Improved process for the preparation of cariprazine

Abstract

The object of the present invention is to provide an improved process for the preparation of cariprazine compounds of formula (1): which comprises the step of adding a base to a mixture comprising phosgene or a carbonate derivative and an aminopiperazine compound of formula (3) in salt form: to obtain an isocyanate compound of formula (2): and / or a compound of formula (11):

Description

Technical Field

[0001] This invention relates to an improved method for preparing cariprazine. Background Technology

[0002] Cariprazine is a second-generation antipsychotic drug used to treat schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It was approved for medical use in the United States in September 2015.

[0003] Cariprazine is an N-alkylpiperazine that is N,N-dimethyl-N'-{trans-4-[2-(piperazin-1-yl)ethyl]cyclohexyl}urea, in which a 2,3-dichlorophenyl group is substituted at the 4-position of the piperazine ring.

[0004] Its chemical name is 3-[trans-4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-1,1-dimethylurea and has the following chemical formula (1):

[0005]

[0006] Cariprazine can be prepared according to several synthetic methods described in the literature.

[0007] The first synthesis of cariprazine is described, for example, in WO 2005012266. The synthetic route is reported on the next page. The synthesis begins with a reaction between 1-bromo-2,3-dichlorobenzene (9) and piperazine-1-carboxylate tert-butyl ester (8) using 2,2-bis-(diphenylphosphine)-1,1-binaphthyl (BINAP), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3) and sodium tert-butoxide to give 4-(2,3-dichlorophenyl)piperazine-1-carboxylate tert-butyl ester (7).

[0008] Compound (7) was then deprotected with gaseous hydrogen chloride using Boc to give 1-(2,3-dichlorophenyl)piperazine (6). Next, under alkaline conditions at room temperature, in dichloromethane, tert-butyl triacetoxyborohydride was used to reductively amination ((1R,4R)-4-(2-oxoethyl)cyclohexyl)carbamate (5) and compound (6) for 20 h to give ((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)-piperazin-1-yl)ethyl)cyclohexyl)carbamate (4). Subsequently, compound 4 was reacted with gaseous hydrogen chloride to give (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexylamine hydrochloride (3). Triethylamine was then added to compound (3), followed by the addition of triphosgene. Finally, the isocyanate compound (2) thus obtained is reacted with dimethylamine to give carilarazine (1).

[0009]

[0010] The main drawback of this synthetic route is the low yield obtained in the conversion of compound (3) to compound (2), which is reported as 52% molar in the patent application (see WO2005012266, Method C on page 20). This low yield is mainly due to the incomplete conversion of compound (3) during the reaction time and the formation of many byproducts such as dimer compounds.

[0011] In WO2010070370, this problem was overcome by adding a suspension of compound (3) and triethylamine in dichloromethane to a dichloromethane solution containing triphosgene during the same reaction. Due to this improvement, the yield of this step was increased to 95% molar (see Example 3 on page 8 of that patent application).

[0012] However, this method is not suitable for industrial scale because the suspension of compound (3) and triethylamine is too viscous to be easily transferred using common industrial equipment. Therefore, as taught in procedure WO2010070370, metering this viscous suspension into the triphosgene solution is only feasible on a small or laboratory scale.

[0013] Furthermore, the method is unsuitable for industrial production due to the use of dichloromethane (DCM) as a solvent. It is well known that DCM is, in fact, one of the solvents to be restricted as much as possible in pharmaceuticals due to its toxicity. DCM should also be avoided for environmental reasons, as chlorinated solvents are frequently found to pollute groundwater systems, posing a serious threat to human health and the environment.

[0014] As another drawback, the synthesis described in WO2010070370 requires a considerable excess of the hazardous reactant triphosgene to ensure the reaction proceeds to completion. The handling of large quantities of triphosgene presents another obstacle to the industrial applicability of the above procedure.

[0015] Furthermore, according to the procedure reported in WO2010070370, a solution of dimethylamine in isopropanol is used in the final step of the method. From the perspective of solvent recovery, which is increasingly important in current industrial production, recovering organic solvents from mixtures of organic solvents is more complex.

[0016] Therefore, it is clear that, despite the higher yields, the method described in WO2010070370 is not suitable for the industrial-scale preparation of carilarazine.

[0017] Therefore, there is an urgent need for a method for preparing carliprazine that is suitable for industrial production and thus fits standard industrial equipment, characterized by high yield and productivity, while also being environmentally sustainable. Summary of the Invention

[0018] Therefore, the problem to be solved by the present invention is to provide an improved method for preparing carliprazine, which simultaneously solves the following problems:

[0019] ● It can prepare cariprazine in higher yields;

[0020] ●Suitable for industrial production and therefore suitable for use on standard industrial equipment.

[0021] As an additional issue, it is desirable to provide an environmentally sustainable method for the preparation of carilarazine.

