Novel substituted aminocyclohexanecarbonitriles

Abstract

The present invention relates to new compounds represented by formula (I), formula (c / s-l) and formula (trans-l) wherein HX is phthalic acid or c / s-cyclohexane-1,3-dicaboxylic acid, and the conditions for the preparation of said substituted formulas. This present invention illustrates the process of isolation of c / s-1-amino-4-methoxycyclohexane-l-carbonitrile, via the contact of cis:trans mixture of 1-amino-4-methoxycyclohexane-l-carbonitrile with phthalic acid or c / s-cyclohexane- 1,3-dicaboxylic acid in the presence of a solvent. The present invention is also related to a process for preparation of spirotetramat pesticide by c / s-1-aminocyclohexane-l-carbonitrile derivatives of formula (c / s-I) prepared by said novel process.

Description

[0001] TITLE: NOVEL SUBSTITUTED AMINOCYCLOHEXANECARBONITRILES

[0002] FIELD OF INVENTION:

[0003] The present invention refers to novel compounds of formula (trans-\), and in particular the compounds of formula (c / s-l) wherein R1is Cl-C6-alkoxy group, and HX is phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3- naphthalene dicarboxylic acid, c / s-cyclohexane-l,3-dicarboxylic acid, cyclobutene-1,1- dicarboxylic acid, process of their preparation and use in the manufacturing of pesticides, such as spirotetra mat.

[0004] BACKGROUND:

[0005] Substituted 1-aminocyclohexane-l-carbonitrile derivatives of formula (II) wherein R1is Cl-C6-alkoxy group. are well known for their extensive use in the agriculture industry as building blocks for insecticides and in particular, spirotetramat. Its preparation process, leads to a mixture of (cis- 11) and (trans-\\) is well known and described for example in WO 2003 / 080557. Among the two isomers, the cis isomer (c / s-ll) is the more valuable one for the preparation of desired insecticides as recited in W02004 / 007448. In addition, the isolation of the desired cis isomer by transforming the free base substances to salt substances in the presence of an acid was disclosed for example in WO2012 / 084862, WO2019 / 233498, WO2022 / 083494. The corresponding salts are separated by precipitation due to the solubility differences between the cis and the trans isomers and eventually transformed back to their free base form. These references disclose salts of formic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methane sulfonic acid, maleic acid, benzoic acid, p-nitro benzoic acid, m-nitro benzoic acid, p-toluic acid, and salicylic acid. By applying specific conditions of solvent mixture, ratio, temperature, and / or ultrasonic vibration, only a few cases show the isolation of the desired cis isomer with acceptable yield and purity. Furthermore, there is an increasing need for chemical industries to adopt more sustainable and eco-friendly processes, where raw materials can be recycled and reused in subsequent batches. It is widely understood that only a limited number of acids used in the aforementioned examples can be recycled for this purpose. Given the fact that the cis salts of 1-aminocyclohexane-l- carbonitrile derivatives are important intermediates for the preparation of widely used pesticides, there is a need for new compounds of this chemical group, and new eco-friendly processes of purification of the desired c / s-salts of 1-aminocyclohexane-l-carbonitrile derivatives.

[0006] SUMMARY:

[0007] The present invention is directed to compounds of formula (c / s-l ) and formula (trans-\) wherein R1is C1-C6 alkoxy group; and HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid.

[0008] The present invention is particularly directed to a compound of formula (c / s-l) wherein R1is Cl-C6-alkoxy group; and HX is phthalic acid or c / s-cyclohexane-l,3-dicaboxylic acid.

[0009] Another aspect of the present invention is related to a process for preparation of compounds of formula (c / s-l) and formula (trans-\), comprising preparing a mixture of a compound of formula

[0010] (ID wherein R1is Cl-C6-alkoxy group; an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid and optionally in the presence of a solvent.

[0011] This present invention is related to a novel mixture of compounds of formula (c / s-l ) and formula (trans-\), wherein the ratio between compound of formula (c / s-l) and compound formula (trans- I) is between 1:99 to 99:1. Another aspect of the present invention is related to a process for preparation of compound of formula (c / s-l) comprising step a) reacting a compound of formula (III), wherein

[0012] R1is C1-C6 alkoxy group; with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, to form a compound of formula (II), wherein R1is as defined above, step b) preparing a mixture of the compound of formula (II), an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-l,3-dicarboxylic acid, cyclobutene-1,1- dicarboxylic acid, and optionally in the presence of a solvent selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, propyl acetate, acetonitrile, water, and the mixtures thereof, at a temperature of from -20 °C to 100 °C, and step c) separating the compound of formula (c / s-l ) by filtration.

[0013] Another aspect of the present invention is related to a process for preparation of a compound of formula (II) wherein R1is C1-C6 alkoxy group; comprising reacting compounds of formula (c / s-l ) and formula (trans-\) with aqueous ammonia, or ammonia in the presence of organic solvents and water.

[0014] Finally, the present invention is related to the preparation of a compound of formula (IV) wherein,

[0015] Z is alkyl, halogen, alkoxy, haloalkyl or haloalkoxy;

[0016] Y is alkyl, alkoxy, halogen, haloalkyl or haloalkoxy

[0017] R1is C1-C6 alkoxy group;

[0018] G is hydrogen, carbonyl, alkoxycarbonyl, alkoxy or aryloxy; using a compound of the formula (c / s-l) prepared as defined according to any one of the embodiments in this present invention.

[0019] DESCRIPTION OF THE INVENTION:

[0020] Definitions:

[0021] Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms to be used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains.

[0022] Throughout the application, descriptions of various embodiments use the term "comprising"; however, it will be understood by one skilled in the art, that in some specific instances, an embodiment can alternatively be described using the language "consisting essentially of" or "consisting of". As used herein, the verb "comprise" as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.

[0023] The term "a" or "an" as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms "a," "an" or "at least one" can be used interchangeably in this application.

[0024] The term "halogen" or "halo" as used herein refers to one or more halogen atoms, defined as F, Cl, Br, and I. Unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages, or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about."

[0025] The term "carbonyl" as used herein refers to the group -C=O

[0026] The term "alkoxy," as used herein, refers to optionally substituted alkyl groups attached to the parent molecular moiety through an oxygen atom.

