is typically terminated by quenching under stirring with water which causes the product of compound X to precipitate. The crude product is collected by filtration and use without further purification .

Polymorphs

The methods herein can give rise to various interesting stable crystalline forms (polymorphs) of 2-{6- [2-(3,5-dichloro-pyridin-4-yl)-acetyl] -2,3-dimethoxy-phenoxy}-N-propyl-acetamide. Form A

As it has been demonstrated herein, one interesting form, i .e. crystalline Form A of compound ( 1), is obtainable by means of a method of the invention .

The crystalline form, i .e. Form A, of 2-{6- [2-(3,5-dichloro-pyridin-4-yl)-acetyl] -2,3- dimethoxy-phenoxy}-N-propyl-acetamide fulfills one or more of the following criteria : (i) belongs to the monoclinic crystal system space group P2Jc having unit-cell parameters a = 21.435 (4) A, b = 5.0676( 10) A, c = 20.847(4)A, β = 112.79(3) degrees, volume V = 2087.7(7) and number of molecules Z = 4;

(ii) has an X-ray powder diffraction pattern that exhibits characteristic peaks expressed in 2Θ at approximately 17.84, 17.95, 19.91 and/or 24.35 (±0.05 degrees) (underlined primary), respectively; and/or

(iii) has an X-ray powder diffraction pattern substantially as appears from the graph in Figure 4.

The isolated crystalline Form A of compound ( 1) preferably has a polymorphic purity of at least 80 %, such as at least 81 %, 82 %, 83 %, 84 %, 85 %, 86 %, 87 %, 88 %, 89 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, or at least 99 %, or even 100 %. Also, the isolated crystalline Form A of compound (1) preferably has a degree of crystallinity of at least 80 %, such as at least 81 %, 82 %, 83 %, 84 %, 85 %, 86 %, 87 %, 88 %, 89 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, or at least 99 %, or even 100 %.

Form B

As it has been demonstrated herein, one novel form, i.e. crystalline Form B of compound (1), is obtainable by means of a method of the invention.

The crystalline Form B of compound (1) preferably fulfills one or more of the following criteria : (i) belongs to the monoclinic crystal system space group C2/c having unit-cell parameters a = 39.791 (5) A, b = 5.0479 (7) A c = 20.935 (3) A, β = 97.563 (2) degrees, volume V = 4168.4 (10) and number of molecules Z = 8; and/or

(ii) has an X-ray powder diffraction pattern that exhibits characteristic peaks expressed in 2Θ at approximately 17.49 and/or 20.66 (±0.05 degrees) (underlined primary), respectively; and/or

(iii) has an X-ray powder diffraction pattern substantially as appears from the graph in Figure 7.

The isolated crystalline Form B of compound (1) preferably has a polymorphic purity of at least 80 %, such as at least 81 %, 82 %, 83 %, 84 %, 85 %, 86 %, 87 %, 88 %, 89 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, or at least 99 %, or even 100 %. Also, the isolated crystalline Form B of compound (1) preferably has a degree of crystallinity of at least 80 %, such as at least 81 %, 82 %, 83 %, 84 %, 85 %, 86 %, 87 %, 88 %, 89 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, or at least 99 %, or even 100 %.

Characteristics of Form A and Form B The crystalline Forms A and B can be characterized by the following details in Tables 1-7 and by the details of Figures 4-9.

Table 1 - Details concerning the Single crystal structure determination of crystalline Form A and Form B of compound (1)

Form A Form B

Chemical formula C20H22CI2N2O5 C20H22CI2N2O5 Mr 441.30 441.30

Crystal system, space group Monoclinic, P2Jc Monoclinic, C2/c

Temperature (K) 120(2) 120

a, b, c (A) 21.435 (4), 5.0676 (10), 20.847 39.791 (5), 5.0479 (7), 20.935 (3)

(4)

β (°) 112.79 (3) 97.563 (2)

ι/ (Α³) 2087.7 (7) 4168.4 (10)

z 4 8

Radiation type Mo Ka Mo Ka

μ (mm^-1) 0.35 0.35

Crystal description Rod Rod

Crystal colour Colourless Colourless

Crystal size (mm) 0.29 x 0.06 x 0.04 0.48 x 0.05 x 0.02

Diffractometer Bruker SMART platform ccd Bruker SMART platform ccd

diffractometer diffractometer

Absorption correction - -

No. of measured, independent and 27706, 5179, 3090 27265, 5184, 3076 , 0.153, 0.93

No. of parameters 283 265

No. of restraints 0 0

H-atom treatment H-atom parameters constrained H-atom parameters constrained

Apmax, Δρηηίη (e A^"3) 0.48, -0.36 0.65, -0.50

Table 2. Atomic coordinates, equivalent isotopic displacement parameter [A²] and site occupancy factors for Form A.

Atom X Y z U_eq S.o.f.

