A process for chiral resolution of trans-2,2-dichloro-3-(3,5-dichlorophenyl)-cyclopropane- 1-carboxylic acid

Abstract

The present invention provides a method for chiral resolution of (trans)-2,2-dichloro-3-(3,5- dichlorophenyl)cyclopropane-1-carboxylic acid. The method comprises the steps of: (a) treating (trans)-2,2- dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid with a chiral base being either (1S,2R)-2- amino-1,2-diphenylethan-1-ol or (1R,2S)-2-amino-1,2-diphenylethan-1-ol in an organic solvent to form a suspension, (b) isolating a diastereoisomeric salt of the desired enantiomer and the chiral base from the suspension, and (c) optionally, treating the isolated diastereoisomeric salt with an acid to obtain the desired enantiomer of 2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid.

Description

[0001] A process for chiral resolution of trans-2, 2-dichloro-3-(3, 5-dichlorophenyl)- cyclopropane-1 -carboxylic acid

[0002] Technical field

[0003] The present invention relates to the field of enantiomer resolution and particularly to a process for chiral resolution of trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid.

[0004] Background

[0005] Trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid has Formula I as shown below. It is one of the intermediates in the synthesis of compounds known from US2018 / 0098541 A1 and WO2016168059 A1. Formula I

[0006] In the present application only the trans isomers, namely the ( / ?, / ?) and (S,S) enantiomers are considered: (1 / ?,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid (“the ( / ?, / ?) enantiomer”) and (1 S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid (“the (S,S) enantiomer”).

[0007] The compound of Formula I is often obtained as a racemic mixture of the ( / ?, / ?) and (S,S) enantiomers. For further use of one of the two enantiomers it is desired to perform chiral resolution of the racemate.

[0008] Chiral resolution in this application means isolating one of the two enantiomers from a racemic mixture. The most frequently used methods for chiral resolution of racemic mixtures are chiral column chromatography and crystallization of diastereoisomeric salts. The resolution by crystallization of diastereoisomeric salts often relies on taking advantage of differences in solubility of the diastereoisomeric salts, although in less frequent cases, enantiospecific co-crystallization involving the selective interaction of the derivatizing agent with one of the two enantiomers to form only one diastereoisomeric salt has also been described (Cryst. Growth Des. 2012, 12, 7, 3374-3378).

[0009] In the case of the chiral resolution of a racemic acid, crystallization is typically achieved by reacting the racemate with a suitable chiral base in a solution to form the corresponding diastereoisomeric salts. Ideally, the pure desired diastereoisomeric salt precipitates from the solution while all other components remain in solution. Once the desired diastereoisomeric salt is isolated by filtration, it can be further processed to obtain the desired acid enantiomer after separation from the chiral base.

[0010] WO2016168059 A1 discloses in Example 100 that the (1 R,3R) enantiomer of the compound with Formula I can be obtained from its racemic mixture by using 0.5 equivalent of (R)-1 -phenylethylamine as the chiral base and acetone as solvent. By applying this protocol, the ( / ?, / ?) enantiomer of the compound of Formula I is isolated in 88 % enantiomeric excess (% ee) and in 32 % yield, after separation from the chiral base. After a second chiral resolution cycle, the optical purity is increased to 97 % ee whereas the isolated yield drops to 24 %. Yield in this application is defined in relation to the racemic starting material, meaning 50 % is the maximum that can be obtained.

[0011] 32 % yield 24 % yield

[0012] In Example 1 of WO2018071320 the resolution of the compound of Formula I into its ( / ?, / ?) enantiomer is achieved by using L-leucinamide as chiral derivatizing agent. In this case, acetonitrile is used as solvent and 0.5 equivalent of L-leucinamide is needed for the resolution. This method leads to the ( / ?, / ?) enantiomer of the compound of Formula I in 91 % ee and in 27 % yield after separation of the chiral base.

[0013] 27 % yield

[0014] As seen above, the use of (R)-1 -phenylethylamine and L-leucinamide only achieves an optical purity of 88 % ee in 32 % yield and 91 % ee in 27 % yield, respectively, after one resolution cycle. In order to reach a higher optical purity, the process needs to be iterated, which is undesired on large scale as this negatively impacts the isolated yield and thus the manufacturing costs. Also, (R)-1 -phenylethylamine and L- leucinamide have other disadvantages such as the price, difficulty to source.