[0027] The term "aryloxy" refers to an optionally substituted aryl group attached to the parent molecular moiety through an oxygen atom.

[0028] The term "alkoxycarbonyl," as used herein, refers to optionally substituted alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0029] The term "alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six carbon atoms.

[0030] The term "one-pot" reaction as used herein, refers to the possibility to perform multiplechemical reactions in one step in a single reaction vessel without the need for isolation (e.g., purification) of the intermediates obtained in each chemical reaction. This process reduces the number of synthetic steps, and decreases waste materials, time, and cost.

[0031] The term "telescopic process" as used herein refers to carrying out several reactions without isolating the intermediate products. In particular, the telescopic process suggests the execution of multiple transformations (including reaction quenches and other workup operations) without the direct isolation of intermediates. Telescoped solutions of intermediates can be extracted, filtered (as long as the desired product remains in the filtrate), and solvent exchanged, but the intermediate is ultimately held in solution and carried forward to the subsequent transformation.

[0032] The term "salts", as used herein, refers to organic salts such as chloride, bromide, fluoride, iodide, acetate, hydrogen sulfates, phosphates, formats, nitrate, carbonate or, if applicable, alkaline metal salts such as sodium, potassium, calcium, lithium, cesium, magnesium, barium and the like.

[0033] According to an embodiment, the present invention relates to novel compounds of formula (cis- I) and formula (trans-\) wherein R1is C1-C6 alkoxy group, and HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-ta rtaric acid, D-(-)-tartaric acid, 1,2-naphthalene dicarboxylic acid, naphthalene-l,4-dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-l,3-dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2- hydroxymandelic acid, 2,3,4,5-tetrahydroxyhexanedioic acid, 2,3-dihydroxypropanoic acid, 2- hydroxy-2-phosphonoacetic acid, (lR,2S)-rel-cyclohex-4-ene-l,2-dicarboxylic acid, cyclohex-1- enecarboxylic acid, cyclobutene-l,l-dicarboxylic acid, heptane dioic acid and azelic acid.

[0034] According to an embodiment, the present invention relates to novel compounds of formula (cis- I) and formula (trans-\) wherein R1is C1-C6 alkoxy group, and HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-l,3-dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid.

[0035] According to an embodiment, the present invention relates particularly to novel compounds of formula (c / s-l) and formula (trans-\) wherein R1is C1-C6 alkoxy group, and HX is phthalic acid or c / s-cyclohexane-l,3-dicaboxylic acid.

[0036] According to an embodiment, the present invention relates to novel compound of formula (cis- wherein R1is C1-C6 alkoxy group, and HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-tartaric acid, D-(- )-tartaric acid, 1,2-naphthalene dicarboxylic acid, Naphthalene-l,4-dicarboxylic acid, 2,3- naphthalene dicarboxylic acid, c / s-cyclohexane-l,3-dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2-hydroxymandelic acid, 2,3,4,5-tetrahydroxyhexanedioic acid, 2,3- dihydroxypropanoic acid, 2-hydroxy-2-phosphonoacetic acid, (lR,2S)-rel-cyclohex-4-ene-l,2- dicarboxylic acid, cyclohex-l-enecarboxylic acid, cyclobutene-l,l-dicarboxylic acid, heptane dioic acid and azelic acid.

[0037] According to an embodiment, the present invention relates to novel compound of formula (c / s- wherein R1is C1-C6 alkoxy group, and HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3- naphthalene dicarboxylic acid, c / s-cyclohexane-l,3-dicarboxylic acid, cyclobutene-1,1- dicarboxylic acid.

[0038] According to an embodiment, the present invention relates particularly to novel compound of formula (c / s-l) wherein R1is C1-C6 alkoxy group, and HX is phthalic acid or c / s-cyclohexane-l,3-dicaboxylic acid.

[0039] According to an embodiment, R1is C1-C6 alkoxy group, more preferably C1-C3 alkoxy group, most preferably Cl-alkoxy group.

[0040] According to an embodiment, R1is propoxy group, more preferably ethoxy group, most preferably methoxy group.

[0041] According to an embodiment, R1is methoxy.

[0042] According to an embodiment, HX is phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-tarta ric acid, D-(-)-tartaric acid, 1,2-naphthalene dicarboxylic acid, naphthalene- 1,4-dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-l,3-dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2-hydroxymandelic acid, 2,3,4,5-tetrahydroxyhexanedioic acid, 2,3-dihydroxypropanoic acid, 2-hydroxy-2-phosphonoacetic acid, (lR,2S)-rel-cyclohex-4- ene-l,2-dicarboxylic acid, cyclohex-l-enecarboxylic acid, cyclobutene-l,l-dicarboxylic acid, heptane dioic acid and azelic acid. According to an embodiment, HX is phthalic acid, terephthalic acid, isophthalic acid, 1,2- naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid or cyclobutene-l,l-dicarboxylic acid.

[0043] According to an embodiment, HX is phthalic acid.

[0044] According to an embodiment, HX is c / s-cyclohexane-l,3-dicaboxylic acid.

[0045] According to another aspect of the present invention, the present invention provides a process for the preparation of compounds of formula (c / 's-l) and formula (trans-\) comprising preparing a mixture of a compound of formula (II) wherein R1is C1-C6 alkoxy group; an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-tarta ric acid, D-(-)-tartaric acid, 1,2-naphthalene dicarboxylic acid, naphthalene-l,4-dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2-hydroxymandelic acid, 2, 3,4,5- tetrahydroxyhexanedioic acid, 2,3-dihydroxypropanoic acid, 2-hydroxy-2-phosphonoacetic acid, (lR,2S)-rel-cyclohex-4-ene-l,2-dicarboxylic acid, cyclohex-l-enecarboxylic acid, cyclobutene-1,1- dicarboxylic acid, heptane dioic acid and azelic acid, and optionally in the presence of a solvent.

[0046] According to an embodiment, the present invention provides a process for the preparation of compounds of formula (cis- 1 ) and formula (trans-\) comprising preparing a mixture of a compound of formula (II) an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid, and optionally in the presence of a solvent.