CI 0. .15978(13) 0, .8541(5) -0.09050(13) 0, .0307(6) 1

C2 0. .20491(12) 0, .9572(5) -0.02846(13) 0, .0281(5) 1

C3 0. .20721(12) 0, .8668(5) 0.03482(12) 0, .0290(6) 1

C4 0. .16113(13) 0, .6670(5) 0.03014(13) 0, .0312(6) 1

C5 0. .11729(13) 0, .5704(5) -0.03360(14) 0, .0355(6) 1

C6 0. .25547(14) 0, .9717(6) 0.10394(13) 0, .0410(7) 1

C7 0. .31548(12) 0, .7893(5) 0.13798(12) 0, .0296(6) 1

C8 0. .35811(12) 0, .8112(4) 0.21437(12) 0, .0237(5) 1

C9 0. .42516(12) 0, .7261(5) 0.23535(13) 0, .0294(6) 1

CIO 0. .47050(12) 0, .7336(5) 0.30383(13) 0, .0300(6) 1

Cl l 0. .44908(12) 0, .8235(5) 0.35462(12) 0, .0292(6) 1

C12 0. .38171(12) 0, .9053(5) 0.33561(12) 0, .0247(5) 1

C13 0. .33707(11) 0, .9013(4) 0.26633(12) 0, .0233(5) 1

C14 0. .25575(12) 1 .2266(4) 0.26492(12) 0, .0254(5) 1

C15 0. .18288(12) 1 .2551(4) 0.25486(11) 0, .0209(5) 1

C16 0. .07406(12) 1 .0402(5) 0.23374(13) 0, .0303(6) 1

C17 0. .02993(13) 0, .8985(5) 0.16640(14) 0, .0375(7) 1

C18 0. .03140(15) 1 .0224(6) 0.10164(14) 0, .0478(8) 1

C19 0. .33482(14) 0, .7694(5) 0.41447(14) 0, .0384(7) 1

C20 0. .55573(13) 0, .7429(6) 0.44722(15) 0, .0481(8) 1

CI1A 0. .25771(5) 1 .20806(18) -0.03589(5) 0, .0334(2) 0.85

CUB 0. .2673(3) 1 .1880(12) 0.0033(4) 0, .0476(15) 0.15

CI2A 0. .15953(5) 0, .54584(19) 0.10723(5) 0, .0375(2) 0.85

CI2B 0. .1304(3) 0, .4374(13) 0.0815(3) 0, .0493(14) 0.15

Nl 0. .11649(10) 0, .6627(4) -0.09364(11) 0, .0344(5) 1

N2 0. .14563(9) 1 .0390(4) 0.24387(10) 0, .0237(4) 1

01 0. .33197(9) 0, .6381(4) 0.10205(9) 0, .0436(5) 1

02 0. .26986(8) 0, .9605(3) 0.25048(8) 0, .0246(4) 1

03 0. .16206(8) 1 .4809(3) 0.25792(8) 0, .0285(4) 1

04 0. .36039(8) 0, .9853(3) 0.38694(8) 0, .0283(4) 1

05 0. .48732(8) 0, .8376(4) 0.42346(8) 0, .0387(5) 1 Table 3. Bond lengths [A] of Form A.

C2- -CI 1 .383 (3) CI1A- -CI1B 0, .768 (7)

C2- -C3 1 .379 (3) CI1B —C2 1 .706 (7)

C3- -C6 1 .508 (3) CI2A —C4 1 .733 (3)

C4- -C3 1 .391 (4) CI2A- -CI2B 0, .849 (6)

C4- -C5 1 .386 (4) CI2B —C4 1 .865 (6)

C7- -C6 1 .518 (3) Nl- -CI 1 .326 (3)

C8- -C7 1 .502 (3) Nl- -C5 1 .330 (3)

C8- -C9 1 .399 (3) N2- ^■C15 1 .322 (3)

C8- C13 1 .401 (3) N2- ^■C16 1 .465 (3)

C10- -C9 1 .382 (3) 01- -C7 1 .216 (3)

C10- -Cll 1 .384 (3) 02- ^■C13 1 .381 (3)

C12- -Cll 1 .404 (3) 02- ^■C14 1 .439 (3)

C13- -C12 1 .390 (3) 03- ^■C15 1 .239 (3)

C14- -C15 1 .500 (3) 04- ^■C12 1 .377 (3)

C16- -C17 1 .534 (4) 04- ^■C19 1 .439 (3)

C17- -C18 1 .500 (4) 05- ^■Cll 1 .351 (3)

CI1A- -C2 1 .748 (3) 05- ^■C20 1 .436 (3)

Table 4. Bond angles [°] of form A.

Nl- -Cl- ^■C2 123.0 (2) C9— C10—Cll 119.4 (2)

Cl- ^■C2- ^■CI1A 115.7 (2) C10- -Cll—C12 119.4 (2)

Cl- ^■C2- ^■CUB 141.4 (3) 05- ^■Cll—CIO 125.8 (2)

C3- ^■C2- ^■CI 121.5 (2) 05- ^■Cll—C12 114.8 (2)

C3- ^■C2- ^■CI1A 122.8 (2) C13- -C12—Cll 120.5 (2)

C3- ^■C2- ^■CUB 97.1 (3) 04- ^■C12—Cll 118.8 (2)

CI1Ei—C2 :—CI1A 25.7 (2) 04- ^■C12—C13 120.6 (2)

C2- ^■C3- ^■C4 114.4 (2) C12- -C13—C8 120.7 (2)

C2- ^■C3- ^■C6 123.6 (2) 02- ^■C13—C8 120.3 (2)

C4- ^■C3- ^■C6 122.0 (2) 02- ^■C13—C12 118.7 (2)

C3- ^■C4- ^■CI2A 117.5 (2) 02- ^■C14—C15 110.66 (18)

C3- ^■C4- ^■CI2B 144.3 (3) N2- ^■C15—C14 118.08 (19)

C5- ^■C4- ^■C3 121.6 (2) 03- ^■C15—C14 117.3 (2)

C5- ^■C4- ^■CI2A 121.0 (2) 03- ^■C15—N2 124.7 (2)

C5- ^■C4- ^■CI2B 94.1 (3) N2- C16—C17 111.7 (2)

CI2i >—C4 —CI2B 27.0 (2) C18- -C17—C16 114.0 (2)

Nl- -C5- ^■C4 122.3 (2) CI1B —CI1A—C2 74.1 (5)

C3- ^■C6- ^■C7 112.0 (2) CI1A —CUB—C2 80.3 (5)

C8- ^■C7- ^■C6 120.5 (2) CI2B —CI2A—C4 85.2 (4)

01- -C7- -C6 119.4 (2) CI2A —CI2B—C4 67.8 (4)

01- -C7- -C8 119.8 (2) CI— Nl—C5 117.2 (2)

C9- ^■C8- ^■C7 116.0 (2) C15- -N2—C16 123.35 (19)

C9- ^■C8- ^■C13 117.3 (2) C13- -02—C14 115.98 (17)

C13- -C8- -C7 126.7 (2) C12- -04—C19 112.23 (18)

CIO- -C9- -C8 122.7 (2) Cll- -05—C20 117.8 (2) Table 5. Atomic coordinates, equivalent isotopic displacement parameter [A²] and site occupancy factors for Form B.

Atom X Y z u_ea S.o.f.

CI 0 07831(8) 0.4039(6) 0 40849(15) 0 0231(7) 1

C2 0 10171(8) 0.2847(6) 0 37334(15) 0 0210(7) 1

C3 0 10372(8) 0.3583(6) 0 30947(14) 0 0181(6) 1

C4 0 08052(8) 0.5494(6) 0 28519(14) 0 0196(6) 1

C5 0 05809(8) 0.6627(6) 0 32232(15) 0 0246(7) 1

C6 0 12870(8) 0.2423(6) 0 26950(15) 0 0205(7) 1

C7 0 15827(8) 0.4342(6) 0 26596(15) 0 0208(7) 1

C8 0 18000(7) 0.4175(6) 0 21231(14) 0 0182(6) 1

C9 0 21307(8) 0.5117(6) 0 22649(15) 0 0224(7) 1

CIO 0 23570(8) 0.5121(7) 0 18189(16) 0 0260(7) 1

Cll 0 22533(8) 0.4215(6) 0 11997(16) 0 0233(7) 1

C12 0 19192(8) 0.3309(6) 0 10346(14) 0 0196(6) 1

C13 0 16978(7) 0.3246(6) 0 14965(14) 0 0180(6) 1

C14 0 13065(8) -0.0108(5) 0 10785(15) 0 0196(6) 1

C15 0 09435(7) -0.0441(6) 0 07674(14) 0 0174(6) 1

C16 0 04012(8) 0.1678(6) 0 03702(15) 0 0229(7) 1

C17 0 01693(8) 0.3028(6) 0 07923(16) 0 0243(7) 1

C18 0 01403(9) 0.1555(7) 0 14099(18) 0 0340(8) 1

C19 0 16808(9) 0.4675(6) 0 00086(16) 0 0292(8) 1

C20 0 27844(9) 0.5196(8) 0 08342(19) 0 0390(9) 1

Cll 0 12811(2) 0.04409(16) 0 41122(4) 0 0293(2) 1

CI2 0 07948(2) 0.65383(16) 0 20613(4) 0 0289(2) 1

Nl 0 05678(7) 0.5926(5) 0 38385(13) 0 0268(6) 1

N2 0 07561(6) 0.1713(5) 0 06722(12) 0 0189(5) 1

01 0 16559(6) 0.5938(5) 0 30904(11) 0 0335(6) 1

02 0 13633(5) 0.2541(4) 0 13045(10) 0 0184(5) 1

03 0 08453(5) -0.2730(4) 0 06223(10) 0 0210(5) 1

04 0 18147(5) 0.2513(4) 0 04125(10) 0 0217(5) 1

05 0 24463(6) 0.4150(5) 0 07103(11) 0 0330(6) 1

Table 6. Bond lengths [A] of Form B.

