RU2775690C2 - Synthesis of trans-8-chlor-5-methyl-1-[4-(pyridine-2-iloxy)-cyclohexyl]-5,6-dihydro-4h-2,3,5,10b-tetraazabenzo[e]azulene and its crystal forms - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention proposes methods for the production of substituted 1-[4-(pyridine-2-iloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenes. A method for the synthesis of a compound of the formula I includes a reaction of a compound of the formula II with a compound of the formula VI.

EFFECT: obtaining 8-chlor-5-methyl-1-[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine in a more economical way, with a smaller number of method stages, under moderate reaction conditions and with a good yield; in addition, unpurified intermediate products can be usually used at following reaction stages without the need for additional purification stages.

7 cl, 23 dwg

Description

Technical field

The present invention provides methods for preparing substituted 1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenes. Also disclosed are compounds useful as intermediates in the methods of the invention.

Prior Art

Autistic spectrum disorders (ASD) are clinically heterogeneous disorders characterized by impairments in socialization and speech. ASD includes a wide range of disorders, including a true inability to make emotional connections, behavioral disorders in social interaction, verbal and non-verbal communication, limited interest in the environment associated with stereotyped movements and repetitive roles (Bourreau et al., 2009) ¹ . Research suggests that a genetic predisposition may be involved, but environmental factors also need to be considered (Bourgeron, 2009) ² . There is currently no effective biological/pharmaceutical treatment for ASD.

1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenes have been previously described in the art ³ .

In addition, WO2004074291 and WO2005068466 ⁴ disclose triazole compounds and a process for their preparation.

Surprisingly, when using the methods of the present invention, 8-chloro-5-methyl-1-[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3 -a][1,4]benzodiazepine and pharmaceutically acceptable salts thereof can be produced more economically with fewer process steps under moderate reaction conditions and in good yield. In addition, crude intermediates can generally be used in subsequent reaction steps without the need for additional purification steps.

In addition, several forms have been identified and, surprisingly, Form F has been found to be the most preferred.

Definitions

The following definitions of the general terms of the present description apply regardless of whether the terms are used alone or in combination with other groups.

The term "room temperature" (RT) refers to a temperature of 18 to 30°C, preferably 20 to 25°C, more preferably 20°C.

"Solution", as used herein, covers liquids in which the reagent or reactant is a solvent in dissolved form (as a solute), or is present partially in undissolved form, or both. Thus, "solution" implies that the solute may not be completely dissolved in it and the solid solute may be present as a dispersion or suspension. Accordingly, "solution" of a particular reagent or reactant includes suspensions and dispersions, as well as solutions of such reagents or reactants. "Solution" or "suspension" may be used interchangeably.

"Solvent" as used herein includes liquids that completely dissolve a reagent or reactant when interacting with a solvent, as well as liquids that only partially dissolve a reagent or reactant, or act as dispersants for a reagent or reactant. Thus, when a particular reaction is carried out in a "solvent", it is assumed that not all of the reagents or reactants are present in dissolved form.

The term "approximately" in combination with 2-theta degrees refers to ±0.2 degrees 2-theta.

The terms "crystalline form" or "form" refer to polymorphs and solvates of the compound.

The term "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with human and animal tissues. Examples of suitable inorganic and organic acids for salt formation include, but are not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid. , p-toluenesulfonic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid, and the like. Formic acid, trifluoroacetic acid and hydrochloric acid are preferred. Most preferred is hydrochloric acid.

The terms “autism spectrum” and “autism spectrum disorders” combine conditions classified as pervasive developmental disorders, which include, but are not limited to, autism, Asperger's syndrome, non-specified pervasive developmental disorder (PDD-NOS), childhood disintegrative disorder, Rett syndrome and fragile X syndrome, in particular autism. These disorders are typically characterized by social impairment, communication difficulties, stereotyped or repetitive behaviors and interests, and delayed cognitive development.

The nomenclature used in this application is based on the IUPAC systematic nomenclature, unless otherwise indicated.

Description of the invention

In detail, the present invention relates to a process for the synthesis of a crystalline form of a compound of formula I

I.

I.

A specific embodiment of the invention relates to crystalline form A of the compound of formula I as described herein, the powder X-ray diffraction pattern of which has characteristic peaks, expressed in 2-theta values, at approximately

Degree 2-theta Degree 2-theta Degree 2-theta 13.0 18.1 21.9 13.5 18.9 23.9 14.5 19.5 27.2 15.9 20.6 17.8 21.0

A specific embodiment of the invention relates to crystalline form A of the compound of formula I as described herein, characterized by the powder x-ray diffraction pattern shown in FIG. one.

A specific embodiment of the invention relates to crystalline form A of the compound of formula I as described herein, characterized by an infrared (IR) spectrum shown in FIG. 2.

A specific embodiment of the invention relates to crystalline form A of the compound of formula I as described above, characterized by the Raman spectrum shown in FIG. 3.

A specific embodiment of the invention relates to crystalline form B of a compound of formula I as described herein, characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in 2-theta values at approximately

Degree 2-theta Degree 2-theta Degree 2-theta 7.5 15.1 20.0 9.9 15.9 21.2 12.4 16.6 24.8 14.3 18.1 25.5

A specific embodiment of the invention relates to crystalline form B of the compound of formula I as described herein, characterized by the powder x-ray diffraction pattern shown in FIG. four.

A specific embodiment of the invention relates to crystalline form B of the compound of formula I as described herein, characterized by the IR spectrum shown in FIG. 5.

A specific embodiment of the invention relates to crystalline form B of the compound of formula I as described herein, characterized by the Raman spectrum shown in FIG. 6.

A specific embodiment of the invention relates to crystalline form B of a compound of formula I as described herein, characterized by the following unit cell parameters

A 12.01Å B 17.91Å C 10.52 Å alpha 90 degrees beta 101.14 degrees gamma 90 degrees

A specific embodiment of the invention relates to crystalline form C of a compound of formula I as described herein, characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in 2-theta values at approximately

Degree 2-theta Degree 2-theta Degree 2-theta 9.0 18.1 20.2 12.6 18.4 20.8 13.7 19.4 22.5 16.6 19.7 23.0

A specific embodiment of the invention relates to crystalline form C of the compound of formula I as described herein, characterized by the powder x-ray diffraction pattern shown in FIG. 7.

A specific embodiment of the invention relates to crystalline form C of the compound of formula I as described herein, characterized by the IR spectrum shown in FIG. eight.

A specific embodiment of the invention relates to crystalline form C of the compound of formula I as described herein, characterized by the Raman spectrum shown in FIG. 9.

A specific embodiment of the invention relates to crystalline form C of the compound of formula I, as described herein, characterized by the following unit cell parameters

A 10.80Å B 18.16 Å C 18.42 Å alpha 108.64 degrees beta 99.57 degrees gamma 106.79 degrees

A specific embodiment of the invention relates to crystalline form D of a compound of formula I as described herein, characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in 2-theta values at approximately

Degree 2-theta Degree 2-theta Degree 2-theta 7.8 15.8 22.6 9.4 18.2 26.3 12.3 19.7 26.9 13.6 20.8 15.2 21.6

A specific embodiment of the invention relates to crystalline form D of a compound of formula I as described herein, characterized by the powder x-ray diffraction pattern shown in FIG. ten.

A specific embodiment of the invention relates to crystalline form D of a compound of formula I as described herein, characterized by the IR spectrum shown in FIG. eleven.

A specific embodiment of the invention relates to crystalline form D of a compound of formula I as described herein, characterized by the Raman spectrum shown in FIG. 12.

A specific embodiment of the invention relates to crystalline form D, characterized by the following parameters

A 11.74 Å B 9.08 Å C 22.93 Å alpha 90 degrees beta 103.84 degrees gamma 90 degrees

A specific embodiment of the invention relates to crystalline form E of a compound of formula I as described herein, characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in 2-theta values at approximately

Degree 2-theta Degree 2-theta Degree 2-theta 9.7 16.7 25.0 12.4 17.8 23.3 14.1 18.1 28.9 15.2 19.7 29.4 15.7 21.1

A specific embodiment of the invention relates to crystalline form E of a compound of formula I as described herein, characterized by the powder x-ray diffraction pattern shown in FIG. 13.

A specific embodiment of the invention relates to crystalline form E of the compound of formula I as described herein, characterized by the IR spectrum shown in FIG. fourteen.

A specific embodiment of the invention relates to crystalline form E of a compound of formula I as described herein, characterized by the Raman spectrum shown in FIG. fifteen.

A specific embodiment of the invention relates to crystalline form F of a compound of formula I as described herein, characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in 2-theta values at approximately

Degree 2-theta Degree 2-theta Degree 2-theta 8.6 15.7 23.0 8.9 17.9 24.0 11.4 19.5 26.5 12.2 20.7 27.0 15.2 22.6

A specific embodiment of the invention relates to crystalline form F of a compound of formula I as described herein, characterized by the powder x-ray diffraction pattern shown in FIG. 16.

A specific embodiment of the invention relates to crystalline form F of a compound of formula I as described in the IR spectrum document shown in FIG. 17.

A specific embodiment of the invention relates to crystalline form F of a compound of formula I as described herein, characterized by the Raman spectrum shown in FIG. eighteen.