[0047] According to an embodiment, the present invention provides a process for the preparation of compounds of formula (cis- 1 ) and formula (trans-\) comprising preparing a mixture of a compound of formula (II) wherein R1is C1-C6 alkoxy group; an acid selected from the group consisting of phthalic acid and c / s-cyclohexane-l,3-dicaboxylic acid, and optionally in the presence of a solvent.

[0048] According to an embodiment, the compound of formula (II) is a mixture of compounds of formula (c / s-ll) and (trans-\\) (trans-ll) wherein R1is C1-C6 alkoxy group; in a ratio of between 1:99 and 99:1.

[0049] According to an embodiment, the compound of formula (II) is a mixture of compounds of formula (c / s-ll) and (trans-\\) in a ratio of between 3:7 and 7:3.

[0050] According to an embodiment, the compound of formula (II) is a mixture of compounds of formula (c / s-ll) and (trans-\\) in a ratio of 5:5. According to another aspect of the present invention provides a process for the preparation of compounds of formula (c / s-l ) comprising step a) preparing a mixture of a compound of formula (ID wherein R1is C1-C6 alkoxy group; an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-tarta ric acid, D-(-)-tartaric acid, 1,2-naphthalene dicarboxylic acid, naphthalene-l,4-dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2-hydroxymandelic acid, 2, 3,4,5- tetrahydroxyhexanedioic acid, 2,3-dihydroxypropanoic acid, 2-hydroxy-2-phosphonoacetic acid, (lR,2S)-rel-cyclohex-4-ene-l,2-dicarboxylic acid, cyclohex-l-enecarboxylic acid, cyclobutene-1,1- dicarboxylic acid, heptane dioic acid and azelic acid, and optionally in the presence of a solvent and step b) separating the compound of formula (c / s-l) by filtration.

[0051] According to an embodiment, the present invention provides a process for the preparation of compounds of formula (c / s-l ) comprising step a) preparing a mixture of a compound of formula (ID wherein R1is C1-C6 alkoxy group; an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid, and optionally in the presence of a solvent, and step b) separating the compound of formula (c / s-l) by filtration. According to an embodiment, the present invention provides a process for the preparation of compounds of formula (c / s-l ) comprising step a) preparing a mixture of a compound of formula (ID wherein R1is C1-C6 alkoxy group; a phthalic acid or c / s-cyclohexane-l,3-dicaboxylic acid, optionally in the presence of a solvent and step b) separating the compound of formula (c / s-l) by filtration.

[0052] According to an embodiment, the amount of compound (II) in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 10 % to 90 % by weight, based on the weight of total mixture.

[0053] According to an embodiment, the amount of compound (II) in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 30 % to 70 % by weight, based on the weight of total mixture.

[0054] According to an embodiment, the amount of compound (II) in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 30 % to 50 % by weight, based on the weight of total mixture.

[0055] According to an embodiment, the amount of compound (II) in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 30 % to 40 % by weight, based on the weight of total mixture.

[0056] According to an embodiment, the amount of the acid in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 10 % to 90 % by weight, based on the weight of total mixture. According to an embodiment, the amount of the acid in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 30 % to 70 % by weight, based on the weight of total mixture.

[0057] According to an embodiment, the amount of the acid in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 30 % to 50 % by weight, based on the weight of total mixture.

[0058] According to an embodiment, the amount of the acid in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 30 % to 40 % by weight, based on the weight of total mixture.

[0059] According to an embodiment, the weight ratio between compound (II) and the acid in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 1:1.1 to 1:0.1.

[0060] Accordingto an embodiment, the weight ratio between compound (II) and the acid in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 1:1.05 to 1:0.5.

[0061] Accordingto an embodiment, the weight ratio between compound (II) and the acid in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 1:1.05 to 1:0.4.

[0062] Accordingto an embodiment, the weight ratio between compound (II) and the acid in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 1:1.05 to 1:0.3.

[0063] Accordingto an embodiment, the weight ratio between compound (II) and the acid in the mixture of the process for the preparation of compounds of formula (cis- 1 )is from 1:1 to 1:0.75.

[0064] According to an embodiment, the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l) is selected from the group comprising aliphatic hydrocarbons (acyclic and cyclic), selected from octane, heptane, hexane, pentane, cyclooctane, cyclopentane, petroleum ether, cyclohexane, cyclopentane, and chlorinated hydrocarbons selected from, carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, methylene chloride and aromatic hydrocarbons selected from toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, and ethers (acyclic and cyclic) selected from diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), cyclopentylmethyl ether, methyl-tert- butyl ether, and aliphatic and aromatic esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and ketones selected from acetone, 2-butanone, cyclohexanone, and alcohols selected from methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butyl alcohol, diethylene glycol, glycerin, ethylene glycol, N-methyl-2- pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, water and the mixtures thereof.

[0065] According to an embodiment, the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l) is selected from the group comprising pentane, hexane, cyclohexane, benzene, toluene, chlorobenzene, dichlorobenzene, trichlorobenzene, dichloromethane, chloroform, tetrachloromethane, acetone, 2-butanone, cyclohexanone, methanol, ethanol, propanol, butanol, pentanol, hexanol, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, N-methyl-2-pyrrolidinone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, methyl acetate, ethyl acetate, isopropyl acetate acetonitrile, and the mixtures thereof.

[0066] According to an embodiment, the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l) is selected from the group comprising toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, isopropyl acetate acetonitrile, and the mixtures thereof.

[0067] According to an embodiment, the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l) is selected from the group comprising, chlorobenzene, methanol, methyl acetate, ethyl acetate, isopropyl acetate, n-Butyl acetate, and acetonitrile.

[0068] According to an embodiment, the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l) is ethyl acetate or methyl acetate.

[0069] According to an embodiment, the amount of the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 10 % to 00 % by weight, based on the weight of total mixture. According to an embodiment, the amount of the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 30 % to 70 % by weight, based on the weight of total mixture.

[0070] According to an embodiment, the amount of the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 50 % to 70 % by weight, based on the weight of total mixture.

[0071] According to an embodiment, the amount of the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 60 % to 70 % by weight, based on the weight of total mixture.

[0072] According to an embodiment, the weight ratio between the compound (II) and the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 1:0.5 to 1:10.

[0073] According to an embodiment, the weight ratio between the compound (II) and the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 1:1 to 1:5.

[0074] According to an embodiment, the weight ratio between the compound (II) and the solvent in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 1:3 to 1:5.

