EA040460B1 - PROTODECARBOXYLATION OF α-HALOACRYLIC ACID DERIVATIVES CATALYSED BY A TRANSITION METAL - Google Patents

Description

The field of technology to which the invention belongs

The invention relates to a process for the synthesis of haloolefins of formula (I)

XR ^{1 R 2} C ^{' X} ^ ^X CR ³ R ⁴ Y ( ^{I )} α-haloacrylic acid of formula (II)

which is carried out in the presence of a catalytic amount of copper and/or silver.

The present invention also relates to intermediate compounds used in the method according to this invention.

Prerequisites for the creation of the invention

Terminal haloolefins are not only useful synthetic intermediates in organic chemistry, but valuable target compounds in their own right: there is a long history of their use as monomers in polymer science (Marvel et al., J. Am. Chem. Soc. 1939, 61, 3241-3244), but more recently they have also attracted interest in the life sciences (e.g., Kolb et al., J. Med. Chem. 1987, 30, 267-272; Nunnery et al., J. Org Chem 2012, 77, 41984208; Akiyama et al., Tetrahedron 2013, 69, 6560-6564). For example, in medicinal chemistry, haloallylamine terminal compounds have been reported to act as amine oxidase inhibitors (WO 2005/082343, WO 2006/094201, WO 2007/120528, WO 2013/163675).

Terminal haloolefins are synthetically available through a limited number of approaches (van Steenis et al., J. Chem. Soc, Perkin Trans. 1, 2002, 2117-2133; Landelle et al., Chem. Soc. Rev. 2011, 40, 2867- 2908; Koh et al., Nature 2016, 531, 459-465, Nguyen et al., Science 2016, 352, 569), e.g. by elimination, addition, electrophilic or nucleophilic halogenation, olefination (e.g., Wittig type), or crossover reactions. metathesis. However, one of the main goals is often to obtain terminal haloolefins with high stereoselectivity.

Recent approaches to terminal haloolefin formation in the context of amine oxidase inhibitor synthesis include the Wittig reaction starting from ketones followed by separation of the E/Z isomers by chromatographic techniques or recrystallization (WO 2005/082343, WO 2007/120528, WO 2013/163675). In addition, the halogenation-dehydrohalogenation of olefins as well as the base-induced decarboxylation halogen elimination of halomethyl malonic ester derivatives have been described (McDonald et al., J. Med. Chem. 1985, 28, 186-193; McDonald et al., Tetrahedron Letters 1985 , 26, 3807-3810; WO 2005/082343, WO 2006/094201).

Another approach to the formation of terminal haloolefins is the protodecarboxylation of α-haloacrylic acid derivatives, which are available, for example, by the Horner Wadsworth-Emmons reaction starting from carbonyl compounds. However, the scope of this protodecarboxylation is limited by the use of specific substrates such as perfluorinated acrylic acids or acrylic acids with unsaturated β-substituents: sodium(I), silver(I) and copper(II) salts of perfluorinated acrylic acid derivatives have been reported to undergo protodecarboxylation at significant heating (Cherstkov et al., Izvestiya Akademii nauk SSSR, Seriya Khimicheskaya 1986, 7, 119-122; Cherstkov et al., Izvestiya Akademii nauk SSSR, Seriya Khimicheskaya 1989, 6, 1336-1340). Similarly, protodecarboxylation of mucohalogen acids ((Z)-2-3-dihalo-4oxo-2-butenoic acids, that is, bearing a carbonyl substituent in the β-position) to obtain (Z)α,β-dihaloacrolein, can be carried out by excessive heating ( Duczek et al., Synthesis 1992, 10, 935-936). Acrylic acid derivatives with β-pyrimidinyl substituents can be protodecarboxylated by acidification at elevated temperatures (DD 259803). Acrylic acids with β-phenyl substituents (i.e., cinnamic acid derivatives) can be decarboxylated by using copper(0)/copper(II)/quinoline and heating above 200°C (Elkik, Bull. Soc. Chim. Fr. 1967 , 5, 1569-71), using excess copper(II) in the presence of a molecular sieve in DMA/DMSO at 140°C (Rousee et al., Chem. Eur. J. 2014, 20, 1500015004) or by cofactor catalysis (Payne et al., Nature 2015, 522, 497-501).

In contrast, no application of the protodecarboxylation step of acrylic acid derivatives with two vicinal saturated carbon substituents has been reported. In addition to the limited volume of the substrate, the use of stoichiometric amounts of metals and heating to high temperatures are additional disadvantages of such transformations reported to date, which have prevented the wider application of this reaction.

Brief description of the figures

Fig. 1: XRPD pattern of Form I (I-k).

Fig. 2: XRPD pattern of form II (I-k).

Fig. 3: DSC curve form I (I-k).

Fig. ^4:13 C CPMAS ssNMR spectrum form I (Ik).

Fig. 5: ¹⁹ F ssNMR spectrum of form I (Ik).

The essence of the invention

In a first aspect, the present invention relates to a process for the synthesis of haloolefins of formula (I)

N. Hal

XR ¹ R ² C cr ³ r ⁴ y (I) where

Hal is selected from the Hal-G1 group consisting of

F, Cl, Br and I, and

R ¹ , R ² , R ³ and R ⁴ are independently selected from the group Ri-G1 consisting of

H, halogen, CN, substituted or unsubstituted C1. ₁₀ alkyl, substituted or unsubstituted C ₃ - ₁₀ cycloalkyl, substituted or unsubstituted C ₂ - ₁₀ alkenyl, substituted or unsubstituted C ₂ - ₁₀ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C1.6 alkylene-, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C1.balalkylene-,

X and Y are independently selected from the groups X-G1 and Y-G1, respectively, each of which consists of

Ri, OR ^X , SR ^X , S(O)R ^X , SO2RX, NR ^y1 R ^y2 , N(O)R ^y1 R ^y2 , PR ^y1 R ^y2 and P(O)R ^Y1 R ^Y2 , where R ^X is selected from the group RX-G1 consisting of Ri, and where R ^Y1 and R ^Y2 are independently selected from the group R ^Y -G1a consisting of

Ri, C(O)Ri and C(O)ORi, or

R ^Y1 and R ^Y2 are selected from the group R ^Y -G1b, in which

R ^Y1 and R ^Y2 are linked to form, together with the N or P to which they are attached, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl, and

R ¹ is selected from the group Ri-G1 as defined above;

or salts thereof, comprising step (S1), (S1): protodecarboxylation of an α-haloacrylic acid derivative of formula (II) O

Hal ^but Λ XR ¹ R ² C • ^/ '^^CR ³ R ⁴ Y (II) where Hal, R ¹ , R ² , R ³ , R ⁴ , X and Y are defined as above and where (S1) carried out in the presence of a catalytic amount of copper and/or silver.

In a second aspect, the present invention relates to intermediates that are included in the method according to the first aspect of the invention.

Other aspects of the present invention will become apparent to those skilled in the art.

- 2 040460 technology directly from the preceding and subsequent description.

General terms and definitions

Unless otherwise indicated, groups, residues and substituents, especially Hal, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , Ri, R ^X , R Y1 , R ^Y2 , R ⁿ¹ , ^{R n2 ,} R ^ar , X and Y are defined as above and below. When groups, residues, or substituents occur multiple times in a compound or reaction scheme, they may have the same or different meanings.

Terms not specifically defined in this application will have the meanings given by a person skilled in the art in light of the disclosure and context. The following terms used in the present description, however, unless otherwise indicated, have the meanings indicated, and the following conventions are observed.

In the groups, radicals or fragments defined below, the number of carbon atoms is often indicated before the group, for example C ₁ . ₆ alkyl means an alkyl group or radical having 1 to 6 carbon atoms. Typically, for groups containing two or more subgroups, the last named subgroup is the point of attachment of the radical, for example substituent aryl-C ₁ . ₃ αkylene- means an aryl group that is linked to C ₁ . ₃ alkylene group, the last of which is linked to the core or to the group to which the substituent is attached.

Term C ₁ . _n -αkyl, where n is an integer from 2 to n, either alone or in combination with another radical, denotes a monovalent acyclic, saturated, linear or branched hydrocarbon radical containing from 1 to n C atoms. For example, the term C ₁ . ₄ alkyl includes the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH( CH3)-CH2-, H3C-C(CH3)2-.

The term C _1-n -alkylene, where n is an integer from 2 to n, either alone or in combination with another radical, denotes a divalent acyclic, saturated, linear or branched hydrocarbon radical containing from 1 to n C atoms. For example, the term C ₁ . ₄ α-alkylene includes the radicals -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)- CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-, -CH2-CH(CH3 )-CH2-, -CH2-C(CH3)2-, -C(CH3 ₎ 2 _- CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH(CH2CH3)-, - CH(CH2CH3)-CH2-, -CH( _CH2CH2CH3 )-, -CH(CH( _CH3 ))2- and -C(CH3)(CH2CH3)-.

Term C ₂ . _n -alkenyl, where n is an integer from 3 to n, denotes a radical as defined for C ₁ . _n -alkyl with at least two C atoms, where at least two carbon atoms are linked to each other by a double bond.

Term C ₂ . _n -alkynyl, where n is an integer from 3 to n, denotes a radical as defined for C ₁ . _n -alkyl with at least two C atoms, where at least two carbon atoms are connected to each other by a triple bond.

Term C ₃ . _n -cycloalkyl, where n is an integer from 4 to n, either alone or in combination with another radical, denotes a cyclic saturated straight hydrocarbon radical containing from 3 to n C atoms. For example, the term C ₃ -7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term aryl, either alone or in combination with another radical, means a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be further fused to a second 5- or 6-membered carbocyclic group, which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, and dihydronaphthyl.

The term heterocyclyl, either alone or in combination with another radical, means a saturated or unsaturated mono- or polycyclic ring system, including aromatic ring systems containing one or more heteroatoms selected from N, O or S(O) _r , where r= 0, 1 or 2, consisting of 3-14 ring atoms, in which none of the heteroatoms is part of the aromatic ring. The term heterocyclyl includes all possible isomeric forms.

The term heteroaryl, either alone or in combination with another radical, means a mono- or polycyclic ring system containing one or more heteroatoms selected from N, O or S(O) _r , where r=0, 1 or 2, consisting of 5-14 ring atoms, where at least one of the heteroatoms is part of an aromatic ring. The term heteroaryl includes all possible isomeric forms.

The term halogen usually means fluorine, chlorine, bromine and iodine.

The term substituted, as used herein, means that any one or more hydrogen atoms on the indicated atom, radical, or moiety are replaced by another radical or moiety (substituent), provided that the normal valences of the atoms are not exceeded and that the substitution results in an acceptably stable connection. Substituents may be, but are not limited to, halogen, hydroxy, oxo, optionally halogenated alkoxy, amino, nitro, amidinyl, guanidinyl, sulfanyl, sulfo, sulfonyl, sulfonamido, silyl, optionally halogenated or hydroxylated alkyl, or cycloalkyl, or alkenyl, optionally halogenated or hydroxylated aryl or heteroaryl or heterocyclyl, cyano, carbonyl, acyl, alkoxy

- 3 040460 carbonyl, amido, carbamate and combinations thereof.

As used herein, the term pharmaceutically acceptable salt refers to derivatives of the disclosed compounds in which the parent compound has been modified by obtaining its acidic or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids and basic residues such as amines; alkali or organic salts of acid residues such as carboxylic acids; etc.

For example, such salts include salts of benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.

Other pharmaceutically acceptable salts may be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)- aminomethane.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acid moiety using conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or mixtures thereof.

Salts of other acids than those mentioned above, which, for example, are useful for purifying or isolating the compounds of the present invention (eg, trifluoroacetate salts) also form part of the invention.

Detailed description of the invention

The present invention discloses a process for the synthesis of haloolefins comprising the step of protodecarboxylation of α-haloacrylic acid derivatives in the presence of a catalytic amount of copper and/or silver.

In a first aspect, the present invention relates to a process for the synthesis of haloolefins of formula (I)

(I) where Hal, R ¹ , R ² , R ³ , R ⁴ , X and Y are defined as above or below, or salts thereof, comprising step (S1), (S1): protodecarboxylation of an α-haloacrylic acid derivative of the formula (II)

ABOUT

xr ¹ r ² c cr ³ r ⁴ y XR ¹ R ² C ^xX '^^CR ³ R ⁴ Y (II) (l)

In addition, in a similar manner, the present invention relates to the synthesis of the E/Z isomer (I) from the corresponding E/Z isomer (II). In order to simplify the following description, only the synthesis of compound (I) as shown above is described in detail. This, however, should not be construed as limiting the scope of the invention.

In particular, the invention provides a process that is carried out under relatively mild and catalytic conditions.

In this aspect, it has been found that protodecarboxylation of an α-acrylic acid derivative can be carried out in a stereospecific manner in the presence of catalytic amounts of copper and/or silver transition metals.

The results of relevant studies are presented in the Examples and Experimental Data section and are listed below.

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For the protodecarboxylation step, the best results in terms of catalytic activity, eg high conversions at low catalyst loadings, short reaction times and some limitations on solvent choice, are obtained in the presence of silver(I). Both oxides and salts of silver (I), in particular, silver oxide (I), silver acetate (I), silver (I) nitrate and silver carbonate (I) can be used as highly efficient catalysts, providing the production of haloolefins with high yields. and cleanliness.

Good results have also been obtained with copper(I), used in the form of its oxides and/or salts, also in complexes with monodentate ligands, as protodecarboxylation catalysts. Non-limiting examples are copper (I) oxide, copper (I) acetate, and copper (I) thiophene-2-carboxylate (CuTc).