[0022] These problems are addressed by the method used to prepare cariprazine compounds of formula (1):

[0023]

[0024] The method includes the following steps:

[0025] a) Add alkali to a mixture containing the following:

[0026] - Aminopiperazine compounds of formula (3):

[0027]

[0028] Wherein the compound of formula (3) is in salt form, and

[0029] - Phosgene or carbonate derivatives of formula (10):

[0030] RO-CO-Z

[0031] (10),

[0032] Where R is C 1-6 Straight-chain or branched alkyl chain or C 1-2 A fully halogenated alkyl group, where Z is OR or X, where R is as described above and X is a halogen.

[0033] To obtain the isocyanate compound of formula (2):

[0034]

[0035] and / or compounds of formula (11):

[0036]

[0037] R is as described above;

[0038] b) React the compound of formula (2) and / or the compound of formula (11) obtained in step a) with dimethylamine to obtain the carilarazine compound of formula (1).

[0039] Further features and advantages of the invention will become apparent from the following description and the appended claims, the definitions of which are an integral part of this description. Detailed Implementation

[0040] This invention relates to a method for preparing cariprazine compounds of formula (1):

[0041]

[0042] It includes the following steps:

[0043] a) Add alkali to a mixture containing the following:

[0044] - Aminopiperazine compounds of formula (3):

[0045]

[0046] Wherein the compound of formula (3) is in salt form, and

[0047] - Phosgene or carbonate derivatives of formula (10):

[0048] RO-CO-Z

[0049] (10),

[0050] Where R is C 1-6 Straight-chain or branched alkyl chain or C 1-2 A fully halogenated alkyl group, where Z is OR or X, where R is as described above and X is a halogen.

[0051] To obtain the isocyanate compound of formula (2):

[0052]

[0053] and / or compounds of formula (11):

[0054]

[0055] R is as described above;

[0056] b) React the compound of formula (2) and / or the compound of formula (11) obtained in step a) with dimethylamine to obtain the carilarazine compound of formula (1).

[0057] It is indeed surprising to find that, as illustrated in the following scheme, the problems present in the prior art methods are overcome by adding a base to a mixture containing a compound of formula (3) in salt form and a carbonic acid derivative.

[0058]

[0059] According to Method C of WO2005012266, compound (2) was obtained by stoichiometric addition of the carbonic acid derivative triphosgene to a mixture comprising a base, triethylamine, and a trihydrochloride salt of compound (3). Upon reaction with dimethylamine, carrillazine compound (1) was obtained. This method was reproduced in Example 7 of this application with very low yields (79% molar yield, 58.3% by weight as determined by HPLC, and 46% molar yield after content correction).

[0060] Following the procedure disclosed in Example 3 of WO2010070370, compound (2) was obtained by adding a suspension of compound (3) in dihydrochloride form and triethylamine in dichloromethane to a solution of triphosgene in dichloromethane. Upon reaction with dimethylamine, carilarazine compound (1) was obtained. This method was reproduced in Example 8 of this application with a better yield (98% molar yield, 93.3% by weight as determined by HPLC, and 91% molar yield after content correction). However, this procedure is very difficult to perform even on a laboratory scale due to problems in transferring the viscous suspension containing compound (3) and triethylamine.

[0061] By following the method of this application, namely by adding triethylamine to a suspension of the compound of formula (3) in the form of dihydrochloride and triphosgene to obtain the compound of formula (2), conversely, after reaction with dimethylamine, the compound of formula (1) with even better yields was obtained (average molar yield of 97%, average HPLC analysis of the product at 97% by weight, and average molar yield after analytical correction of 94%). Furthermore, because the transfer involved in the method of this application is the transfer of a solution or liquid substance to a suspension, the problem of transferring viscous suspensions present in the procedure of WO2010070370 is overcome. See the comparative table of Example 9 of this application for a clear understanding of the specific effects provided by the present invention.

[0062] In all the procedures cited above, namely the procedure from Method C of WO2005012266, the procedure from Example 3 of WO2010070370, and the procedure according to this application, the base primarily acts to capture one or more anions of the compound of formula (3) as a salt, thus allowing the compound of formula (3) to be obtained as a free amine. A second function of the base is to neutralize any acidic byproducts produced by the reaction of the amine of compound (3) with the carbonic acid derivative of formula (10). Therefore, the amount of base to be added according to all the procedures should be such that the base can perform both of the above-mentioned functions, namely, to liberate the primary amine functional group of the compound of formula (3) and capture any acidic byproducts.

[0063] The above considerations regarding the amount of alkali to be added also apply to this invention.

[0064] According to a preferred aspect of the method of the present invention, in step a), the base is triethylamine or diisopropylethylamine.

[0065] In a more preferred aspect of the method according to the invention, in step a), the base is triethylamine.

[0066] According to another preferred aspect of the method of the invention, in step a), the alkali is added over a period of time between 30 minutes and 5 hours.

[0067] According to a more preferred aspect of the method of the present invention, in step a), the alkali is added over a period of time between 30 minutes and 1 hour.

[0068] According to a preferred aspect of the method of the present invention, in step a), the alkali is added at a temperature in the range of -30°C to 20°C.