[0075] According to an embodiment, the weight ratio between compound (c / s-l) and compound (transll) in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 99:1 to 1:99.

[0076] According to an embodiment, the weight ratio between compound (c / s-l) and compound (trans- II) in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 85:15 to 15:85.

[0077] According to an embodiment, the weight ratio between compound (c / s-l) and compound (trans- II) in the mixture of the process for the preparation of compounds of formula (c / s-l) is from 70:30 to 30:70. According to an embodiment, the weight ratio between compound (c / s-l) and compound (transIl) in the mixture of the process for the preparation of compounds of formula (c / s-l ) is from 60:40 to 40:60.

[0078] According to an embodiment, the weight ratio between compound (c / s-l) and compound (trans- II) in the mixture of the process for the preparation of compounds of formula (c / s-l) is 50:50.

[0079] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at a temperature interval from -20 to 100 °C.

[0080] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at a temperature interval from 0 to 80 °C.

[0081] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at a temperature interval from 10 to 60 °C.

[0082] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at a temperature interval from 20 to 40 °C.

[0083] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated t a decreasing temperature interval over time.

[0084] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at an agitation speed interval from 0 Rpm to 300 Rpm.

[0085] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at an agitation speed interval from 10 Rpm to 200 Rpm.

[0086] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at an agitation speed interval from 20 Rpm to 100 Rpm.

[0087] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at agitation speed interval from 20 Rpm to 50 Rpm.

[0088] According to an embodiment, the mixture of the process for the preparation of compounds of formula (c / s-l) is agitated at a decreasing agitation speed intervals over time. According to an embodiment, the process for the preparation of compounds of formula (c / s-l) comprising the addition of the compound of formula (II) or its salts thereof, to the acid selected from phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3- naphthalene dicarboxylic acid, c / s-cyclohexane-l,3-dicarboxylic acid, cyclobutene-1,1- dicarboxylic acid, and further mixing between the compound of formula (II) and the acid.

[0089] According to an embodiment, the process for the preparation of compounds of formula (c / s-l) comprising the addition of the compound of formula (II) or its salts thereof, to the acid selected from phthalic acid, c / s-cyclohexane-l,3-dicarboxylic acid, and further mixing between the compound of formula (II) and the acid.

[0090] According to an embodiment, the process for the preparation of compounds of formula (c / s-l) comprising the addition of the compound of formula (II) or its salts thereof, to phthalic acid or c / s-cyclohexane-l,3-dicarboxylic acid, and further mixing between the compound of formula (II) and the acid.

[0091] According to an embodiment, the process for the preparation of compounds of formula (c / s-l) comprising the addition of the acid selected from phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid, to the compound of formula (II) or its salts thereof and further mixing between the compound of formula (II) and the acid.

[0092] According to an embodiment, the process for the preparation of compounds of formula (c / s-l) comprising the addition of the acid selected from phthalic acid and c / s-cyclohexane-1,3- dicarboxylic acid to the compound of formula (II), or its salts thereof and further mixing between the acid and the compound of formula (II).

[0093] According to an embodiment, the process for the preparation of compounds of formula (c / s-l) comprising the addition of the acid selected from phthalic acid or c / s-cyclohexane-1,3- dicarboxylic acid to the compound of formula (II), or its salts thereof and further mixing between the acid and the compound of formula (II). According to an embodiment, the reaction mixture of the process for the preparation of compounds of formula (c / 's-l) is monitored by HPLC analytical process, and the process ends when the concentration of the compound of formula (II) is between 0-99%, preferably from 0-50%, most preferably, in particular, when no more than 5% of compound of formula (II) remains in the reaction media.

[0094] According to an embodiment, the compound of formula (c / 's-l) is precipitating form the mixture of the process for the preparation of compounds of formula (c / 's-l) spontaneously.

[0095] According to an embodiment, the compound of formula (c / s-l) is precipitating form the mixture of the process for the preparation of compounds of formula (c / s-l) after seeding a compound of formula (c / s-l) to the mixture.

[0096] According to an embodiment, compound of formula (c / s-l ) is isolated by filtration.

[0097] According to an embodiment, the content of impurities in the compound of formula (c / s-l), is less than 30% by weight more preferably less than 15%, most preferably less than 5%.

[0098] According to an embodiment, the content of the compound of formula (trans-\) in the compound of formula (c / s-l), is less than 30% by weight, more preferably less than 15%, most preferably less than 5%.

[0099] Finally, the reaction mixture containing the resulting compound of formula (c / s-l) is worked up. This stage may include washing with water, washing with organic solvent, drying processes, adding water, adding organic solvent, stirring, cooling, heating, phases separation, distillation, additional precipitation, recrystallization, concentration, additional filtration, additional seeding, purification, pH adjustment, extraction.

[0100] According to an embodiment, the next step in the process can be performed as separate processes wherein the compound of formula (c / 's-l) is transferred to another reaction mixture or as combined process, such as one-pot reaction or telescopic-reaction wherein the next step is performed where the compound of formula (c / 's-l) is located. According to another embodiment, the present invention is related to a process for the preparation of compound of formula (c / 's-l) according to any of the preceding embodiments. comprising an initial step of reacting a compound of formula (III), wherein R1is C1-C6 alkoxy group; with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, as described in WO2012084862 to form a compound of formula (II) and proceeding with the process as described according to any of the preceding embodiments in this present invention.

[0101] According to an embodiment, the present invention is related to a process for the preparation of compounds of formula (c / 's-VI) and formula (trans-\ / \) wherein HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, 1,2-naphthalene dicarboxylic acid, naphthalene-l,4-dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, cis- cyclohexane-l,3-dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2-hydroxymandelic acid, 2,3,4,5-tetrahydroxyhexanedioic acid, 2,3-dihydroxypropanoic acid, 2-hydroxy-2- phosphonoacetic acid, (lR,2S)-rel-cyclohex-4-ene-l,2-dicarboxylic acid, cyclohex-1- enecarboxylic acid, cyclobutene-l,l-dicarboxylic acid, heptane dioic acid and azelic acid, comprising step a) reacting a compound of formula (VII), with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, as described in WO2012084862 to form a compound of formula (VI) step b) preparing a mixture of the compound of formula (VI); an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-tarta ric acid, D-(-)-tartaric acid, 1,2-naphthalene dicarboxylic acid, naphthalene-l,4-dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2-hydroxymandelic acid, 2, 3,4,5- tetrahydroxyhexanedioic acid, 2,3-dihydroxypropanoic acid, 2-hydroxy-2-phosphonoacetic acid, (lR,2S)-rel-cyclohex-4-ene-l,2-dicarboxylic acid, cyclohex-l-enecarboxylic acid, cyclobutene-1,1- dicarboxylic acid, heptane dioic acid and azelic acid, and optionally a solvent selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, propyl acetate, n-Butyl acetate, acetonitrile, water, and the mixtures thereof, at a temperature of from -20 °C to 100 °C.