Form B - Bond lencjths_[A]_

Cl- -C2 1 .397 (4) Cll- -05 1 .359 (4)

C2- -Cll 1 .729 (3) C12- -04 1 .374 (3)

C3- -C2 1 .400 (4) C13- -C8 1 .402 (4)

C4- -C3 1 .385 (4) C13- -C12 1 .391 (4)

C4- -CI2 1 .732 (3) C13- -02 1 .385 (3)

C5- -C4 1 .382 (4) C14- -02 1 .426 (3)

C5- -Nl 1 .344 (4) C15- -C14 1 .514 (4)

C6- -C3 1 .500 (4) C15- -N2 1 .318 (4)

C6- -C7 1 .533 (4) C15- -03 1 .244 (3)

C7- -C8 1 .507 (4) C16- -C17 1 .520 (4)

C7- -01 1 .216 (4) C16- -N2 1 .469 (4)

C9- -C8 1 .394 (4) C18- -C17 1 .509 (5)

C10 -C9 1 .380 (4) C19- -04 1 .439 (4)

Cll' -CIO 1 .385 (5) C20- -05 1 .437 (4)

Cll' -C12 1 .405 (4) Nl- -CI 1 .338 (4) Table 7. Bond angles [°] of Form B.

Nl- -Cl- -C2 122.7 (3) CIO- -Cll- -C12 119.6 (3)

Cl- -C2- ^■C3 121.0 (3) 05- -Cll- -CIO 125.8 (3)

Cl- -C2- -Cll 117.9 (2) 05- -Cll- -C12 114.6 (3)

C3- -C2- -Cll 121.1 (2) C13- -C12- -Cll 120.1 (3)

C2- ^■C3- ^■C6 123.7 (3) 04- -C12- -Cll 119.1 (3)

C4- ^■C3- -C2 114.6 (3) 04- -C12- -C13 120.8 (3)

C4- ^■C3- ^■C6 121.7 (3) C12- -C13- -C8 120.7 (3)

C3- -C4- -CI2 119.6 (2) 02- -C13- -C8 120.5 (3)

C5- -C4- ^■C3 122.0 (3) 02- -C13- -C12 118.4 (3)

C5- -C4- -CI2 118.4 (2) 02- -C14- -C15 110.3 (2)

Nl- -C5- -C4 122.6 (3) N2- -C15- -C14 117.5 (3)

C3- ^■C6- -C7 110.4 (2) 03- -C15- -C14 117.3 (3)

C8- -C7- ^■C6 121.3 (3) 03- -C15- -N2 125.1 (3)

01- -C7- -C6 119.6 (3) N2- -C16- -C17 111.5 (3)

01- -C7- -C8 119.0 (3) C18- -C17- -C16 113.4 (3)

C9- -C8- -C7 116.1 (3) Cl- ^■Nl—C5 117.0 (3)

C9- -C8- -C13 117.6 (3) C15- -N2- -C16 123.2 (3)

C13- -C8- -C7 126.3 (3) C13- -02- -C14 116.2 (2)

CIO- -C9- -C8 122.6 (3) C12- -04- -C19 112.2 (2)

C9- ^■CIO- -Cll 119.5 (3) Cll- -05- -C20 117.6 (3)

The presently preferred crystalline Form A and Form B of compound (1) are believed to possess physical properties which facilitate the manufacture and long-term storage of dosage forms of the compound, not least its stability towards interconversion with other solid forms thereof, which typically have different densities and crystal habits than crystalline Form A and Form B of compound (1).

EXPERIMENTAL^

Methods and reagents

All chemicals and reagents used are available from Sigma Aldrich Chemicals.

HPLC:

Column Sample Flow Detector Mobile phase (% vol ./vol.)

(ml/min)

Aeris Peptide 10 μΙ/5 mg Isocratic:

3.6 μηη, sample in 5 1.2 220 nm 60 % H₂0, 40 % ACN, XB-C18 ml eluent 0.1 % TFA Instrumentation

X-ray powder diffraction (XRPD) : The diffractogram was obtained on a conventional STADI P diffractometer from STOE & CIE Gmb configured with transmission geometry and equipped with a curved germanium (111) monochromator and a linear PSD detector. A continuous 2Θ scan range of 3-30° was used with a CuKa radiation λ = 1.5418 A source and a generator power of 40KV and 40mA. A 2Θ step size of 0.01°/step with a step time of 1560 s was used. Samples were gently flattened onto for transmission measurements. The well was rotated and all experiments were performed at room temperature.

Single-crystal X-ray diffraction (XRC) data were collected using a Bruker SMART Apex diffractometer with a CCD area detector (Temperature: 120(2) K; Mo Ka Radiation λ = 0.7107 A; data collection method : co/2q scans). Further details can be found in Example 5.

Program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997).

The given error ranges in this application for the diffraction characteristics, including those in the claims, may be more or less depending on factors well known to a person skilled in the art of X-ray diffraction and may for example depend on sample preparation, such as particle size distribution and preferred orientation, or if the crystal form is part of a formulation, on the composition of the formulation, as well as instrumental fluctuations, and other factors.

An error range of ±0.05 includes, but is not limited to variations of ±0.05, ±0.04, ±0.03, ±0.02, and ±0.01.