[0069] According to a more preferred aspect of the method of the present invention, in step a), the alkali is added at a temperature in the range of -20°C to 0°C.

[0070] According to a preferred aspect of the method of the present invention, in step a), the alkali is added at a temperature ranging from -30°C to 20°C for a time period ranging from 30 minutes to 5 hours.

[0071] According to a more preferred aspect of the method of the present invention, in step a), the alkali is added at a temperature ranging from -20°C to 0°C for a time period ranging from 30 minutes to 1 hour.

[0072] According to a preferred aspect of the method of the present invention, in step a), the carbonate derivative is methyl chloroformate.

[0073] In a more preferred aspect of the method according to the invention, the carbonate derivative (10) in step a) is diphosgene or triphosgene.

[0074] In an even more preferred aspect of the method according to the invention, the carbonate derivative (10) in step a) is triphosgene.

[0075] As described in this application, the term "weight" (W) refers to the weight of reactant per unit of product. Thus, for example, 1W means 1 kilogram of reactant per kilogram of product, or 1 gram of reactant per gram of product, or 1 milligram of reactant per milligram of product. Therefore, 10W means, for example, 10 grams of reactant per gram of substance.

[0076] According to the procedure of Method C in WO2005012266, only 0.26 W (relative to the dihydrochloride form of compound (3)) of triphosgene was used to convert compound (3) to compound (2). However, as mentioned above, this procedure resulted in a very low yield. On the other hand, according to the procedure of Example 3 in WO2010070370, 0.76 W of triphosgene (relative to the dihydrochloride form of compound (3)) was used for the same conversion, resulting in a higher method yield.

[0077] Surprisingly, it was found that, following the method of this application, using 0.36 W - 0.55 W (relative to the dihydrochloride form of compound (3)) of triphosgene to convert compound (3) to compound (2) yielded even better yields than those obtained by the method in Example 3 of WO2010070370. Considering the molar yield (HPLC wt%) corrected for product content, the method of this application actually yielded 92-97% molar yield, compared to 91% yield when reproducing the method in Example 3 of WO2010070370 (see Example 10 of this application).

[0078] As is well known, triphosgene is a hazardous reactant, and inhalation can be fatal. Therefore, when applying this method on an industrial scale, reducing the amount of reagent required for complete reaction while maintaining high process performance is an important objective. The method of this application allows for even higher process yields (+3% higher average yield) while reducing the amount of triphosgene required to complete the reaction by 30%-50%.

[0079] According to a preferred aspect of the method of the invention, the reaction in step a) is carried out using 0.36 W - 0.55 W (relative to the dihydrochloride form of compound (3)) of triphosgene as a carbonic acid derivative.

[0080] In a more preferred aspect of the method according to the invention, the reaction in step a) is carried out using 0.36 W (relative to the dihydrochloride form of compound (3)) of triphosgene as a carbonic acid derivative.

[0081] The prior art methods disclosed in Method C of WO2005012266 and Example 3 of WO2010070370 both use DCM as a solvent to convert the compound of formula (3) into the compound of formula (2).

[0082] Industrial production is fully aware that DCM is listed as a solvent to be restricted as much as possible in pharmaceuticals due to its toxicity. Because chlorinated solvents are frequently found to pollute groundwater systems, posing a serious threat to human health and the environment, DCM should also be avoided for environmental reasons.

[0083] Because it uses non-chlorinated solvents, and in particular avoids DCM as a solvent, the method of the present invention is particularly suitable for industrial production, while also taking into account safety and sustainability.

[0084] According to a preferred aspect of the method of the invention, in fact, the reaction in step a) is carried out in a solvent selected from the list including 2-methyltetrahydrofuran, tetrahydrofuran, acetone, and acetonitrile.

[0085] According to a preferred aspect of the method of the invention, in fact, the reaction in step a) is carried out in an aprotic solvent.

[0086] In a more preferred aspect of the method according to the invention, the reaction in step a) is carried out in 2-methyl-tetrahydrofuran, tetrahydrofuran, or acetone.

[0087] In an even more preferred aspect of the method according to the invention, the reaction in step a) is carried out in 2-methyl-tetrahydrofuran.

[0088] According to a preferred aspect of the method of the invention, in step a), after the addition of the alkali, the reaction is carried out at a temperature in the range of -30°C to 20°C.

[0089] According to a more preferred aspect of the method of the present invention, in step a), after the addition of the alkali, the reaction is carried out at a temperature in the range of -20°C to 0°C.

[0090] According to another preferred aspect of the method of the invention, in step a), after the addition of the alkali, the reaction is carried out over a period of time between 30 minutes and 6 hours.

[0091] According to a more preferred aspect of the method of the present invention, in step a), after the addition of the alkali, the reaction is carried out over a period of time between 1 hour and 4 hours.

[0092] According to an even more preferred aspect of the method of the invention, in step a), the addition of the alkali is carried out at a temperature ranging from -30°C to 20°C for a time period ranging from 30 minutes to 5 hours, and after the addition of the alkali, the reaction is carried out at a temperature ranging from -30°C to 20°C for a time period ranging from 30 minutes to 6 hours.