A specific embodiment of the invention relates to crystalline form F of compound I, as described herein, characterized by the following unit cell parameters

A 8.98 Å B 11.30 Å C 12.02 Å alpha 117.01 degrees beta 102.48 degrees gamma 94.76 degrees

A specific embodiment of the invention relates to crystalline form G of a compound of formula I as described herein, characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in 2-theta values at approximately

2-theta degrees 2-theta degrees 2-theta degrees 7.4 15.8 21.1 9.8 16.4 22.5 12.3 17.9 24.5 14.1 18.1 25.3 14.9 20.0 29.2

A specific embodiment of the invention relates to crystalline form G of a compound of formula I as described herein, characterized by the X-ray powder diffraction pattern shown in FIG. 19.

A specific embodiment of the invention relates to crystalline form G of a compound of formula I as described herein, characterized by the IR spectrum shown in FIG. twenty.

A specific embodiment of the invention relates to crystalline form G of a compound of formula I as described herein, characterized by the Raman spectrum shown in FIG. 21.

A specific embodiment of the invention relates to a crystalline form G of a compound of formula I as described herein, characterized by the following unit cell parameters

A 12.02 Å B 18.04 Å C 10.29 Å alpha 90 degrees beta 100.63 degrees gamma 90 degrees

A specific embodiment of the invention relates to a crystalline form H of a compound of formula I as described herein, characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in 2-theta values at approximately

2-theta degrees 2-theta degrees 2-theta degrees 12.8 18.6 23.6 14.2 20.8 25.3 17.0 21.2 28.4 17.7 22.2

A specific embodiment of the invention relates to crystalline form H of a compound of formula I as described herein, characterized by the powder x-ray diffraction pattern shown in FIG. 22.

A specific embodiment of the invention relates to crystalline form H of a compound of formula I as described herein, characterized by the Raman spectrum shown in FIG. 23.

A specific embodiment of the invention relates to a crystalline form H of a compound of formula I as described herein, characterized by the following unit cell parameters:

A 22.76 Å B 8.52 Å C 12.55 Å alpha 90 degrees beta 99.18 degrees gamma 90 degrees

A specific embodiment of the invention relates to a process for transforming Form A into Form F.

.

.

A specific embodiment of the invention relates to the trihydrate of a compound of formula I.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising reacting a compound of formula II with a compound of formula VI

.

.

The amidine free base II can be thermally reacted with a compound of formula VI to form a compound of formula I. The presence of an acid increases the reactivity and purity of the crude active pharmaceutical ingredient. This is usually achieved by using amidine-bis-hydrochloride III as a substrate. III can be isolated as a crystalline intermediate, thus providing a fine point in this synthesis.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising reacting a compound of formula III with a compound of formula VI.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising reacting a compound of formula III with a compound of formula VI, whereby they react thermally, in particular at a temperature of 95°C plus/minus 35°C, in particular 85 °C plus/minus 15°C, in particular 80°C plus/minus 5°C. Specific temperatures are 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C and 85°C.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising the reaction of a compound of formula III with a compound of formula VI in an organic solvent such as THF, dioxane, DMF, NMP, acetonitrile and alcohols, in particular in an alcohol solvent, such as ethanol, n-propanol, isopropanol, n-butanol, especially isopropanol and n-propanol, isopropanol is most preferred. Compound I can be directly isolated as the hydrochloride by filtration when the reaction is carried out in a suitable solvent such as isopropanol. Alternatively, I as a free base can be isolated by adding an aqueous base such as aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium bicarbonate, aqueous potassium bicarbonate, aqueous sodium carbonate, aqueous potassium carbonate, in particular aqueous sodium hydroxide, aqueous potassium hydroxide especially aqueous sodium hydroxide. Compound I is then isolated as a trihydrate (form H) which changes to anhydrous form A after drying.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising reacting a compound of formula II with a compound of formula VI, wherein the free base of product I is isolated at a pH greater than 8, in particular a pH greater than 10, in particular a pH over 12.

A specific embodiment of the invention relates to the isolation of the free base of product I at a pH greater than 8, in particular a pH greater than 10, in particular a pH greater than 12, using an appropriate solvent mixture, such as an alcohol/water mixture, in particular ethanol/water, isopropanol/water , n-propanol/water, in particular isopropanol/water, free from the unwanted side product 4-(2-pyridyloxy)-N'-[4-(2-pyridyloxy)cyclohexanecarbonyl]cyclohexanecarbonhydrazide (VI').

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein comprising reacting a compound of formula II with a compound of formula VI wherein 4-(2-pyridyloxy)-N'-[4-(2-pyridyloxy)cyclohexanecarbonyl] cyclohexane-carbohydrazide VI' is a by-product.

VI'.

VI'.

A specific embodiment of the invention relates to a process as described above, further comprising converting a compound of formula XI or its hydrochloride salt to a compound of formula III:

.

.

A specific embodiment of the invention relates to a process as described above, further comprising converting a compound of formula X to a compound of formula XI via the following steps:

The compound of formula XI may be isolated as the bis-hydrochloride. Alternatively, it can be prepared in-situ and directly further converted into a compound of formula III.

A specific embodiment of the invention relates to a process as described above, further comprising converting a compound of formula X to a compound of formula III via the following steps:

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I comprising the following steps:

The aldehyde of formula XXV is described in the prior art (Aubé et al.) ⁵ and was obtained by ortho-lithiation with sec-butyllithium (s-BuLi) at -78°C, then raising the temperature to -20°C before quenching with DMF. The product was obtained in 54% yield after chromatography. The present reaction is carried out at a higher temperature (up to -30° C.) and with n-butyllithium (n-BuLi) in higher yields in excess of 80% without chromatography and after crystallization. The method described in this document is much more efficient and scalable.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula XXV from a compound of formula X, wherein the lithiation is carried out in tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-Me-THF) or methyl tert-butyl ether (MTBE), in particular THF and MTBE, in particular MTBE.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula XXV from a compound of formula X, wherein the lithiation is carried out at a temperature of from -60°C to -10°C, in particular from -40°C to -20°C, in particular at - 30 plus/minus 2°C.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula XXV from a compound of formula X, wherein the lithiation is carried out in the presence of an additive like (but not limited to) tetramethylethylenediamine (TMEDA) or pentamethyldiethylenetriamine (PMDTA), in particular TMEDA.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula XXV from a compound of formula X, wherein the lithiation is carried out with n-butyllithium, n-hexyllithium or sec-butyllithium, in particular n-butyllithium.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula XXV from a compound of formula X, wherein lithiation is carried out with n-BuLi, in the presence of tetramethylethylenediamine (TMEDA) in MTBE and at -30 plus/minus 2°C.

The compound of formula XXV can be isolated as a crystalline intermediate and then converted in a second step to an imine of formula IX. Crystallization can be carried out, for example, in ethanol or isopropanol.

Alternatively, the crude extract of compound XXV can be introduced into the imine formation step by changing the solvent to the desired solvent, followed by imine formation and isolation of the compound of formula IX.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula XXV to a compound of formula IX, wherein the imine formation is carried out in an alcohol such as methanol, ethanol, isopropanol or n-propanol, in particular in ethanol or methanol or their mixtures.

The imine of formula IX is isolated as a crystalline intermediate by direct crystallization from the reaction mixture. Imine crystallization has been found to provide a very efficient purification point in the synthesis.

The imine of formula IX can be reduced by catalytic hydrogenation to provide an intermediate of formula VIII.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, wherein the reduction is carried out with hydrogen in the presence of a catalyst such as platinum on carbon (Pt/C), in particular hydrogen and Pt/C in methanol.

A specific embodiment of the invention relates to a process as described above, comprising the reduction of a compound of formula IX to a compound of formula VIII, wherein the reduction is carried out with hydrogen over Pt/C at a temperature between 15°C and 50°C, in particular between 20 and 30° C, in particular between 20 and 25°C.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, in which reduction is carried out with hydrogen over Pt/C at a pressure between 1 and 10 bar (between 100,000 and 1,000,000 Pa), in particular at 5 bar (500000 Pa).

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, wherein the reduction is carried out with hydrogen over Pt/C in methanol at a pressure of 5 bar (500,000 Pa) and room temperature.

Alternatively, an imine of formula IX can be reduced to an intermediate of formula VIII by the use of sodium borohydride.

Although the reduction is carried out in an aprotic solvent such as THF in the presence of a carboxylic acid (acetic acid, caproic acid, 2-ethylhexanoic acid and pivalic acid, in particular acetic acid and pivalic acid), better results can be obtained in protic organic solvents such as methanol or ethanol, in particular methanol.

Carrying out the reaction in a homogeneous reaction system like THF/methanol mixtures and in the presence of methylamine as an additive minimizes the formation of the next 2 main by-products of dimer 1 and dimer 2.

The homogeneous system maximizes the concentration of the Formula IX imine in solution, thus increasing the rate of productive reduction vs. dimer formation. Because the imine substrate has a medium to low solubility in methanol, an additive such as, for example, THF is used to provide a clear solution before dosing the reductant.