Example 1

Step 1 - Preparation of 2-(3,5-dichloro-4-pyrididyl)-l-(2,3,4-trimethoxyphenyl)ethanone:

(6) (5) (4)

The reaction is carried out by dissolving 1.08 kg (11.2 mol) of sodium tert-butoxide in 3.08 kg (3.26 L) of DMF (Ν,Ν-dimethylformamide) in a Schott bottle. The reactor is charged with 1.07 kg of l-(2,3,4-trimethoxyphenyl)ethanone (6) and 1.12 kg of 3,4,5-trichloropyridine (5) followed by 1.03 kg (1.08 L) of DMF. The slurry is cooled towards 0 to 5 °C (jacket temperature = -10 °C) and the DMF solution of sodium tert-butoxide is added over a period of 6 hours. The reaction mixture is stirred at 0 to 5 °C overnight (approx. 12 to 18 hours) . In- Process Control (HPLC) is carried out in order to verify conversion (Area% of (6) NMT 5%) . The reaction is quenched by addition of 1.32 kg (1.70 L) of EtOH followed by the addition of 6.42 kg (6.42 L) of water, during which the temperature increases to 20 to 25 °C. The resulting slurry is heated to 50 °C and stirred for 5 to 17 hours before cooling to 0 °C and isolation by filtration on paper filter is taking place. The crude product is washed on the filter with 2 x 1.50 L of ethanol/water (1 : 5 v/v) and dried in vacuo at 40 to 50 °C. The off-white to beige 2-(3,5-dichloro-4-pyrididyl)-l-(2,3,4-trimethoxyphenyl)ethanone (4), 1.52 kg is obtained in 84 % chemical yield in high purity (> 99 % by HPLC) .

Step 2 - Preparation of 2-(3,5-dichloro-4-pyrididyl)-l-(2-hydroxy-3,4-dimethoxyphenyl)- ethanone (2) using 1 M BC in toluene.

(4) (2) The reactor is charged with 0.75 kg of (4) and 2.17 kg (2.50 L) of toluene. The slurry is stirred at 25 °C and 2.64 kg (2.90 L) of 1.0 M boron trichloride in toluene are added over a period of 1 hour keeping the temperature between 20 - 25 °C. The tubing used for the addition is rinsed with 0.173 kg (0.200 L) of toluene. The temperature is increased to 38 °C to 42 °C and maintained overnight. After 15 to 22 hours; in-process control (HPLC) is applied to verify that area% of (4) is NMT 5 % by HPLC. If area% of (4) is > 5%; additionally 0.380 kg (0.418 L, 0.420 mol) of 1.0 M boron trichloride are added and the mixture is stirred at 38 °C to 42 °C for additional 5 to 10 hours. The reaction is quenched by addition of 1.80 kg of water/27.7 w/v-% aqueous sodium hydroxide (1 : 2) over a period of 30 minutes. NB! Strong dose-controlled exothermic reaction during the initial addition of aqueous base (the initial one third) . Next, 0.788 kg (0.625 L) of ethanol is added and the mixture is heated to 80 °C. After 5 to 15 hours a sample is withdrawn, tested for pH and adjusting using AcOH or NaOH in order to ensure a pH = 6 to 7. If adjustment is needed the reaction mixture must be kept at 80 °C for another 2 to 4 hours before progressing . The reaction mixture is cooled to 0 °C and tested for pH again. If needed another adjustment is performed prior to isolating 2-(3,5- dichloro-4-pyrididyl)-l-(2-hydroxy-3,4-dimethoxyphenyl)ethanone (2) by filtration. The filter- cake is washed with 4 x 1 L of EtOH/water (2 : 3 v/v) and dried in vacou at 40 to 50 °C. The (2) is obtained as a grey to greyish solid/powder in approximately 81 % chemical yield.

Step 2 - Preparation of 2-(3,5-dichloro-4-pyrididyl)-l-(2-hydroxy-3,4-dimethoxyphenyl)- ethanone (2) using BC gas.

The reactor is charged with 0.77 kg of (4) and 4.66 kg (5.38 L) of toluene. The slurry is stirred at 25 °C and 0.40 kg of boron trichloride is added over a period of V/2 hour keeping the temperature between 20 to 25 °C. The temperature is increased to 38 °C - 42 °C and maintained overnight. After 15 to 22 hours; in-process control (HPLC) is applied to verify that area% of (4) is NMT 5 % by HPLC. If area% of (4) is > 5%; additionally 0.10 kg (or less, depending on the amount of (4)) of boron trichloride is added and the mixture is stirred at 38 °C to 42 °C for additional 1 to 5 hours. The reaction is quenched by addition of a mixture of water/27.7 w/v-% aqueous sodium hydroxide/EtOH (0.43 L water, 0.87 L NaOH(aq) and 0.60 L EtOH) over a period of 30 minutes. NB! Strong dose-controlled exothermic reaction, during the initial addition of this mixture (the initial one third) . After the addition the mixture is heated to 80 °C. After 5 to 15 hours a sample is withdrawn, tested for pH and adjusting using AcOH or NaOH in order to ensure a pH= 6 to 7. If adjustment is needed the reaction mixture must be kept at 80 °C for another 2 to 4 hours before progressing . The reaction mixture is cooled to 0 °C and tested for pH again. If needed another adjustment is performed prior to isolating (2) by filtration. The filter-cake is washed with 2 x 1 L of EtOH/water (2 : 3 v/v) and dried in vacou at 40 to 50 °C. The (2) is obtained as a grey to greyish solid/powder in approximately 75 % chemical yield (0.55 kg) . Step 3 - Preparation of 2-f 6- [2-(3 ,5-dichloro-pyridin-4-yl)-acetyn -2,3-dimethoxy-phenoxy>- N-propyl -acetamide ( 1) :

The reactor is charged with 30 g (87.7 mmol) of (2), 12.1 g (87.7 mmol) of potassium carbonate, 17.8 g ( 131.6 mmol) of 2-chloro-N-propyl -acetamide (3) and 45 ml of DMSO (dimethylsulfoxide) . The temperature is increased to 60 °C and the slurry is stirred for 20 hours. In-process control (H PLC) showed that area% of (2) was 2 % by H PLC. The reaction temperature was reduced to 50 °C and addition of a mixture of 25 ml AcOH in 45 ml acetone (or alternatively 45 ml EtOH) took place during 15 min . Upon complete addition the reaction mixture was stirred for 15 min and added 45 ml H₂0. The mixture was stirred at 60 °C for 1 hour before the temperature was decreased to 40 °C. The mixture was stirred for 16 hours at which time the mixture had precipitated . Addition of another 45 ml H₂0 took place and stirring was continued at room temperature for 24 hours and a third addition of 45 ml H₂0 was performed . Stirring was continued for 6 hours before the crude 2-{6- [2-(3,5-dichloro-pyridin- 4-yl)-acetyl] -2,3-dimethoxy-phenoxy}-N-propyl -acetamide ( 1) was collected by filtration and washed on the filter using 5 x 30 ml acetone/H₂0 ( 1 : 2, v :v) (or alternatively the same amounts of EtOH/water (2 : 3, v/v)) followed by drying in vacuum at 50 °C. This produced 32.4 g (84 %) of crude ( 1) as yellow solid . The crude ( 1) was dissolved using 120 ml toluene (or alternatively the same amount of TH F/heptane ( 1 : 2, v/v) or EtOAc/heptane ( 1 : 2, v/v)) at 65 °C and added 5.3 g activated charcoal and stirred for 2 hours at 65 °C. Filtration and evaporation returned a yellow solid that was re-dissolved in 50 ml acetone at 65 °C. Once dissolved, slow addition of 50 ml H₂0 and stirring at 65 °C produces a homogenous solution that is cooled to 40 °C during 3 hours and stirred overnight. The product starts to precipitate around 45 °C normally. Aftermaturing a few hours at 40 °C addition of a second portion of 50 ml H₂0 causes further precipitation . The suspension is cooled and stirred at room temperature for 6 hours, added a third portion of 50 ml H₂0, stirred 2 hours and filtered . The filter-cake was washed using 5 x 30 ml H₂0 and dried in vacuum at 50 °C. The (1) was collected in 25.0 g (64%) as white solid .