[0015] Therefore, it is an object of the present invention to provide a robust, reproducible and scalable method for the chiral resolution of the racemic compound of Formula I. Preferably, the method leads to a high optical purity and high yield of the desired enantiomer and does not require more than one crystallization cycle. It is also preferred to use a chiral base that is relatively cheap, easy to source and that can be easily recovered and reused in the resolution process.

[0016] Summary of invention The present invention provides a method for obtaining (1 R,3 / ?)-2,2-dichloro-3-(3,5- dichlorophenyl)cyclopropane-1 -carboxylic acid or a salt thereof, comprising the steps of:

[0017] (a) treating trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid with a chiral base being (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol in an organic solvent to form a suspension,

[0018] (b) isolating a diastereoisomeric salt of (1 / ?,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-

[0019] 1 -carboxylic acid and the chiral base from the suspension,

[0020] (c) optionally, treating the isolated diastereoisomeric salt with an acid to obtain (1 R,3 / ?)-2,2- dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid and a salt of the chiral base.

[0021] The invention further provides a method for obtaining (1 S,3S)-2,2-dichloro-3-(3,5- dichlorophenyl)cyclopropane-1 -carboxylic acid or a salt thereof, comprising the steps of:

[0022] (a) treating trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid with a chiral base being (1 R,2S)-2-amino-1 ,2-diphenylethan-1-ol in an organic solvent to form a suspension,

[0023] (b) isolating a diastereoisomeric salt of (1 S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1- carboxylic acid and the chiral base from the suspension,

[0024] (c) optionally, treating the isolated diastereoisomeric salt with an acid to obtain (1 S,3S)-2,2- dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid and a salt of the chiral base.

[0025] In another aspect, the invention also provides a diastereoisomeric salt of (1 R,3 / ?)-2,2-dichloro-3-(3,5- dichlorophenyl)cyclopropane-1 -carboxylic acid and (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol.

[0026] In yet another aspect, the invention provides a diastereoisomeric salt of (1 S,3S)-2,2-dichloro-3-(3,5- dichlorophenyl)cyclopropane-1 -carboxylic acid and (1 R,2S)-2-amino-1 ,2-diphenylethan-1-ol.

[0027] In yet another aspect, the invention provides the use of (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol or (1 R,2S)-

[0028] 2-amino-1 ,2-diphenylethan-1-ol in chiral resolution of trans-2, 2-dichloro-3-(3, 5- dichlorophenyl)cyclopropane-1 -carboxylic acid.

[0029] Detailed description

[0030] Surprisingly it was found that chiral resolution of the compound with Formula I can be done with a high yield and high optical purity by using specific chiral bases, namely (fS,2R)-2-amino-1 ,2-diphenylethan-1-ol (Formula Ila) or (f / ?,2S)-2-amino-1 ,2-diphenylethan-1-ol (Formula lib). Formula Ila Formula lib

[0031] Finding a suitable chiral base for achieving chiral resolution of a given racemic compound is not straightforward and may not even be achievable in some cases. The base must embed different properties to be suited for the resolution. It must a) be sufficiently soluble in the solvents used for solubilizing the racemic acid; b) have a pKa that allows for the formation of a salt when added to the racemic acid and c) lead to the formation of diastereoisomeric salts with sufficiently divergent solubilities. Unlike many other chiral bases which were found unsuitable for the chiral resolution of diastereoisomeric salts of compound of Formula I, the inventors have found that compounds of Formula Ila and lib possess all required properties.

[0032] The present invention provides a method for chiral resolution of (frans)-2,2-dichloro-3-(3,5- dichlorophenyl)cyclopropane-1 -carboxylic acid. The method comprises the steps of: (a) treating (trans)-2,2- dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid with a chiral base being either (1S,2R)-2- amino-1 ,2-diphenylethan-1-ol or (f / ?,2S)-2-amino-1 ,2-diphenylethan-1-ol in an organic solvent to form a suspension, (b) isolating a diastereoisomeric salt of the desired enantiomer and the chiral base from the suspension, and (c) optionally, treating the isolated diastereoisomeric salt with an acid to obtain the desired enantiomer of 2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid.

[0033] The method according to the invention starts from a racemate (racemic mixture) of the compound of Formula I. The racemate comprises both the ( / ?, / ?) and (S,S) enantiomers of trans-2, 2-dichloro-3-(3, 5- dichlorophenyl)cyclopropane-1 -carboxylic acid.