[0102] According to an embodiment, the present invention is related to a process for the preparation of compounds of formula (c / s-VI) and formula (trans-VI) (trans-VI); wherein HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, cis- cyclohexane-l,3-dicarboxylic acid, comprising step a) reacting a compound of formula (VII), with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, as described in WO2012084862 to form a compound of formula (VI) and step b) preparing a mixture of the compound of formula (VI); an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, and a solvent selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, propyl acetate n-Butyl acetate, acetonitrile, water, and the mixtures thereof, at a temperature of from -20 °C to 100 °C.

[0103] According to an embodiment, the present invention is related to a process for the preparation of compounds of formula (c / 's-VI) and formula (trans-\ / \) wherein HX is an acid selected from the group consisting of phthalic acid, c / s-cyclohexane-1,3- dicarboxylic acid, comprising step a) reacting a compound of formula (VII), with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, as described in WO2012084862 to form a compound of formula (VI)

[0104] Step b) preparing a mixture of the compound of formula (VI); an acid selected from the group consisting of phthalic acid, c / s-cyclohexane-l,3-dicarboxylic acid, and optionally a solvent selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, propyl acetate, n-Butyl acetate, acetonitrile, water, and the mixtures thereof, at a temperature of from 0 °C to 100 °C.

[0105] According to an embodiment, the present invention is related to a process for the preparation of compounds of formula (c / s-VI) wherein HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, 1,2-naphthalene dicarboxylic acid, naphthalene-l,4-dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, cis- cyclohexane-l,3-dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2-hydroxymandelic acid, 2,3,4,5-tetrahydroxyhexanedioic acid, 2,3-dihydroxypropanoic acid, 2-hydroxy-2- phosphonoacetic acid, (lR,2S)-rel-cyclohex-4-ene-l,2-dicarboxvlic acid, cyclohex-1- enecarboxylic acid, cyclobutene-l,l-dicarboxylic acid, heptane dioic acid and azelic acid, comprising step a) reacting a compound of formula (VII), with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, as described in WO2012084862 to form a compound of the formula (VI)

[0106] Step b) preparing a mixture of the compound of formula (VI); and an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, malonic acid, lactic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, 1,2-naphthalene dicarboxylic acid, naphthalene-l,4-dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, succinic acid, citric acid, mandelic acid, 2-hydroxymandelic acid, 2, 3,4,5- tetrahydroxyhexanedioic acid, 2,3-dihydroxypropanoic acid, 2-hydroxy-2-phosphonoacetic acid, (lR,2S)-rel-cyclohex-4-ene-l,2-dicarboxylic acid, cyclohex-l-enecarboxylic acid, cyclobutene-1,1- dicarboxylic acid, heptane dioic acid and azelic acid, optionally in the presence of a solvent selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, propyl acetate, n-Butyl acetate, acetonitrile, water, and the mixtures thereof, at a temperature of from 0 °C to 100 °C and step c) separating the compound of formula (c / 's-VI) by filtration. According to an embodiment, the present invention is related to a process for the preparation of compounds of formula (c / s-VI) wherein HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, cis- cyclohexane-l,3-dicarboxylic acid, comprising step a) reacting a compound of formula (VII), with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, as described in WO2012084862 to form a compound of the formula (VI) preparing a mixture of compound of formula (VI); an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, and optionally in the presence of a solvent selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, propyl acetate, n-Butyl acetate, acetonitrile, water, and the mixtures thereof, at a temperature of from 0 °C to 100 °C and step c) separating the compound of formula (c / s-VI) by filtration.

[0107] According to an embodiment, the present invention is related to a process for the preparation of compounds of formula (c / s-VI) wherein HX is an acid selected from the group consisting of phthalic acid and c / s-cyclohexane- 1,3-dicarboxylic acid, comprising step a) reacting a compound of formula (VII), with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, as described in WO2012084862 to form a compound of the formula (VI) step b) preparing a mixture of the compound of formula (VI); and phthalic acid or c / s-cyclohexane-l,3-dicarboxylic acid, and optionally in the presence of a solvent selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, propyl acetate, n-Butyl acetate, acetonitrile, water, and the mixtures thereof, at a temperature of from 0 °C to 100 °C and step c) separating compound of formula (c / s-VI) by filtration. According to an embodiment, the present invention is related to a process for the preparation of a compound of formula (VI) comprising reacting of a compound of formula (trans-\ / \) and / or compound of formula (c / s-VI): wherein HX is c / s-cyclohexane-l,3-dicarboxylic acid with aqueous ammonia, or ammonia in the presence of organic solvent and water.

[0108] According to another embodiment, the present invention is related to an isomerization process for the preparation of a compound of formula (II) wherein R1 is C1-C6 alkoxy group; comprising reacting of a compound of formula (c / s-l) and / or compound of formula(trans-l): wherein R1and HX are defined according to any of the preceding embodiments in this present invention with aqueous ammonia, or ammonia in the presence of organic solvent and water as described in WO2012084862. According to an embodiment, the present invention is related to an isomerization process for the preparation of a compound of formula (VI) comprising reacting of a compound of formula (c / s-VI ) and / or compound of formula (trans-\ / \): wherein HX is selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid or cyclobutene-l,l-dicarboxylic acid, with aqueous ammonia, or ammonia in the presence of organic solvent and water. According to an embodiment, the present invention is related to an isomerization process for the preparation of a compound of formula (VI) comprising reacting of a compound of formula (c / s-VI) and / or compound of formula (trans-VI): and HX is phthalic acid or c / s-cyclohexane-l,3-dicarboxylic acid with aqueous ammonia, or ammonia in the presence of organic solvent and water. According to an embodiment, the preparation of compound of formula (c / s-l) comprising the isomerization process for the preparation of a compound of formula (II) as described according to any of the preceding embodiments of this resent invention.