Step 3 (alternative) - Preparation of 2--f6-|^"2-(3,5-dichloro-pyridin-4-yl)-acetyl^'l-2,3- dimethoxy-phenoxyVN-propyl-acetamide (1) : The reactor is charged with 100 g (0.292 mol) of (2), 40.4 g (0.292 mol) of potassium carbonate, 59.4 g (0.438 mol) of (3) and 165 g of DMSO. The temperature is increased to 48- 52 °C and the slurry is stirred for 15-24 hours. In-process control (HPLC) is applied to verify that area% of (2) is < 5 % by HPLC. If the area% of (2) is > 5 % the reaction time is prolonged with 1-24 hours. When the area% of (2) is < 5 % by HPLC the reaction mixture is diluted by addition of 550 g of DMSO. Next, 750 g of water are added over a period of 2-4 hours. The slurry is allowed to cool to 22-27 °C and stirred for 15-24 hours. The slurry is cooled to 0-5 °C and stirred for additionally 1-3 hours. The crude product is isolated by filtration and washed on the filter 3 x 100 g of water. The crude (1) is dried in vacuo at 48-52 °C for 17-48 hours. The yellow solid is suspended in 4000 ml of EtOAc/heptane (1 :2) and heated to 68-72 °C and stirred until all solid dissolves. Next, 50 g of Kiesel gel (60 A, mesh 35-75) and 50 g of activated carbon is added to the warm solution. The slurry is stirred for 25-35 minutes and filtered over 2 x filter paper. The filter cake is washed with the filtrate (in order to remove traces of carbon from the filtrate) and then with 4 x 500 ml of warm (70 °C) EtOAc/heptane (1 : 2) . The solvents are removed from the combined filtrates by evaporation under reduced pressure at 48-52 °C and the residue is suspended 333 ml of ethyl acetate, warmed to 68-70 °C and stirred until all solids dissolves. The clear solution is filtered warm and 666 ml of heptane is added to the filtrate. The resulting slurry is warmed to 68-70 °C and stirred until all solids dissolves. Finally, the solution is cooled to 0-5 °C and stirred for additionally 1-3 hours. The precipitate is isolated by filtration and washed on the filter with 2 x 50 ml of heptane. The filter cake is dried in vacuo at 48-52 °C, yielding 77-103 g (60-80%) of (1) as white solid .

Example 2

Procedure :

The reactor is charged with 1.00 kg (2.92 mol) of (2), 0.404 kg (2.92 mol) of potassium carbonate, 0.594 kg (4.38 mol) of (3) and 1.65 kg (1.50 L) of DMSO (dimethylsulfoxide) . The temperature is adjusted to 55-65 °C and the slurry is stirred for 16-20 hours. In-process control (HPLC) showed that area% of (2) was < 2 % by HPLC. The reaction mixture was quenched by addition of a mixture of 0.175 kg (0.167 L) of acetic acid in 1.58 kg (2.00 L) of 2-propanol. The mixture was stirred for 30-60 min at 55-65 °C. Next, 2.00 kg of water were added over a period of 15-45 minutes and the mixture was stirred at 45-55 °C for 15-24 hours. The slurry was cooled towards 20-30 °C and stirred for additionally 2-5 hours before crude (1) was isolated by filtration. The filter-cake was washed with 3 x 1.00 L DMSO/2- propanol/water (3 :4 :8) and dried in vacuo at 50 °C. This produced 1.00 kg of crude (1) as off-white to light yellow solid .

Purification of crude (1) procedure A) : applied when HPLC analysis show area% (2) < 0.2%

1.00 kg of crude (1) was suspended in and 1.58 kg (2.00 L) of acetone. The temperature was adjusted towards 45-55 °C. Next, 2.00 kg of water were added over a period of 15-45 minutes and the mixture was stirred at 40-50 °C for 15-24 hours. The slurry was cooled towards 20-30 °C and stirred for additionally 2-5 hours before (1) was isolated by filtration. The filter-cake was washed with 3 x 1.00 L acetone/water (1 : 2) and dried in vacuo at 50 °C. This produced 0.840 kg of (1) (65 %) as off white solid .

Purification of crude (1) procedure B) ; applied when HPLC analysis show area% (2) > 0.2% 1.00 kg of crude (1) was suspended in and 1.65 kg (1.50 L) of DMSO and 1.58 kg (2.00 L) of 2-propanol . The temperature was adjusted towards 40-50 °C and the mixture was stirred until all solids dissolved . Next, 2.00 kg of water were added over a period of 15-45 minutes and the mixture was stirred 40-50 °C for 15-24 hours. The slurry was cooled towards 20-30 °C and stirred for additionally 2-5 hours before (1) was isolated by filtration. The filter-cake was washed with 3 x 1.00 L DMSO/2-propanol/water (3 :4 :8) and then with 2 x 1.00 L of water before it was dried in vacuo at 50 °C. This produced 0.780 kg of (1) (60 %) as off white solid .

Example 3

Step 1 - Preparation of methyl 2-hydroxy-3,4-dimethoxy-benzoate (9)

(12) (9) To a reactor blanked with nitrogen was added 1.0 kg of 2-hydroxy-3,4-dimethoxy-benzoic acid (12) (5.04 mol) followed by 6 litres of MeOH and the mixture was stirred at RT followed by slow addition of 300 grams cone. H₂S0₄ (1.7 mol). The reaction mixture was heated to reflux at 80 °C for 18 hours. A sample was analysed by HPLC and if the content of (12) was below 8 % the reaction was considered completed. In case that the content of (12) was more than 8 % another addition of 30 grams cone. H₂S0₄ (0.17 mol) took place and the reaction mixture stirred for another 12 hours. Upon completion of the reaction, the total volume was reduced by 50-60 % by evaporation of MeOH and the slurry cooled to 0 °C for 12 hours. The product methyl 2-hydroxy-3,4-dimethoxy-benzoate (9) was collected by filtration and washed with 500 ml cold MeOH before the solid material was dried at RT using vacuum to constant weight. This produced 900 grams of (9) (4.24 mol; 84 %) .