[0034] The racemate of Formula I can be provided in a suitable form, e.g. solid form or as a solution. If it is provided as a solid, it needs to be dissolved in a suitable solvent. Preferably, the solvent is selected from organic solvents such as cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC), toluene, 2- methyltetrahydrofuran (2-MeTHF), or ethyl acetate. More preferably, cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC) or ethyl acetate is used, since these solvents allow to achieve a high yield of the desired diastereoisomeric salt. Most preferably, ethyl acetate is used since it allows to reach both a high yield and a high optical purity of the desired diastereoisomeric salt.

[0035] The racemate of Formula I can be dissolved in an organic solvent of choice at an elevated temperature e.g. in the range 30-100°C, preferably 50-90°C, more preferably 70-90°C.

[0036] In step (a) of the method according to the invention, frans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane- 1 -carboxylic acid is treated with a chiral base in an organic solvent to form a suspension containing a diastereoisomeric salt of a desired enantiomer of Formula I. The chiral base in this step is 2-amino-1 ,2- diphenylethan-1-ol. The mention of “2-amino-1 ,2-diphenylethan-1-ol” encompasses both enantiomers, (7S,2 / ?)-2-amino-1 ,2-diphenylethan-1-ol and (7 / ?,2S)-2-amino-1 ,2-diphenylethan-1-ol. The chiral base is either (7S,2 / ?)-2-amino-1 ,2-diphenylethan-1-ol or (7 / ?,2S)-2-amino-1 ,2-diphenylethan-1-ol, depending on the desired enantiomer to be isolated. The chiral base can be added as a solid or in the form of a solution. Preferably it is added as a solid.

[0037] Step (a) takes place in an organic solvent. The same solvent as mentioned above can be used, that is, for example, cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC), toluene, 2-methyltetrahydrofuran (2-MeTHF), or ethyl acetate. More preferably, cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC) or ethyl acetate is used, even more preferably ethyl acetate.

[0038] The reaction in step (a) can take place at an elevated temperature, e.g. in the range 30-90°C, more preferably 50-90°C, yet more preferably 70-90°C.

[0039] Preferably, the chiral base in step (a) is used in a molar ratio of 0.5-0.9 to 1 equivalent of the racemate of Formula I (composed of equal amounts of each of the enantiomers). In some embodiments, the stoichiometry of the chiral base can be in the range from 0.5 to 0.7, or from 0.6 to 0.8, and is most preferably about 0.7.

[0040] Preferably, in order to induce precipitation in a second stage of step (a), the temperature is lowered from between 50 to 90°C to 5 to -5°C, or to 0 to -5°C. The temperature can be gradually lowered, preferably within 10 to 15 hours.

[0041] In step (b) the diastereoisomeric salt of the desired enantiomer of the compound of Formula I and of the chiral base is isolated from the suspension. Isolation can be performed by conventional separation techniques, such filtration or centrifugal separation. Preferably, filtration is used.

[0042] The optical purity of diastereoisomeric salt isolated in step (b) can be increased by known methods, such as trituration in a suitable solvent at a suitable temperature followed by filtration. Trituration is a process to purify crude chemical compounds containing soluble impurities based on differences in solubility in a particular solvent. Suitable solvent and suitable temperature can be readily determined by the skilled person. For example, suitable solvent can be selected from organic solvents such as cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC), toluene, 2-methyltetrahydrofuran (2-MeTHF), or ethyl acetate. More preferably, cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC) or ethyl acetate, most preferably ethyl acetate. Suitable temperature is preferably from ambient to 40°C, preferably ambient temperature ( / .e. room temperature, 20-25°C).

[0043] In an optional step (c), the diastereoisomeric salt isolated in step (b) is treated with an acid to obtain the corresponding enantiomer of the compound with Formula I in a free form, and a salt of the chiral base. The acid used is preferably a strong acid. Suitable acids generally have a dissociation constant pKa of significantly less than 4.8 in the solvent (e.g. water), preferably less than 2, more preferably less than 0. Dissociation constants of acids are commonly known and can be looked up in e.g. handbooks or otherwise can be determined by known methods, e.g. by titration. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid. Preferably, hydrochloric acid (HCI) is used.