[0093] According to an even more preferred aspect of the method of the present invention, in step a), the addition of the alkali is carried out at a temperature between -20°C and 0°C for a period of 30 minutes to 1 hour, and after the addition of the alkali, the reaction is carried out at a temperature between 10°C and 20°C for a period of 1 hour to 4 hours.

[0094] According to a preferred aspect of the method of the invention, the base added in step a) is in the range of 2 molar equivalents to 10 molar equivalents relative to the compound of formula (3).

[0095] In a more preferred aspect of the method according to the invention, the base added in step a) is in the range of 2 to 5 molar equivalents relative to the compound of formula (3).

[0096] Molar equivalent or equivalent (eq) refers to the amount of one mole of a substance reacting with another molar amount of another substance in a given chemical reaction.

[0097] As described herein, a salt or ionic compound is a chemical compound composed of a collection of positively charged ions (cations) and negatively charged ions (anions), resulting in the compound having no net charge (electroneutrality). Therefore, monovalent, divalent, or trivalent salts are ionic compounds comprising one, two, or three pairs of charges (cations / anions).

[0098] According to a preferred aspect of the method of the present invention, in step a), the compound of formula (3) is a monovalent, divalent or trivalent salt.

[0099] According to a preferred aspect of the method of the present invention, in step a), the compound of formula (3) is a salt containing an anion, said anion being a portion of a strong acid.

[0100] A strong acid is an acid that is completely or nearly completely ionized in its solution. Hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfonic acid are examples of strong acids.

[0101] Therefore, according to a preferred aspect of the method of the present invention, the compound of formula (3) is a salt of a strong acid selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfonic acid.

[0102] According to a more preferred aspect of the method of the present invention, in step a), the compound of formula (3) is a monovalent, divalent or trivalent salt containing an anion, said anion being a portion of a strong acid.

[0103] In an even more preferred aspect of the method according to the invention, the compound of formula (3) is a monohydrochloride, a dihydrochloride, or a trihydrochloride.

[0104] In a particularly preferred aspect of the method according to the invention, the compound of formula (3) is a dihydrochloride.

[0105] According to the method of the present invention, in step a), an alkali is added to a mixture comprising:

[0106] Aminopiperazine compounds of formula (3):

[0107]

[0108] The compound of formula (3) is in salt form, and

[0109] Phosgene or carbonate derivatives of formula (10):

[0110] RO-CO-Z

[0111] (10),

[0112] Where R is C 1-6 Straight-chain or branched alkyl chain or C 1-2 A fully halogenated alkyl group where Z is OR or X, where R is as described above and X is a halogen.

[0113] The isocyanate compound of formula (2) is obtained:

[0114]

[0115] and / or compounds of formula (11):

[0116]

[0117] R is as described above. Then, in step b), the compound of formula (2) and / or the compound of formula (11) is reacted with dimethylamine to obtain the carilarazine compound of formula (1).

[0118] According to a preferred aspect of the method of the invention, the isocyanate compound of formula (2) and / or the compound of formula (11) are separated before step b), or the isocyanate compound of formula (2) and / or the compound of formula (11) are reacted in situ in step b) without separation.

[0119] A more preferred aspect of the method according to the invention is that the compounds of formula (2) and / or formula (11) are not separated.

[0120] Therefore, in a more preferred aspect of the method according to the invention, steps a) and b) are carried out as a one-pot reaction.

[0121] In step b), the compound of formula (2) and / or the compound of formula (11) is reacted with dimethylamine. This reaction can be carried out by metering dimethylamine or a dimethylamine solution into a mixture containing the compound of formula (2) and / or the compound of formula (11).

[0122] In another respect, the reaction can be carried out by metering a mixture of compounds of formula (2) and / or formula (11) into a solution containing dimethylamine.

[0123] Therefore, according to a preferred aspect of the method of the present invention, in step b), the reaction of compound (2) and / or compound (11) with dimethylamine is carried out by metering dimethylamine or a dimethylamine solution into a mixture containing compound (2) and / or compound (11), or metering a mixture containing compound (2) and / or compound (11) into dimethylamine or a dimethylamine solution.

[0124] The prior art method disclosed in Example 3 of WO2010070370 uses a solution of dimethylamine in isopropanol.

[0125] It is well known that industrial production should strive to develop more sustainable methods. From this perspective, water should be used to replace organic solvents whenever possible.

[0126] Surprisingly, it was found that the reaction in step b) of the method according to the invention could be carried out using dimethylamine in aqueous form instead of dimethylamine hydrochloride or a solution of dimethylamine in isopropanol without negatively impacting process performance. As shown in Example 10, in fact, in all cases where dimethylamine (DMA) was used in aqueous form according to the method of this application, a higher product content-corrected yield (HPLC wt%) was obtained (94% average corrected molar yield, compared to 91% corrected molar yield obtained according to the method of Example 3 of WO2010070370).