The reaction can also proceed in the presence of copper (II).

Catalytically active compounds of copper(I) and silver(I) can also be formed in situ from other oxidation states.

Thus, according to one embodiment of the first aspect of the present invention, the protodecarboxylation of the α-acrylic acid derivative is carried out in the presence of copper and/or silver.

Preferably the copper and/or silver is used in the form of copper (I) oxide, copper (I) salts, silver (I) oxide and/or silver (I) salts. More preferably silver(I) oxide or silver(I) salts are used, even more preferably silver(I) acetate and/or nitrate and/or carbonate, most preferably silver(I) acetate and/or nitrate.

Preferably, copper and/or silver can be used in substoichiometric amounts so that the protodecarboxylation proceeds rapidly with complete conversion. Catalyst loadings of 50 mol % and below are used very successfully (mol % denotes the number of catalytically active copper and/or silver atoms relative to the molecules of the compound of formula (II)). It has also been found that, for example, by adjusting the solvent volume and the reaction temperature, and depending on the reaction conditions, the catalyst loading can be further reduced, at least to the low single digit mole % range. The actual optimum catalytic amount will, of course, depend on factors known to those skilled in the art, such as structural characteristics of the starting materials, additional reaction conditions and parameters, acceptable reaction times, and potential side reactions.

Thus, in accordance with another embodiment, the copper and/or silver in the protodecarboxylation is used in catalytic amounts, i.e. in amounts of not more than 50 mol%, for example in the range from 2.5 to 50 mol%, preferably not more than 20 mol% , more preferably not more than 10 mol.%, most preferably not more than 7.5 mol.%. Preferred lower limits of the catalytic range may be 7.5, 5, 2.5 or 1 mole%. Most preferably the range is from 5 to 10 mol%.

The protodecarboxylation of the present invention is advantageously carried out in dipolar aprotic solvents: for example, N-methylpyrrolidinone (NMP), N,N-dimethylacetamide (DMA), pyridine and/or acetonitrile can be successfully used. Anhydrous operation and shielding from oxygen and light are beneficial to the performance of the catalyst and the result of the reaction.

Thus, in another embodiment, the protodecarboxylation is carried out in a medium that contains one or more dipolar aprotic solvents, preferably selected from the group consisting of acetonitrile, N,N-dimethylacetamide, pyridine or NMP, most preferably NMP.

The protodecarboxylation of the present invention can be carried out without the need for excessive heating. Temperatures below 150°C are sufficient for the reaction to proceed, the most preferred range is 120-130°C. Complete conversion can also be achieved at significantly lower temperatures, eg below 100° C., which can be used to advantage for temperature sensitive compounds if potentially longer conversion times are unacceptable. The actual optimum reaction temperature will, of course, depend on factors known to those skilled in the art such as the structural characteristics of the starting materials, additional reaction conditions and parameters, acceptable reaction time, and potential side reactions.

Thus, according to another embodiment, the protodecarboxylation is carried out at a temperature of at most 150°C, preferably at most 140°C, most preferably at most 130°C, for example at a temperature of about 130°C, about 120°C, about 100°C. C or approximately 80°C. Most preferably, the temperature range is from 120 to 140°C.

Optionally, step (S1) may include steps and steps known to those skilled in the art to introduce, remove, or manipulate protective groups in compounds of formula (II) and/or (I). Such measures and steps may be considered necessary by a person skilled in the art, depending on the significance of the substituents, in particular X and Y, for example in order to prevent side reactions.

- 5 040460

Optionally, step (S1) may include steps and steps known to those skilled in the art to convert the compound of formula (I) to its salt, preferably a pharmaceutically acceptable salt, most preferably its hydrochloride salt. Such measures and steps may be considered suitable by a person skilled in the art, depending on the significance of the substituents, in particular Y, for example to improve the physical and/or chemical properties of the compound (I), in particular to obtain the compound of formula (I) in a suitable solid, for example crystalline form that is suitable for use in pharmaceutical development.

For example, the preferred solid form of the compound (I-k)

is form I, a crystalline refractory stable form (I-k), which is not prone to polymorphic transformations. Form I is found to contain water: the molar ratio (I-k) to H2O ranges from 3:1 to 5:1, more specifically 4:1; form I, therefore, can be considered as tetrathohydrate.

X-ray powder diffraction (XRPD) Form I peaks are shown in the examples and experimental data section. Therefore, in particular Form I is characterized by an XRPD pattern containing peaks at 3.82, 7.63, 13.55 and 15.29 degrees 2θ, in particular containing peaks at 3.82, 7.63, 13.55, 15.29, 16.03 and 17.80 degrees 2θ, more specifically containing peaks at 3.82, 7.63, 11.46, 13.55, 15.29, 16.03, 17.80 and 19.02 degrees 2θ, even more specifically containing peaks at 3.82, 7.63, 11.46, 13.55, 15.29, 16.03, 17.80, 19.02 19.69, 20.80, 22.64, 23.63, 26.93, 27.30.93, 27.30.30.30.30.93, 27.30.93, 27.30.93, 27.30 and 27.79 degrees 2θ (for all peaks mentioned above: ±0.2 degrees 2θ, using CuKa1 radiation), even more specifically containing peaks at degrees 2θ, as indicated in the examples and experimental data section (point (7)) or as shown in Fig. . 1 of this document.

Form I is further characterized by a melting point of approximately 181° C.±5° C. (determined by differential scanning calorimetry (DSC); estimated as initial temperature; heating rate 10° C./min). The Form I DSC curve is shown in FIG. 3.

In addition, representative Solid State Nuclear Magnetic Resonance (ssNMR) data for Form I are presented in terms of ¹³ C and ¹⁹ F chemical shifts in the Examples and Experimental Data section. Therefore, in particular Form I is characterized by a ¹³ C spectrum containing peaks at 161.1, 162.5 and 167.9 ppm, in particular containing peaks at 148.4, 149.0, 151.4, 154.0, 156.6, 161.1, 162.5 and 167.9 ppm. , more specifically containing peaks at 128.3, 129.2, 130.1, 131.3, 148.4, 149.0, 151.4, 154.0, 156.6, 161.1, 162.5 and 167.9 ppm, even more specifically containing peaks at 29.0, 29.9, 128.2, 129. 131.3, 148.4, 149.0, 151.4, 154.0, 156.6, 161.1, 162.5 and 167.9 ppm (for all peaks mentioned above: ±0.2 ppm), even more specifically containing peaks as indicated in the examples and experimental data section (point (9)) or as shown in FIG. 4 of this document.

Form I, in addition, is characterized by a chemical shift ¹⁹ F -115.1 ppm. (± 0.2 ppm).

Form I (I-k) can be obtained from compound (I-j')

in a manner that includes the following steps:

(a) adding at least one molar equivalent of HCl to the solution (I-j'), (b) optionally performing and/or maintaining precipitation (I-k), (c) allowing crystallization (I-k), (d) optional precipitation in steps (a), and/or (b), and/or (c), (e) optional recrystallization of the precipitate in steps (a), and/or (b), and/or (c), and/or ( d), (f) selection of form I (I-k).

In step (a), said solution can be obtained by dissolving (I-j') in any form that can be obtained, in particular in solid form, for example crystalline or amorphous, in

- 6 040460 solvent or mixture of solvents, as described below. Alternatively, step (a) may be added directly to the synthesis (I-j'), ie without isolation or purification (I-j'). For example, said solution can be obtained by diluting a concentrated solution (I-j') which was obtained by isolating the product from the reaction mixture in which (I-j' was formed), for example according to WO 2013/163675 or this document.

Preferably the solution (I-j') obtained in step (a) is a saturated or nearly saturated solution at a given temperature. The terms saturated or almost saturated refer to the starting material (I-j') used in step (a). In particular, the concentration of (I-j') in the solution of step (a) may range from about 150 to about 600 mmol/l, for example about 175 mmol/l, about 270 mmol/l, about 315 mmol/l, about 370 mmol/l or approximately 500 mmol/l.

The solution (I-j') used in step (a) preferably contains at least two different solvents to provide both sufficient solubility for (I-j') and the required crystallization characteristics for (I-k) in subsequent process steps. Therefore, the medium contains at least one protic solvent, preferably selected from alcohols, more preferably from ethanol and isopropyl alcohol, most preferably isopropyl alcohol. In addition, the medium preferably contains at least one aprotic solvent, preferably selected from alkanes, aromatic solvents, ethers and esters, more preferably from heptane, toluene, 2-methyltetrahydrofuran (2-Me-THF), methyl tert-butyl ether (MTBE) and ethyl acetate, most preferably from heptane, toluene and ethyl acetate.

In particular, the medium may consist of two different solvents, one of which is a protic solvent. One preferred solvent mixture is isopropyl alcohol/ethyl acetate, where the volume ratio of isopropyl alcohol to ethyl acetate is in the range of about 1:1 to 1:3, eg the volume ratio is about 1:2.

In addition, the medium may, in particular, consist of three different solvents, one of which is a protic solvent. One preferred solvent mixture is isopropyl alcohol/heptane/toluene, in which the volume ratio of isopropyl alcohol to heptane is in the range from about 1:1 to about 1:1.5 and where the volume ratio of isopropyl alcohol to toluene is in the range from about 1:3 to about 1:5, for example the volume ratio of the three components is about 1:1.2:3.4. Another preferred solvent mixture is isopropyl alcohol/2-Me-THF/ethyl acetate, wherein the volume ratio of isopropyl alcohol to 2-MeTHF is in the range from about 1:0.3 to about 1:1, and where the volume ratio of isopropyl alcohol to ethyl acetate is in the range of about 1:1 to about 1:2, for example, the volume ratio of the three components is about 1:0.5:1.2, about 1:0.4:1.3, about 1:0.6:1.5, or about 1:0.5:1.8.

The solution can be heated to the boiling point of the solvent mixture or to a temperature in the range from about 65 to about 80°C, for example up to about 68°C, up to about 70°C or up to about 75°C. The solution can be filtered, for example, on charcoal.

In step (a), HCl is preferably added as a solution, for example to isopropyl alcohol at concentrations of about 5-6 mol/l or to diethyl ether at concentrations of about 1-2 mol/l. For complete conversion of (I-j') to (I-k), at least 1.0 molar equivalent (eq.) of HCl must be added, preferably from 1.0 to 1.5 eq., for example about 1.2 eq. The temperature during the HCl addition may be room temperature, i.e. about 20-30°C, for example about 25°C, or about 60-75°C, for example about 68°C, depending, inter alia, on the solvent system used.

In the optional step (b), measures may be taken to produce and/or maintain precipitation (I-k), for example to facilitate nucleation. Such methods are well known to those skilled in the art and include, but are not limited to, seeding, cooling, solvent evaporation, anti-solvent addition, and mechanical intervention such as scratching or rubbing. Preferably, seed crystals (I-k) are added to the solution obtained in step (a), optionally after a filtration step. The weight of the seed crystals relative to the total weight (I-k) can be in the range up to about 5%, more preferably from about 0.001 to 1%. The seed crystals are preferably added at a temperature in the range from about 50 to 80°C, most preferably from about 60 to 75°C, for example at 68°C.

In step (c), steps can be taken to ensure crystallization, preferably to completion, for example to ensure further crystal growth. Such methods are well known to the person skilled in the art and include, but are not limited to, cooling, optionally keeping the suspension still while stirring, and adding additional solvents, in particular to reduce the solubility of the solute, such as adding an anti-solvent.

Preferably MTBE is added, for example about twice the total volume of isopropyl alcohol used in step (a).

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Preferably, the temperature is lowered to room temperature, if applicable, to obtain a high yield of precipitated form (I-k). The duration of step (c) may range from about 3 to about 12 hours, during which stirring should preferably be applied. As is known to the person skilled in the art, the size, shape and quality of the resulting crystals may vary depending on the time period and temperature difference in step (c).

In optional steps (d) and (e), the crystals formed in steps (b) and/or (c) may be isolated and recrystallized to improve the purity and quality of the crystals. The techniques used in these steps are well known to those skilled in the art.

Selection methods are detailed below for step (f).

The recrystallization according to step (e) can advantageously be carried out using solvent systems which correspond to those described or result from steps (a)-(c). Thus, the solvent system contains at least one protic solvent and at least one aprotic solvent. Preferably one or more protic solvents are selected from water and alcohols, more preferably water, methanol, ethanol and isopropyl alcohol, most preferably isopropyl alcohol. The one or more aprotic solvents are preferably selected from alkanes, ketones, ethers and esters, more preferably from heptane, acetone, 2-methyltetrahydrofuran (2-Me-THF), methyl tert-butyl ether (MTBE), isopropyl acetate and ethyl acetate, most preferably from MTBE and ethyl acetate. Preferred solvent systems are selected from the group consisting of water/ethanol/ethyl acetate, water/isopropyl alcohol/ethyl acetate, isopropyl alcohol/ethyl acetate/MTBE, methanol/ethyl acetate, water/isopropyl acetate/acetone and water/isopropyl alcohol/heptane, preferably selected from water /ethanol/ethyl acetate, water/isopropyl alcohol/ethyl acetate and isopropyl alcohol/ethyl acetate/MTBE; more preferably, the solvent system is isopropyl alcohol/ethyl acetate/MTBE, where the volume ratio of isopropyl alcohol to ethyl acetate is in the range from about 1:1 to about 1:0.75 and where the volume ratio of isopropyl alcohol to MTBE is in the range from about 1:0.9 to about 1:0.65, for example, the volume ratio of the three components is 9:8:7.