[0044] As a result of step (c), the chiral base is present in the form of an acid addition salt. Free chiral base can be obtained from the salt by adjusting the pH to a value above its pKa, e.g. by treating the salt with an inorganic base in an optional step (d). This is typically done by adding the inorganic base as an aqueous solution. Skilled person is familiar with this type of reactions and can use any suitable inorganic base. Examples of suitable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate. The free chiral base can then be extracted from the neutralized aqueous solution by using a non-water miscible organic solvent (e.g. such as those mentioned above for step (a)).

[0045] The recovered chiral base in the free base form can be reused in step (a) of the method according to the invention, which makes the process economically attractive.

[0046] The invention will now be further described by the following, non-limiting, examples.

[0047] Examples

[0048] Analytical methods

[0049] Method A

[0050] Agilent UHPLC 1290 series composed of:

[0051] Flexible pump G7104A included degasser

[0052] Multisampler G7167B, MCT

[0053] Column oven G7116B

[0054] Diode array detector G7117B

[0055] Chromatographic systems:

[0056] Column information: LUX Amylose 1 , Phenomenex, 250*4.6 mm, 5 p

[0057] Eluent: 970 mL / so-Hexane / 30 mL Ethanol

[0058] Add 1 mL Trifluoroacetic acid per L solvent premix

[0059] Flow: 1.0 mL / min

[0060] Oven temperature: 35 °C

[0061] Injection volume: 5 pL

[0062] Run time: 20 min

[0063] Detection method: UV at 254 nm and 220 nm

[0064] Method B:

[0065] Agilent UHPLC / MS 1290 series composed of:

[0066] High speed pump G7120A included degasser

[0067] Well plate sampler G4226A Column oven G7116B, MCT

[0068] Diode array detector G7117B

[0069] Mass detector G6135B XT Quadrupole LC / MS with ESI-Jetstream-source

[0070] Chromatographic systems:

[0071] Column information: XBridge BEH C18 from Waters, 2.1 *50 mm, 2.5 p Solvent A: water I formic acid: 99.95 1 0.05 % vol. I vol.

[0072] Solvent B: acetonitrile / formic acid: 99.95 / 0.05 % vol. I vol.

[0073] Gradient: from 2 % to 100 % acetonitrile in 1 .2 min, 0.5 min 100 % acetonitrile

[0074] Flow: 0.8 mL / min

[0075] Oven temperature: 40 °C

[0076] Injection volume: 0.3 pL

[0077] Run time: 2.2 min (0.4 min equilibration time included)

[0078] Detection method: UV at 254 nm and 210 nm

[0079] ESI / MS (100-1000 m / z), positive and negative ions

[0080] Example 1 : Preparation of (1 / ?,3 / ?)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid

[0081] A vacuum jacketed glass reactor (3 L) equipped with a reflux condenser, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with frans-2,2-dichloro-3-(3,5- dichlorophenyl)cyclopropane-1-carboxylic acid (121.4 g, 405 mmol) and ethyl acetate (1350 mL) at room temperature. After the addition of chiral base (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol (60.4 g, 283 mmol) to the resulting solution, the reaction mixture was quickly heated to 77 °C within 40 min under vigorous stirring affording a clear solution. The reaction mixture was further stirred for 5 min at this temperature before cooling down to -2 °C over 14 h.

[0082] The formed precipitate was filtered off (frit pore 3), the wet cake was washed (approx. 3 times) with ethyl acetate (each 420 mL) until an optical purity of 99 % ee was obtained. The resulting precipitate was suspended in aqueous 1 N hydrochloric acid (1000 mL) and ethyl acetate (2500 mL). After 1 h under vigorous stirring ethyl acetate (250 mL) and water (500 mL) were added to afford two clear layers within 15 min. The phases were separated and the organic phase was washed with water (2 x 400 mL), followed by brine (250 mL), was filtered over a filter filled with a pad of sodium sulfate and was concentrated under reduced pressure to obtain (1 R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid as beige solid (49.98 g, 167 mmol, yield 41 %, 99 % ee).

[0083] Method A: Ret. Time: 15.686 min.

[0084] Method B: Ret. Time: 1.196 min, m / z 598.9.

