Process for preparation of pyrimidino-diazepine derivative

Abstract

To provide a process for preparation of pyrimidino-diazepine derivatives.SOLUTION: A process for preparing a compound of formula (XII) (where PG is a protecting group) or a compound of formula (XI) is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to processes for preparing pyrimido-diazepinone derivatives and intermediates useful therein. [Background technology]

[0002] Polo-like kinases are a family of serine-threonine kinases that are critical regulators of cell cycle progression and DNA damage response (Petronczki et al, Curr Opin Cell Biol. 2008 Dec; 20(6):650-60). PLK1 is frequently overexpressed in cancer, and its levels are significantly increased. PLK1 correlates with aggressiveness and has prognostic value in predicting outcome (Kanaji et al. Oncology. 2006; 70(2):126-33). Cancer cell proliferation is blocked in vitro and in vivo by small molecule PLK1 inhibitors and PLK1 antisense / siRNA (Spankuch et al, Oncogene, 2007 Aug 23; 26(39):5793-807). PLK1 inhibitors cause mitotic arrest and subsequent apoptosis induction. Due to the central role of PLK1 in mitosis and cell division, rapidly proliferating normal cells are also affected by PLK1 inhibitors. As a result, clinical PLK1 inhibitors have been shown to exhibit a narrow therapeutic window and cause significant hematologic toxicity (Schoffski et al, Eur J Cancer, 2012 Jan; 48(2):179-86). Widening the Therapeutic Window Identification of patient / tumor selectivity markers and treatment regimens that will lead to these drugs is crucial for the successful development. Mutant TP53 has been shown to be one such predictive marker for sensitivity to PLK1 inhibitors (Degenhardt et al, Clin Cancer Res. 2010 Jan 15;16(2):384-9).

[0003] Small molecule benzothiazole-3-oxide PLK1 inhibitors and their use in the treatment of proliferative disorders are described in International Patent Application WO 2004 / 067000 in the name of Cyclacel Limited, Inc. In addition, a series of pyrimido-diazepinone molecules have also been shown to potently and selectively inhibit PLK1 (see International Patent Application WO 2009 / 040556; Cyclacel Limited, Inc.), demonstrating strong antiproliferative activity in vitro and in vivo.

[0004] 4-((9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro-[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazepin]-2'-yl)amino)-3-methoxy-N-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)benzamide, or 4-(9'-cyclopentyl-5'-methyl-6'- Compound I, also known as oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-2′-ylamino)-N((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-3-methoxybenzamide, was first disclosed in WO 2009 / 040556 and has the structure shown below:

[0005] [ka]

[0006] Studies have demonstrated that Compound I is a potent inhibitor of polo-like kinase 1 (PLK1), thereby making Compound I therapeutically useful in the treatment of a range of proliferative disorders (including, but not limited to, cancer, leukemia, lymphoma, glomerulonephritis, rheumatoid arthritis, and psoriasis), immune-mediated and inflammatory disorders, autoimmune and autoimmune-mediated disorders, renal disorders, and viral disorders.

[0007] WO 2009 / 040556 discloses that compound I can be prepared by reacting compound of formula (II) with 4-(4-methylpiperazin-1-yl)cyclohexanamine in the presence of DIPEA and TBTU in DMF, followed by separation of the trans isomers by preparative RP-HPLC-MS to produce the desired product in 18% yield:

[0008] [ka]

[0009] WO 2009 / 040556 discloses that 4-(4-methylpiperazin-1-yl)cyclohexanamine in the form of a mixture of cis / trans isomers can be prepared by treating N-benzyloxycarbonyl-4-aminocyclohexanone with N-methylpiperazine in the presence of acetic acid and sodium triacetoxyborohydride, followed by hydrogenation.