[0109] According to an embodiment, the preparation of compound of formula (c / s-VI) comprising the isomerization process for the preparation of a compound of formula (VI) as described according to any of the preceding embodiments of this resent invention.

[0110] According to an embodiment, the acid that was used in the processes described according to any of the preceding embodiments can be recycled and reused by simple common methods known for any person skilled in the art as, but not limited to, washing, precipitation and distillation. According to another embodiment, the compound of formula (IV) wherein

[0111] X is alkyl, halogen, alkoxy, ha loalkyl or haloalkoxy;

[0112] Y is alkyl, alkoxy, halogen, haloalkyl or haloalkoxy R1is alkoxy;

[0113] G is hydrogen, carbonyl, alkoxycarbonyl, alkoxy or aryloxy; is prepared by step a) reacting a compound of formula (III) with an alkali metal cyanide, ammonium chloride and ammonia in a two-phases mixture of organic solvent and water, as described in WO2012084862 to form compound of the formula (II). wherein R1is alkoxy group;, step b) the process for preparing a mixture of a compound of formula (c / 's-l) and (trans-\) according to any of the preceding embodiment of this present invention, step c) separating compound of formula (c / 's-l) by filtration, and finally step d) reacting compound of formula (c / 's-l) according to a known process in W02004 / 007448. According to another embodiment, the compound of formula (IV) wherein

[0114] X is alkyl, halogen, alkoxy, ha loalkyl or haloalkoxy;

[0115] Y is alkyl, alkoxy, halogen, haloalkyl or haloalkoxy R1is alkoxy;

[0116] G is hydrogen, carbonyl, alkoxycarbonyl, alkoxy or aryloxy; is prepared by step a) reacting a compound of formula (III) wherein R1is alkoxy group; with an alkali metal cyanide, ammonium chloride and ammonia in a two-phases mixture of organic solvent and water, as described in WO2012084862 to form compound of the formula (II). wherein R1is alkoxy group;, step b) preparing a mixture of a compound of formula (II), an acid selected from the group consisting of phthalic acid, c / s-cyclohexane-l,3-dicarboxylic acid, and optionally a solvent selected from the group consisting methyl acetate, ethyl acetate, and the mixtures thereof, at a temperature of from 0 °C to 100 °C, to form compounds of formula (c / 's-l) and (trans-\), wherein R1is alkoxy group;, and HX is an acid selected from the group consisting of phthalic acid and c / s-cyclohexane-1,3- dicarboxylic acid, separating compound of formula (c / 's-l) by filtration, and finally step c) reacting compound of formula (c / 's-l) according to a known process in W02004 / 007448.

[0117] According to yet another embodiment, the compound of formula (V) is prepared by step a) reacting a compound of formula (VII) wherein the compounds covered by formula (VII) is known and can be purchase from multiple chemical suppliers, with an alkali metal cyanide, ammonium chloride and ammonia in a two-phases mixture of organic solvent and water, as described in WO2012084862 to form a compound of formula (VI)

[0118] Step b) the process for preparing a mixture of a compound of formula (c / s-VI) and (trans-VI) according to any of the preceding embodiment of this present invention, step c) separating compound of formula (c / s-VI) by filtration, and finally step d) reacting compound of formula (c / s-VI) according to a known process in W02004 / 007448.

[0119] According to yet another embodiment, the compound of formula (V) is prepared by step a) reacting a compound of formula (VII) wherein the compounds covered by formula (VII) is known and can be purchase from multiple chemical suppliers, with an alkali metal cyanide, ammonium chloride and ammonia in a two-phases mixture of organic solvent and water, as described in WO2012084862 to form a compound of formula (VI) step b) preparing a mixture of a compound of formula (VI), an acid selected from the group consisting phthalic acid or c / s-cyclohexane-l,3-dicarboxylic acid, and optionally a solvent selected from the group consisting of methyl acetate, ethyl acetate, and the mixtures thereof, at a temperature of from 0 °C to 100 °C, to form compounds of formula (c / s-VI) and (trans-VI), (trans- VI); wherein, HX is phthalic acid or c / s-cyclohexane-l,3-dicarboxylic acid, separating compound of formula (c / s-VI) by filtration, and finally step c) reacting the compound of formula (c / s-VI) according to a known process in

[0120] W02004 / 007448. RESULTS AND DISCUSSION:

[0121] Objective: Evaluating conditions for purification c / s-l-amino-4-methoxycyclohexane-l- carbonitrile (compound c / s-VI).

[0122] Process: General procedure for the preparation of l-amino-4-methoxycyclohexane-l-carbonitrile (compound (VI)) salt and the purification of c / s-l-amino-4-methoxycyclohexane-l-carbonitrile (compound (c / s-VI)):

[0123] To a 100 mL 4-neck round bottom flask equipped with a mechanical stirrer, a thermometer, condenser, and stopper, l-amino-4-methoxycyclohexane-l-carbonitrile and organic solvent were charged, and the mixture was kept at 25 °C. Acid was mixed into the mixture at 25 °C, and the mixture was allowed to swirl at selected temperature for certain time. The solid precipitation was filtered at 25 °C, washed with organic solvent, and vacuum dried at (>700mm / Hg) at 35 °C. The product cis / trans ratio was examined by HPLC.

[0124] Table 1. Experiments conditions and results of the purification of c / s-l-amino-4- methoxycyclohexane-l-carbonitrile phthalic acid salt from c / s.Trans-l-amino-4- methoxycyclohexane-l-carbonitrile phthalic acid mixture:

[0125] Phthalic acid was found to be very useful for the isolation and purification c / s-l-amino-4- methoxycyclohexane-l-carbonitrile leading to precipitation of c / s-l-amino-4- methoxycyclohexane-l-carbonitrile phthalic acid salt from while keeping the trans-l-amino-4- methoxycyclohexane-l-carbonitrile phthalic acid salt in the solvent. The mixing of l-amino-4- methoxycyclohexane-l-carbonitrile and phthalic acid in organic solvent led to solid precipitation of the c / s-salt with cis purity of between 81 to 98 % and yield of 18 to 32 %. While O-xylene and MTBE (methyl tert-butyl ether) led to poor result with only 64-67 % c / s-purity, the most promising solvent was ethyl acetate leading to as high as 98.6 % c / s-purity. This conditions also led to the highest trans-salt content in the MLR (Mother liquor) of 95.77%. It is worth to note that cis- cyclohexane-l,3-dicarboxylic acid also led to relatively high purity of the c / s-l-amino-4- methoxycyclohexane-l-carbonitrile with 92.42% purity.