[0085] 1H NMR (300 MHz, d6-DMSO) 5 (ppm): 13.37 (s, 1 H), 7.61 - 7.53 (m, 3H), 3.56 (d, J = 8.7 Hz, 1 H), 3.49 (d, J = 8.7 Hz, 1 H). Example 2: Preparation of (1 / ?,3 / ?)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid including the recovery of the chiral base

[0086] A jacketed glass reactor (10 L) equipped with a reflux condenser, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with trans-2, 2-dichloro-3-(3, 5- dichlorophenyl)cyclopropane-1 -carboxylic acid (319.5 g, 1065 mmol) and ethyl acetate (3 L) at room temperature. The temperature was raised to 72°C and the reaction mixture was stirred at this temperature until a clear solution was obtained. After the addition of the chiral base (1 S,2R)-2-amino-1 ,2-diphenylethan- 1-ol (159 g, 746 mmol) and ethyl acetate (550 mL) to the resulting solution, the reaction mixture was maintained for 5 min under vigorous stirring at 77°C affording a clear solution before cooling down to -2°C over 14 h and maintaining the temperature at -2 °C for additional 3 h.

[0087] The formed precipitate was filtered off (frit pore 3), the wet cake was washed (approx. 5 times) with ethyl acetate (each 1100 mL) until an optical purity of 99 % ee was obtained.

[0088] Recovery of a first crop of the chiral base ( 1 S,2R)-2-amino-1 ,2-diphenylethan-1 -ol

[0089] The filtrate was acidified with aqueous 1 N hydrochloric acid (500 mL). After the addition of water (3 L) the mixture was stirred for 20 min followed by the separation of the phases. The aqueous phase was basified with 4N aqueous sodium hydroxide (100 mL) and extracted with ethyl acetate (3 L and 2 L were added). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a first crop of (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol (solid, 36.95 g, 173 mmol, recovery 23 %).

[0090] Isolation of (1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid

[0091] The beige precipitate was suspended in aqueous 1 N hydrochloric acid (2600 mL) and ethyl acetate (6500 mL). After 1 h under vigorous stirring water (1300 mL) was added to afford two clear layers within 15 min. The phases were separated and the organic phase was washed with water (2 x 1000 mL), followed by brine (600 mL) and was filtered over a filter filled with a pad of sodium sulfate. The volume of the solution was reduced to about 400 mL by evaporation under reduced pressure. The precipitate formed after evaporation was filtered off (frit pore 3) to obtain (1 / ?,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane- 1-carboxylic acid as beige solid (104.6 g, 349 mmol, yield 33 %, >99 % ee). Further precipitation from the filtrate occurred and the formed precipitate was filtered off (frit pore 3) to obtain further (1 R,3 / ?)-2,2-dichloro- 3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid as beige solid (15.1 g, 50.2 mmol, yield 5 %, 97 % ee).

[0092] Recovery of a second crop of the chiral base ( 1 S,2R)-2-amino-1 ,2-diphenylethan-1 -ol

[0093] To the aqueous phases obtained above 4N aqueous sodium hydroxide (2 L) was added affording a suspension. After extraction with ethyl acetate (2 x 2 L) the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a second crop of (1 S,2R)-2-amino-1 ,2-diphenylethan- 1-ol (81.43 g, 382 mmol, recovery 51 %).

[0094] Example 3: Preparation of (1S,2 / ?)-2-hydroxy-1 ,2-diphenylethan-1-aminium (1S,3S)-2,2-dichloro-3- (3,5-dichlorophenyl)cyclopropane-1 -carboxylate A three neck round bottom flask (100 mL) equipped with a reflux condenser, a stir bar, an internal thermometer and placed under nitrogen atmosphere was charged with trans-2, 2-dichloro-3-(3, 5- dichlorophenyl)cyclopropane-1 -carboxylic acid (2.70 g, 9 mmol) and ethyl acetate (30 mL) at room temperature. The temperature was raised to 60 °C and (1 R,2S)-2-amino-1 ,2-diphenylethan-1-ol (1 .34 g, 6.3 mmol) was added slowly. After the addition the reaction mixture was heated to reflux within 20 min under vigorous stirring. The reaction mixture was further stirred for 10 min at this temperature before cooling to 0°C over 14 h.

[0095] After 1 h at 0°C the precipitate formed was filtered off (frit pore 3), was slurry washed (approx. 2 times) with ethyl acetate (30 mL and 20 mL) to afford : (1 S,2 / ?)-2-hydroxy-1 ,2-diphenylethan-1-aminium (1 S,3S)- 2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylate as beige solid (1.81 g, 3.53 mmol, 39% yield) with an optical purity of 99 % ee.