In step (f), Form I (I-k) is isolated from solution by means known to the person skilled in the art, which include, but are not limited to, centrifugation and filtration. In particular, step (f) includes filtration, washing the filter cake and drying under vacuum. The resulting crystals are preferably washed with a solvent or solvent mixture, the solvent being preferably selected from MTBE and a 3:1 (v/v) heptane/isopropyl alcohol mixture, followed by the addition of heptane. The most preferred solvent is MTBE. Preferably, the remaining solvent(s) are preferably removed from the crystals in a vacuum drying step, e.g. at a temperature of about 60° C., for about 5 to 12 hours. pressure and duration of the drying stage.

Alternatively, Form I (I-k) can be prepared from Form II, Anhydrous Form (I-k).

Form II can be obtained by over-drying (I-k) or from a solution (I-k) by evaporating the solvent, for example from a solution of (I-k) in acetone by slowly evaporating the solvent at ambient conditions, or from a 50 mg/ml solution of (I-k) in methanol by rapidly evaporation of the solvent, i.e. for 15 min at 60° C. under vacuum, preferably with dry nitrogen or dry air as exhaust gas in a vacuum oven.

Form I can be prepared from Form II by recrystallization according to the procedures described herein or known to those skilled in the art, e.g. from water/ethanol/ethyl acetate, water/isopropyl alcohol/ethyl acetate, isopropyl alcohol/ethyl acetate/MTBE, methanol/ ethyl acetate, water/isopropyl acetate /acetone and water/isopropyl alcohol/heptane, heptane, ethyl acetate, isopropyl acetate, isopropyl alcohol, anisole, methyl ethyl ketone, α,α,α-trifluorotoluene and mixtures thereof, preferably from heptane, ethyl acetate, isopropyl acetate, anisole, ethyl acetate /isopropyl alcohol 1:1 and α,α,α-trifluorotoluene/methyl ethyl ketone 1:1. In addition, the recrystallization procedure described in step (e) above can be used.

In addition, form I can be obtained by reducing form II, that is, by exposing form II to a relative humidity of at least 15%.

Differentiation between Form I and Form II and therefore monitoring of conversion completeness can be achieved by collecting X-ray Powder Diffraction (XRPD) and/or Differential Scanning Calorimetry (DSC) and/or Solid State Nuclear Magnetic Resonance (ssNMR) data as far as they are characteristic of various crystalline forms.

As a further alternative, Form I (I-k) may be formed from ethanol solvates (I-k).

Ethanol solvates (I-k), in particular in a 1:1 molar ratio, can be recovered from ethanol and ethanol/heptane solvent systems, for example with ethanol:heptane volume ratios of 2:1, 1:1, and

- 8 040460

1:2, preferably from ethanol or ethanol/heptane 1:1, by evaporation at room temperature.

Form I can be prepared from ethanol solvates by recrystallization according to procedures described herein or known to those skilled in the art, e.g. from water/ethanol/ethyl acetate, water/isopropyl alcohol/ethyl acetate, isopropyl alcohol/ethyl acetate/MTBE, methanol/ethyl acetate , water/isopropyl acetate/acetone and water/isopropyl alcohol/heptane, heptane, ethyl acetate, isopropyl acetate, isopropyl alcohol, anisole, methyl ethyl ketone, α,α,α-trifluorotoluene and mixtures thereof, preferably from heptane, ethyl acetate, isopropyl acetate, anisole, ethyl acetate/ isopropyl alcohol 1:1; and α,α,α-trifluorotoluene/methyl ethyl ketone 1:1. In addition, the recrystallization procedure described in step (e) above can be used.

In addition, form I can be obtained from solvates of ethanol (I-k) by desolvation by drying at ambient conditions or heating to temperatures in the range from about 75°C to about 110°C.

The present invention also provides a process for the synthesis of haloolefins of formula (I)

To Hal

XR ¹ R ² CT ^CR ³ R ⁴ Y (I) where Hal, R ¹ , R ² , R ³ , R ⁴ , X and Y are defined as above or below, comprising steps (S2): α- derivative formation haloacrylic acid of formula (II) from ketone (III) and (S1) as defined above or below:

In particular, a process is provided for the stereoselective conversion of a ketone of formula (III) to a haloolefin of formula (I).

Previous approaches to the formation of a terminal haloolefin (I) from ketones (III) have generally been via Wittig reactions, which often provide poor E/Z selectivity and therefore require additional potentially cumbersome separation steps and affect the overall reaction yield (van Steenis et al. ., J. Chem. Soc, Perkin Trans. 1, 2002, 2117-2133; Landelle et al., Chem. Soc. Rev. 2011, 40, 2867-2908).

The protodecarboxylation (S1) of the present invention, on the other hand, paves the way for said transformation of (III) to (I) by means of the α-haloacrylic acid derivatives of formula (II). Compounds of formula (II) are readily prepared from ketones(III) by the Horner Wadsworth-Emmons reaction which, with the right choice of base, can provide improved E/Z selectivity over Wittig olefinations. This improved selectivity is maintained by stereospecific protodecarboxylation (II) to form the olefin (I). In general, the incorporation of protodecarboxylation into said conversion of (III) to (I) thus allows the improved E/Z selectivity established in formation (II) (step (S2)) and maintained in its protodecarboxylation (step (S1)) to be obtained. This more appropriate isomeric purity, in turn, can help to simplify or avoid further separation of the isomers, for example by crystallization or chromatography, and improve the yield of the reaction. In addition, in this reaction sequence, it is possible to carry out the separation of isomers - additionally or only - at the stage of the intermediate compound (II), which, depending on the specific circumstances, may be more efficient and/or efficient than at the stage of the product (I).

Step (S2) is explained in more detail below.

The α-haloacrylic acid derivative of formula (II') can in principle be prepared from ketones (III) according to the Horner-Wadsworth-Emmons protocols known in the art (e.g., Maryanoff et al., Chem. Rev. 1989, 89, 863 -927; Al Jasem et al., J. Chem. Res. 2014, 38, 453-463; Sano et al., Tetrahedron Letters 2014, 55, 6248-6251), for example using phosphonates of formula (IV) as reagents in the presence of basic additives

- 9 040460

where Hal, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , X and Y are defined as above or below.

In the case where R ⁰ is not H, (S2) preferably also includes saponification of acrylic acid ester (P') to acrylic acid (P), for example in situ saponification, according to procedures known to the person skilled in the art.

Saponification can be carried out either before or after separation and/or isolation of the E/Z isomers. The formation of acrylic acid by saponification can also be useful for separating the E and Z isomers, either by chromatographic methods or by crystallization.

Synthesis example according to step (S2) is o o

EY

F (IV-a)

Base

It has been found that the conversion of (III) to (II) in the presence of (IV), in particular (III-j) to (II-j) in the presence of (IV-a), which is favorable for very good reaction yields, can be achieved with a number of different bases, such as n-BuLi, NaHMDS, NaH, t-BuONa, t-BuOK, (t-BuO) ₂ Mg and n-Bu ₂ Mg. However, the best results in terms of product E/Z ratio are observed when organomagnesium halides such as MeMgCl, MeMgBr, MeMgI, EtMgBr and iPrMgCl are used as bases. Preferably, organomagnesium bromides or iodides such as MeMgBr, MeMgI and EtMgBr are used.

Thus, in one embodiment, the process for synthesizing haloolefins of formula (I) comprises steps (S2) and (S1):

(S2): reacting a ketone of formula (III) with a phosphonate of formula (IV) in the presence of at least one basic additive, preferably an organomagnesium halide, more preferably C _1-4 alkyl magnesium chloride or C _1-4 alkyl magnesium bromide, for example MeMgBr, MeMgCl, EtMgBr or i-PrMgCl, most preferably EtMgBr; and saponification of an acrylic acid ester of formula (II') (in case R ⁰ is not H), and (S1): protodecarboxylation of an α-haloacrylic acid derivative of formula (II) which is carried out in the presence of a catalytic amount of copper and/or silver .

In addition, (S2) may optionally include measures and steps known to the person skilled in the art to separate the E and Z isomers to improve the purity of the product, for example by chromatographic methods or crystallization. For example, the E/Z separation can be carried out by crystallization of compound (II), for example after saponification of (II') to (II).

Thus, according to another embodiment, (S2) further comprises an E/Z purification of the compound of formula (II).

According to another embodiment, the haloolefin of formula (I) is formed from the ketone (III) with an E/Z selectivity of at least 80:20, preferably at least 90:10, most preferably at least 95:5, via steps (S2) involving saponification in the case where R ⁰ is not H, and optionally including E/Z cleaning, and (S1).

According to another embodiment (S2) is carried out at temperatures ranging from -20°C to 70°C, preferably in the range from -10°C to 40°C.

According to another embodiment (S2) is carried out in an aprotic medium, preferably selected from the group consisting of tetrahydrofuran (THF), 2-methyl-THF, dimethyl sulfoxide (DMSO), dimethyl ether (DME), toluene (PhMe) and mixtures thereof, preferably from THF, 2-methylTHF and mixtures thereof.

According to another embodiment, the compound of formula (IV) on (S2) is used in an amount of 1 to 2.5 equivalents relative to the compound (III), preferably in an amount of 1.1 to 1.5 equivalents, most preferably in an amount of about 1.2 equivalents.

Optionally, step (S2) may include steps and steps known to those skilled in the art to introduce, remove, or manipulate protective groups in compounds of formula (III) and/or (II). Such measures and steps may be considered necessary by a person skilled in the art, depending on the significance of the substituents, in particular X and Y, for example in order to prevent side reactions.

In the methods of this invention, the following meanings of groups, residues and substituents are preferred. Any and all of the above and below definitions of groups, residues and substituents may be combined with each other.

In one embodiment, Hal is selected from the Hal-G1 group consisting of F, Cl, Br, and I.

In another embodiment, Hal is selected from the Hal-G2 group consisting of F and Cl.

In another embodiment, Hal is selected from the Hal-G3 group consisting of F.

According to another embodiment, R ¹ , R ² , R ³ and R ⁴ are independently selected from the group Ri-G1 consisting of H, halogen, CN, substituted or unsubstituted C ₁ . ₁₀ alkyl, substituted or unsubstituted C ₃ . ₁₀ cycloalkyl, substituted or unsubstituted C ₂ . ₁₀ alkenyl, substituted or unsubstituted C ₂ . ₁ oalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylC ₁ .6αalkylene-, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C ₁ .6alkylene-.

According to another embodiment, R ¹ , R ² , R ³ and R ⁴ are independently selected from the group Ri-G2 consisting of H, halogen, CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl , iso-butyl, tert-butyl and cyclopropyl, where said methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl or cyclopropyl may be partially or fully halogenated, preferably fluorinated.

According to another embodiment, R1, ^R2 , ^R3 and ^R4 are independently selected from the group Ri-G3 consisting of H, halogen, CN and methyl, where said methyl may be partially or fully halogenated, preferably fluorinated.

According to another embodiment, R1, ^R2 , ^R3 and ^R4 are independently selected from the group Ri-G4 consisting of H.

In another embodiment, X is selected from the group X-G1 consisting of Ri, OR ^X , SR ^X , S(O)R ^X , SO2RX, NR ^Y1 R ^Y2 , N(O)R ^Y1 R ^Y2 , PR ^Y1 R ^Y2 , and P(O)R ^Y1 R ^Y2 , where Ri, R ^x , R ^y1 and R ^Y2 are defined as above or below.

In another embodiment, X is selected from the group X-G2 consisting of ORX, SRX, S(O)R ^X , and SO2RX, where RX is defined as above or below.

According to another embodiment, X is selected from the group X-G3 consisting of ORX, where RX is defined as above or below.

According to another embodiment, R ¹ is selected from the group R ¹ -G1 as defined above.

According to another embodiment, R ¹ is selected from the group R ¹ -G2 as defined above.

According to another embodiment, Ri is selected from the group Ri-G3 as defined above.

According to another embodiment, Ri is selected from the group Ri-G4 as defined above.

According to another embodiment, R ^X is selected from the group R ^X -G1 consisting of R ¹ as defined above or below.

According to another embodiment, R ^X is selected from the group R ^X -G2 consisting of H, substituted or unsubstituted C ₁ . ₁ oαkyl, substituted or unsubstituted C ₃ . ₁ ocycloalkyl, substituted or unsubstituted C ₂ _ ₁₀ alkenyl, substituted or unsubstituted C ₂ _ ₁₀ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C ₁ . ₆ alkylene-, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroaryl-C ₁ . ₆ alkylene-.

In another embodiment, RX is selected from the group RX-G3 consisting of aryl and heteroaryl, all of which are substituted with R ^ar , where R ^ar is defined as above or below.

In another embodiment, RX is selected from the group RX-G4 consisting of phenyl substituted with R ^ar , where R ^ar is defined as above or below.

According to another embodiment, R ^ar is selected from the group R ^ar -G1 consisting of

C(O)NR ⁿ¹ R ⁿ² and SO ₂ NR ⁿ¹ R ⁿ² , where R ^N1 and R ^N2 are defined as above or below.

According to another embodiment, R ^ar is selected from the group R ^ar -G2 consisting of

C(O)NR ⁿ¹ R ⁿ² , where R ⁿ¹ and R ^N2 are defined as above or below.

In another embodiment, R ^ar is selected from the group R ^ar -G3 consisting of C(O)NHt-Bu.

In another embodiment, R ^N1 and R ^N2 are independently selected from the group RN-G1 consisting of H, substituted or unsubstituted C ₁ .6 alkyl, and substituted or unsubstituted

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_C3 . ₇ cycloalkyl.