The presence of methylamine competes with the formula VIII product when reacting with the formula IX imine substrate, thus reducing the amount of dimer 1 and/or dimer 2 by-products.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, in which reduction is carried out using sodium borohydride in a mixture of THF and methanol, in particular with a sufficient amount of methanol to ensure reactivity, and a sufficient amount of THF to ensure the solubility of the imine substrate.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, wherein the reduction is carried out with sodium borohydride in methanol or a mixture of THF and methanol, in particular a mixture of THF and methanol, in particular a mixture of methanol and THF 2:1.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, in which reduction with sodium borohydride is carried out in the presence of a carboxylic acid, such as (but not limited to) acetic acid or pivalic acid, in particular in the presence of acetic acid.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, wherein the reduction with sodium borohydride is carried out in the presence of methylamine. A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, wherein the reduction with sodium borohydride is carried out in methanol/THF 2:1, in the presence of acetic acid and methylamine.

A specific embodiment of the invention relates to a process comprising the reduction of an imine of formula IX to an intermediate of formula VIII, in which dimer 1 and dimer 2 are formed as by-products in amounts of less than 1%. Intermediate VIII can be isolated by crystallization, eg from a mixture of iPrOH and water, or as a salt, eg its acetic acid salt.

Extraction of the crude product of formula VIII (from the sodium borohydride reduction step) in an aqueous phase at an acidic pH (for example, but not limited to pH 4 to 6), followed by washing out impurities with an organic solvent, followed by extraction of the product into an organic solvent at Neutral to basic pH gives a product of very high purity. The extract can then be introduced into the next step (alkylation) without the need for crystallization and drying steps.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula IX to a compound of formula VIII, in which the purification of the crude intermediate compound of the formula is carried out by extractive treatment, in particular acid extraction of the product in the aqueous phase, followed by washing with an organic solvent, with subsequent extraction of the product with an organic solvent at a pH from neutral to basic.

Alkylation of a compound of formula VIII to obtain a compound of formula VII can be carried out with chloro-, bromo-, or iodo-acetonitrile. The reactivity of chloroacetonitrile can be increased by using a source of bromide or iodide, such as, for example, potassium iodide or bromide.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula VIII to a compound of formula VII, in which the alkylation is carried out with chloroacetonitrile, in particular chloroacetonitrile in the presence of potassium iodide or potassium bromide, in particular with chloroacetonitrile in the presence of potassium iodide.

Although alkylation can be carried out in polar aprotic solvents like DMF, NMP, DMA or DMSO, alternative solvents are preferred for better handling of all types of waste. Suitable solvents include THF, 2-Me-THF, acetone, toluene, acetonitrile or ethyl acetate. For kinetic reasons, in particular acetonitrile, acetone and ethyl acetate, in particular ethyl acetate, are used.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula VIII to a compound of formula VII, wherein the alkylation is carried out with chloroacetonitrile and potassium iodide, in acetone, acetonitrile or ethyl acetate, in particular ethyl acetate. Ethyl acetate has the additional advantage of allowing direct extraction isolation without changing the solvent prior to extraction or using an additional phase separating solvent.

A specific embodiment of the invention relates to a process as described above, comprising converting a compound of formula VIII to a compound of formula VII, wherein the alkylation is carried out with chloroacetonitrile in the presence of a suitable base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, cesium hydrogen carbonate or cesium carbonate, in particular with sodium hydrogen carbonate or potassium hydrogen carbonate, in particular with sodium hydrogen carbonate.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula VIII to a compound of formula VII, in which the alkylation is carried out with chloroacetonitrile, in ethyl acetate under reflux, in the presence of iodide and sodium hydrogen carbonate as a base.

The product of formula VII can be isolated by crystallization, for example, in isopropanol or ethanol/water mixtures.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula VII to a compound of formula III, wherein the reaction is carried out in the presence of an excess of HCl, in an alcohol such as methanol, ethanol, trifluoroethanol, isopropanol, in particular isopropanol or trifluoroethanol, in in particular isopropanol, or in an alcohol/dichloromethane mixture, in particular trifluoroethanol/dichloromethane (for the use of trifluoroethanol as a solvent for the preparation of amidines from nitrile, see Caron et al.⁶).

A specific embodiment of the invention relates to a process as described above comprising the conversion of a compound of formula VII to a compound of formula III, wherein the compound of formula VII is converted to a compound of formula XI. 2 HCl, which is not isolated but subsequently converted in situ to a compound of formula III.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula VII to a compound of formula III, which forms alkyl-2-[(2-amino-5-chloro-phenyl)methyl-methyl-amino]acetate, the corresponding by-products products based on imidate or orthoester, using the RO moiety coming from the alcohol.

Compared to the use of linear alcohols like ethanol, the amount of these side products (III', III'', III''') is reduced by the use of less nucleophilic alcohols like isopropanol or trifluoroethanol. Isopropanol is a new and cheaper alternative to trifluoroethanol.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula VII to a compound of formula III, wherein the reaction is carried out in the presence of an excess of HCl, in isopropanol.

A specific embodiment of the invention relates to a process as described above, comprising converting a compound of formula VII to a compound of formula III, wherein the starting material is dosed into solution, followed by deprotection of the Boc groups in the compound of formula XI (as hydrochloride salt) in a manner that allows control outgoing CO ₂ .

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I further comprising converting a compound of formula X to a compound of formula XI via the following steps:

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I comprising the following steps:

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I further comprising converting a compound of formula XV to a compound of formula XI via the following steps:

.

.

The compound of formula XII may also be isolated as the hydrochloride salt.

The conversion of a compound of formula XV to a compound of formula XII was based on WO2005/68466 ⁷ .

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I comprising the following steps:

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I further comprising converting a compound of formula XVI to a compound of formula XI via the following steps:

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I comprising the following steps:

A specific embodiment of the invention relates to the synthesis of a compound of formula I comprising the conversion of a compound of formula XXVI to a compound of formula XI through the following steps:

.

.

The compound of formula XII is described in the prior art by Venkov et al. ⁸ as an intermediate, which was not isolated and used directly in the subsequent reaction.

A specific embodiment of the invention relates to a process as described above, comprising converting a compound of formula XXVI to a compound of formula XII, wherein the compound of formula XII is isolated from the reaction mixture.

A specific embodiment of the invention relates to a process as described above, comprising the conversion of a compound of formula XXVI to a compound of formula XI, wherein the reductive amination and alkylation step are performed in the same vessel.

A specific embodiment of the invention relates to intermediate compound XI.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I comprising the following steps:

.

.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising the following steps:

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising converting a compound of formula XXIII to a compound of formula VI by aromatic nucleophilic substitution of 2-halopyridine with 4-hydroxycyclohexanecarboxylic acid.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising converting a compound of formula XXIV to a compound of formula XXIII, which can use bases such as sodium t-amyl alcoholate (tAmONa), potassium t-amyl alcoholate (tAmOK) , sodium tert-butoxide (tBuONa), potassium tert-butoxide (tBuOK), in particular tAmONa.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising the conversion of a compound of formula XXIV to a compound of formula XXIII, in which the solvent is N-methyl-2-pyrrolidone (NMP) or dimethylacetamide (DMA), in particular NMP.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising the conversion of a compound of formula XXIV to a compound of formula XXIII, in which the reaction is carried out at a temperature of from 80 to 120°C, in particular from 88 to 92°C.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising converting a compound of formula XXIV to a compound of formula XXIII, wherein the 2-halopyridines are selected from 2-fluoropyridine and 2-chloropyridine, in particular 2-chloropyridine.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein comprising converting a compound of formula XXIV to a compound of formula XXIII wherein the compound of formula XXIV is reacted with 2-chloropyridine in NMP in the presence of t-amyl oxide at a temperature of 85 to 95 °C

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising converting a compound of formula XXIII to a compound of formula VI, wherein XXIII is activated by reaction with a suitable alkyl chloroformate such as isobutyl, ethyl or methyl chloroformate, in particular isobutyl chloroformate.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein comprising converting a compound of formula XXIII to a compound of formula VI wherein XXIII is activated with a suitable alkyl chloroformate in the presence of a suitable base such as triethylamine, Hoenig's base, pyridine, collidine or N-methylmorpholine, in particular N-methylmorpholine.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising converting a compound of formula XXIII to a compound of formula VI, wherein XXIII is activated with carbonyldiimidazole (CDI) to provide the corresponding acylimidazole intermediate, which is then reacted with hydrazine.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising the conversion of a compound of formula XXIII to a compound of formula VI, in which the reaction is carried out in a suitable solvent such as DMF, NMP, THF, 2-MeTHF, in particular THF .

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising the conversion of a compound of formula XXIII to a compound of formula VI, in which the activation of CDI is carried out at a temperature of from 10°C to 50°C, preferably from 20°C to 30 °C, more preferably at 25°C.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I as described herein, comprising converting a compound of formula XXIII to a compound of formula VI, in which the acylimidazole intermediate is then reacted with hydrazine, in particular an excess of hydrazine is used, more preferably at least 2- multiple excess of CDI at the activation stage.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising converting a compound of formula XXIII to a compound of formula VI, wherein the order of addition is to add the activated acid to the hydrazine.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising converting a compound of formula XXIII to a compound of formula VI, wherein the acylimidazole reaction mixture can be degassed after activation and prior to reaction with hydrazine to remove dissolved CO ₂ .

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising converting a compound of formula XXIII to a compound of formula VI, wherein 4-(2-pyridyloxy)-N'-[4-(2 -pyridyloxy)cyclohexanecarbonyl]cyclohexane-carbohydrazide (VI').