[0126] Table 2. (comparative results): Experiments conditions and results of the purification of cis-1- amino-4-methoxycyclohexane-l-carbonitrile salt from c / s:tra / ?s-l-amino-4- methoxycyclohexane-l-carbonitrile mixture:

[0127] None of the above acids, and conditions displayed any superior purification capabilities than of the phthalic acid or the c / s-cyclohexane-l,3-dicarboxylic acid for the purification of the cis-1- amino-4-methoxycyclohexane-l-carbonitrile salt. BRIEF DESCRIPTION OF THE DRAWINGS: Figure 1. shows a single crystal structure of c / s-l-amino-4-methoxycyclohexane-l-carbonitrile

[0128] (compound (c / s-VI ) with phthalic acid salt obtained by a process disclosed in this present invention.

[0129] EXAMPLES: -1-carbonitrile

[0130] To a 3.0 liter 4-neck round bottom flask equipped with a mechanical stirrer, a thermometer, condenser, ammonium chloride (138.5 g, 2.54 moles, 1.1 eq.), aq.NHs (392.0 g, 5.765 moles, 2.5 eq.), solution and water (225.0 mL, 0.75 vol.) was charged at 25 °C and clear solution was observed. Sodium cyanide (131.0 g, 2.54 moles, 1.1 eq.) was charged in one portion at 25 °C. (Hazy solution was observed). In a separate 1-liter flask 4-methoxy cyclohexanone (300g, 2.306 moles, 1.0 eq.) was dissolved in Toluene (300 mL, 1 vol.) at 25 °C. The 4-methoxy cyclohexanone solution in Toluene slowly to the reaction mass drop wise over a period of 2 hours at 25 °C. (Hazy solution was observed). The reaction mixture was allowed to swirl at 25 °C for 8.0 hours. The reaction was monitored by HPLC and was completed when 4-methoxy cyclohexanone content was <2.0%. Then, the reaction mixture was stopped agitated for 20 minutes at 25 °C. and phase separation was conducted. Aqueous layer was extracted with toluene (2x 150 mL, 0.5 Vol.) at 25 °C, and organic layers was distilled out Toluene in at 60 °C, under reduced pressure. Oily mass was obtained, with 309.0 g yield of the desire product (87.02 crude weight yield %), and purity of cis: trans isomers of 55.20:44.79 %. Procedure for the preparation of l-amino-4-methoxycyclohexane-l-carbonitrile

[0131] (compound (V)) phthalic acid salt and the purification of c / s-l-amino-4-methoxycyclohexane-l- carbonitrile (compound (c / s-VI))

[0132] To a 100 mL 4-neck round bottom flask equipped with a mechanical stirrer, a thermometer, condenser, and stopper, l-amino-4-methoxycyclohexane-l-carbonitrile (10.0 gr, 0.065 moles) and ethyl acetate (50 mL) were charged, and the mixture was kept at 25 °C. Phthalic acid (3.82 g, 0.023 moles) was mix into the mixture at 25 °C, and the mixture was allowed to swirl at 25 °C for 16 hours. The solid precipitation was filtered at 25 °C and washed with ethyl acetate (10 mL). The solid was vacuum dried at (>700mm / Hg) 35 °C for 9 hours. 3.6 gr (55% yield) of the desire product c / s-(l-amino-4-methoxycyclohexane-l-carbonitrile phthalic salt) was obtained with purity of 96.56% (by HPLC) and cis:trans isomer ratio of 98.60:1.40 %.

[0133] Example 3: Procedure for the preparation of l-amino-4-methoxycyclohexane-l-carbonitrile (compound (V)) phthalic acid salt and the purification of c / s-l-amino-4-methoxycyclohexane-l- carbonitrile (compound (c / s-VI))

[0134] To a 100 mL 4-neck round bottom flask equipped with a mechanical stirrer, a thermometer, condenser, and stopper. C / s:trans-l-amino-4-methoxycyclohexane-l-carbonitrile (50.0 g, 0.3052 moles) and ethyl acetate (235 mL, 5.0 vol.) were charged, and the mixture was kept at 25 °C. cis -1- amino-4-methoxycyclohexane-l-carbonitrile-phthalic acid salt (pure cis isomer seeding 0.49 g, 0.3 mmol, 0.0035 eq) and phthalic acid (17.93 g, 0.114 moles, 0.35 eq.) was mix into the mixture at 25 °C, and the mixture was allowed to swirl at 25 °C for 16 hours. The solid precipitation was filtered at 25 °C and washed with ethyl acetate (47 mL) and Hexane (47 mL). The solid was vacuum dried at (>700mm / Hg) 35 °C for 9 hours. 27.5 gr (26.46 % crude weight yield) of the desire product cis (l-amino-4-methoxycyclohexane-l-carbonitrile phthalic salt) was obtained with purity of 94.86 % (by HPLC) and cis:trans isomer ratio of 98.37:1.62.