Step 2 - Preparation of methyl 3,4-dimethoxy-2-[2-oxo-2-(propylamino)ethoxylbenzoate (7)

(9) (3) (7) A reactor blanked with nitrogen was added 1.0 kg of (9) (4.7 mol), 1.05 kg K₂C0₃ (7.6 mol), 8 litre of DMF followed by addition of 0.715 kg (3) (5.3 mol) . The mixture was stirred and heated to 60 °C for 18 hours. A sample was analysed by HPLC and if the content of (9) <8 % the reaction was considered completed . If the content of (9) was more than 8 % further addition of (3) took place (typically 0.10 kg of (3) was enough in those cases) and the reaction mixture stirred at 60 °C for another 6-8 hours before another samples was analysed . When the reaction was completed slow addition of 15 litres of H₂0 at 50-60 °C caused the product to precipitate. When the addition was completed the mixture was cooled to 0 °C and filtered . The solid product was washed with 10 litres of H20 before drying at 40-50 °C in vacuum resulting in 1.18 kg of (7) (3.79 mol, 80 %) as off-white solid .

Step 3 - Preparation of 2-f 6-[2-(3,5-Dichloro-pyridin-4-yl)-acetyn-2,3-dimethoxy-phenoxy>-

N-propyl-acetamide (1)

(7) (8) (1) To a reactor blanked with nitrogen was added 1.0 kg of (7) (3.2 mol), 0.677 kg of 3,5- dichloro-4-methyl-pyridine (8) (4.2 mol) followed by 20.8 kg of THF and stirred at -5 to -10 °C. Once dissolved slow addition of 6.7 kg of a 24 %-wt Li HMDS solution in THF took place over a period of 1-3 hours while keeping the temperature below 0 °C. After complete addition the reaction temperature was raised to 20 °C for 1 hour before testing using HPLC analysis. If the content of (7) was more than 5 % the reaction mixture was stirred at 20 °C for a longer period until testing proved the content of (7) to be less than 5 %. Once completed the reaction mixture was quenched by addition of a saturated NH₄CI solution (made from 2.97 kg NH₄CI dissolved in 10 kg of water). The mixture was stirred vigorously for 1-3 hours before stirring was stopped and allowed for the two phases to separate. The lower aqueous phase was discarded while the upper organic phase was stirred another 1-3 hours with brine (made from 3.2 kg NaCI dissolved in 8.8 kg of water) before allowing for phase separation to occur. The lower aqueous phase was discarded and the organic phase concentrated by evaporation at 50 °C using vacuum producing a thick slurry. The slurry was redissolved in 15 litres of acetone and filtered to remove any particles. The filtrate was heated to 65 °C and 30 liters of water was added and stirring at 65 °C was continued for 1 hour before controlled cooling to 30 °C using a ramp of 10 °C/hr took place. This cooling produced a slurry that was matured at 30 °C for up to 24 hours before cooling to 10 °C caused the remaining product to precipitate as well. After filtration, washing using 10 litres of water and drying at 40 °C in vacuum produced 1.2 kg of (1) (2.7 mol; 85 %) as white solid.

Example 4

Step 1 - Preparation of 2,3-dimethoxy-phenoxy)-N-propyl-acetamide (10) :

(11) (3) (10)

In a round bottom flask was placed 50.0 g 2-hydroxy-3,4-dimethoxyacetophenone (11) (254 mmol), 41.5 g 2-chloro-N-propyl-acetamide (3) (305 mmol) and 70.4 g K₂C0₃ (510 mmol) followed by addition of 250 ml DMF. The mixture was stirred at 80 °C for 4-5 hours and addition of 750 ml H₂0 at 80 °C produced a homogenous solution which upon cooling to RT formed a precipitate that was stirred overnight at RT. Filtration and washing with 500 ml H₂0 followed by drying at 40 °C in vacuum produced 58 g 2-(6-acetyl-2,3-dimethoxy-phenoxy)-N- propyl-acetamide (10) (196 mmol; 77 %) as off-white solid.

Step 2 - Preparation of 2-f 6- [2-(3 ,5-Dichloro-pyridin-4-yl)-acetyn -2,3-dimethoxy-phenoxy>- N-propyl -acetamide ( 1)

( 10) (5) ( 1) A mixture of 1.0 g 2-(6-acetyl -2,3-dimethoxy-phenoxy)-N-propyl -acetamide ( 10) (3.4 mmol), 1.0 g 3,4,5-trichloropyridine (5) (5.5 mmol) and 1.0 g tert-BuONa ( 10.2 mmol) was stirred at 5 °C in 20 ml DM F for 4 hours. After 4 hours no further reaction was detected by H PLC and addition of 50 ml water caused a precipitate to form which was isolated by filtration and washed with 10 ml water before drying at 40 °C in vacuum . By this method was isolated 120 mg of ( 1) (0.2 mmol ; 6 %) as yellow material having 75 % purity judged from H PLC analysis.

Example 5

Crystal Structure of Form A of compound ( 1)

Crystalli ne material as obtained from Example 2 or Example 3 was identified as form A with X-ray powder diffraction having the characteristics as shown in Figure 4. Form A is fully identified and characterized on suitable crystal where a 0.9 A data set was collected at 120K on a Bruker Smart diffractometer. The crystal structure solution was found and refinement was performed using the SH ELXTL-97 system . See, Sheldrick, G . M . , 1990 and 1997.

Hydrogen atoms on fixed ideal positions were included . The shifts calculated in the final cycle of least squares refinement were all less than 0.1 of their corresponding standard deviations, and the final R index was 5.8 percent. A final difference Fourier revealed no missing or misplaced electron density. Experimental details concerning the single crystal structure determination are provided in Table 1. Selected atomic coordinates, equivalent isotopic displacement parameter and site occupancy factors are provided in Table 2. Bond lengths and angles are provided in Table 3 and Table 4. Example 6

Crystal Structure of Form B of compound (1)

The Experiment was conducted as for the crystal of Form A in Example 5, however, the crystalline material was obtained from a modified process according to Example 2 or Example 3. Experimental details concerning the single crystal structure determination are provided in Table 1. Selected atomic coordinates, equivalent isotopic displacement parameter and site occupancy factors are provided in Table 5. Bond lengths and angles are provided in Table 6 and Table 7.

CLAUSES In view of the description, tables and figures herein, the present inventors have in particular provided :

Clause 1. A method for the preparation of a compound of the formula I

wherein

R₃ is selected from hydrogen, Ci-₆-alkyl, C₃.₈-cycloalkyl, and Ci-₃-alkyl-(C₃.₈-cycloalkyl); R₄ is selected from Ci-6-alkyl, C₃.₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci-₃-alkyl-phenyl and Ci-₃-alkyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; or R₃ and R₄ together with the intervening nitrogen atom represent an N-heterocyclic ring optionally substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; and each Q is selected from chloro, bromo and fluoro, in particular chloro; comprising the step of alkylating a compound of the formula II

wherein R_lr R₂ and Q are as defined above for the compound of the formula I, with a compound of the formula III

wherein X is selected from chloro and bromo, and R₃ and R₄ are as defined above for the compound of the formula I.