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I comprising the following steps:

Specific oxadiazole precursors are described in the prior art ⁹ .

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I as described herein, comprising the following steps:

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I comprising the following steps:

.

.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I, in which, as an intermediate, a compound of formula INT, its tautomer or salt is formed:

INT.

INT.

A specific embodiment of the invention relates to an INT intermediate, tautomer or salt thereof. A specific embodiment of the invention relates to an INT intermediate.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula I, wherein the compound of formula III is formed as an intermediate.

A specific embodiment of the invention relates to intermediate II, its tautomer or salt:

II: свободное основание, III: 2HCl.

II: free base, III: 2HCl.

A specific embodiment of the invention relates to intermediate II or a salt thereof.

A specific embodiment of the invention relates to intermediate compound III.

A specific embodiment of the invention relates to a process for the synthesis of a compound of formula VI.

.

.

A specific embodiment of the invention relates to a process for synthesizing a compound of formula I comprising the following steps:

.

.

A specific embodiment of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, in all cases obtained by the method described in this document.

A specific embodiment of the invention relates to a compound of formula I, as described herein, for use as a drug.

A specific embodiment of the invention relates to a compound of formula I, as described herein, for use in the therapeutic and/or prophylactic treatment of inappropriate vasopressin secretion, anxiety, depressive disorders, obsessive-compulsive disorder, autistic disorders, schizophrenia, aggressive behavior and disorders associated with sleep phase shift, in particular desynchronosis.

Brief description of graphic materials

Fourier transform infrared spectroscopy (FTIR) data were collected in suspension in paraffin oil, so that additional peaks are visible in the IR region due to the mineral oil dispersant.

Fig. 1: X-ray powder diffraction pattern of form A.

Fig. 2: IR spectrum of form A.

Fig. 3: Raman spectrum of form A.

Fig. 4: X-ray powder diffraction pattern of Form B.

Fig. 5: IR spectrum of form B.

Fig. 6: Raman spectrum of form B.

Fig. 7: X-ray powder diffraction pattern of form C.

Fig. 8: IR spectrum of form C.

Fig. 9: Raman spectrum of form C.

Fig. 10: Form D X-ray powder diffraction pattern.

Fig. 11: Form D IR spectrum.

Fig. 12: Raman spectrum of form D.

Fig. 13: X-ray powder diffraction pattern of form E.

Fig. 14: IR spectrum of form E.

Fig. 15: Raman spectrum of form E.

Fig. 16: X-ray powder diffraction pattern of Form F.

Fig. 17: IR spectrum of form F.

Figure 18: Raman spectrum of form F.

Fig. 19: X-ray powder diffraction pattern of form G.

Fig. 20: IR spectrum of form G.

Fig. 21: Raman spectrum of form G.

Fig. 22: X-ray powder diffraction pattern of form H.

Fig. 23: Raman spectrum of form H.

experimental part

The following experiments are given as illustrations of the invention. They should not be considered as limiting the scope of the invention, but only as an illustration of it.

Form A of Compound I

100 mg of I was dissolved in a closed vessel at 22° C. in 5.0 ml of ethanol/water 1:1 (v/v). After dissolution, the solution was filtered through a 0.45 µm filter. Then the clear solution was evaporated at 22°C for 10 days. After complete evaporation, the product was dried (50°C/less than 20 mbar (2000 Pa) for more than 24 h) and analyzed.

Form B compound I

100 mg of compound I was dissolved in a closed vessel at 22°C in 3.0 ml of ethyl acetate. After dissolution, the solution was filtered through a 0.45 µm filter. Then the clear solution was evaporated at 22°C for 10 days. The experiment produced single crystals of Form B suitable for single crystal structure analysis. After complete evaporation, the product was dried (50°C/less than 20 mbar (2000 Pa) for more than 24 h) and analyzed.

Form C compound I

100 mg of I was dissolved in a closed vessel at 22° C. in 1.4 ml of a mixture of water saturated with butanol (approximately 20% v/v). After dissolution, the solution was filtered through a 0.45 µm filter. Then the clear solution was evaporated at 22°C for 1 month. The experiment produced Form C single crystals suitable for single crystal structure analysis. After complete evaporation, the product was dried (50°C/less than 20 mbar (2000 Pa) for more than 24 h) and analyzed.

Form D (p-xylene hemisolvate) of compound I

100 mg of compound I were suspended in a closed vessel at 22°C in 0.35 ml of p-xylene and left to stir at 60°C. After 14 days of equilibration at 60°C, the suspension was filtered and the product was dried (50°C/less than 20 mbar (2000 Pa) for more than 24 h) and analyzed. Evaporation of the filtrate (3 days at 22° C.) gave Form D single crystals suitable for single crystal structure analysis.

Form E (acetic acid hemisolvate) of compound I

100 mg of compound I was dissolved in a closed vessel at 22° C. in 0.4 ml of acetic acid. After dissolution, the solution was filtered through a 0.45 µm filter. Then the clear solution was evaporated at 22°C for 14 days. The experiment produced an oily residue which turned to powder after scraping with a spatula. The product was dried (50°C/less than 20 mbar (2000 Pa) for more than 24 h) and analyzed.

Form F compound I

100 mg of form B was suspended in a closed vessel at 22°C in 0.3 ml of isopropanol and stirred at 22°C. After one day stirring, 10 mg of API/Form C was added and the suspension was stirred at 22°C. After 14 days of equilibration at 22°C, the suspension was filtered, the product was dried (50°C/less than 20 mbar (2000 Pa) for more than 24 h) and analyzed.

Form G (butyronitrile solvate) of compound I

100 mg of compound I was dissolved in a closed vessel at 22° C. in 1.5 ml of butyronitrile. Immediately after dissolution, the solution began to precipitate upon stirring. The suspension was partially evaporated, while continuing to stir, at 22°C for 10 days. After partial evaporation (approximately 50%), the suspension was filtered, the product was dried (50°C/less than 20 mbar (2000 Pa) for more than 24 h) and analyzed. Evaporation of the filtrate (2 weeks at 22° C.) gave form G single crystals suitable for single crystal structure analysis.

Form H (trihydrate) of compound I

100 mg of compound I was dissolved in 1.9 ml of ethanol/water 1:1 (v/v) at 65°C in a closed vessel. The clear solution was linearly cooled from 65° C. to -20° C. over 8 hours without stirring. The experiment produced Form H single crystals suitable for single crystal structure analysis. The product was isolated by removing the mother liquor with a pipette and analyzed wet.

Tert-butyl-N-(4-chloro-2-formylphenyl)carbamate XXV

tert-Butyl-4-chlorophenylcarbamate (40 g, 175 mmol, Eq: 1.00) was dissolved in THF (248 g, 280 ml). The solution was cooled to -30°C. N,N,N',N'-tetramethylethylenediamine (44.5 g, 57.8 ml, 379 mmol, Eq: 2.17) was added dropwise. After 5 minutes, n-butyl lithium 2.5 M in hexane (210 ml, 524 mmol, Eq: 3.00) was added dropwise over 60 minutes at -30°C to -20°C. After 5 hours at -30° DMF (38.4 g, 40.5 ml, 524 mmol, Eq: 3.00) was added over 35 minutes. After 1 h at -30°C, cold (0 to 5°C) methyl tert-butyl ether (MTBE) (207 g, 280 ml) (0°C) was added. 25% aqueous hydrogen chloride (HCl) (178 g, 149 ml, 1.22 mol, Eq: 7.0) was added over 30 min at -30° to 0°C. The aqueous phase was separated and extracted with MTBE (74.0 g, 100 ml). The organic phases were washed successively with 10% aqueous sodium chloride (NaCl) (100 ml), 5% aqueous sodium hydrogen carbonate (NaHCO ₃ ) (100 ml) and half-saturated aqueous NaCl (100 ml). The organic phases were combined, dried over magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure (40°C/ reduced to 10 mbar (1000 Pa)) to obtain 45.2 g of the crude product. The crude product was dissolved in 2-propanol (157 g, 200 ml) at 80°C. The clear solution was slowly cooled to 0°C, during which time the product began to crystallize. The suspension was stirred for 1 h at 0°C and filtered. The filter cake was washed with cold (0 to 5° C.) 2-propanol (15.7 g, 20 ml), dried at 50° C./10 mbar (1000 Pa) to give 38.8 g of the title compound.

tert-Butyl-N-[4-chloro-2-[(E)-methyliminomethyl]phenyl]carbamate IX

MTBE method

N-Boc-4-chloroaniline (121 g, 531 mmol, Eq: 1.00) was dissolved in MTBE (648 g, 875 ml). The solution was cooled to -25°C. TMEDA (tetramethylethylenediamine) (72 g, 92.9 ml, 620 mmol, Eq: 1.17) was added. 2.5 M n-butyllithium (BuLi) in hexane (398 g, 572 ml, 1.43 mol, Eq: 2.69) was added after 70 min keeping the temperature below -20°C. After 2.5 hours, dimethylformamide (DMF) (113 g, 120 ml, 1.55 mol, Eq: 2.91) was added over 30-45 minutes maintaining the temperature between -30°C and -20°C. After 1 h, 25% aqueous HCl (526 g, 470 ml, 3.61 mol, Eq: 6.79) was added at such a rate that the internal temperature was maintained between -30°C and 0°C. The reaction mixture was warmed to room temperature (RT) for 30 min. The aqueous phase was separated and extracted with MTBE (333 g, 450 ml). The organic phases were combined and washed successively with saturated aqueous NaCl (600 ml), 10% aqueous NaHCO ₃ (600 ml) and aqueous NaCl (600 ml). The organic phase was concentrated to approximately 550 ml and the MTBE solvent was changed to ethanol (EtOH) at constant volume (Tj max 55°C). The crude aldehyde suspension was diluted with EtOH (250 ml). 33% methylamine in EtOH (150 g, 1.59 mol, Eq: 3) was added and the reaction mixture was stirred for more than 2 h at 25° C. (until less than 2% aldehyde remained, IPC). If necessary, the reaction mixture was seeded at 20°C. The resulting suspension was cooled for 1 h to -10°C. After 3 hours at -10°C, the suspension was filtered. The filter cake was washed with cold (approximately -10° C.) EtOH and dried at 60° C./5 mbar (500 Pa) to give 109 g of the title compound as light yellow crystals.