[0135] Example 4: Procedure for the isomerization of trans-l-amino-4-methoxycyclohexane-l- carbonitrile (compound (c / s-VI)) phthalic acid salt to c / s-l-amino-4-methoxycyclohexane-l- carbonitrile (compound (c / s-VI)):

[0136] To a 3.0 litre 4-Neck Round bottom flask equipped with a mechanical stirrer, a thermometer, condenser, ammonium chloride (7.28 g, 0.1320 moles, 1.1 eq.), aq. NH3 (20.4 g, 0.30 moles, 2.5 eq.), solution and water (12.0 mL, 0.75 vol.) was charged at 25 °C and clear solution was observed. Sodium cyanide (6.81 g, 0.1320 moles, 1.1 eq.) was charged in one portion at 25 °C. (Hazy solution was observed). In a separate 1 litre flask 4-methoxy cyclohexanone (15.53 g, 0.120 moles, 1.0 eq.) was dissolved in toluene (16 ml, 1 vol.) at 25 °C. The 4-methoxy cyclohexanone solution in toluene slowly to the reaction mass drop wise over a period of 20 minutes at 25 °C (Hazy solution was observed). Aq. NH3 (20.4 g, 0.30 moles, 2.5 eq.) was charged to the reaction solution followed by ethyl acetate mother liquor from the previous batch of c / s-l-amino-4- methoxycyclohexane-l-carbonitrile salt isolated, containing c / s.Trans-l-amino-4- methoxycyclohexane-l-carbonitrile salt is charged into the Aq. NH3 solution. The reaction mixture was allowed to swirl at 25 °C for 8.0 hours. The reaction was monitored by HPLC and was completed when 4-methoxy cyclohexanone content was <5.0%. Then, the reaction mixture was stopped agitated for 20 minutes at 25 °C and phase separation was conducted. Aqueous layer was extracted with toluene 2x 25 mL, 1.6 Vol.) at 25 °C, and organic layers was distilled out Toluene in at 60 °C, under reduced pressure. Oily mass was obtained, with 57.6 g yield of the desire product (crude weight yield 83.33%), and purity of cis: trans isomers of 52.40:47.60 %.

Claims

CLAIMS:

1. Compounds of formula (c / s-l) and formula (trans-\)wherein R1is Cl-C6-alkoxy group; and HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid.

2. The compound of formula (c / s-l)wherein R1is C1-C6 alkoxy group; and HX is phthalic acid or c / s-cyclohexane-l,3-dicaboxylic acid.

3. The compound according to any of claims 1-2 wherein R1is methoxy, ethoxy, or propoxy.

4. A process for the preparation of compounds of formula (c / s-l) and (trans-\), comprising preparing a mixture of a compound of formula (II)wherein R1is C1-C6 alkoxy group;, an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid,and optionally a solvent.

5. The process according to claim 4, wherein the solvent is selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl process, ethyl acetate, isopropyl acetate, n-Butyl acetate, acetonitrile, water, and the mixtures thereof.

6. The process according to any one of claims 4-5, wherein the weight ratio between the compound (II) or its salts thereof and the solvent is from 1:0.5 to 1:10.

7. The process according to any one of claims 4-6, wherein the temperature of the mixture is from -20°C to 100°C.

8. The process according to any one of claims 4-7, wherein the weight ratio between the compound (II) or its salts thereof and the acid is from 1:1.1 to 1:0.1.

9. The process according to any one of claims 4-8, wherein the mixture is agitated in a speed interval from 0 Rpm to 300 Rpm.

10. The process according to any one of claims 4-9, comprising addition of the compound of formula (II) or its salts thereof, to acid selected from phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid, and further mixing between the compound of formula (II) and the acid.

11. The process according to any one of claims 4-9, comprising addition of acid selected from phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3- naphthalene dicarboxylic acid, cis-cyclohexane-l,3-dicarboxylic acid, cyclobutene-1,1- dicarboxylic acid to compound of formula (II), or its salts thereof, and further mixing between the acid and the compound of formula (II).

12. The process according to any one of claims 4-11, wherein the compound of formula (c / s-l), is isolated by filtration.

13. The process according to any one of claims 4-12, wherein the content of impurities in the compound of formula (c / s-l ), is less than 5% by weight.

14. The process according to any one of claims 4-13, wherein the content of the compound of formula (trans-\) in the compound of formula (c / s-l), is less than 5% by weight.

15. The mixture of compound of formula (c / s-l) and compound formula (trans-\), wherein the ratio between compound of formula (c / s-l) and compound formula (trans-\) is between 1:99 to 99:1.

16. A process for preparation selectively of compound of formula (c / s-l)wherein R1 is Cl-C6-alkoxy group; and HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, cis-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid, comprising: step a) reacting a compound of formula (III),wherein R1is C1-C6 alkoxy group; with an alkali metal cyanide, ammonium chloride and ammonia in a two-phase system of organic solvent and water, to form a compound of formula (II),wherein R1is as defined above, step b) preparing a mixture of the compound of formula (II); and an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, optionally in the presence of a solvent selected from the group consisting of toluene, chlorobenzene, dichlorobenzene, methanol, ethanol, propanol, butanol, pentanol, methyl acetate, ethyl acetate, propyl acetate acetonitrile, water, and the mixtures thereof. at a temperature of from -20 °C to 100 °C, and step c) separating the compound of formula (c / s-l ) by filtration.

17. A process for the preparation of a compound of formula (II)wherein R1is C1-C6 alkoxy group; comprising reacting of a compound of formula (trans-\) and / or compound of formula (c / s-l):wherein R1is defined as above, and HX is selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, c / s-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid, with aqueous ammonia, or ammonia in the presence of organic solvent and water.

18. A process for preparation of compound of formula (c / s-l)wherein R1 is Cl-C6-alkoxy group; and HX is an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, cis-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid, comprising preparing a mixture of a compound of formula (II)wherein R1is C1-C6 alkoxy group; obtained by the process according to claim 16, and an acid selected from the group consisting of phthalic acid, terephthalic acid, isophthalic acid, 1,2-naphthalene dicarboxylic acid, 2,3-naphthalene dicarboxylic acid, cis-cyclohexane-1,3- dicarboxylic acid, cyclobutene-l,l-dicarboxylic acid, at a temperature of from -20 °C to 100 °C, and separating the compound of formula (c / s-l) by filtration.

19. A process for preparation of compound of formula (IV)wherein,Z is alkyl, halogen, alkoxy, haloalkyl or haloalkoxy;Y is alkyl, alkoxy, halogen, haloalkyl or haloalkoxyR1is C1-C6 alkoxy group;G is hydrogen, carbonyl, alkoxycarbonyl, alkoxy or aryloxy; using a compound of formula (c / s-l) according to any of claims 1-3.

20. A process for preparation of compound of formula (V), i.e., Spirotetramatusing a compound of the formula (c / s-VI)wherein HX is phthalic acid or c / s-cyclohexane-l,3-dicarboxylic acid, prepared by the process according to any one of the preceding claims.

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