Clause 2. The method according to Clause 1, wherein the alkylation is conducted in an aprotic polar solvent, e.g . selected from DMSO, DMF, DMI, NMP, EtOAc, MeCN and THF, and mixtures hereof, in the presence of a base, e.g . selected from K₂C0₃, Na₂C0₃, KHC0₃, NaHC0₃, tert- BuONa, tert-BuOK, Et₃N and DIPEA.

Clause 3. The method according to any one of the preceding Clauses, wherein the compound of the formula II is prepared by dealkylation of a compound of the formula IV

wherein R_lr R₂ and Q are as defined in Clause 1 for the compound of the formula I, and R_x is selected from Ci_₃ al koxy, in particular methoxy.

Clause 4. The method according to Clause 3, wherein the deal kylation reaction is conducted using BCI₃ in an apolar solvent, e.g . toluene, or using BCI₃ as a gas.

Clause 5. The method according to any one of the Clauses 3-4, wherein the compound of the formula IV is prepared by alkylating a pyridine of the formula V

wherein Q is as defined in Clause 1 for the compound of the formula I, preferably chloro, and Q_x is selected from fluoro, chloro, bromo, iodo, preferably chloro, with an anion of the formula VI

wherein R_lr R₂ and R_x are as defined above for the compound of the formula I.

Clause 6. The method according to Clause 5, wherein the anion of the formula VI is prepared in-situ by deprotonation of the corresponding acetophenone in an aprotic polar solvent, e.g. selected from THF, methyl-THF, DMF, DMSO, NMP and MeCH, in the presence of a strong non- nucleophilic base, e.g. selected from lithium bis(trimethylsilyl)amide (LHMDS), potassium bis(trimethylsilyl)amide (KHMDS), tert-BuONa, tert-BuOK, tert-BuOLi, K₂C0₃ and KHC0₃.

Clause 7. The method according to any one of the Clauses 1-5, wherein R_x and R₂ are both methyl, R₃ is hydrogen, and R4 is prop-l-yl. Clause 8. The method according to any one of the Clauses 1-5, wherein R_x and R₂ are both methyl, R₃ is hydrogen, and R4 is -CH₂-cyclohexyl.

Clause 9. A method for the preparation of a compound of the formula I

(I) wherein

R₃ is selected from hydrogen, Ci-₆-alkyl, C₃-₈-cycloalkyl, and Ci-₃-alkyl-(C₃-₈-cycloalkyl); R₄ is selected from Ci-₆-alkyl, C₃.₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci-₃-alkyl-phenyl and Ci-₃-alkyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; or R₃ and R₄ together with the intervening nitrogen atom represent an N-heterocyclic ring optionally substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; and each Q is selected from chloro, bromo and fluoro, in particular chloro; comprising the step of nucleophilic substitution of a compound of the formula VII

wherein R_x, R₂, R₃ and R₄ are as defined above for the compound of the formula I, and wherein R_y is selected from Ci-₆-alkyl, aryl and Ci_₃-alkyl-aryl, wherein any aryl may be optionally substituted with Ci-₆-alkyl, Ci-₆-alkoxy and halogen, using an anion of the formula VIII

wherein Q is as defined above for the compound of the formula I, in particular chloro.

Clause 10. The method according to Clause 9, wherein the anion of the formula VIII is prepared in-situ by deprotonation of the corresponding pyridine in an aprotic polar solvent, e.g. selected from THF, methyl-THF, dioxane, diethyl ether and methyl ter-butyl ether, in the presence of a strong non-nucleophilic base, e.g. selected from lithium bis(trimethylsilyl)amide (LHMDS), LDA, potassium bis(trimethylsilyl)amide (KHMDS), MeLi, sec-BuLi, tert-BuLi, MeMgCI, EtMgCI, PhLi, LiNH₂ and KNH₂.

Clause 11. The method according to any one of the Clauses 9-10, wherein the compound of the formula VII is prepared by alkylating a compound of the formula IX

wherein R_x, R₂ and R_y are as defined in Clause 10 for the compound of the formula VII, with a compound of the formula III

(III) wherein X is selected from chloro and bromo, and R₃ and R₄ are as defined above for the compound of the formula I.

Clause 12. The method according to Clause 11, wherein the alkylation of the compound of the formula IX is conducted in an aprotic polar solvent, e.g. selected from DMSO, DMF, DMI, NMP, EtOAc, MeCN and THF, in the presence of a base, e.g. selected from K₂C0₃, Na₂C0₃, KHC0₃, NaHC0₃, tert-BuONa, tert-BuOK, Et₃N and DIPEA. Clause 13 The method according to any one of Clauses 11-12, wherein the compound of the formula IX is prepared by esterification of a compound of the formula XII

wherein R_x and R₂ are as defined above for the compound of the formula IX.

Clause 14. The method according to any one of the Clauses 9-13, wherein R_x and R₂ are both methyl, R₃ is hydrogen, and R4 is prop-l-yl.

Clause 15. The method according to any one of the Clauses 9-13, wherein R_x and R₂ are both methyl, R₃ is hydrogen, and R4 is -CH₂-cyclohexyl.

Clause 16. A method for the preparation of a compound of the formula I

wherein Ri and R₂ are independently selected from Ci-6-alkyl, C₃-₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈- cycloalkyl) and C₂-6-alkenyl;

R₃ is selected from hydrogen, Ci-₆-alkyl, C₃.₈-cycloalkyl, and Ci-₃-alkyl-(C₃-₈-cycloalkyl); R₄ is selected from Ci-₆-alkyl, C₃.₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci-₃-alkyl-phenyl and Ci-₃-alkyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; or R₃ and R₄ together with the intervening nitrogen atom represent an N-heterocyclic ring optionally substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; and each Q is selected from chloro, bromo and fluoro, in particular chloro; comprising the step of alkylating a pyridine of the formula V

wherein Q is as defined above for the compound of the formula I, in particular chl and Q_x is selected from fluoro, chloro, bromo and iodo, in particular chloro, with an anion of the formula X

wherein R_x, R₂, R₃ and R₄ are as defined above for the compound of the formula I. Clause 17. The method according to Clause 16, wherein the anion of the formula X is prepared in-situ by deprotonation of the corresponding acetophenone in an aprotic polar solvent, e.g. selected from THF, methyl-THF, DMF, DMSO, NMP and MeCN, in the presence of a non-nucleophilic base, e.g. selected from lithium bis(trimethylsilyl)amide (LHMDS), potassium bis(trimethylsilyl)amide (KHMDS), tert-BuONa, tert-BuOK, tert-BuOLi, K₂C0₃ and KHC0₃.

Clause 18. The method according to any one of the Clauses 16-17, wherein the acetophenone corresponding to the compound of the formula X is prepared by alkylating a compound of the formula XI

wherein R_x and R₂ are as defined in Clause 16 for the compound of the formula I, with a compound of the formula III

(III) wherein X is selected from chloro and bromo, and R₃ and R₄ are as defined in Clause 17 for the compound of the formula I.