In another embodiment, R ^N1 and R ^N2 are independently selected from the group RN-G2 consisting of H and substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. According to another embodiment, R ^N1 and R ^N2 are independently selected from the group RN-G3 consisting of H and tert-butyl. According to another embodiment, Y is selected from the group Y-G1 consisting of Ri, OR ^X , SR ^X , S(O)R ^X , SO ₂ R ^X , NR ^Y1 R ^Y2 , N(O)R ^Y1 R ^Y2 , PR ^Y1 R ^Y2 and P(O)R ^Y1 R ^Y2 where Ri, R ^x , R ^y1 and R ^Y2 are defined as above or below. In another embodiment, Y is selected from the group Y-G2 consisting of NR ^Y1 R ^Y2 , PR ^Y1 R ^Y2 , and P(O)R ^Y1 R ^Y2 , where R ^Y1 and R ^Y2 are defined as above or below. According to another embodiment, Y is selected from the group Y-G3 consisting of NR ^Y1 R ^Y2 , where R ^Y1 and R ^Y2 are defined as above or below. According to another embodiment, Y is selected from the group Y-G4 consisting of NR ^Y1 R ^Y2 , where R ^Y1 and R ^Y2 are defined as above or below. In another embodiment, R ^Y1 and R ^Y2 are independently selected from the group R ^Y -Gla consisting of Ri, C(O)Ri and C(O)ORi, where Ri is defined as above, or R ^Y1 and R ^Y2 are selected from a group R ^Y -G1b in which R ^Y1 and R ^Y2 are bonded to form, together with the N or P to which they are attached, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl.

According to another embodiment, R ^Y1 and R ^Y2 are independently selected from the group R ^Y -G2a consisting of H, substituted or unsubstituted C ₁ . ₁₀ αkyl, substituted or unsubstituted C ₃ . ₁₀ cycloalkyl, substituted or unsubstituted C _2-10 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C ₁ . ₆ alkylene-, substituted or unsubstituted C ₁ . ₁₀ alkylC(O)-, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-C ₁ . ₆ alkyleneC(O)-, substituted or unsubstituted C ₁ . ₁₀ αkyl-OC(O)-, substituted or unsubstituted aryl-OC(O) and substituted or unsubstituted aryl-C ₁ . ₆ alkylene-OC(O)-, or R ^Y1 and R ^Y2 are selected from the group R ^Y -G2b, in which R ^Y1 and R ^Y2 are linked to form, together with the N or P to which they are attached, a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

According to another embodiment, R ^Y1 and R ^Y2 are independently selected from the group R ^Y -G3a consisting of H, substituted or unsubstituted C ₁ . ₆ αkyl, substituted or unsubstituted C ₂ . ₆ alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C ₁ - ₄ alkylene-, substituted or unsubstituted C ₁ . ₆ alkyl-C(O)-, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-C ₁ - ₄ alkylene-C(O)-, substituted or unsubstituted C ₁ . ₆ alkyl-OC(O)-, substituted or unsubstituted aryl-OC(O)- and substituted or unsubstituted aryl-C _1-4 alkylene-OC(O)-, or

R ^Y1 and R ^Y2 are selected from the group R ^Y -G3b in which R ^Y1 and R ^Y2 are linked to form, together with the N or P to which they are attached, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl.

In another embodiment, R ^Y1 and R ^Y2 are independently selected from the group R ^Y -G4a consisting of H, substituted or unsubstituted Ac (acetyl), substituted or unsubstituted Boc (threobutyloxycarbonyl), substituted or unsubstituted Cbz (carboxybenzyl), substituted or unsubstituted Fmoc (fluorenylmethyloxycarbonyl), substituted or unsubstituted Alloc (allyloxycarbonyl), substituted or unsubstituted t-Bu (t-butyl), substituted or unsubstituted Bn (benzyl), and substituted or unsubstituted phthaloyl, or

R ^Y1 and R ^Y2 are selected from the group R ^Y -G4b in which R ^Y1 and R ^Y2 are linked to form, together with the N to which they are attached, a substituted or unsubstituted phthalimide or a substituted or unsubstituted pyrrole.

In another embodiment, R ^Y1 and R ^Y2 are independently selected from the group R ^Y -G5a consisting of H and a substituted or unsubstituted phthaloyl, or R ^Y1 and R ^Y2 are selected from the group R ^Y -G5b in which R ^Y1 and R ^Y2 are linked to forming, together with the N to which they are attached, a substituted or unsubstituted phthalimide.

According to another embodiment, R ^Y1 and R ^Y2 are independently selected from the group RY-G6 consisting of H.

Additional sub-generic variants of the compounds of formula (I) are presented as variants (Ia)-(If) in the following table, which uses the above definitions of substituents (R ¹ , R ² , R ³ and R ⁴ and R ^N1 and R ^N2 are independently selected from this group, R ^Y1 and R ^Y2 are independently selected from the given subgroup, denoted a, or selected from the given subgroup, denoted b).

- 12 040460

Option Deputies Hal units •''f. X ^Rx R ^ar R ⁿ¹ , r ^N2 Y R ^Y1 , R ^Y2 (1-a) Hal-G2 R-G2 X-G2 R ^x -G2 Rar ^- Gl R ⁿ -G1 Y-G3 R ^Y -G4a or R ^Y -G4b (1-b) Hal-G2 R'-G3 X-G3 R ^x -G3 Rar ^- Gl R ⁿ -G2 Y-G4 R ^Y -G4a or R ^Y -G4b (1-s) Hal-G2 R'-G3 X-G3 R ^x -G4 Rar ^- Gl R ⁿ -G2 Y-G4 R ^Y -G4a or R ^Y -G4b (I-d) Hal-G2 R'-G3 X-G3 R ^x -G4 Rar ^- G2 R ⁿ -G2 Y-G4 R ^Y -G5a or R ^Y -G5b (1st) Hal-G3 R'-G3 X-G3 R ^x -G4 Rar ^- G2 R ⁿ -G2 Y-G4 R ^Y -G5a or R ^Y -G5b (I-f) Hal-G3 R<G4 X-G3 R ^x -G4 Rar ^- G2 R ⁿ -G2 Y-G4 R ^Y -G5a or R ^Y -G5b

According to one embodiment, in step (S1), the compound of formula (II) is compound (II-g)

where R ^ar and RY ¹ and RY ² are defined as above or below, preferably Rar is selected from the group R ^ar -G1, as defined above, more preferably from the group R ^ar -G2, as defined above, where

R ^N1 and R ^N2 are preferably independently selected from the group RN-G2 as defined above, more preferably from the group RN-G3 as defined above, and preferably RY ¹ and RY ² are independently selected from the group RY-G4a as defined above, or selected from the group RY-G4b as defined above, more preferably independently selected from the group RY-G5a as defined above, or selected from the group RY-G5b as defined above, and the compound of formula (I) is a compound (Ig)

where Rar as well as RY ¹ and RY ² are defined as above. In another embodiment, in step (S1), the compound of formula (II) is compound (II-h)

where Rar is selected from the group R ^ar -G2, as defined above, in connection with RN-G2, as defined above, and the compound of formula (I) is compound (Ih)

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where R ^ar is defined as above. In another embodiment, in step (S1), the compound of formula (II) is compound (II-i)

where RY ¹ and RY ² are independently selected from the group RY-G4a, as defined above, or selected from the group RY-G4b, as defined above, and the compound of formula (I) is compound (Ii)

where RY ¹ and RY ² are defined as above. In another embodiment, in step (S1), the compound of formula (II) is compound (II-j)

In one embodiment, step (S1) includes deprotection of compound (I-g) and compound of formula (I) is compound (I-j)

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where R ^ar and RY ¹ and RY ² are defined as above or below, preferably R ^ar is selected from the group R ^ar -G1, as defined above, more preferably from the group R ^ar -G2, as defined above, where R ^N1 and R ^N2 are preferably independently selected from the group RN-G2 as defined above, more preferably from the group RN-G3 as defined above, and preferably RY ¹ and RY ² are independently selected from the group RY-G4a as defined above, or selected from RY-G4b as defined above, more preferably independently selected from R ^Y -G5a as defined above, or selected from R ^Y -G5b as defined above to give compound (I-g')

where R ^ar is defined as above.

In another embodiment, step (S1) includes deprotection of compound (I-h)

(lh) where R ^ar is selected from the group R ^ar -G2, as defined above, in connection with RN-G2, as defined above, to obtain compound (I-h')

where R ^ar is defined as above.

According to another embodiment, step (S1) includes deprotection of compound (I-i)

where R ^Y1 and R ^Y2 are independently selected from the group R ^Y -G4a, as defined above, or selected from the group R ^Y -G4b, as defined above, to obtain compound (I-j')

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According to another embodiment, step (S1) comprises deprotecting compound (I-j) to obtain compound (I-j')

In another embodiment, step (S1) comprises converting compound (I-j') to give compound (I-k)

According to another embodiment, the compound (I-k) is prepared as Form I. Preferred substituents of the compound of formula (IV)

where Hal is defined as above or below,

- 16 040460 in step (S2) are as follows.

According to one embodiment

R is selected from the group R-G1 consisting of

H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl, where said methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl may be partially or fully halogenated, preferably fluorinated.

According to another embodiment

R is selected from the group R-G2 consisting of H and ethyl.

According to one embodiment

R ⁰ is selected from the group R ⁰ -G1 consisting of H and C _1-6 alkyl.

According to another embodiment

R ⁰ is selected from the group R ⁰ -G2 consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.

According to another embodiment

R ⁰ is selected from the group R0-G3 consisting of ethyl.

In another embodiment, in step (S2), the compound of formula (IV) is compound (IV-a)

In one embodiment, in step (S2), the compound of formula (III) is compound (III-g)

where R ^ar and RY ¹ and RY ² are defined as above or below, preferably R ^ar is selected from the group R ^ar -G1, as defined above, more preferably from the group R ^ar -G2, as defined above, where r ⁿ¹ and R ^N2 are preferably independently selected from the group R ^N -G2 as defined above, more preferably from the group R ^N -G3 as defined above, and preferably RY ¹ and RY ² are independently selected from the group RY-G4a as defined above, or selected from the group RY-G4b as defined above, more preferably independently selected from the group RY-G5a as defined above, or selected from the group RY-G5b as defined above and the compound of formula (II) is compound (II-g)

where R ^ar and RY ¹ and RY ² are defined as above.

In another embodiment, in step (S2), the compound of formula (III) is compound (III-h)

- 17 040460 where R ^ar is selected from the group R ^ar -G2, as defined above, in connection with RN-G2, as defined above, and the compound of formula (II) is a compound (II-h)

where R ^ar is defined as above.

In another embodiment, in step (S2), the compound of formula (III) is compound (III-i)

where RY ¹ and RY ² are independently selected from the group RY-G4a, as defined above, or selected from the group RY-G4b, as defined above, and the compound of formula (II) is compound (II-i)

where RY ¹ and RY ² are defined as above. According to another embodiment in step (S2), the compound of formula (III) is compound (III-j)

In one embodiment, step (S2) comprises saponification of compound (II'-g) and compound of formula (II) is compound (II-j)

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where R ⁰ , Rar, and R ^Y1 and R ^Y2 are defined as above or below, preferably R ⁰ is selected from the group R0-G2, as defined above, more preferably from the group R0-G3, as defined above, and preferably Rar selected from the group R ^ar -G1, as defined above, more preferably from the group R ^ar -G2, as defined above, where

R ^N1 and R ^N2 are preferably independently selected from the group RN-G2 as defined above, more preferably from the group RN-G3 as defined above, and preferably R ^Y1 and R ^Y2 are independently selected from the group R ^Y -G4a as defined above, or selected from the group R ^Y -G4b as defined above, more preferably independently selected from the group R ^Y -G5a as defined above, or selected from the group R ^Y -G5b as defined above to give compound (II-g)

where Rar and R ^Y1 and R ^Y2 are defined as above. According to another embodiment, step (S2) comprises saponification of compound (II'-h)

where R ⁰ is selected from the group R ⁰ -G2, as defined above, and Rar is selected from the group R ^ar -G2, as defined above, in connection with RN-G2, as defined above, to obtain compound (II-h)

where Rar is defined as above. According to another embodiment, step (S2) comprises saponification of compound (II'-i)

- 19 040460 where R ⁰ is selected from the group R ⁰ -G2, as defined above, and

RY ¹ and RY ² are independently selected from the group RY-G4a as defined above or selected from the group RY-G4b as defined above to give compound (II-i)

where RY ¹ and RY ² are defined as above. According to another embodiment, step (S2) comprises saponification of compound (II'-j)

In another embodiment, in step (S2), the compound of formula (III) is compound (III-j)

and the compound of formula (II') is a compound (II'-k) o

According to another embodiment, step (S2) comprises saponification of compound (II'-k)

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to obtain compound (II-j) to improve the E/Z selectivity.

In another embodiment, step (S2) comprises converting compound (II-k)

In another embodiment, in step (S1), the compound of formula (II) is compound (II-j)

- 21 040460

and the compound of formula (I) is compound (I-j) o

According to another embodiment, step (S1) comprises deprotecting compound (I-j) o

to obtain a compound (I-j')

In another embodiment, step (S1) comprises converting compound (I-j')

ⁿ ίί^ 1 o to obtain compound (Ik) ⁿ ίΓ^ 1 O F C) /X. ./ΝΑ (i-j') F _χ Ο Cl' (lk)

- 22 040460

In a second aspect, the present invention relates to intermediates that are included in the method according to the first aspect of the invention.