THF method

Alternatively, tert-butyl-4-chlorophenylcarbamate (120 g, 511 mmol, Eq: 1.00) was dissolved in tetrahydrofuran (THF) (745 g, 840 ml). The solution was cooled to -30°C. N,N,N',N'-tetramethylethylenediamine (129 g, 168 ml, 1.1 mol, Eq: 2.15) was added. N-butyl lithium 2.5 M in hexane (613 ml, 1.53 mol, Eq: 3.00) was added over 60 min at a temperature between -30°C and -20°C. After 5 hours at -30°C, DMF (112 g, 118 ml, 1.53 mol, Eq: 3.00) was added over 45 minutes at a temperature between -30° and -20°C. 25% HCl (522 g, 435 ml, 3.58 mol, Eq: 7.0) was added over 30 min at −30° C. to 0° C. (pH 4 to 5). The aqueous phase was separated and extracted with a mixture of THF (106 g, 120 ml) and hexane (79.1 g, 120 ml). The organic phases were washed successively with half-saturated aq. NaCl (240 ml), 5% aq. NaHCO ₃ (240 ml) and half-saturated aq. NaCl (240 ml). The organic phases were combined and concentrated to approximately 300 ml and divided into two parts.

Part 1 was diluted with THF (887 g, 1 L) and azeotroped at 45° C./400 mbar (40,000 Pa). The solution was the solvent, changed to methanol to give 285 g of a yellow suspension (residual water: 0.14%). 9.8 M methylamine in methanol (36.5 ml, 358 mmol, Eq: 1.4 relative to theoretical aldehyde content) was added. A clear yellow solution was obtained. After 15 min, the imine began to crystallize (if no spontaneous crystallization was observed, seeding was introduced). After 2 hours at 20 to 25°C, the suspension was stirred for 1 hour at 40°C, cooled to -10°C for 1 hour and filtered. The filter cake was washed with cold (-10° C.) methanol (47.5 g, 60 ml) and dried at 40° C. under reduced pressure to give 57 g of the title compound as a light yellow powder.

Part 2 was azeotroped and the solvent changed to ethanol at 45°C / 200 mbar (20000 Pa) to obtain 281 g of a yellow suspension (water: less than 0.1%). 9.8 M methylamine in methanol (36.5 ml, 358 mmol, Eq: 1.4 to theoretical aldehyde content) was added at RT. After 4 h at RT and 1 h at -10° C., the suspension was filtered. The filter cake was washed with cold (-10° C.) ethanol (47.4 g, 60 ml) and dried at 40° C. under reduced pressure to give 51.5 g of the title compound as a yellow powder.

tert-Butyl-N-[4-chloro-2-[(E)-methyliminomethyl]phenyl]carbamate IX

tert-Butyl-4-chloro-2-formylphenylcarbamate (38 g, 149 mmol, Eq: 1.00) was suspended in methanol (195 g, 247 ml). A 9.8 M solution of methylamine in methanol (21.2 ml, 208 mmol, Eq: 1.40) was added over 30 minutes at RT. The reaction mixture was stirred for 1 h and the resulting solution was cooled to -10°C (at approximately 0°C the product began to spontaneously crystallize). After 2 hours at -10°C, the suspension was filtered. The filter cake was washed with cold (-10° C.) methanol (15.0 g, 19.0 ml) and dried under reduced pressure (10 mbar (1000 Pa) /50° C.) to give 36.4 g of the title compound as white crystalline powder.

tert-Butyl-N-[4-chloro-2-(methylaminomethyl)phenyl]carbamate VIII

tert-Butyl N-[4-chloro-2-[(E)-methyliminomethyl]phenyl]carbamate (50 g, 184 mmol, Eq: 1.00) was dissolved in a mixture of methanol (253 g, 320 ml) and THF ( 142 g, 160 ml). The solution was cooled to RT. A 40% solution of methylamine in methanol (MeOH) (14.4 g, 185 mmol, Eq: 1.01) was added followed by acetic acid (AcOH) (22.0 g, 21.0 ml, 365 mmol, Eq: 1 .98). Venpure 20-20 (sodium borohydride (NaBH ₄ ) 20% / sodium hydroxide (NaOH) 20% in water, 35 g, 28.8 ml, 185 mmol, Eq: 1.00) was added at 0°C for 45- 60 min. After 30 minutes, acetone (21.4 g, 27.0 ml, 366 mmol, Eq: 1.99) was added over 30 minutes at 0°C. After more than 0.5 h at 0°C, the reaction mixture was added to a mixture consisting of 5% aqueous Na ₂ CO ₃ (500 ml), half-saturated aqueous NaCl (125 ml) and MTBE (370 g, 500 ml). The organic phase was separated and washed with 10% aqueous NaCl (210 g, 200 ml). The organic phase was extracted twice with a mixture of 9 ml of formic acid in 0.5 l of water. The aqueous phases were combined and washed twice with MTBE (370 g, 500 ml). The organic phases were removed. MTBE (0.5 L) was added and the pH was adjusted to 12-13 by adding 32% aqueous NaOH (41.9 g, 31 ml, 335 mmol, Eq: 1.82). The aqueous phase was separated and extracted with MTBE (250 ml). The organic phases were combined and washed with saturated aqueous NaHCO ₃ (209 g, 200 ml) and 10% aqueous NaCl (210 g, 200 ml) (pH 7-8). The crude product solution was concentrated to approximately half volume (KFT less than 0.5% water). The crude product mixture was filtered to remove salts. The solution was concentrated under reduced pressure to give 51 g of the crude product (greater than 99.5 abs.% according to high performance liquid chromatography (HPLC), contains approximately 8% residual MTBE). In the crude product solution, the solvent was changed to ethyl acetate (AcOEt) and introduced into the next step without further purification.

The product can be recrystallized from isopropanol (iPrOH)/water:

1.0 g of tert-butyl-N-[4-chloro-2-(methylaminomethyl)phenyl]carbamate was dissolved at 40° C. in 2-propanol (3.92 g, 5 ml). The clear solution was cooled to RT and water (3.00 g, 3 ml) was added. The solution was seeded (the crude dried product slowly crystallized on standing to give the first seed crystals) and crystallization slowly began. After 30 minutes, water (7.00 g, 7 ml) was added dropwise over 10 minutes. The white suspension was stirred for 1 h at RT and filtered. The filter cake was washed with water and dried at 40° C./5 mbar (500 Pa) to give 1 g of product as white crystals. Alternatively, tert-butyl N-[4-chloro-2-[(E)-methyliminomethyl]phenyl]carbamate (2 g, 7.29 mmol, Eq.: 1) was suspended in methanol (20 ml). Pt/C 5% (185 mg) was added, the mixture was purged with hydrogen (5 bar (500,000 Pa)) and stirred at RT. After completion of the reaction, the catalyst was filtered off and the solution was concentrated under reduced pressure to obtain 1.85 g of crude tert-butyl N-[4-chloro2-(methylaminomethyl)phenyl]carbamate. The title compound was crystallized as described above.

tert-Butyl-N-[4-chloro-2-[[cyanomethyl(methyl)amino]methyl]phenyl]carbamate VII

tert-Butyl-N-[4-chloro-2-(methylaminomethyl)phenyl]carbamate (49.9 g, 184 mmol, Eq: 1.00) was dissolved in AcOEt (226 g, 250 ml). Sodium bicarbonate (16.6 g, 198 mmol, Eq: 1.07) and potassium iodide (KI) (6 g, 36.0 mmol, Eq: 0.196) were added in one batch. 2-Chloroacetonitrile (15.4 g, 13.0 mL, 200 mmol, Eq: 1.09) was added in one portion and the reaction mixture was heated at reflux for 15 h (less than 2% starting material). The reaction mixture was cooled to RT. 10% aqueous NaCl (262 g, 250 ml) was added. The organic phase was separated and washed with semi-saturated aqueous NaHCO ₃ (261 g, 250 ml). The organic phase was stirred overnight with 10% aqueous sodium thiosulfate (291 g, 250 ml, 184 mmol, Eq: 1.00) and tetrabutylammonium chloride (1 g, 3.6 mmol, Eq: 0.02). The organic phase was separated and washed with 10% aqueous NaCl (262 g, 250 ml). The organic phase was concentrated to approximately half the volume and filtered. The volume was adjusted to approximately 200 ml with EtOH and the solvent in the solution was changed to EtOH at constant volume. The solution was cooled to approximately 28-30° C. and seeded. After 30 minutes the suspension was cooled to RT and water (40 ml) was added dropwise. The suspension was stirred overnight at RT and 2 h at 0 to 5°C. The suspension was filtered. The filter cake was washed with EtOH/water 1:1 (100 ml) and dried at 60° C./5 mbar (500 Pa) to give 46.8 g of the title compound as white crystals.