Clause 19. The method according to Clause 18, wherein the alkylation is conducted in an aprotic polar solvent, e.g. selected from DMSO, DMF, DMI, NMP, EtOAc, MeCN and THF, in the presence of a base, e.g. selected from K₂C0₃, Na₂C0₃, KHC0₃, NaHC0₃, tert-BuONa, tert- BuOK, Et₃N and DIPEA. Clause 20. The method according to any one of the Clauses 16-19, wherein R_x and R₂ are both methyl, R₃ is hydrogen, and R₄ is prop-l-yl .

Clause 21. The method according to any one of the Clauses 16-19, wherein R_x and R₂ are both methyl, R₃ is hydrogen, and R₄ is -CH₂-cyclohexyl .

Clause 22. A crystalline form of 2-{6-[2-(3,5-dichloro-pyridin-4-yl)-acetyl]-2,3-dimethoxy- phenoxy}-N-propyl-acetamide fulfills one or more of the following criteria :

(i) belongs to the monoclinic crystal system space group P2Jc having unit-cell parameters a = 21.435 (4) A, b = 5.0676(10) A, c = 20.847(4)A, β = 112.79(3) degrees, volume V

= 2087.7(7) and number of molecules Z = 4;

(iii) has an X-ray powder diffraction pattern substantially as appears from the graph in Figure 4 herein.

Clause 23. A crystalline form of 2-{6-[2-(3,5-dichloro-pyridin-4-yl)-acetyl]-2,3-dimethoxy- phenoxy}-N-propyl-acetamide fulfills one or more of the following criteria :

(i) belongs to the monoclinic crystal system space group C2/c having unit-cell parameters a = 39.791 (5) A, b = 5.0479 (7) A c = 20.935 (3) A, β = 97.563 (2) degrees, volume V = 4168.4 (10) and number of molecules Z = 8; and/or

(iii) has an X-ray powder diffraction pattern substantially as appears from the graph in Figure 7 herein.

Claims

1. A method for the preparation of a compound of the formula I

wherein

R₃ is selected from hydrogen, Ci-₆-alkyl, C₃-₈-cycloalkyl, and Ci-₃-alkyl-(C₃-₈-cycloalkyl); R₄ is selected from Ci-6-alkyl, C₃.₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci-₃-alkyl-phenyl and Ci-₃-alkyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; or R₃ and R₄ together with the intervening nitrogen atom represent an N-heterocyclic ring optionally substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; and each Q is selected from chloro, bromo and fluoro; comprising the step of alkylating a compound of the formula II

2. The method according to claim 1, wherein the al kylation is conducted in an aprotic polar solvent in the presence of a base.

3. The method according to any one of the preceding claims, wherein the compound of the formula II is prepared by deal kylation of a compound of the formula IV

wherein R_lr R₂ and Q are as defined in claim 1 for the compound of the formula I, and R_x is selected from Ci_₃ al koxy.

4. The method according to claim 3, wherein the deal kylation reaction is conducted using BCI₃ in an apolar solvent, or usi ng BCI₃ as a gas.

5. The method according to any one of the claims 3-4, wherein the compound of the formula IV is prepared by al kylating a pyridine of the formula V

wherein Q is as defined in claim 1 for the compound of the formula I and Q_x is selected from fl uoro, chloro, bromo, iodo, with an anion of the formula VI

6. The method according to claim 5, wherein the anion of the formula VI is prepared in-situ by deprotonation of the corresponding acetophenone in an aprotic polar solvent in the presence of a strong non-nucleophilic base.

7. A method for the preparation of a compound of the formula I

wherein

Ri and R₂ are independently selected from Ci-6-al kyl, C₃-₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈- cycloalkyl) and C₂-6-alkenyl ;

R₃ is selected from hydrogen, Ci-₆-alkyl, C₃-₈-cycloalkyl, and Ci-₃-alkyl-(C₃-₈-cycloalkyl) ; R₄ is selected from Ci-₆-al kyl, C₃.₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci-3-alkyl-phenyl and Ci-₃-alkyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-6-alkyl, Ci-₆-alkoxy and halogen; or R₃ and R₄ together with the intervening nitrogen atom represent an N-heterocyclic ring optionally substituted with one or more selected from Ci-6-alkyl, Ci-₆-alkoxy and halogen; and each Q is selected from chloro, bromo and fluoro; comprising the step of nucleophilic substitution of a compound of the formula VII

wherein Q is as defined above for the compound of the formula I.

8. The method according to claim 7, wherein the anion of the formula VIII is prepared in-situ by deprotonation of the corresponding pyridine in an aprotic polar solvent in the presence of a strong non-nucleophilic base.

9. The method according to any one of the claims 7-8, wherein the compound of the formula VII is prepared by alkylating a compound of the formula IX

wherein R_x, R₂ and R_y are as defined in claim 7 for the compound of the formula VII, with a compound of the formula III

10. The method according to claim 9, wherein the alkylation of the compound of the formula IX is conducted in an aprotic polar solvent in the presence of a base.

11. A method for the preparation of a compound of the formula I

wherein

R₃ is selected from hydrogen, Ci-₆-alkyl, C₃-₈-cycloalkyl, and Ci-₃-alkyl-(C₃-₈-cycloalkyl); R₄ is selected from Ci-6-alkyl, C₃.₈-cycloalkyl, Ci-₃-alkyl-(C₃.₈-cycloalkyl), Ci-₆-alkoxy, phenyl, Ci-₃-alkyl-phenyl and Ci-₃-alkyl-pyridyl, wherein any phenyl and pyridyl may be substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; or R₃ and R₄ together with the intervening nitrogen atom represent an N-heterocyclic ring optionally substituted with one or more selected from Ci-₆-alkyl, Ci-₆-alkoxy and halogen; and each Q is selected from chloro, bromo and fluoro; comprising the step of alkylating a pyridine of the formula V

(V) wherein Q is as defined above for the compound of the formula I, in particular chloro, and Q_x is selected from fluoro, chloro, bromo and iodo, with an anion of the formula X

wherein R_x, R₂, R3 and R₄ are as defined above for the compound of the formula I.

12. The method according to claim 11, wherein the anion of the formula X is prepared in-situ by deprotonation of the corresponding acetophenone in an aprotic polar solvent in the presence of a non-nucleophilic base.

13. The method according to any one of the claims 11-12, wherein the acetophenone corresponding to the compound of the formula X is prepared by alkylating a compound of the formula XI

wherein R_x and R₂ are as defined in claim 11 for the compound of the formula I, with a compound of the formula III

wherein X is selected from chloro and bromo, and R₃ and R₄ are as defined in claim 12 for the compound of the formula I

14. The method according to claim 13, wherein the alkylation is conducted in an aprotic polar solvent in the presence of a base.

15. The method according to any one of the claims 1-6, 7-10 and 11-14, wherein R_x and R₂ are both methyl, R₃ is hydrogen, and R₄ is prop-l-yl or -CH₂-cyclohexyl.