[0127] Therefore, the purpose of the method in this application is to allow water to be used instead of the organic solvent used to dilute dimethylamine, while ensuring that the process performance is not affected and is still higher than that obtained when using prior art methods.

[0128] According to a preferred aspect of the method of the present invention, dimethylamine is used in step b) in the form of an aqueous solution.

[0129] Therefore, according to a preferred aspect of the method of the present invention, in step b), the dimethylamine is an aqueous solution of dimethylamine.

[0130] The present invention also relates to pharmaceutical compositions comprising a compound of formula (1) obtained by the methods of this application and at least one pharmaceutically acceptable excipient.

[0131] Therefore, the present invention also relates to a method for preparing a pharmaceutical composition comprising a compound of formula (1), comprising the following steps:

[0132] a1) Prepare compound of formula (1) according to the method of this application;

[0133] b1) Mix the compound of formula (1) obtained in step a1) with at least one pharmaceutically acceptable excipient.

[0134] The present invention also relates to methods for preparing compounds of formula (2) and / or formula (11):

[0135]

[0136] Where R is C 1-6 Straight-chain or branched alkyl chain or C 1-2 A fully halogenated alkyl group, wherein Z is OR or X, where R is as described above and X is a halogen, the method comprising adding a base to a mixture comprising:

[0137] - Aminopiperazine compounds of formula (3):

[0138]

[0139] Wherein the compound of formula (3) is in salt form, and

[0140] - Phosgene or carbonate derivatives of formula (10):

[0141] RO-CO-Z

[0142] (10),

[0143] Where R is C 1-6 Straight-chain or branched alkyl chain or C 1-2 A fully halogenated alkyl group, wherein Z is OR or X, where R is as described above and X is a halogen.

[0144] All the features and preferred aspects of the methods of the present invention provided above can be combined in every possible combination to carry out the claimed method.

[0145] Example

[0146] Compound (5) is commercially available, for example through abcr GmbH. Compound (4) can be prepared, for example, according to Example 2 of WO2005012266 (page 19). Compound (3) can be prepared, for example, according to Example 3 of WO2005012266 (page 19).

[0147] As described herein, the term C1-C6 linear or branched alkyl refers to an alkyl group characterized by one to six carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, and 1-hexyl, etc.

[0148] Room temperature (RT) refers to the temperature between 20 and 25°C, which is defined as the comfortable temperature range indoors.

[0149] As described herein, drying a wet substance under vacuum involves heating the substance to a given temperature for a given time while applying a reduced pressure. This operation is performed to remove residual solvent from the product.

[0150] As described herein, concentrating a mixture under vacuum refers to heating a substance to a given temperature for a given time while applying reduced pressure. This operation is performed to remove residual solvent from the mixture.

[0151] Molar concentration, or volumetric molarity, is a measure of the concentration of a chemical substance, specifically the concentration of a solute in a solution, expressed as the number of moles of the substance per unit volume of solution. In chemistry, the most commonly used unit for molar concentration is moles per liter, with the symbol mol / L. A solution with a concentration of 1 mol / L is called a molar concentration, usually designated as 1 M.

[0152] The following are abbreviations used in this article: DMA = dimethylamine; TEA = triethylamine; DIPEA = N,N-diisopropylethylamine; DCM = dichloromethane; THF = tetrahydrofuran; Me-THF = 2-methyl-tetrahydrofuran.

[0153] Example 1: Preparation of compound of formula (1)

[0154] In a round-bottom flask equipped with a crescent-shaped stirrer, 5.0 g of compound (3) in dihydrochloride form, 1.8 g of triphosgene, and 70 mL of Me-THF were added. The mixture was stirred at RT for 10 min, and then cooled to T = -20 °C over 1.5 h. TEA (5.9 g) was metered into the mixture over 45 min, maintaining the batch temperature at T = -20 °C. The mixture was heated to RT for 1 h to allow the reaction to proceed to completion, and then cooled again to T = 0 °C over 45 min and maintained at that temperature. An aqueous solution of DMA (2.6 g of 40% by weight solution) was metered into the mixture over 40 min. After stirring at T = 0 °C for 4 h, the batch was divided into two equal portions. Half of the organic solution was stored for analytical purposes. The second half of the solution (34.5 g) was diluted with water (10 mL), and the two-phase mixture was stirred at RT for 40 min, and then heated to T = 60 °C for 1.5 h. The resulting suspension was filtered at the same temperature, and the wet filter cake was washed with a mixture of preheated water (10 mL) and methanol (10 mL) at T = 55 °C. The resulting white solid was dried under vacuum at T = 50 °C, yielding 2.5 g of compound (1). Molar yield (uncorrected for content): 100%; HPLC determination: 92.6% by weight; molar yield (corrected for content): 93%.