tert-butyl-N-[4-chloro-2-[[cyanomethyl(methyl)amino]methyl]phenyl]-carbamate VI

tert-Butyl-4-chloro-2-((methylamino)methyl)phenylcarbamate (9.0 g, 31.6 mmol, Eq: 1.00) was dissolved in ethyl acetate (40.6 g, 45.0 ml). Sodium bicarbonate (3.18 g, 37.9 mmol, Eq: 1.2) was added followed by potassium iodide (1.06 g, 6.34 mmol, Eq: 0.201). 2-Chloroacetonitrile (2.92 g, 2.46 ml, 37.9 mmol, Eq: 1.2) was added and the suspension heated to 78° C. (80° C. oil bath) and stirred overnight. The reaction mixture was cooled to RT and water (22.5 g, 22.5 ml) was added. The organic phase was separated and washed with half-saturated aqueous NaHCO ₃ (22.5 ml), 10% aqueous sodium thiosulfate solution (22.5 ml) and water (22.5 g, 22.5 ml). The organic phase was concentrated under reduced pressure (45° C./180 mbar (18000 Pa), approximately 50 ml) to approximately half the volume. The solvent in the crude product solution was changed to 2-propanol (final volume approx. 30 ml). The 2-propanol solution was seeded and stirred for 1 h at RT, then the white suspension was cooled to a temperature of 0°-2°C, stirred for another hour and filtered through a glass-ceramic funnel. The crystals were washed with cold 2-propanol (7.84 g, 10 ml) and dried to constant weight (5 mbar (500 Pa)/50° C.) to give 8.8 g of the title compound as a white crystalline powder.

7-chloro-4-methyl-3,5-dihydro-1,4-benzodiazepine-2-amine dihydrochloride III

2-propanol (312 g, 400 ml) was loaded into the reactor at a temperature of from 20 to 25°C. Acetyl chloride (AcCl) (255 g, 231 ml, 3.22 mol, Eq: 9.97) was added dropwise over 45 minutes. After 15 minutes, a warm (45-55°C) solution of tert-butyl-N-[4-chloro-2-[[cyanomethyl(methyl)amino]methyl]phenyl]carbamate in 2-propanol (468 g, 600 ml) was added for 45-60 minutes, maintaining the temperature in the range from 20 to 40°C, during which most of the Boc-protective groups are removed and the cyclization step begins. After 2 hours at 40°C, AcCl (127 g, 115 ml, 1.6 mol, Eq: 4.97) was added dropwise at 35 to 40°C. After 4 hours at 40°C, AcCl (127 g, 115 ml, 1.6 mol, Eq: 4.97) was added at 35 to 40°C. The suspension was stirred overnight at 40°C. The reaction mixture was concentrated at Tj=60°C, under reduced pressure to a volume of approximately 400 ml. The solvent in the slurry was replaced at constant volume with additional 2-propanol (936 g, 1.2 L) and stirred over 1 hour at RT. The suspension was filtered and the filter cake washed with 2-propanol (195 g, 250 ml). The crystals were dried at 60° C./10 mbar (1000 Pa) to give 85.8 g of product as white crystals (99.2 abs.% purity according to HPLC).

8-chloro-5-methyl-1-[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine I, form A

The reactor was charged with 7-chloro-4-methyl-3,5-dihydro-1,4-benzodiazepine-2-amine dihydrochloride (92.3 g, 326 mmol, Eq: 1.00) and 4-(2-pyridyloxy) scyclohexanecarbohydrazide (76.8 g, 326 mmol, Eq: 1.00) followed by 2-propanol (504 g, 646 ml). The suspension was heated under reflux for 18 hours at 80 to 83° C. (until complete conversion of the amidine and intermediate). The reaction mixture was cooled to RT with the addition of water (775 g, 775 ml). The almost clear solution was filtered. The filter was washed with water (24.9 g, 24.9 ml) to give 1.5 L of crude product solution (pH 4).

The filtrate (1.5 L) was divided into two parts: 1 L into reactor B (217 mmol theoretical) and 0.5 L into reactor A (109 mmol theoretical).

Compound I is best isolated as the free base. However, its hydrochloride can also be isolated: after complete conversion of the amidine and the intermediate, the reaction mixture was cooled to a temperature of from 0 to 5°C. The resulting suspension was stirred for 1 hour at 0 to 5°C and filtered. The filter cake was washed with cold isopropanol and dried under reduced pressure 50° C./10 mbar (1000 Pa) to give I.HCl.

Reactor A, crystallization at pH 9-10.- 1.7 eq. NaOH

8% aqueous NaOH (approximately 95 g, corresponds to approximately 1.7 eq.) was added over 15 min, maintaining the temperature from 20 to 25°C (spontaneous crystallization with the addition of 79 g, pH 10 at the end of the addition). Seed crystals I, form A (75 mg) were added (in the absence of spontaneous crystallization). The light yellow suspension was stirred for 1.5 h at RT and cooled to 0-5°C over 30 min. After 5 hours of stirring at 0-5°C, the suspension was filtered. The filter cake (form H) was washed with cold (0-5° C.) 2-propanol/water 1:2 (123 ml) and water (42.0 g, 42 ml) and dried at 60° C. under reduced pressure with obtaining 38.4 g of the title compound as a white crystalline powder (crystal form A according to powder x-ray analysis, 99.3 abs.% purity according to HPLC, 0.4 abs.% of the compound of formula VI').

Reactor B, crystallization at pH equal to or greater than 12:

The pH was adjusted to a value equal to or greater than 12 by adding 222 g of approximately 8% aqueous NaOH (approx. 2 eq.) over 30 min, maintaining the temperature from 20 to 25°C (pH 10-11 after addition of 201 g, spontaneous crystallization after adding 130 g). Seed crystals I, form A (75 mg) were added (in the absence of spontaneous crystallization). The yellow suspension was stirred for 2 h at RT, then cooled to 0-5°C over 30 min. After 5 hours of stirring at 0-5°C, the suspension was filtered. The filter cake (form H) was washed with cold (0-5° C.) 2-propanol/water 1:2 (246 ml) and water (83.0 g, 83 ml) and dried at 60° C. under reduced pressure with obtaining 74.6 g of the title compound as a white crystalline powder (99.7 abs.% purity according to HPLC, the compound of formula VI' was not detected, form A according to powder X-ray diffraction analysis).

8-chloro-5-methyl-1-[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine I, form F

8-chloro-5-methyl-1-[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (38 .1 g, 92.8 mmol, Eq: 1.00) was suspended in methyl acetate (698 g, 750 ml), the suspension was heated to 55°C. The resulting cloudy solution was filtered and cooled to a temperature of 43-45°C for 30 min. The solution was seeded with 0.75 g of the compound of formula I, form F and cooled for 2 hours to RT. The suspension was stirred overnight and replaced with approximately 550 ml of methyl acetate (MeOAc) at a constant volume (Tj max 45°C / 400 to 450 mbar (45000 Pa)) with n-heptane (374 g, 550 ml), achieving approximately 45- 55% w/w MeOAc content.

The suspension was cooled to 0° C. and stirred at 0° C. for more than 4 hours. The suspension was filtered. The filter cake was washed with n-heptane (102 g, 150 ml) and dried at 60° C. under reduced pressure to give 36 g of the title compound as crystalline Form F (by X-ray powder analysis).

8-chloro-5-methyl-1-[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine I, form F

8-chloro-5-methyl-1-[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (13 .6 g) was dissolved in 2-propanol (213 g, 272 ml) at 55°C. The hot solution was filtered. The solution was concentrated to approximately 130-140 ml. n-heptane (93.0 g, 136 ml) was added at 55° C. over 15 min. The clear solution was cooled to approximately 45°C and seeded with 300 mg of crystalline compound I, Form F. The mixture was cooled over 20 hours to 0°C. The resulting suspension was filtered. The filter cake was washed with cold (0° C.) 2-propanol/n-heptane 1:1 (54.4 ml) and dried to give 11.7 g of the title compound as crystalline form F (by X-ray powder analysis).

Trans-4-(2-pyridyloxy)cyclohexanecarboxylic acid XXIII

The reactor was charged with sodium tert-amyl oxide (tAmONa) (444 g, 3.83 mol, Eq: 2.26), N-methyl-2-pyrrolidone (NMP) (2.06 kg, 2 L) and heated at Tj= 90°C. A solution of trans-4-hydroxycyclohexanecarboxylic acid (244 g, 1.69 mol, Eq: 1.00) in NMP (515 g, 500 ml) was added over 15 min at 80 to 85°C. 2-chloropyridine (239 g, 2.11 mol, Eq: 1.24) was added over 5 minutes at 80 to 85°C. After more than 60 hours, the reaction mixture was cooled to 50°C and water (8.00 kg, 8 L) was added at 50°C. The reaction mixture was cooled to RT. The pH was adjusted to approximately 5 by adding 25% aqueous HCl (280 g, 250 ml). The suspension was cooled to a temperature of 0-5°C, stirred for more than 2 h and filtered. The filter cake was washed with water (8.00 kg, 8 L) and dried at 50° C. under reduced pressure to give 245 g of the title compound (greater than 99 abs.% purity by gas chromatography (GC)).