[0010] The present invention relates to an alternative method for preparing compound I, and to a compound for use in said method. The present invention is intended to provide an intermediate. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2004 / 067000 [Patent Document 2] International Publication No. 2009 / 040556 [Non-patent literature]

[0012] [Non-Patent Document 1] Petronczki et al, Curr Opin Cell Biol. 2008 Dec; 20(6):650-60 [Non-patent document 2] Kanaji et al. Oncology. 2006; 70(2):126-33 [Non-patent document 3] Spankuch et al, Oncogene, 2007 Aug 23; 26(39):5793-807 [Non-patent document 4] Schoffski et al, Eur J Cancer, 2012 Jan; 48(2):179-86 [Non-Patent Document 5] Degenhardt et al, Clin Cancer Res. 2010 Jan 15; 16(2):384-9 Summary of the Invention [Means for solving the problem]

[0013] A first aspect of the present invention is a compound of formula (XII) (wherein PG is a protecting group), or A process for preparing a compound of formula (XI), comprising:

[0014] [ka]

[0015] (i) treating a compound of formula XIII (wherein PG is a protecting group) with N-methylpiperazine to produce a compound of formula XII, wherein said compound of formula XII is in the form of a mixture of cis and trans isomers; (ii) combining the mixture produced in step (i) with an organic solvent and heating the solvent mixture so produced; (iii) isolating the trans isomer of the compound of formula XII from the solvent mixture produced in step (ii); (iv) optionally treating said trans isomer of a compound of formula XII with an acid to produce a compound of formula XI and isolating said compound of formula XI. The present invention relates to the method comprising the steps of:

[0016] Compound XI is a useful intermediate in the preparation of compound (I). Prior art methods for preparing compound (I) describe the use of a cis / trans mixture of compound XI as an intermediate in the synthesis. Advantageously, the trans isomer of compound XII (and thus XI) is used. Isolation leads to a significant improvement in yield.

[0017] A second aspect of the present invention is a method for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (I) preparing a compound of formula XI by the method as described above in the first aspect; (II) contacting said compound of formula XI with a compound of formula II to produce a compound of formula I;

[0018] [ka]

[0019] (III) isolating said compound of formula I; (IV) optionally converting said compound of formula I into its pharmaceutically acceptable salt form; The present invention relates to the method comprising the steps of:

[0020] A third aspect of the present invention is a method for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (A) Hydrogenating a compound of formula VIII in the presence of a Raney nickel catalyst to form a compound of formula VII generating a compound;

[0021] [ka]

[0022] (B) contacting said compound of formula VII with cyclopentanone in the presence of a reducing agent to form a compound of formula VI generating a compound;

[0023] [ka]

[0024] (C) contacting said compound of formula VI with a compound of formula IX to produce a compound of formula V;

[0025] [ka]

[0026] (D) treating said compound of formula V with Fe powder in the presence of acetic acid to produce a compound of formula IV;

[0027] [ka]

[0028] (E) treating said compound of formula IV with MeI to produce a compound of formula III;

[0029] [ka]

[0030] (F) contacting said compound of formula III with a compound of formula X to produce a compound of formula II. Pu and,

[0031] [ka]

[0032] (G) contacting said compound of formula II with a compound of formula XI to produce a compound of formula I, preferably wherein the compound of formula XI is substantially free of cis isomers;

[0033] [ka]

[0034] (H) isolating the compound of formula I; (I) optionally converting said compound of formula I into its pharmaceutically acceptable salt form; The present invention relates to the method comprising the steps of:

[0035] A fourth aspect of the present invention is a method for preparing a compound of formula II, comprising the steps of contacting a compound of formula III with a compound of formula X in N-methylpyrrolidone and isolating the compound of formula II. :

[0036] [ka]

[0037] The present invention relates to a method, including:

[0038] A fifth aspect of the present invention is a method for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (I') preparing a compound of formula II by a method as described in the fourth aspect above; (II') contacting said compound of formula II with a compound of formula XI to produce a compound of formula I;

[0039] [ka]

[0040] (III') isolating the compound of formula I; (IV') optionally converting said compound of formula I into its pharmaceutically acceptable salt form. DETAILED DESCRIPTION OF THE INVENTION

[0041] Process for preparing compounds of formula XII or XI A first aspect of the present invention is a method for preparing a compound of formula XII, wherein PG is a protecting group. A method for

[0042] [ka]

[0043] (i) treating a compound of formula XIII (wherein PG is a protecting group) with N-methylpiperazine to produce a compound of formula XII, wherein said compound of formula XII is in the form of a mixture of cis and trans isomers; (ii) combining the mixture produced in step (i) with an organic solvent and heating the solvent mixture so produced; (iii) isolating the trans isomer of the compound of formula XII from the solvent mixture produced in step (ii); The present invention relates to the method comprising the steps of:

[0044] In one embodiment, the method comprises treating the compound of formula trans XII with an acid. and converting said compound of formula trans XII into a compound of formula XI, and The method further includes the step of releasing the

[0045] As used herein, "PG" refers to an amino-protecting group. Those skilled in the art will be familiar with suitable amino-protecting groups. Examples of amino-protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry", (Wiley, 2nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino-protecting groups include formyl, acetyl (Ac, acetyl ), trifluoroacetyl, benzyl (Bn, benzyl), dibenzyl (Bn2, dibenzyl), methyl carbamate, formamide, benzyloxycarbonyl (CBZ, benzyloxycarbonyl), tert-butoxycarbonyl (BOC, t-butoxycarbonyl), trimethyl Examples of aryloxycarbonyl groups include, but are not limited to, trimethylsilyl (TMS), 2-trimethylsilylethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitroveratryloxycarbonyl (NVOC), and the like.

[0046] Studies by the Applicant have demonstrated that the nature of the protecting group PG, in combination with the choice of reducing agent, can influence the ratio of trans to cis isomers produced in step (i) of the method according to the first aspect of the present invention. In this regard, certain protecting groups lead to preferential production of trans isomers relative to cis isomers. Without wishing to be bound by theory, it is believed that mixtures containing a greater proportion of trans to cis isomers are generally easier to manipulate and purify, and in some cases, may be more effective in reducing the amount of the desired trans isomer. It is believed that the isomers may be obtained without the need for chromatography, which has obvious benefits in terms of scale-up.

[0047] Preferably, the ratio of trans to cis isomers is at least about 60 to about 40 (by weight percent), more preferably at least about 65 to about 35, even more preferably at least about 70 to about 30, even more preferably at least about 75 to about 25, more preferably at least about 80 to about 20, more preferably at least about 85 to about 15, and even more preferably at least about 90 to about 10.

[0048] Preferably, the mixture produced in step (i) of the process comprises at least a 60% proportion of trans isomers relative to cis isomers, more preferably at least about 65%, even more preferably at least about 70%, even more preferably at least about 75%, more preferably at least about 80%, more preferably at least about 85%, and even more preferably at least about 90% trans isomers.

[0049] Preferably, the ratio of trans to cis isomers is at least 60% (by weight) in favor of the trans isomer, more preferably at least about 65%, even more preferably at least about 70%, even more preferably at least about 75%, more preferably at least about 80%, more preferably at least about 85%, and even more preferably at least about 90% in favor of the trans isomer compared to the cis isomer.

[0050] In one preferred embodiment, the ratio of trans to cis isomers is from about 60 to about 40 (by weight percent), more preferably from about 65 to about 35, even more preferably from about 70 to about 30, even more preferably from about 75 to about 25, more preferably from about 80 to about 20, more preferably from about 85 to about 15, and even more preferably from about 90 to about 10.

[0051] In one particularly preferred embodiment, PG is an acetyl group. Illustratively, studies by the applicant have demonstrated that the use of an acetyl protecting group leads to a particularly advantageous ratio of trans XII to cis XII in step (i) in the crude material so produced, for example, a ratio of trans XII to cis XII of about 65:35%. The trans isomer (trans XII) can then be separated from the crude mixture and further purified. The acetyl group is then removed, and the resulting product is purified. Compound XI can then be further purified by conventional means.

[0052] In another particularly preferred embodiment, PG is tert-butoxycarbonyl (BOC). By way of example, studies by the present applicant have demonstrated that the use of a BOC protecting group leads to an even more favorable ratio of trans / cis isomers in the crude material so produced, e.g., a ratio of trans XII to cis XII of about 75:25%. The trans isomer (trans XII) can then be separated from the crude mixture and further purified. The use of a BOC protecting group The use of the acetyl protecting group resulted in improved yields of trans XII (approximately 32%) compared to the acetyl protecting group (approximately 25%). The BOC group is then removed and compound XI can be further purified by conventional means. Advantageously, the BOC-protected derivative XII is crystalline and therefore experimentally It is easy to handle and purify in-house (e.g., by avoiding the need for chromatography), which is an important factor in yield optimization and scale-up. Furthermore, the BOC protecting group can be removed under mild conditions, which is also an important factor for developing scale-up procedures.

[0053] In another preferred embodiment, PG is dibenzyl (Bn2).