The invention thus relates to intermediates of formulas (III), (II'), (II), and (I)

in particular to intermediates of formulas (II') and (II) wherein Hal, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , X and Y are defined as for the first aspect of the present invention.

In particular, the invention relates to those intermediates of formulas (III), (II'), (II) and (I) as described above in the embodiments of the first aspect of the invention.

According to one embodiment, the intermediate compound of formula (III) is compound (III-j)

According to one embodiment, the intermediate compound of formula (II') is compound (II'-g) as defined above.

According to another embodiment, the intermediate compound of formula (II') is compound (II'-h) as defined above.

According to another embodiment, the intermediate compound of formula (II') is compound (II'-i) as defined above.

According to another embodiment, the intermediate compound of formula (II') is compound (II'-j) as defined above.

According to another embodiment, the intermediate compound of formula (II') is compound (II'-k)

In one embodiment, the intermediate of formula (II) is compound (II-g) as defined above.

- 23 040460

According to another embodiment, the intermediate compound of formula (II) is compound (II-h) as defined above.

According to another embodiment, the intermediate compound of formula (II) is compound (II-i) as defined above.

According to another embodiment, the intermediate compound of formula (II) is compound (II-j) o

According to another embodiment, the intermediate compound of formula (II) is compound (II-k)

According to one embodiment, the intermediate compound of formula (I) is compound (I-g) as defined above.

According to another embodiment, the intermediate compound of formula (I) is compound (I-g') as defined above.

According to another embodiment, the intermediate compound of formula (I) is compound (I-h) as defined above.

According to another embodiment, the intermediate compound of formula (I) is compound (I-h') as defined above.

According to another embodiment, the intermediate compound of formula (I) is compound (I-i) as defined above.

According to one embodiment, the intermediate compound of formula (I) is compound (I-j)

According to another embodiment, the intermediate compound of formula (I) is compound (I-j')

- 24 040460

Examples and experimental data

The following abbreviations are used above and below:

Ac - acetyl;

Boc - tert-butyloxycarbonyl;

Bu - butyl;

equiv. - molar equivalents;

Et - ethyl;

DBU - 1,8-diazabicyclo(5.4.0)undec-7-ene;

DMA - Ν,N-dimethylacetamide;

DME - dimethyl ether;

DMF - Ν,N-dimethylformamide;

DMSO - dimethyl sulfoxide;

DSC - differential scanning calorimetry;

EtOAc - ethyl acetate;

h - hour;

HMDS - hexamethyldisilazide (bis(trimethylsilyl)amide);

HPLC - high performance liquid chromatography;

HWE reaction - Horner-Wadsworth-Emmons reaction;

IPC - technological control;

i-Pr - iso-propyl;

MCH - methylcyclohexane;

Me is methyl;

2-MeTHF - 2-methyltetrahydrofuran;

MTBE - methyl tert-butyl ether;

n-Bu - n-butyl;

NMP - N-methylpyrrolidinone;

Ph - phenyl;

ssNMR - solid state nuclear magnetic resonance;

t-Bu - tert-butyl;

Tc - thiophene-2-carboxylate;

Tf - triflyl (trifluoromethanesulfonyl);

THF - tetrahydrofuran;

XRPD - powder x-ray diffraction.

(1) Method of formation (Ill-j).

a) Obtaining (VII-j) (path A).

ABOUT

Χ,α °h/=\ \ / DMF, P o η ^zemH1 ° (VII-j)

A mixture of potassium phthalimide (100.0 g, 539.9 mmol, 1.0 equiv.), potassium carbonate (11.2 g, 81.0 mmol, 0.15 equiv.) and N,N-dimethylformamide (DMF) (200 ml) was treated with chloroacetone (47.3 ml, 54.9 g, 593.9 mmol, 1.1 equiv.) at a rate that maintains an internal temperature of no more than 40°C. After completion of the addition, the reaction mixture was stirred for about 12 hours at a temperature of about 20-25°C. Water (333 ml) was loaded into the reaction mixture at a rate to maintain an internal temperature of no more than 30°C. The mixture was stirred at a temperature of about 20-25°C for about 1 hour and then the mixture was filtered. The filter cake was washed with water (200 ml) and the product was dried at ca. 70-80° C. under vacuum under nitrogen flow for ca. 12 h. .%,

- 25 040460 80% yield.

b) Acquisition (VII-j) (path B).

A mixture of phthalimide (110.4 kg, 750.5 mol, 1.0 equiv.), potassium carbonate (59.2 kg, 428.4 mol, 0.57 equiv.), and DMF (195 kg) was heated to 60–70°C and stirred at this temperature for at least 10 min. The solution was cooled to 50-60°C and chloroacetone (80.0 kg, 864.9 mol, 1.15 equiv.) was added over 1 h at 50-70°C. The reaction mixture was heated to 80-86°C and stirred at this temperature for at least 90 min. A control sample (IPC) was taken at 80-86° C. to measure the conversion (criterion <3.0% area of phthalimide, result 0.0% area after 3 h). The reaction mixture was transferred to a second reactor and the first reactor was washed into the last with DMF (60 kg). Then the reaction mixture was heated to 30-70°C and added water (576 l) to maintain an internal temperature of approximately 50°C. The suspension was cooled to 0-10°C, stirred at this temperature for at least 1 hour and then filtered. The filter cake was washed with water (4x50 L) and the product was dried at ca. 70-80°C under vacuum for ca. 12 h. area 99.8%, yield: 96.5%).

c) Obtaining (VI-j) (path A).

A mixture of phthalimidoacetone (100.0 g, 492.2 mmol, 1.0 eq.), pyridinium perbromide hydrobromide (192.4 g, 90 wt% purity, 541.4 mmol, 1.1 eq.) and acetic acid (400 ml) was stirred for about 12 h at a temperature of about 20 25°C. Water (400 ml) was loaded into the reaction mixture at a rate to maintain an internal temperature of no more than 30°C. The mixture was stirred at about 20-25° C. for about 2 hours and then the mixture was filtered. The filter cake was washed with water (400 ml) and the product was dried at about 50-60° C. under vacuum with a stream of nitrogen for about 12 hours. The crude product was then recrystallized in toluene (400 ml) and heated to about 90° C. for 30 minutes, cooled to 20-25°C and kept at this temperature for about 2 h, then filtered off the solid, washing it with toluene/heptane, 1:2 v/v. (100 ml) and heptane (100 ml), and finally dried at 20-30°C under vacuum to obtain the purified product (VI-j) as a white solid (94.0 g, purity 96.0 wt.%, yield 65 %).

d) Acquisition (VI-j) (path B).

A mixture of phthalimidoacetone (140.0 kg, 689.0 mol, 1.0 equiv.) and i-PrOAc (957 kg) was heated to 30-50°C. Bromine (110.1 kg, 689.0 mol, 1.0 eq.) was added to maintain the internal temperature at 30-50°C. The reaction mixture was stirred for 6-14 h at 30-50°C. The reaction mixture was cooled to 15-25° C. and stirred at this temperature for 12-18 hours. The reaction mixture was transferred to a second reaction vessel and washed with i-PrOAc (261 kg). The reaction mixture was heated to 60-70°C and pre-heated water (50-70°C) (420 kg) was added to the reaction mixture to keep its internal temperature at 50-70°C. The reaction mixture was heated to 65-71°C and stirred for 10 min at this temperature. The aqueous phase was separated from the organic phase at 65-71°C. To the organic phase was added pre-heated water (50-70°C) (420 kg) at 50-70°C. The biphasic mixture was heated to 65-71°C and stirred for 10 min at this temperature. The aqueous phase was separated from the organic phase at 65-71°C. The organic phase was heated to 70-80°C and the solvent (980 l) was distilled off under vacuum at 70-85°C. The residual product solution was heated to 67-73° C. and seed crystals (200 g) were added. A thin suspension of the product was stirred at 67-73°C for 30-120 min before it cooled to (-15)-(-5)°C for 120 min and stirred at this temperature for 60-180 min, then

- 26 040460 filtered. The filter cake was washed with methylcyclohexane (MCH) (354 kg) and the product was dried at about 60°C under vacuum for about 2-3 hours. α-dione (VI-j) as a white crystalline solid (153.7 kg, HPLC organic purity: 94.5% area, 75.3% yield).

Optional recrystallization procedure for 2-(4-bromo-3-oxobutyl)-1H-isoindole-1,3(2H)-dione.

A mixture of 2-(4-bromo-3-oxobutyl)-1H-isoindole-1,3(2H)-dione (20.0 g, 71.7 mmol, 1.0 equiv.) and toluene (80 ml) was heated to 105°C and stirred in for 10-20 minutes at this temperature. When the temperature of the resulting solution was reduced to 90°C, seed crystals were added. The resulting suspension was stirred for 25-35 min at 90°C. The suspension was cooled to 15-25°C over 90 min and stirred at 15-25°C for another 90 min, then filtered. The filter cake was washed with toluene/MSH (29.6 ml/32 ml), then MCH (32 ml) and the product was dried at ca. 60° C. under vacuum for ca. 5 h. The product was obtained as a white crystalline solid (18.2 g, organic grade HPLC: area 98.0%, yield: 91%).

e) Receipt (V-j).

A mixture of 4-hydroxybenzonitrile (200.0 g, 1.68 mol, 1.0 equiv.) and glacial acetic acid (420.4 g, 7.00 mol, 4.2 equiv.) was stirred at room temperature for 5 min. tert-Butanol (236.5 g, 3.19 mol, 1.9 eq.) (slightly endothermic) was added and the mixture was stirred at 15-25° C. for min.

Added concentrated sulfuric acid (247.0 g, 2.52 mol, 1.5 eq.) for about 130 min at an internal temperature of 18-30°C. The reaction mixture was heated to 40°C for about 30 minutes and stirred at this temperature for 60 minutes. A sample of IPC was taken at 40°C to measure the conversion (criterion <1.0 area % of 4-hydroxybenzonitrile, result 0.61 area % after 1 h). Ethyl acetate (300 ml) was added to the reaction mixture at 40° C., followed by water (440 ml) over 20 minutes, and stirred at this temperature for 10 minutes. Seed crystals were added. The resulting suspension was stirred for 10 min at 40°C. The resulting suspension was cooled to 20°C over 90 min. Water (360 ml) was added to the suspension at this temperature over 15 minutes. The suspension was cooled to (-5)-(5)°C and stirred for 120 min at this temperature, and then filtered. The filter cake was washed with water (3x400 ml) and the product was dried at ca. 70° C. under vacuum for ca. 26 h. ).

Optional recrystallization procedure for (V-j).

A mixture of (V-j) (20.0 g, 0.10 mol, 1.0 equiv.) and acetonitrile (110 ml) was heated to 80°C and stirred for 15 min at this temperature. The temperature of the resulting solution was lowered to 70°C and seed crystals were added. The resulting suspension was stirred for 30 min at 70°C. The suspension was cooled to 20°C over 120 min. The suspension was cooled to 5°C over 30 min and stirred for another 60 min, then filtered. The filter cake was washed with cold acetonitrile (3x30 ml) and the product was dried at ca. 60° C. under vacuum for ca. 12 h. %).

f) Preparation (III-j) (path A).

A mixture of (VI-j) (100.0 g, 354.5 mmol, 1.0 eq.), (V-j) (75.4 g, 389.9 mmol, 1.1 eq.), potassium carbonate (53.9 g, 389.9 mmol, 1.1 eq., 325 mesh) and acetone (600 ml) was stirred for about 12 hours at a temperature of about 20-25°C. Water (600 ml) was loaded into the reaction mixture at a rate to maintain an internal temperature of no more than 30°C. The mixture was stirred at about 20-25°C for about 1 hour, then the mixture was filtered. The filter cake was washed with water (200 ml) followed by the addition of heptane (200 ml) and the product was dried at about 80-90° C. under nitrogen flow vacuum for about 12 hours. substances (109.5 g,

- 27 040460 purity 95.8 wt.%, yield 75%). g) Preparation (III-j) (route B).

A mixture of compound (V-j) (107.9 g, 558.0 mmol, 1.05 eq.), compound (VI-j) (150.0 g, 532.0 mmol, 1.0 eq.) and potassium carbonate (77.5 g, 561.0 mmol, 1.05 eq.) in 2 -butanone (1200 ml) was stirred for 10 min at room temperature before it was heated to 70° C. for 180 min. After reaching 70°C, an IPC sample was taken to measure the conversion (<2.5 area% test (VI-j), result 0.9 area%). After cooling to 30-45°C, water (620 ml) was added to the suspension and stirred for about 5 minutes. The aqueous phase was separated from the organic phase. The solvent (520 ml) was distilled off from the organic phase. Methanol (MeOH) (1000 ml) was added and the solvent was again distilled off (885 ml) under vacuum. MeOH (800 ml) was added a second time and the solvent (780 ml) was distilled off under vacuum. Methyl tert-butyl ether (MTBE) (615 ml) was added at a temperature of at least 50°C and the mixture was cooled to -5°C and stirred for 90 min at this temperature. Then the suspension was filtered. The filter cake was washed with MeOH (65 ml) and then with MTBE (2x130 ml) and the product was dried at about 65°C under vacuum for about 12 hours. : area 99.3%, yield: 80.2%).

(2) Formation method (II-j) (Horner-Wadsworth-Emmons (HWE) reaction). a) Preparation (II-k) (path A).