Trans-4-(2-pyridyloxy)cyclohexanecarbohydrazide VI

1,1'-carbonyldiimidazole (CDI) (215 g, 1.32 mol, Eq: 1.21) was suspended in THF (1.07 kg, 1.2 L) at 20°C. A solution of trans-4-(2-pyridyloxy)cyclohexanecarboxylic acid (243 g, 1.1 mol, Eq: 1.00) in THF (1.07 kg, 1.2 L, Eq: -) was added over 70 minutes. After 16 hours the reaction mixture was degassed (vacuum/N2 cycles). Approximately 100 ml of the solvent was distilled off under reduced pressure at Tr less than 30°C. The resulting activated acid solution was added at a temperature of 15 to 25°C to a solution of hydrazine monohydrate (75.2 g, 73 ml, 1.5 mol, Eq: 1.4) in a mixture of THF (1.07 kg, 1.3 L) /water (1.2 kg, 1.3 l). After more than 2 hours of stirring at a temperature of 20-25°C, 3.2 liters of solvent were distilled off at Tj 50-55°C / 300-200 mbar (30000-20000 Pa), continuously adding 3.5 liters of water. The resulting suspension was stirred overnight at RT and filtered. The filter cake was washed with water (750 g, 0.75 L) and dried at 50° C. under reduced pressure to give 223 g of the title compound (98.9 abs.% by HPLC, 0.4% compound of formula VI').

1-(5-chloro-2-nitrophenyl)-N-methylmethanimin XIV

5-Chloro-2-nitrobenzaldehyde (45 g, 243 mmol, Eq: 1.00) was treated with 2 M methylamine in MeOH (141 g, 180 ml, 360 mmol, Eq: 1.48). The reaction mixture was stirred at RT for 5 hours and concentrated under reduced pressure to give 48.06 g of the title compound. The crude product was taken directly to the next step without further purification.

1-(5-chloro-2-nitrophenyl)-N-methylmethanamine XIII

(E)-N-(5-chloro-2-nitrobenzylidene)methanimine (47.5 g, 239 mmol, Eq: 1.00) was dissolved in methanol (447 g, 565 ml). The solution was cooled to 0°C and sodium borohydride (7.64 g, 194 mmol, Eq: 0.811) was added in portions over 25 minutes. The reaction mixture was stirred overnight at RT (approximately 98% conversion). Additional sodium borohydride (1.77 g, 44.9 mmol, Eq: 0.19) was added and the reaction mixture was stirred for 3 hours. The solvent was changed to dichloromethane (DCM) (final volume approx. 400 ml) and washed with saturated aqueous NaHCO ₃ (200 ml). The aqueous phase was separated and extracted twice with DCM (318 g, 240 ml). The organic phases were washed twice successively with half-saturated aqueous NaHCO ₃ (200 ml). The organic phases were combined, dried over magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure to give 47.1 g of the title compound.

4-chloro-2-(methylaminomethyl)aniline XII

1-(5-chloro-2-nitrophenyl)-N-methyl-methanamine (23 g, 109 mmol, Eq.: 1) was dissolved in methanol (690 ml), 46% Raney nickel catalyst (6.91 g, 55 mmol, 0.5 eq.) and the mixture was stirred under a hydrogen atmosphere (1 bar (100,000 Pa)) at RT. After completion of the reaction, the suspension was filtered and the filtrate was concentrated under reduced pressure to obtain 19 g of the crude title compound.

1-(5-chloro-2-nitrophenyl)-N-methyl-methanamine hydrochloride XIII.HCl

40% methylamine in methanol (90.0 ml, 882 mmol, Eq: 12.1) was charged into the reactor and a solution of 4-chloro-2-(chloromethyl)-1-nitrobenzene (15 g, 72.8 mmol, Eq: 1.00) in MeOH (94.8 g, 120 ml) for 50 min at RT. The light yellow solution was stirred at RT for 5.5 h (until the reaction was complete). The reaction mixture was concentrated under reduced pressure to give 21.5 g of a yellow solid which was taken up in AcOEt (108 g, 120 ml). The resulting suspension was filtered. The filter cake (methylamine hydrochloride) was washed three times with AcOEt (135 g, 150 ml). The filtrate was evaporated to give 14.6 g of a yellow oil. The crude 1-(5-chloro-2-nitro-phenyl)-N-methyl-methanamine was dissolved in AcOEt (108 g, 120 ml). 4.4 M hydrochloric acid (HCl) in AcOEt (33.6 ml, 147 mmol, Eq: 2.02) was added slowly. The resulting pale yellow suspension was stirred overnight at RT. The suspension was filtered. The filter cake was washed twice with AcOEt and dried at 10 mbar (1000 Pa) 50° C. to give 15.6 g of the title compound as a light yellow powder.

4-chloro-2-(methylaminomethyl)aniline hydrochloride XII.HCl

1-(5-chloro-2-nitrophenyl)-N-methyl-methanamine hydrochloride (50 g, 208 mmol, Eq.: 1) was dissolved in methanol (790 ml), 46% Raney nickel catalyst (13 g, 104 mmol) was added , 0.5 eq.) and the mixture was stirred in an atmosphere of hydrogen (1 bar (100,000 Pa)) at RT. After completion of the reaction, the suspension was filtered and the filtrate was concentrated under reduced pressure to obtain 43 g of the crude title compound.

The crude product can be recrystallized:

The crude product (22.5 g) was dissolved in methanol (400 ml). Water (3.7 ml) and activated charcoal (2.5 g) were added. The suspension was heated to 50°C, then cooled to RT and filtered. The filtrate was concentrated under reduced pressure to about half the volume. Isopropanol (200 ml) was added and the solution was concentrated under reduced pressure to approximately 220 g, during which time crystallization began, leading to the formation of a thick suspension. Isopropanol (50 ml) was added. The suspension was stirred for 2 h at RT and filtered. The filter cake was washed with isopropanol (30 ml) and dried at 50°C/10 mbar (1000 Pa) to give 15 g of the title compound as an off-white powder.

2-[(2-amino-5-chloro-phenyl)methyl-methyl-amino]acetonitrile XI

4-chloro-2-((methylamino)methyl)aniline hydrochloride (10 g, 48.3 mmol, Eq: 1.00) was suspended in acetonitrile (78.0 g, 100 ml). Sodium bicarbonate (8.92 g, 106 mmol, Eq: 2.2) was added and the suspension heated to 85°C. 2-Chloroacetonitrile (3.91 g, 3.28 ml, 50.7 mmol, Eq: 1.05) was added and the reaction mixture was stirred for 24 h. The reaction mixture was cooled to RT and water (150 g, 150 ml) was added . Toluene (173 g, 200 ml) was added and most of the acetonitrile was removed using a rotary evaporator. The aqueous phase was separated and extracted with toluene (86.7 g, 100 ml). The organic phases were washed with half-saturated aqueous NaHCO ₃ (100 ml) and half-saturated aqueous NaCl. The organic phases were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 9.95 g of the title compound as a light yellow solid. Alternatively, alkylation can also be performed using the free base XII as a starting material.

Trans-N'-(2-chloroacetyl)-4-(2-pyridyloxy)cyclohexanecarbohydrazide XXI

Trans-4-(2-pyridyloxy)cyclohexanecarbohydrazide (4 g, 17.0 mmol, Eq: 1.00) was suspended in DCM (66.2 g, 50.0 ml). 2,4,6-trimethylpyridine (sim-collidine) (2.29 g, 2.5 ml, 18.7 mmol, Eq: 1.1) was added. The suspension was cooled to 0°C and 2-chloroacetyl chloride (2.04 g, 1.43 ml, 17.9 mmol, Eq: 1.05) was added dropwise over 30 minutes at 0 to 5°C. After 1 hour at 0-5°C, the suspension was filtered. The filter cake was washed with cold dichloromethane (40 ml) and dried under reduced pressure at 40° C. to give 5.1 g of the title compound.

Trans-2-(chloromethyl)-5-[4-(2-pyridyloxy)cyclohexyl]-1,3,4-oxadiazole XX

N'-(2-chloroacetyl)-4-(2-pyridyloxy)cyclohexanecarbohydrazide (44 g, 141 mmol, Eq: 1.00) was suspended in acetonitrile (257 g, 330 ml, Eq: -). The suspension was cooled to 0° C. and trifluoromethanesulfonic aldehyde (48.8 g, 28.7 ml, 169 mmol, Eq: 1.2) was added over 30 minutes. The reaction mixture was stirred at RT until the degree of conversion exceeded 95% (more than 15 h). The resulting solution was cooled to 0°C and a solution of sodium hydrogen carbonate (27.0 g, 322 mmol, Eq: 2.28) in water (440 g, 440 ml) was added, followed by dichloromethane (437 g, 330 ml). The aqueous phase was extracted twice with dichloromethane (662 g, 500 ml). The organic phases were washed successively with half-saturated aqueous NaCl (500 ml). The organic phases were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 44.0 g of the crude title compound.