[0155] Example 2: Preparation of compound of formula (1)

[0156] In a reactor equipped with a propeller stirrer, 5.0 g of compound (3) in dihydrochloride form, 1.8 g of triphosgene, and 70 mL of Me-THF were added. The mixture was stirred at RT for 5 minutes, then cooled to T = -20 °C over 40 minutes. TEA (5.9 g) was metered into the mixture over 40 minutes, maintaining the batch temperature at T = -20 °C. The reaction was allowed to proceed to completion by heating to RT for 1 hour, after which the mixture was cooled again to T = -20 °C over 45 minutes and maintained at that temperature. An aqueous solution of DMA (30 mL of a 40% by weight solution) was metered into the mixture over 35 minutes. After stirring at T = -20 °C for 15 minutes, the batch was heated to RT and stirred at that temperature for 1 hour, and finally heated to T = 70 °C. The resulting suspension was concentrated under reduced pressure to a residual volume of 40 mL, stirred for an additional 10 minutes at T = 60 °C, and then filtered. The wet filter cake was washed with a mixture of preheated water (10 mL) and methanol (10 mL) at T = 55 °C. The resulting white solid was dried under vacuum at T = 50 °C, yielding 4.9 g of compound (1). Molar yield (uncorrected): 98%; HPLC purity: 95.6% by weight; molar yield (corrected): 94%.

[0157] Example 3: Preparation of compound of formula (1)

[0158] In a reactor equipped with an impeller stirrer, 5.0 g of compound (3) in dihydrochloride form, 1.8 g of triphosgene, and 70 mL of Me-THF were added. The mixture was stirred at RT for 25 min, then cooled to T = -20 °C over 35 min. TEA (5.9 g) was metered into the mixture over 35 min, maintaining the batch temperature at T = -20 °C. The reaction was allowed to proceed to completion by heating to RT for 4 h, then the mixture was cooled again to T = -20 °C over 40 min and maintained at that temperature. An aqueous solution of DMA (30 mL of 40% by weight solution) was metered into the mixture over 1.5 h. After stirring at T = -20 °C for 30 min, the batch was heated to RT, then heated to T = 45 °C. The resulting suspension was concentrated under reduced pressure to a residual volume of 30 mL, then diluted with a mixture of water (15 mL) and isopropanol (5 mL). After concentrating to a residual volume of 25 mL under reduced pressure, the batch was diluted again with water (15 mL) and concentrated to a residual volume of 30 mL under the same conditions. After adding isopropanol (10 mL), the mixture was heated to T = 60 °C for 15 minutes and then filtered. The wet filter cake was washed at T = 60 °C with a mixture of preheated water (20 mL) and isopropanol (20 mL). The resulting white solid was dried under vacuum at T = 50 °C, yielding 4.9 g of compound (1). Molar yield (uncorrected): 98%; HPLC purity: 97.8% by weight; molar yield (corrected): 96%.

[0159] Example 4: Preparation of compound of formula (1)

[0160] In a reactor equipped with an impeller stirrer, 5.0 g of compound (3) in dihydrochloride form, 2.75 g of triphosgene, and 70 mL of Me-THF were added. The mixture was stirred at RT for 10 min, then cooled to T = -20 °C over 50 min. TEA (5.9 g) was metered into the mixture over 40 min, maintaining the batch temperature at T = -20 °C. The reaction was allowed to proceed to completion by heating to RT for 1 hour, after which the mixture was cooled again to T = -20 °C over 50 min and maintained at this temperature. An aqueous solution of DMA (30 mL of 40% by weight solution) was metered into the mixture over 40 min. The batch was divided into two equal portions. One portion was stored for analytical purposes. The remaining portion was cooled to T = 0 °C and then filtered. The wet filter cake was washed at T = 0 °C with a mixture of water (20 mL) and methanol (20 mL). The white solid obtained by drying at T = 50 °C under vacuum yielded 2.4 g of compound (1). Molar yield (uncorrected for content): 100%; HPLC content determination: 97.4% by weight; molar yield (corrected for content): 97%.

[0161] Example 5: Preparation of compound of formula (1)

[0162] In a reactor equipped with an impeller stirrer, 10.0 g of compound (3) in the form of dihydrochloride, 3.6 g of triphosgene, and 140 mL of Me-THF were added. The mixture was stirred at RT for 15 min, then cooled to T = -20 °C over 45 min. TEA (11.8 g) was metered into the mixture over 55 min, maintaining the batch temperature at T = -20 °C. The mixture was heated to RT and held for 1 h to allow the reaction to proceed to completion, then cooled again to T = -20 °C over 30 min and maintained at that temperature. An aqueous solution of DMA (60 mL of 40% by weight solution) was metered into the mixture over 50 min. After stirring at T = -20 °C for 25 min, the batch was concentrated to a residual volume of 60 mL under reduced pressure. The mixture was back-extracted twice with water (2 x 30 mL) under the same conditions, then diluted with isopropanol (30 mL) and heated to T = 60 °C. After stirring at this temperature for 25 min, the suspension was filtered. The wet filter cake was washed with a mixture of water (40 mL) and isopropanol (40 mL) preheated to T = 60 °C. The resulting white solid was dried under vacuum at T = 50 °C, yielding 9.25 g of compound (1). Molar yield (uncorrected): 93%; HPLC purity: 99.2% by weight; molar yield (corrected): 92%.