A solution of (IV-a) (104.4 g, 431.0 mmol, 1.7 eq.) and THF was cooled to about -10°C and treated with a solution of EtMgBr (431.0 ml, 431.0 mmol, 1.7 eq., 1.0 M solution in THF) at a rate keeping the temperature below 10°C. A separate reactor was charged with (III-j) (100.0 g, 253.5 mmol, 1.0 eq.) and THF (1000 ml) and the resulting suspension was heated to about 40°C. A solution of the anion (IV-a) in THF was added to the warm slurry (III-j) in THF at a rate to maintain the temperature of the product batch between 40-55°C. After the addition was complete, the batch was held for about 1 hour at about 40°C. Approximately 1200 ml of THF was then distilled off and isopropanol (800 ml) was added. The distillation was continued to remove about 600 ml of solvent. Isopropanol (400 ml) was added, followed by a solution of sodium hydroxide (60.85 g, 1521.2 mmol, 6 eq.) in water (450 ml). The reaction mixture was stirred at about 25°C for about 1 hour. Concentrated hydrochloric acid (147.8 mL, 1799.9 mmol, 7.1 eq.) Was added at a rate to keep the temperature below 35°C. The resulting suspension was stirred at a temperature of about 20-25°C for about 12 hours, then the mixture was filtered. The filter cake was washed with a mixture of isopropanol and water, 2:1 by volume (300 ml) and the product was dried at about 50-65°C under vacuum with a stream of nitrogen for about 12 hours. The product (II-k) was obtained as a white solid (82.8 g, purity 94.0 wt.%, yield 65%, ratio E/Z=97:3).

b) Preparation (II-k) (path B).

2-Methyl-THF (40 ml) was cooled to -10°C under nitrogen and EtMgBr (40% in 2-methyl-THF, 25.3 g, 76.1 mmol, 1.5 eq.) was added to maintain the internal temperature below 10°C. reaction mixture

- 28 040460 was cooled to -10°C and added (IV-a) to maintain the internal temperature below 10°C. The mixture was heated to about 20°C and stirred at this temperature for at least 30 minutes. (III-j) 2-methyl-THF (40 ml) and THF (10 ml) were added to the second reactor and the suspension was heated to about 35°C. At this temperature, the content of the first reactor (deprotonated (IV-a)) at 35±5°C (below 40°C/preferably 35°C) was added and the first reactor was washed with 2-methyl-THF (10 ml) into the second reactor.

The solution was stirred for at least 30 minutes at about 35°C. An IPC sample was taken for conversion measurement (<1.0 area % test (III-b), result 0.42 area %). Added citric acid (10% aqueous solution, 60 ml) at about 35°C. After 15 min stirring at about 35°C, the aqueous phase was separated from the organic phase. Added a second portion of citric acid (10% aqueous solution, 60 ml) at about 35°C and after 15 min of stirring, the aqueous phase was again separated from the organic phase. The solvent (75 ml) was distilled off under vacuum from the organic phase. Isopropanol (80 ml) was added and the solvent (75 ml) was again distilled off under vacuum. Isopropanol (80 ml), water (40 ml) was added at about 35°C followed by sodium hydroxide at 40±5°C (below 45°C/preferably 40°C) (45% aqueous solution, 18.0 g, 203 mmol , 4.0 equiv.).

Water (10 ml) was added at about 45°C. A sample of IPC was taken to measure the conversion (criterion <1.0% area of ethyl ester (II-k), result <0.1% area). The reaction mixture was cooled to about 20°C and hydrochloric acid (36%, 15.4 g, 152.1 mmol, 3.0 eq.) was added. Seed crystals were added at 20° C. and the resulting slurry was stirred for 60 minutes at this temperature.

Hydrochloric acid (36%, 7.7 g, 76.1 mmol, 1.5 eq.) and water (16 ml) were added and stirred for another 60 min at 20°C, then the suspension was filtered. The filter cake was washed with water (40 ml) and twice with isopropanol (40 ml each wash) and the product was dried at about 60°C under vacuum for about 12 hours. The product was obtained as an off-white crystalline solid (16.2 g, organic purity: 96.1% area, E/Z ratio: 96.4/3.6% area, yield: 67.7%).

c) Preparation (II-j) (path A).

A mixture of (II-k) (100.0 g, 211.7 mmol, 1.0 eq.) and acetic acid (400 ml) was heated at about 110°C for about 7 hours. About 200 ml of acetic acid was then distilled off under slight vacuum, and then the mixture was cooled to approximately 25°C. Water (400 ml) was charged to the reaction mixture for about 1 hour at a rate to maintain an internal temperature of no more than 25°C. The mixture was stirred at about 20-25°C for about 3 hours, then the mixture was filtered. The filter cake was washed with water (400 ml) followed by the addition of heptane (200 ml) and the product was dried at ca. 5060° C. under vacuum under nitrogen flow for ca. 12 h. , purity 97.0 wt.%, yield 90%).

d) Preparation (II-j) (path B).

A mixture of (II-k) (80.0 g, 169.0 mmol, 1.0 eq.) and acetic acid (320 ml) was rapidly heated to 115°C and stirred at this temperature for at least 3.5 h. Water (320 ml) was added to for 30 minutes at a temperature of 90-115°C. The suspension was cooled to room temperature over 120 min.

The product suspension was further stirred for 2 hours at room temperature and then filtered.

The filter cake was washed with water (160 ml) and MTBE (160 ml) and the product was dried at about 60° C. under vacuum for about 5 hours. The product was obtained as an off-white crystalline solid (63.4 g, organic purity HPLC: 99.7% area , yield: 82.4%).

(3) Method of formation (I-j).

a) Preparation of (I-j) (protodecarboxylation of (II-j)) (route A).

- 29 040460 about

CH) (i-j)

A mixture of (II-j) (100.0 g, 220.0 mmol, 1.0 eq.) and NMP (185 ml) was heated to about 130°C. A slurry of silver(I) acetate (1.84 g, 11.0 mmol, 0.05 eq.) in NMP (15 ml) was added and the reaction mixture was kept at about 130°C for about 3 hours. The mixture was then cooled to about 20-25°C. Ethyl acetate (250 ml) and diatomaceous earth (Celite®) (10.0 g) were added, the mixture was stirred at 20-25°C for about 1 hour. The mixture was then filtered through a pad of celite and the pad was washed with EtOAc (2x100 ml). The combined filtrates were distilled off to remove EtOAc (about 450 ml) at about 40-45°C under vacuum. The mixture was cooled to about 20-25°C. A solution of sodium thiosulfate pentahydrate (70.6 g) in water (380 ml) was added over 1 h, the mixture was stirred at 20-25° C. for about 12 h and then filtered. The filter cake was washed with water (3x300 ml) followed by the addition of heptane (300 ml) and the product was dried at ca. 50-60° C. under vacuum under nitrogen flow for ca. 12 h. 89.3 g, purity 97.1 wt.%, yield 96%).

b) Preparation of (I-j) (protodecarboxylation of (II-j)) (route B).

O

A mixture of (II-j) (35.0 g, 77.0 mmol, 1.0 equiv.) and silver(I) acetate (0.95 g, 6 mmol, 0.075 equiv.) was suspended in NMP (52.5 ml), then heated to about 130-140° C. The reaction mixture was kept at about 130-140° C. for about 3 hours. An IPC sample was taken to measure the conversion (<1.0 area % criterion (II-j)).

The mixture was then cooled to about 20-25°C. Ethyl acetate (70 ml), diatomaceous earth (Celite®) (0.85 g) and activated carbon (0.85 g) were added, the mixture was stirred at 20-25°C for about 5-30 min. The mixture was then filtered through a deep filtration filter plate (KD 7), then the filter was washed with EtOAc (35 ml). The combined filtrates were distilled to remove EtOAc (about 105 ml) at about 80°C under vacuum. The mixture was heated to about 60° C., then MeOH (52.5 ml) and water (52.5 ml) were added. The solution was cooled to 55-50°C, then seeded (I-j) and cooled to 45-40°C for about 45 minutes. Water (52.5 ml) was added over about 30 min and the suspension was cooled to 5-10°C and stirred for about 30 min, then filtered. The filter cake was washed with a mixture of water (35 ml) and MeOH (35 ml) followed by the addition of water (35 ml) and the product was dried at about 75°C under vacuum for about 12 hours. The product (I-j) was obtained as a tan solid (30.4 g, HPLC organic purity: 99.9%, 96.0% yield).

(4) Screening for protodecarboxylation conditions.

For protodecarboxylation (II-j), different copper and silver catalysts were tested in different solvents and at different temperatures.

Compound (II-j) (70 mg, 0.15 mmol), copper or silver particles (50 mol %, unless otherwise indicated) and reaction solvent (1 ml) were loaded into a reaction vessel. The vessel was inerted three times by evacuating and removing the vacuum with argon. The reaction vessel was then placed in an oil bath preheated to the reaction temperature. The reaction mixture was stirred for 1-22 h under positive argon pressure.

- 30 040460

a) Screening of catalysts and solvents.

Catalyst Solvent T [°C] * Conversion [%], (time) Si ₂ O pyridine 120 100 (5 h) Si ₂ O NMP 120 96 (22 h) SIOAc pyridine 120 65 (22 hours) CITs pyridine 120 91 (5 hours) _{Ag2CO3 _} pyridine 120 100 (18h) _{Ag2CO3 _} NMP 120 100 (1.5 h) _{Ag2CO3 _} DMA 120 100 (1.5 h) _{Ag2CO3 _} CH ₃ CN** 90 97 (24h)

* oil bath temperature ** sealed vessel b) Screening of silver catalysts.

Catalyst Solvent T [°C] Conversion [%)] (time) _Ag2O NMP 120 100 (1 hour) AgOAc NMP 120 100 (1 hour) _AgNO3 NMP 120 100 (2.5 h)

c) Catalyst loading screening.

Catalyst Load [mol %] Solvent T [°C] Transformation [%L (time) _{Ag2CO3 _} 50 NMP 120 100 (1.5 h) _{Ag2CO3 _} 10 NMP 120 100 (3 hours) _{Ag2CO3 _} 5 NMP 120 100 (4.0 h) AgOAc 50 NMP 120 100 (1 hour) AgOAc 10 NMP 120 100 (2.5 h) AgOAc 5 NMP 120 53 (7 h) AgOAc 5 NMP* 130 100 (2.5 h) AgOAc 2.5 NMP 120 26 (7 h)

* only two NMP volume equivalents were used (instead of 4 volume equivalents as for other tests) (5) Formation method (I-j').

a) Acquisition (I-j') (deprotection of (I-j)) (path A).

ethanolamine

2-MeTHF, H ₂ O

hh ₂

A mixture of (I-j) (100.0 g, 243.6 mmol, 1.0 eq.), ethanolamine (200 ml), 2-methyltetrahydrofuran (2MeTHF) (200 ml) and water (100 ml) was heated to about 70°C. The reaction mixture was stirred for about 4 hours at about 70°C. Added 10% aq. a solution of NaCl (660 ml) and 2-MeTHF (300 ml) and the reaction mixture was cooled to about 25-30°C. The phases were separated and the organic phase was washed with 10% aq. NaCl solution (440 ml). About 300 ml of 2-MeTHF was then distilled off under vacuum at about 50° C. and toluene (500 ml) was added. The distillation was continued until approximately 400 ml of solvent had been removed. Then added toluene (500 ml) and the mixture was heated to about 75-80°C. The resulting solution was filtered and the filter was washed with 50 ml of hot (about 80°C) toluene. The combined filtrates were cooled to about 40-50° C. and heptane (500 ml) was added slowly. The mixture was cooled to about 20-25°C and stirred at this temperature for about 1 hour, then filtered. The filter cake was washed with heptane. The product was dried at about 35° C. under nitrogen flow for about 12 hours. The product was obtained as an off-white solid.

b) Obtain (I-j') (unprotect (I-j)) (path B).

- 31 040460

(1-j) (Ι-G)

A mixture of (I-j) (10.0 g, 24.0 mmol, 1.0 eq.), ethanolamine (20.2 g, 331.0 mmol, 13.6 eq.), 2-MeTHF (20 ml) and water (10 ml) was heated to 68-70°C. After stirring the solution at this temperature for 3.5 h (IPC, >95% conversion), water (40 ml) was added. The reaction mixture was cooled to 25-30°C and MTBE (20 ml) and EtOAc (40 ml) were added. The resulting two phases were separated and water (60 ml) was added to the organic phase. The two phases were again separated and the organic phase was heated to 65°C and the solvent (60 ml) was distilled off under vacuum at this temperature. Toluene (50 ml) was added. The organic phase was heated to 65°C and the solvent (50 ml) was distilled off under vacuum at this temperature. Additional toluene (50 ml) was added and the mixture was cooled to about 40-50° C. and heptane (50 ml) was added slowly. The mixture was cooled to about 20-25°C and stirred at this temperature for about 1 hour, then filtered. The filter cake was washed with heptane. The product was dried at about 35° C. under nitrogen flow for about 12 hours. The product was obtained as an off-white solid.

(6) Method of formation (I-k).

a) Preparation of Form I (I-k) (deprotection of (I-j) and salt formation) (route A).