Crystallization: The crude product (39.0 g) was crystallized from isopropanol to give 19.08 g of the title compound.

Trans-4-chloro-2-[[methyl-[[5-[4-(2-pyridyloxy)cyclohexyl]-1,3,4-oxadiazol-2-yl]methyl]amino]methyl]aniline XIX

Trans-2-(chloromethyl)-5-[4-(2-pyridyloxy)cyclohexyl]-1,3,4-oxadiazole (6.7 g, 21.9 mmol, Eq: 1.00), 4-chloro- 2-((methylamino)methyl)aniline (4.33 g, 24.1 mmol, Eq: 1.1), sodium bicarbonate (2.21 g, 26.3 mmol, Eq: 1.2) and acetonitrile (54 .8 g, 70.3 ml) was charged to the reactor and heated under reflux for 4 h. Additional 4-chloro-2-((methylamino)methyl)aniline (393 mg, 2.19 mmol, Eq: 0. 1) and the reaction mixture was stirred for 20 h under reflux. The reaction mixture was cooled to RT. Water (20.0 g, 2.0 ml) and dichloromethane (79.5 g, 60.0 ml) were added. The aqueous phase was separated and extracted with dichloromethane (26.5 g, 20.0 ml). The organic phases were washed successively with half-saturated aqueous ammonium chloride (NH ₄ Cl) (25.0 ml), 10% aqueous NaCl (25.0 ml) and saturated aqueous NaCl (25.0 ml). The organic phases were combined, dried over MgSO ₄ and filtered. The filtrate was filtered through 25 g of silica gel (SiO ₂ ) and concentrated under reduced pressure to give 5.3 g of the title compound.

Trans-8-chloro-5-methyl-1-[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine I

Trans-4-chloro-2-[[methyl-[[5-[4-(2-pyridyloxy)cyclohexyl]-1,3,4-oxadiazol-2-yl]methyl]amino]methyl]aniline (5 g, 10.1 mmol, Eq: 1.00) was dissolved in tetrahydrofuran (44.4 g, 50 ml). Trifluoroacetic acid (2.02 g, 1.36 ml, 17.4 mmol, Eq: 1.72) was added and the reaction mixture was heated to 60°C for 2.5 h. The reaction mixture was cooled to RT, saturated aqueous NaHCO was added ₃ (25 ml) (pH = 8) and the mixture was stirred for 15 min (formation of a yellow suspension). Water (25.0 g, 25 ml) and AcOEt (36.1 g, 40 ml) were added. After 30 min stirring, the aqueous phase was separated and extracted with AcOEt (18.0 g, 20 ml). The organic phases were washed twice with saturated aqueous NaCl (17 ml) (pH about 7). The organic phases were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 5.03 g of the crude title compound. The crude product was taken up in isopropanol (20 ml) and evaporated, redissolved in isopropanol (20 ml) and evaporated. The precipitate was dissolved in isopropanol (11.8 g, 15 ml) and seeded with form F of compound I. Crystallization began and the suspension was stirred for 18 h at RT. The suspension was filtered. The filter cake was washed twice with isopropanol (7.84 g, 10 ml) and dried under reduced pressure to give 3.11 g of the title compound (Form F by X-ray powder analysis).

4-chloro-2-(methylaminomethyl)aniline dihydrochloride XII.2HCl

tert-Butyl-4-chloro-2-((methylamino)methyl)phenylcarbamate (1.0 g, 3.69 mmol, Eq: 1.00) was dissolved in AcOEt (4.5 g, 5.00 ml). 4 M HCl in AcOEt (4.62 ml, 18.5 mmol, Eq: 5.00) was added. The resulting suspension was heated overnight at 40°C. The suspension was cooled to RT, stirred for 1 h and filtered. The filter cake was washed with AcOEt (20 ml) and dried under reduced pressure at 50° C. to give 0.9 g of the title compound.

2-[(2-amino-5-chlorophenyl)methyl-methyl-amino]acetonitrile

4-Chloro-2-((methylamino)methyl)aniline dihydrochloride from the previous step (0.8 g, 3.28 mmol, Eq: 1.00) was suspended in acetonitrile (6.24 g, 8.00 ml). Sodium bicarbonate (883 mg, 10.5 mmol, Eq: 3.2) was added. The white suspension was heated to 85°C. 2-Chloroacetonitrile (266 mg, 223 μl, 3.45 mmol, Eq: 1.05) was added and stirred overnight at 85°C. The reaction mixture was cooled to RT, water (12.0 g, 12.0 ml) was added and the mixture was stirred for 10 min. Toluene (13.9 g, 16.0 ml) was added and most of the acetonitrile was removed under reduced pressure. The aqueous phase was separated and extracted with toluene (6.94 g, 8.00 ml). The organic phases were washed with half-saturated aqueous NaHCO ₃ (8.00 ml) and half-saturated NaCl (8.00 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 840 mg of the title compound. The crude product was dissolved in MTBE (5 ml) under reflux. The colorless solution was slowly cooled to RT. The resulting white suspension was filtered. The filter cake was washed with n-heptane (20 ml) and dried under reduced pressure to give 410 mg of the title compound as a white powder.

4-chloro-2-(methylaminomethyl)aniline XII

2-amino-5-chlorobenzaldehyde (500 mg, 3.12 mmol, Eq: 1.00) was dissolved at RT in ethanol (5.93 g, 7.50 ml). A 41% aqueous solution of methylamine (472 mg, 527 μl, 6.23 mmol, Eq: 2.00) was added and the yellow solution was stirred for 1 h at RT. NaBH ₄ (118 mg, 3.12 mmol, Eq: 1.00) was added and the suspension was stirred for 18 h at RT. Ethyl acetate (18.0 g, 20 ml) and semi-saturated aqueous NaCl (20 ml) were added. The organic phase was separated, dried over MgSO ₄ , filtered and evaporated to dryness to give 550 mg of the title compound.

7-chloro-4-methyl-3,5-dihydro-1,4-benzodiazepine-2-amine II

7-chloro-4-methyl-4,5-dihydro-1H-benzo[e][1,4]diazepine-2(3H)-imine dihydrochloride (1.75 g, 6.19 mmol, Eq: 1.00 ) was suspended in AcOEt (50 ml). Saturated aqueous sodium hydrogen carbonate (30 ml) was added and the mixture was stirred for 30 minutes at RT. The aqueous phase was separated and extracted twice with AcOEt (20 ml). The organic phases were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 930 mg of the title compound.

7-chloro-4-methyl-3,5-dihydro-1,4-benzodiazepine-2-amine dihydrochloride III

2-((2-Amino-5-chlorobenzyl)(methyl)amino)acetonitrile (11.1 g, 51.4 mmol, Eq: 1.00) was dissolved in trifluoroethanol (138 g, 100 ml). 4M HCl in dioxane (38.5 ml, 154 mmol, Eq: 3.0) was added. The reaction mixture was stirred 6 hours at 40° C. to complete the reaction, then concentrated under reduced pressure to give 17.95 g of the title compound (containing approximately 9% dioxane and 11% residual trifluoroethanol).

Alternatively, a compound of formula XI can be converted to a compound of formula III under conditions similar to those used to directly convert a compound of formula VII to a compound of formula III as described in the previous example.

Acetic acid salt of tert-butyl-N-[4-chloro-2-(methylaminomethyl)phenyl]carbamate VIII.AcOH

tert-Butyl-4-chloro-2-((methylamino)methyl)phenylcarbamate (1.0 g, 3.1 mmol, Eq: 1.00) was dissolved in MTBE (8.21 g, 12 ml) at RT. Acetic acid (206 mg, 196 μl, 3.41 mmol, Eq: 1.1) was added dropwise during which time the product began to crystallize. After 2 hours at RT, the suspension was filtered. The filter cake was washed with MTBE and dried under reduced pressure (10 mbar (1000 Pa)/50° C.) to give 0.58 g of the title compound.

Links

1 Genes, Brain and Behavior (2011) 10: 228-235

2 Curr. Opin. neurobiol. 19, 231-234 (2009)

3 W02010060836

4 WO 2004074291 and WO 2005068466

5 Aubé et al, J. Org. Chem., Vol. 65, no. 3, 2000

6 Caron, L. Wei, J. Douville, A. Ghosh, J. Org. Chem. 2010, 75, 945-947

7 WO2005/68466

8 Venkov et al., Synthesis, 1990, 253

9 WO 2004074291, WO 2005068466 and WO 2006021882.

Claims (14)

1. A process for the synthesis of a compound of formula I comprising the reaction of a compound of formula II with a compound of formula VI

. 2. The method of claim 1 further comprising converting a compound of formula XI to a compound of formula III:

. 3. The method according to claim 1 or 2, further comprising converting the compound of formula X into a compound of formula XI or a pharmaceutically acceptable salt thereof through the following steps:

. 4. The method of claim 1 or 2, further comprising converting a compound of formula XV to a compound of formula XI, or a pharmaceutically acceptable salt thereof, through the following steps:

. 5. The method of claim 1 or 2, further comprising converting a compound of formula XXVI to a compound of formula XI, or a pharmaceutically acceptable salt thereof, through the following steps:

. 6. The method according to claim 1 or 2, in which a compound of the formula INT is formed as an intermediate:

INT. 7. Intermediate II or its salt III:

II: free base, III: .2HCl.

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