[0163] Example 6: Preparation of compound of formula (1)

[0164] In reactor A equipped with an impeller stirrer, 5.0 g of compound (3) in dihydrochloride form, 1.8 g of triphosgene, and 70 mL of Me-THF were added. The mixture was stirred at RT for 15 min and then cooled to T = -20 °C over 35 min. TEA (5.9 g) was metered into the mixture over 45 min, maintaining the batch temperature at T = -20 °C. The mixture was then heated to RT for 4 h to allow the reaction to proceed to completion. In another reactor B, an aqueous solution of DMA (30 mL of a 40% by weight solution) was added and adjusted to T = -10 °C. The mixture from reactor A was transferred to reactor B under nitrogen pressure, maintaining the temperature, and then reactor A was washed with Me-THF (10 mL). Subsequently, the batch was concentrated to a residual volume of 30 mL under reduced pressure. The mixture was back-extracted twice with water (2 x 15 mL) under the same conditions, then diluted with isopropanol (15 mL) and heated to T = 60 °C. After stirring at this temperature for 25 minutes, the suspension was filtered. The wet filter cake was washed with a mixture of water (20 mL) preheated to T = 60 °C and isopropanol (20 mL). The white solid obtained was dried under vacuum at T = 50 °C, yielding 4.7 g of compound (1). Molar yield (uncorrected for content): 94%; HPLC determination: 100.4% by weight; molar yield (corrected for content): 94%.

[0165] Example 7: Preparation of compound of formula (1) by reproducing method C of patent application WO2005012266.

[0166] In a round-bottom flask equipped with a crescent-shaped stirrer, 5.0 g of compound (3) in dihydrochloride form and 500 mL of DCM were added, followed by 5.0 g of TEA. After stirring at RT for 15 min, a solution of DCM containing 1.28 g of triphosgene (5.0 mL) was added metered over 1 hour. After stirring at RT for 1 hour, 4.74 g of dimethylamine hydrochloride was added to the mixture, followed by 6.0 g of TEA. After stirring at RT for 20 hours, the mixture was filtered, and the wet filter cake was washed with 20 mL of water. The solid was dried under vacuum at T=45 °C to yield 4.85 g of compound (1). Molar yield (uncorrected for content): 79%; HPLC content determination: 58.3% by weight; molar yield (corrected for content): 46%.

[0167] Example 8: Preparation of compound of formula (1), reproducing Example 3 of patent application WO2010070370.

[0168] In reactor A equipped with a propeller stirrer, 5.0 g of compound (3) in the form of dihydrochloride was added, followed by 97 mL of DCM solution containing TEA (7.0 g). After stirring at RT for 1 hour, the thick suspension was cooled to T=5°C. Simultaneously, in a different reactor B equipped with an impeller stirrer, 39 mL of DCM solution containing triphosgene (3.8 g) was prepared and cooled to T=-10°C. The thick suspension from reactor A was transferred to reactor B over 15 minutes and the mixture was allowed to react at T=-10°C for 1 hour. In a different reactor C equipped with an impeller stirrer, a dimethylamine isopropanol solution (46 mL of 2 M solution) was added and cooled to T=-10°C. The suspension from reactor B was transferred to reactor C and the resulting mixture was heated to T=-5°C. After stirring at T=-5°C for 1 hour, the batch was diluted with water (78 mL) and the same temperature was maintained, and an aqueous solution of hydrochloric acid (3.2 mL of 32% by weight solution) was added. The mixture was then heated to RT and concentrated under reduced pressure to a residual volume of 100 mL. The residue was diluted with water (54 mL) and concentrated again under reduced pressure to a residual volume of 130 mL. After stirring at RT for 20 minutes, the resulting suspension was filtered and the wet filter cake was dried under vacuum at T=50 °C to yield 4.9 g of compound (1). Molar yield (uncorrected): 98%; HPLC content: 93.3% by weight; molar yield (corrected): 91%.

[0169] Example 9: Comparison of process performance between prior art and the present application

[0170] The table below summarizes the molar yields, HPLC content determinations, and content-corrected molar yields for converting compounds of formula (3) to carilarazine compounds of formula (1) using the methods of the prior art reported in WO2005012266 and WO2010070370 and the methods of this application. The highlighted entries (Example No. Avg) in the table represent average values ​​obtained when applying the methods of this application.

[0171] The results reported in the table clearly demonstrate that, compared to methods known in the prior art, the method of this application allows for the acquisition of carilarazine in significantly higher, content-corrected yields. Furthermore, since the method of the present invention does not involve the transfer of viscous suspensions that are infeasible in standard industrial equipment, it is suitable for industrial production.

[0172] Example 10: Comparison of process performance between prior art and this application

[0173] The table below summarizes the amount of triphosgene added, the solvent used in the reaction, and the source of DMA used, as well as the content-corrected molar yield, in accordance with the methods of the prior art reported in WO2005012266 and WO2010070370 and the method of this application, for converting the compound of formula (3) into the carilarazine compound of formula (1).