(I-j) (1-Yu

A mixture of (I-j) (100.0 g, 243.6 mmol, 1.0 eq.), ethanolamine (200 ml), 2-methyltetrahydrofuran (2MeTHF) (200 ml) and water (100 ml) was heated to about 70°C. The reaction mixture was stirred for about 4 hours at about 70°C. Added 10% aq. a solution of NaCl (660 ml) and 2-MeTHF (300 ml) and the reaction mixture was cooled to about 25-30°C. The phases were separated and the organic phase was washed with 10% aq. NaCl solution (440 ml). Approximately 300 ml of 2-MeTHF was then distilled off under vacuum at about 50° C., toluene (500 ml) was added. The distillation was continued until approximately 400 ml of solvent had been removed. Then added toluene (500 ml) and the mixture was heated to about 75-80°C. The resulting solution was filtered and the filter was washed with 50 ml of hot (about 80°C) toluene. The combined filtrates were then diluted with isopropyl alcohol (250 ml) and heptane (300 ml) and the solution was cooled to about 20-25°C. A solution of hydrogen chloride in isopropyl alcohol (5.64 M, 51.8 ml, 292.4 mmol, 1.2 eq.) was added at a rate to maintain the internal temperature no more than 30°C. The mixture was stirred at about 20-25° C. for about 12 hours, then filtered. The filter cake was washed with a mixture of heptane and isopropyl alcohol, 3:1 by volume (400 ml), followed by the addition of heptane (200 ml). The product was dried at about 50-65° C. under vacuum under a stream of nitrogen for about 12 hours. The product (I-k) was obtained as an off-white solid (69.2 g, 98.2 wt% purity, 88% yield).

b) Preparation of Form I (I-k) (deprotection of (I-j) and salt formation) (route B-1).

(I-j) (I-k)

A mixture of (I-j) (10.0 g, 24.0 mmol, 1.0 eq.), ethanolamine (20.2 g, 331.0 mmol, 13.6 eq.), 2-methyltetrahydrofuran (2-MeTHF) (20 ml) and water (10 ml) was heated to 68-70 °C After stirring the solution at this temperature for 3.5 h (IPC, >95% conversion product), water (40 ml) was added. The reaction mixture was cooled to 25-30° C. and methyl tert-butyl ether (MTBE) (20 ml) and ethyl acetate (EtOAc) (40 ml) were added. The resulting two phases were separated and water (60 ml) was added to the organic phase. The two phases were again separated and the organic phase was heated to 65°C and the solvent (60 ml) was distilled off under vacuum at this temperature. EtOAc (50 ml) was added. The organic phase was heated to 65°C and the solvent (50 ml) was distilled off under vacuum at this temperature. Added EtOAc (25 ml) and isopropyl alcohol (20 ml) and the solution was heated to 68°C.

A solution of HCl in isopropyl alcohol (5 mol/L, 5.31 g, 29.0 mmol, 1.2 equiv.) was added over

- 32 040460 min at this temperature. Added seed crystals and the resulting suspension was stirred for 25-35 min at 68°C. MTBE (50 ml) was added and the suspension was cooled to room temperature over 25-35 minutes.

The product suspension was further stirred for 2 hours at room temperature and then filtered. The filter cake was washed with MTBE (40 mL) and the product was dried at ca. 60° C. under vacuum for ca. 5 h. 87.7%).

c) Preparation of Form I (I-k) (deprotection of (I-j), salt formation and recrystallization) (route B-2).

(l-j) (I-k)

A mixture of (I-j) (200.0 g, 487.3 mmol, 1.0 eq.), ethanolamine (404.8 g, 662.7 mmol, 13.6 eq.), 2-methyltetrahydrofuran (2-MeTHF) (400 ml) and water (200 ml) was heated to 68-70 °C After stirring the solution at this temperature for 3.5 h (IPC, >95% conversion product), water (800 ml) was added. The reaction mixture was cooled to 40°C and was added ethyl acetate (EtOAc) (1200 ml). The resulting two phases were separated and water (1200 ml) was added to the organic phase. The two phases were separated again and the organic phase was heated to 65°C and the solvent (1070 ml) was distilled off under vacuum at this temperature. EtOAc (1000 ml) was added. The organic phase was heated to 65°C and the solvent (980 ml) was distilled off under vacuum at this temperature. Added EtOAc (500 ml) and isopropyl alcohol (500 ml) and the solution was heated to 68°C.

A solution of HCl in isopropyl alcohol (5 mol/L, 106.3 g, 585 mmol, 1.2 eq.) was added over 30 min at this temperature. Added seed crystals and the resulting suspension was stirred for 25-35 min at 68°C. MTBE (1000 ml) was added and the suspension was cooled to room temperature over 25-35 minutes.

The product suspension was further stirred for 16 hours at room temperature and then filtered. The filter cake was washed with MTBE (800 mL) and the product was dried at ca. 60° C. under vacuum for ca. 5 h. 87.4%).

Recrystallization Form I (I-k).

Isopropyl alcohol/ethyl acetate (EtOAc)/methyl tertiary butyl ether (MTBE) solvent system.

(I-k) (20 g, 63.1 mmol) was suspended in isopropyl alcohol (90 ml) and heated to 82°C. Ethyl acetate (EtOAc) (80 ml) was added to the reflux solution. After seed crystals were added at 75-80°C, the mixture was stirred for 5 minutes. The resulting suspension was cooled to 56°C over 1 h. Methyl tert-butyl ether (MTBE) (70 ml) was added over 5 min at >50°C. The product suspension was cooled to 0-5°C, stirred for 30 min and filtered. The filter cake was washed with MTBE (40 ml) and the product was dried at 75°C for about 12 hours under vacuum. The product (I-k) was obtained as an off-white crystalline solid (18.8 g, HPLC organic purity: 99.7 area %, yield: 93.9%).

Or alternatively.

Ethanol (EtOH)/water/ethyl acetate (EtOAc) solvent system.

(Ik) (11 g, 34.7 mmol) was suspended in ethanol (5.3 ml), H ₂ O (2.1 ml) and ethyl acetate (28.4 ml). The mixture was heated to 70°C to dissolve (Ik). The resulting solution was cooled to ~55°C, seeded, and kept for 1 h. Ethyl acetate (70.4 mL) was added over 1 h at ~55°C, kept for 1 h, and cooled to 15°C for 1 h. for 1 h and filtered. The filter cake was washed with EtOAc (24.7 ml) and the product was dried at 65°C for about 12 hours under vacuum. The product (Ik) was obtained as an off-white crystalline solid (10.1 g, HPLC organic purity: 99.9 area %, yield: 91.8%).

Or alternatively.

Isopropyl alcohol/water/ethyl acetate (EtOAc) solvent system.

(I-k) (10 g, 31.5 mmol) was suspended in isopropyl alcohol (17.8 ml) and water (2 ml). The mixture was heated to 72°C to dissolve (I-k). The resulting solution was cooled to 50°C, seeded and stirred for 1 h. Ethyl acetate (118 ml) was added over 1 h at 50°C and stirred for 1 h. The suspension was cooled to 10°C for 2 h, stirred for 2 h and filtered. The filter cake was washed with EtOAc (22.5 mL) to give (I-k) as an off-white crystalline solid (8.8 g, HPLC organic purity: 99.5 area%, yield: 88%)

d) Obtaining Form II (I-k).

- 33 040460 (I-k), for example, as was obtained using the methods described here, was dissolved in methanol at a concentration of about 50 mg/ml. The solution was heated to 60°C and quickly transferred to a vacuum oven at 60°C and dried for 15 min with dry air or dry nitrogen as off-gas to form II.

(7) XRPD experiments.

a) Collection of XRPD data.

Powder X-ray diffraction profiles were obtained using a Bruker D8 Advance diffractometer in reflection mode equipped with a position sensitive detector using CuKa1 radiation (λ=1.54060 A). For this purpose, the sample (I-k) should have a purity greater than 99% as measured by HPLC, preferably a purity greater than 99.5%, even more preferably greater than 99.7%, most preferably greater than 99.8%.

To account for experimental errors, the 2θ values described here should be considered with an accuracy of ±0.2 degrees 2θ, in particular ±0.1 degrees 2θ, even more specifically ±0.05 degrees 2θ. That is, when evaluating whether a given sample of crystals (I-k) is a crystalline form according to the present invention, the 2θ value that is experimentally observed for the sample should be considered identical to the characteristic value described here if it is within ±0.2 degrees 2θ, in particular ±0.1 degree 2θ, even more specifically ±0.05 degree 2θ characteristic value.

b) Form I (I-k) XRPD data (obtained by paths A, B-1 and B-2) The characteristic peaks of Form I (I-k) XRPD are shown in the following table.

The corresponding XRPD pattern is shown in Fig. 1.

- 34 040460

Peak 20[°] 1 3.82 2 7.63 3 11.46 4 13.55 5 15.29 6 16.03 7 16.38 8 17.15 9 17.80 10 18.73 AND 19.02 12 19.35 13 19.69 14 20.80 15 21.65 16 22.20 17 22.64 18 23.03 19 23.63 20 24.58 21 25.11 22 25.83 23 26.21 24 26.93 25 27.30 26 27.79 27 28.93 28 29.24 29 31.03 thirty 31.52 31 32.28 32 32.94 33 33.60 34 34.27

c) XRPD Form II data (I-k).

The characteristic peaks of XRPD form II (I-k) are shown in the following table.

The corresponding XRPD pattern is shown in Fig. 2.

- 35 040460

Peak 20[°] 1 4.42 2 8.72 3 11.00 4 13.11 5 13.35 6 15.64 7 16.58 8 17.82 9 17.94 10 18.31 AND 18.81 12 19.26 13 20.75 14 21.53 15 21.88 16 22.92 17 24.13 18 26.30 19 May 27 20 27.90 21 28.27 22 28.99 23 29.98 24 30.78 25 31.85 26 33.43

(8) DSC experiments.

The melting point of form I (I-k) was determined as 181°C ±5°C using DSC as the temperature of the onset of melting. Data were acquired by DSC using a TA Instruments Q2000 DSC at 25 to 225°C at a heating rate of 10°C/min.

The corresponding DSC curve is shown in Fig. 3.

(9) ssNMR experiments.

a) Data acquisition ¹³ With ssNMR.

ssNMR data were obtained on a Bruker Avance III NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) at 9.4 T (1H=400.46 MHz, ¹³ C=100.70 MHz). Samples were packed in 4 mm OD zirconia rotors with Kel-F® drive tips. A Bruker model 4BL CP BB DVT probe was used to collect data and rotate the sample around the magic angle (54.74°). A rotation speed of 12 kHz was used to obtain the spectrum of the sample. A standard sequence of cross-polarization pulses was applied with a linear matched Hartman-Khan pulse on the proton channel at ambient temperature and pressure. In the pulse train, a contact pulse of 2 ms and a recovery wait time of 5 s were used. Two-pulse phase-modulated (ppm) decoupling was also applied to the pulse train. Prior to the Fourier transform of the free decay of induction, exponential line broadening was not used. Chemical shifts were referenced using an adamantane secondary standard with the high field resonance set to 29.5 ppm. The magic angle was set using the 79Br signal of the KBr powder at a rotation frequency of 5 kHz.

In order to take into account experimental errors, the chemical shifts described here should be considered with an accuracy of ±0.2 ppm, in particular ±0.1 ppm. That is, when evaluating whether a given sample (I-k) is a form according to the invention, the chemical shift that is experimentally observed for the sample should be considered identical to the characteristic value described herein if it is within ±0.2 ppm ., in particular ±0.1 ppm characteristic value.

b) Data ¹³ C ssNMR Form I (Ik).

The C peaks of NMR Form I (Ik) are shown in the following table (see a) for error range). The corresponding ¹³ C CPMAS ssNMR spectrum is depicted in FIG. 4.

-

Claims (13)