[0096] Comparative Example 4: Preparation of ( / ?)-1-phenylethan-1-aminium (1 / ?,3 / ?)-2,2-dichloro-3-(3,5- dichlorophenyl)cyclopropane-1 -carboxylate

[0097] A three neck round bottom flask (50 mL) equipped with a reflux condenser, a stir bar, an internal thermometer and placed under nitrogen atmosphere was charged with trans-2, 2-dichloro-3-(3, 5- dichlorophenyl)cyclopropane-1 -carboxylic acid (2.70 g, 9 mmol) and ethyl acetate (15 mL) at room temperature. The temperature was raised to 50°C and (R)-phenylethylamine (0.556 g, 4.5 mmol) was added slowly. After 10 min the temperature of the resulting suspension was heated to reflux and the mixture was stirred at this temperature for 2 h. After cooling to ambient temperature the precipitate formed was filtered off (frit pore 3), the slurry was washed (approx. 3 times) with ethyl acetate (each 10 mL) to afford (R)-1-phenylethan-1-aminium (1 / ?,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylate (1 .20 g, 2.85 mmol, yield 32 %) with an optical purity of 95 % ee.

[0098] Comparative Example 5: Preparation of (S)-1-amino-4-methyl-1 -oxopentan-2 -aminium (1 R,3R)-2,2- dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylate

[0099] A three neck round bottom flask (50 mL) equipped with a reflux condenser, a stir bar, an internal thermometer and placed under nitrogen atmosphere was charged with trans-2, 2-dichloro-3-(3, 5- dichlorophenyl)cyclopropane-1 -carboxylic acid (2.70 g, 9 mmol) and dimethyl carbonate (18 mL) at room temperature. The temperature was raised to 60°C and L-leucinamide (0.820 g, 6.30 mmol) was added slowly. After 10 min the temperature of the resulting suspension was heated to reflux and the mixture was stirred at this temperature for 1 h. After cooling to ambient temperature the precipitate formed was filtered off (frit pore 3), the slurry was washed (approx. 3 times) with dimethyl carbonate (each 10 mL) to afford (S)- 1-amino-4-methyl-1-oxopentan-2-aminium (1 / ?,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1- carboxylate (1 .46 g, 3.39 mmol, yield 38 %) with an optical purity of 87 % ee.

Claims

Claims1. A method for obtaining (1 / ?,3 / ?)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid or a salt thereof, comprising the steps of:(a) treating trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid with a chiral base being (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol in an organic solvent to form a suspension,(b) isolating a diastereoisomeric salt of (1 / ?,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane- 1 -carboxylic acid and the chiral base from the suspension,(c) optionally, treating the isolated diastereoisomeric salt with an acid to obtain (1 R,3 / ?)-2,2- dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid and a salt of the chiral base.

2. A method for obtaining (1 S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid or a salt thereof, comprising the steps of:(a) treating trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid with a chiral base being (1 R,2S)-2-amino-1 ,2-diphenylethan-1-ol in an organic solvent to form a suspension,(b) isolating a diastereoisomeric salt of (1 S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1- carboxylic acid and the chiral base from the suspension,(c) optionally, treating the isolated diastereoisomeric salt with an acid to obtain (1 S,3S)-2,2- dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid and a salt of the chiral base.

3. The method according to any one of claims 1-2, wherein the acid used in step (c) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and oxalic acid.

4. The method according to any one of claims 1-3, wherein the organic solvent in step (a) is selected the group consisting of cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC), toluene, 2- methyltetrahydrofuran (2-MeTHF) and ethyl acetate.

5. The method according to any one of claims 1-4, wherein step (a) takes place at a temperature in the range 30-90°C.

6. The method according to any one of claims 1-5, wherein the chiral base in step (a) is used in a molar ratio of 0.5-0.9 to 1 equivalent of trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid.

7. The method according to any one of claims 1-6, further comprising:(d) treating the salt of the chiral base obtained in step (c) with an inorganic base to recover the chiral base.

8. The method according to claim 7, wherein the inorganic base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate.

9. The method according to claim 7 or 8, wherein the chiral base recovered in step (d) is used in step (a).

10. A diastereoisomeric salt of (1 / ?,3 / ?)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid and (1 S,2 / ?)-2-amino-1 ,2-diphenylethan-1-ol.

11. A diastereoisomeric salt of (1 S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid and (1 R,2S)-2-amino-1 ,2-diphenylethan-1-ol.

12. The use of (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol or (1 R,2S)-2-amino-1 ,2-diphenylethan-1-ol in chiral resolution of trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid.

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