[0174] The results reported in the table clearly demonstrate that the method of WO2005012266, which uses only 0.26 W of triphosgene, is characterized by an extremely low yield (46%), while the method of this application allows for a reduction in the amount of the toxic reagent triphosgene. Conversely, by reducing the amount of triphosgene from 0.76 W (the amount of reactant used in WO2010070370) to 0.55 W or 0.36 W (the amount used in the method according to the invention), even the process performance in terms of yield after content correction is improved (an average yield of 94% was obtained according to the method of this application, while a yield of 91% was obtained according to the method disclosed in WO2010070370).

[0175] Furthermore, the method of this application allows the use of Me-THF instead of toxic and environmentally polluting DCM as a reaction solvent.

[0176] Specifically, Me-THF can be produced from biomass feedstocks, such as hydrogenated products of levulinic acid or furfural produced from lignocellulosic biomass. Derived from renewable resources, Me-THF is a promising solvent option in the search for environmentally friendly synthetic strategies.

[0177] In addition, the issue of transferring viscous suspensions related to WO2010070370 was resolved.

[0178] Using DMA in aqueous solution instead of solution in isopropanol is an additional contribution to the environmental friendliness of the method in this application.

[0179] Therefore, it is clear that the method of the present invention is also more environmentally sustainable than the methods of the prior art.

Claims

1. A method for preparing cariprazine compounds of formula (1): It includes the following steps: a) Add alkali to a mixture containing the following: - Aminopiperazine compounds of formula (3): The compound of formula (3) is in salt form, and - Phosgene or carbonate derivatives of formula (10): RO-CO-Z (10)， Where R is C 1-6 Straight-chain or branched alkyl chain or C 1-2 A fully halogenated alkyl group, where Z is OR or X, wherein R is as described above and X is a halogen. To obtain the isocyanate compound of formula (2): and / or compounds of formula (11): Where R is as described above; b) React the compound of formula (2) and / or the compound of formula (11) obtained in step a) with dimethylamine to obtain the carilarazine compound of formula (1).

2. The method according to claim 1, wherein the base in step a) is triethylamine or diisopropylethylamine.

3. The method according to any one of claims 1 or 2, wherein in step a), the alkali is added over a period of time between 30 minutes and 5 hours.

4. The method according to any one of claims 1 to 3, wherein in step a), the alkali is added at a temperature in the range of -30°C to 20°C.

5. The method according to any one of claims 1 to 4, wherein in step a), the carbonic acid derivative (10) is triphosgene or diphosgene.

6. The method according to any one of claims 1 to 5, wherein step a) is carried out in a solvent selected from the following list, which includes 2-methyltetrahydrofuran, tetrahydrofuran, acetone, and acetonitrile.

7. The method according to any one of claims 1 to 6, wherein the compound of formula (3) is a salt of a strong acid selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfonic acid.

8. The method according to any one of claims 1 to 7, wherein the compound of formula (3) is a monovalent, divalent or trivalent salt.

9. The method according to any one of claims 1 to 8, wherein the compound of formula (3) is in the form of a salt of a monohydrochloride, a dihydrochloride or a trihydrochloride.

10. The method according to any one of claims 1 to 9, wherein the compound of formula (3) is a dihydrochloride.

11. The method according to any one of claims 1 to 10, wherein the isocyanate compound of formula (2) and / or the compound of formula (11) are separated before step b), or the isocyanate compound of formula (2) and / or the compound of formula (11) are reacted in situ in step b) without separation.

12. The method according to any one of claims 1 to 11, wherein in step b), the reaction of compound (2) and / or compound (11) with dimethylamine is carried out by metering dimethylamine or a dimethylamine solution into a mixture containing compound (2) and / or compound (11), or metering a mixture containing compound (2) and / or compound (11) into dimethylamine or a dimethylamine solution.

13. The method according to any one of claims 1 to 12, wherein the dimethylamine in step b) is dimethylamine in an aqueous solution.

14. A method for preparing a pharmaceutical composition comprising a compound of formula (1), comprising the following steps: a1) Prepare compound of formula (1) by the method according to any one of claims 1 to 13; b1) Mix the compound of formula (1) obtained in step a1) with at least one pharmaceutically acceptable excipient.

15. Methods for preparing compounds of formula (2) and / or formula (11): Where R is C 1-6 Straight-chain or branched alkyl or C 1-2 A fully halogenated alkyl group, wherein Z is OR or X, where R is as described above and X is a halogen, the method comprising adding a base to a mixture comprising: - Aminopiperazine compounds of formula (3): Wherein the compound of formula (3) is in salt form, and - Phosgene or carbonate derivatives of formula (10): RO-CO-Z (10)， Where R is C 1-6 Straight-chain or branched alkyl chain or C 1-2 A fully halogenated alkyl group, wherein Z is OR or X, where R is as described above and X is a halogen.

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