Peak ¹³ C Chemical shift (ppm) 1 167.9 2 162.5 3 161.1 4 156.6 5 154.0 6 151.4 7 149.0 8 148.4 9 131.3 10 130.1 AND 129.2 12 128.3 13 119.3 14 113.1 15 112.0 16 110.9 17 67.4 18 65.2 19 51.9 20 35.2 21 29.9 22 29.0 c) Data collection ¹⁹ F ssNMR ssNMR data were acquired on a Bruker Avance III NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) at 9.4 T. ¹⁹ F ssNMR data were acquired using a 3.2 mm HFX DVT triple resonance probe. The samples were packed in 3.2 mm OD zirconium rotors with a Vespel® drive tip. The sample was rotated around the magic angle (54.74°). A rotation speed of 22 kHz was used to obtain the spectrum of the sample. Used a single pulse with the separation of the sequence of pulses. Recovery wait time was set to 15 s and 256 pulses were received. Chemical shifts were referenced using a polyvinyl difluoride secondary standard, with the main CF2 resonance set to -92.1 ppm. Multiple spin population is present due to the asymmetric nature of the line shape. The main resonance is at -115.1 ppm. In order to take into account experimental errors, the chemical shifts described here should be considered with an accuracy of ±0.2 ppm, in particular ±0.1 ppm. In other words, when evaluating whether a given sample (I-k) is a form according to the invention, the chemical shift that is experimentally observed for the sample should be considered identical to the characteristic value described herein if it is within ±0.2 m. d., in particular ±0.1 ppm. characteristic value. d) ¹⁹ F ssNMR Form I data (Ik). The ¹⁹ F Form I chemical shift (Ik) is defined as -115.1 ppm. (range of error see point c)). The corresponding ¹⁹ F ssNMR spectrum is depicted in FIG. 5. CLAIM 1. Method for the synthesis of a haloolefin of formula (I) where Hal is selected from the Hal-G1 group consisting of F, Cl, Br and I, and R ¹ , R ² , R ³ and R ⁴ are independently selected from the group Ri-G1 consisting of H, halogen, CN, substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted C _3-10 cycloalkyl, substituted or unsubstituted C _{2 -10} alkenyl, substituted or unsubstituted C _2-10 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C _1-6 alkylene-, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C _1-6 alkylene-, and X and Y are independently selected from the groups X-G1 and Y-G1, respectively, each consisting of Ri, ORX, SRX, S(O)R ^X , SO2RX, NR ^Y1 R ^Y2 , N(O)R ^Y1 R ^Y2 , PR ^Y1 R ^Y2 and P(O)R ^Y1 R ^Y2 , where R ^X is selected from the group RX-G1 consisting of Ri, and - 37 040460 where R ^Y1 and R ^Y2 are independently selected from the group R ^Y -G1a consisting of R ¹ , C(O)Ri and C(O)ORi, or R ^Y1 and R ^Y2 are selected from the group R ^Y -G1b, in which R ^Y1 and R ^Y2 are linked to form, together with the N or P to which they are attached, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl, and Ri is selected from the group Ri-G1 consisting of H, halo, CN, substituted or unsubstituted C ₁ . ₁₀ alkyl, substituted or unsubstituted C ₃ . ₁₀ cycloalkyl, substituted or unsubstituted C ₂ . ₁₀ alkenyl, substituted or unsubstituted C ₂ . ₁₀ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C ₁ . ₆ alkylene-, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroaryl-C ₁ . ₆ alkylene-; where aryl denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be optionally fused with a second 5 - or 6-membered carbocyclic group, which may be aromatic, saturated or unsaturated; where heteroaryl denotes a mono- or polycyclic ring system containing one or more heteroatoms selected from N, O or S(O) _r , where r= 0, 1 or 2, consisting of 5-14 ring atoms, where at least one of heteroatoms is part of an aromatic ring; where heterocyclyl denotes a saturated or unsaturated mono- or polycyclic ring system, including aromatic ring systems containing one or more heteroatoms selected from N, O or S(O) _r , where r=0, 1 or 2, consisting of 3-14 ring atoms in which none of the heteroatoms is part of an aromatic ring; where substituted means that any one or more hydrogen atoms on the specified atom, radical or fragment is substituted by halogen, hydroxy, oxo, optionally halogenated alkoxy, amino, nitro, amidinyl, guanidinyl, sulfanyl, sulfo, sulfonyl, sulfonamido, silyl, optionally halogenated or hydroxylated alkyl, or cycloalkyl, or alkenyl, optionally halogenated or hydroxylated aryl, or heteroaryl, or heterocyclyl, cyano, carbonyl, acyl, alkoxycarbonyl, amido, carbamate, and combinations thereof, provided that the normal valencies of the atoms are not exceeded and that the substitution results in to an acceptably stable connection; or a salt thereof, comprising step (S1); (S1): protodecarboxylation of an α-haloacrylic acid derivative of formula (II) where Hal, R ¹ , R ² , R ³ , R ⁴ , X and Y are defined as above, and where (S1) is carried out in the presence of a catalytic amount of copper and/or silver in the form of their oxides and/or salts. 2. The method according to claim 1, where copper and/or silver are used in the form of oxides and/or salts selected from the group consisting of copper (I) oxide, copper (I) salts, silver (I) oxide and silver salts ( I). 3. The method according to any one of claims 1 or 2, wherein Hal is selected from the Hal-G3 group consisting of F. 4. The method according to any one of claims 1 to 3, where R ¹ , R ² , R ³ and R ⁴ are independently selected from the group Ri-G2 consisting of H, halogen, CN and optionally partially or fully halogenated methyl, ethyl, npropyl , iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclopropyl. 5. The method according to any one of claims 1 to 4, wherein Ri is selected from the group Ri-G3 consisting of H, halogen, CN and optionally partially or fully halogenated methyl. 6. The method according to any one of claims 1-5, where X is selected from the group X-G2 consisting of OR ^X , SR ^X , S(O)R ^X and SO ₂ R ^X , where R ^X is selected from the group RX-G2 consisting of H, substituted or unsubstituted _{C1_10} alkyl, substituted or unsubstituted C ₃ - ₁₀ cycloalkyl, substituted or unsubstituted C ₂ - ₁₀ alkenyl, substituted or unsubstituted C ₂ _ ₁₀ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C ₁ - ₆ alkylene-, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C ₁ _ ₆ alkylene-, where aryl denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be further condensed with a second 5 - or 6-membered carbocyclic group, which may be aromatic, saturated or unsaturated; where heteroaryl denotes a mono- or polycyclic ring system containing one or more heteroatoms selected from N, O or S(O) _r , where r=0, 1 or 2, consisting of 5-14 ring atoms, where at least one of heteroatoms is part of an aromatic ring; - 38 040460 where heterocyclyl denotes a saturated or unsaturated mono - or polycyclic ring system, including aromatic ring systems containing one or more heteroatoms selected from N, O or S(O) _r , where r=0, 1 or 2, consisting of 3-14 ring atoms in which none of the heteroatoms is part of an aromatic ring; where substituted means that any one or more hydrogen atoms on the specified atom, radical or fragment is substituted by halogen, hydroxy, oxo, optionally halogenated alkoxy, amino, nitro, amidinyl, guanidinyl, sulfanyl, sulfo, sulfonyl, sulfonamido, silyl, optionally halogenated or hydroxylated alkyl, or cycloalkyl, or alkenyl, optionally halogenated or hydroxylated aryl, or heteroaryl, or heterocyclyl, cyano, carbonyl, acyl, alkoxycarbonyl, amido, carbamate, and combinations thereof, provided that the normal valencies of the atoms are not exceeded and that the substitution results in to an acceptably stable connection. 7. The method according to any one of claims 1-6, where Y is selected from the group Y-G2 consisting of NR ^Y1 R ^Y2 , PR ^Y1 R ^Y2 and P(O)R ^Y1 R ^Y2 , where R ^Y1 and RY ² are independently selected from the group R ^Y -G2a consisting of H, substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted C _3-10 cycloalkyl, substituted or unsubstituted C _2-10 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C _1-6 alkylene-, substituted or unsubstituted C _1-10 αalkyl -C(O)-, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-C _1-6 alkylene-C(O)-, substituted or unsubstituted C _1-10 alkylOC(O)-, substituted or unsubstituted aryl-OC(O)- and substituted or unsubstituted aryl-C _1-6 alkylene-OC(O)-, or R ^Y1 and RY ² are selected from the group R ^Y -G2b, in which R ^Y1 and RY ² are linked to form, together with the N or P to which they are attached, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocyclyl, where aryl is a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be optionally fused to the second a 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated; where heteroaryl denotes a mono- or polycyclic ring system containing one or more heteroatoms selected from N, O or S(O) _r , where r = 0, 1 or 2, consisting of 5-14 ring atoms, where at least one of heteroatoms is part of an aromatic ring; where heterocyclyl denotes a saturated or unsaturated mono- or polycyclic ring system, including aromatic ring systems containing one or more heteroatoms selected from N, O or S(O) _r , where r=0, 1 or 2, consisting of 3-14 ring atoms in which none of the heteroatoms is part of an aromatic ring; where substituted means that any one or more hydrogen atoms on the specified atom, radical or fragment is substituted by halogen, hydroxy, oxo, optionally halogenated alkoxy, amino, nitro, amidinyl, guanidinyl, sulfanyl, sulfo, sulfonyl, sulfonamido, silyl, optionally halogenated or hydroxylated alkyl, or cycloalkyl, or alkenyl, optionally halogenated or hydroxylated aryl, or heteroaryl, or heterocyclyl, cyano, carbonyl, acyl, alkoxycarbonyl, amido, carbamate, and combinations thereof, provided that the normal valencies of the atoms are not exceeded and that the substitution results in to an acceptably stable connection. 8. The method according to any one of claims 1-7, wherein the compound of formula (II) is a compound (II-g) wherein Rar is selected from the group R ^ar -G1 consisting of C(O)NR ^N1 RN ² or SO2NR ^N1 RN ² where RN ¹ and RN ² are independently selected from the group RN-G2 consisting of H, substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C _3-7 cycloalkyl, and where R ^Y1 and RY ² are independently selected from the group R ^Y - G4a consisting of H, substituted or unsubstituted Ac, substituted or unsubstituted Boc, substituted or unsubstituted Cbz, substituted or unsubstituted Fmoc, substituted or unsubstituted Alloc, substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl, and substituted or unsubstituted phthaloyl, or R ^Y1 and RY ² are selected from the group R ^Y -G4b, in which R ^Y1 and RY ² are linked to form, together with the N to which they are attached, a substituted or unsubstituted phthalimide or a substituted or unsubstituted pyrrole; - 39 040460 where substituted means that any one or more hydrogen atoms on the specified atom, radical or fragment is substituted by halogen, hydroxy, oxo, optionally halogenated alkoxy, amino, nitro, amidinyl, guanidinyl, sulfanyl, sulfo, sulfonyl, sulfonamido, silyl , optionally halogenated or hydroxylated alkyl, or cycloalkyl, or alkenyl, optionally halogenated or hydroxylated aryl, or heteroaryl, or heterocyclyl, cyano, carbonyl, acyl, alkoxycarbonyl, amido, carbamate, and combinations thereof, provided that the normal valencies of the atoms are not exceeded, and that the substitution results in an acceptably stable connection; and the compound of formula (I) is compound (I-g) where Rar, RY ¹ and RY ² are defined as above. 9. The method of claim 8 wherein step (S1) comprises deprotection of a compound of formula (I-g) where Rar is selected from the group R ^ar -G1 consisting of C(O)NR ^N1 R ^N2 or SO ₂ NR ^N1 R ^N2 , where R ^N1 and R ^N2 are independently selected from the group RN-G2 consisting of H, substituted or unsubstituted C _1-6 alkyl and substituted or unsubstituted C _3-7 cycloalkyl, and wherein RY ¹ and RY ² are independently selected from the group RY-G4a consisting of H, substituted or unsubstituted Ac, substituted or unsubstituted Boc, substituted or unsubstituted Cbz, substituted or unsubstituted Fmoc, substituted or unsubstituted Alloc, substituted or unsubstituted t-butyl, substituted or unsubstituted benzyl, and substituted or unsubstituted phthaloyl, or R ^Y1 and R ^Y2 are selected from the group R ^Y -G4b, in which R ^Y1 and R ^Y2 are linked to form, together with the N to which they are attached, a substituted or unsubstituted phthalimide or a substituted or unsubstituted pyrrole; where substituted means that any one or more hydrogen atoms on the specified atom, radical or fragment is substituted by halogen, hydroxy, oxo, optionally halogenated alkoxy, amino, nitro, amidinyl, guanidinyl, sulfanyl, sulfo, sulfonyl, sulfonamido, silyl, optionally halogenated or hydroxylated alkyl, or cycloalkyl, or alkenyl, optionally halogenated or hydroxylated aryl, or heteroaryl, or heterocyclyl, cyano, carbonyl, acyl, alkoxycarbonyl, amido, carbamate, and combinations thereof, provided that the normal valencies of the atoms are not exceeded and that the substitution results in to an acceptably stable connection; to obtain a compound (I-g') where Rar is defined as above. 10. The method according to any one of claims 1-8, where the compound of formula (II) is a compound (II-j) and the compound of formula (I) is compound (I-j) - 40 040460 11. The method according to any one of claims 1 to 10, comprising the step (S2) of forming an α-haloacrylic acid derivative of formula (II) (S2): reacting a ketone of formula (III) with a phosphonate of formula (IV) where Hal is selected from the Hal-G1 group consisting of F, Cl, Br and I, and R ⁰ is selected from the group R ⁰ -G1 consisting of H and C ₁ _ ₆ alkyl, and R is selected from the group R-G1 consisting of optionally partially or fully halogenated methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl, phenyl, in the presence of at least one main additive; and if R ⁰ is not H, then the saponification of the resulting ester of formula (II') and optional separation of the E and Z isomers of the compound of formula (II). 12. The method according to claim 11, where in step (S2) the compound of formula (III) is a compound (III-g) where Rar is selected from the group R ^ar -G1 consisting of C(O)NRN1RN ² or SO2NRN1RN ² where RN ¹ and RN ² are independently selected from the group RN-G2 consisting of H, substituted or unsubstituted C ₁ . ₆ alkyl and substituted or unsubstituted C ₃ . ₇ cycloalkylα, and where RY ¹ and RY ² are independently selected from the group RY-G4a consisting of H, substituted or unsubstituted Ac, substituted or unsubstituted Boc, substituted or unsubstituted Cbz, substituted - 41 040460 or unsubstituted Fmoc, substituted or unsubstituted Alloc, substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl and substituted or unsubstituted phthaloyl, or RY ¹ and RY ² are selected from the group RY-G4b, in which RY ¹ and RY ² are linked to form, together with the N to which they are attached, a substituted or unsubstituted phthalimide or a substituted or unsubstituted pyrrole, where substituted means that any one or more hydrogen atoms on the indicated atom, radical or fragment is substituted by halogen, hydroxy, oxo, optionally halogenated alkoxy, amino, nitro, amidinyl, guanidinyl, sulfanyl, sulfo, sulfonyl, sulfonamido, silyl, optionally halogenated or hydroxylated alkyl, or cycloalkyl, or alkenyl, optionally halogenated or hydroxylated aryl, or heteroaryl, or heterocyclyl, cyano, carbonyl, acyl, alkoxycarbonyl, amido, carbamate, and combinations thereof, provided that the normal valences of the atoms are not exceeded and that substitution results in an acceptably stable compound, and Hal in the phosphonate of formula (IV) is selected from the Hal-G3 group consisting of F, and the compound of formula (II) is compound (II-g) where R ^ar , RY ¹ and RY ² are defined as above. 13. The method according to any one of claims 11, 12, where in step (S2) the compound of formula (III) is a compound (III-j) -