[0054] In one preferred embodiment, step (i) comprises: (a) forming a mixture comprising a compound of Formula XIII, N-methylpiperazine, a solvent, and an acid; and heating the mixture. nothing.

[0055] In one preferred embodiment, step (i) further comprises the step of: (b) cooling the mixture obtained in step (a) and diluting with a solvent.

[0056] In one preferred embodiment, step (i) further comprises the step of: (c) treating the mixture obtained in step (b) with a reducing agent.

[0057] In one preferred embodiment, step (i) further comprises the step of: (d) isolating the compound of formula XII as a mixture of cis and trans isomers.

[0058] In one preferred embodiment, step (i) comprises: (a) forming a mixture comprising a compound of Formula XIII, N-methylpiperazine, a solvent, and an acid, and heating the mixture; (b) cooling the mixture obtained in step (a) and diluting with a solvent; (c) treating the mixture obtained in step (b) with a reducing agent; (d) isolating the compound of formula XII as a mixture of cis and trans isomers; Includes:

[0059] In one preferred embodiment, the reaction mixture in step (i)(a) is heated to a temperature of at least 60°C, even more preferably at least 70°C, more preferably at least 80°C, even more preferably at least 90°C.

[0060] Preferably, the reaction mixture in step (i)(a) is subjected to azeotropic distillation. More preferably, the azeotropic distillation is carried out using a Dean-Stark apparatus.

[0061] Dean-Stark apparatuses are typically used in azeotropic distillation, such as for the removal of water produced during a reaction. When using a Dean-Stark apparatus, the reaction is carried out in a water-immiscible solvent, which forms a lower-boiling azeotrope with water, which has a lower density than water. Under reflux conditions, the Dean-Stark apparatus allows the solvent to be continuously returned to the reaction mixture, while water is collected within the apparatus and then discharged. Examples of solvents suitable for the extraction of water from a reaction using a Dean-Stark apparatus include toluene, benzene, and xylene.

[0062] In one preferred embodiment, the solvent in step (i)(a) is immiscible with water.

[0063] In one preferred embodiment, the solvent in step (i)(a) forms a lower boiling azeotrope with water.

[0064] In one preferred embodiment, the solvent in step (i)(a) has a density lower than water.

[0065] In one preferred embodiment, the solvent in step (i)(a) is immiscible with water, forms a lower boiling azeotrope with water, and has a lower density than water.

[0066] In one preferred embodiment, the solvent in step (i)(a) is selected from toluene, benzene, and xylene.

[0067] In one preferred embodiment, the solvent in step (i)(a) is toluene.

[0068] In one preferred embodiment, the acid is a sulfonic acid, more preferably selected from benzenesulfonic acid, para-toluenesulfonic acid and methanesulfonic acid, hi one particularly preferred embodiment, the acid is methanesulfonic acid.

[0069] In one highly preferred embodiment, the solvent in step (i) is toluene and the acid is methanesulfonic acid.

[0070] In one preferred embodiment, step (i)(a) comprises heating the mixture to reflux. Preferably, the mixture is heated at reflux for at least 2 hours, more preferably at least 3 hours, more preferably at least 4 hours, and even more preferably at least 5 hours. Preferably, the reaction is carried out in a Dean-Stark apparatus.

[0071] In one preferred embodiment, step (i)(b) comprises cooling the mixture to a temperature of about 50°C to about 60°C, more preferably about 50°C to about 55°C, and even more preferably about 50°C.

[0072] As used throughout, the term "cooling" refers to lowering the temperature, e.g., the temperature of a reaction mixture. The term encompasses active methods (e.g., subjecting the reaction mixture to cooling conditions, such as immersing the reaction vessel in a cooling bath) and passive methods, such as allowing the reaction mixture to cool (e.g., to room temperature) by removing the heat source.

[0073] In one preferred embodiment, step (i)(b) comprises diluting the mixture with an alcohol, more preferably an alkyl alcohol, more preferably ethanol or methanol, even more preferably ethanol.

[0074] In one preferred embodiment, step (i)(c) comprises treating the mixture produced in step (i)(b) (including the intermediate enamine species) with a reducing agent.

[0075] [ka]

[0076] Preferably, the reducing agent is a borohydride reducing agent, more preferably NaBH4 or LiBH4.

[0077] In one particularly preferred embodiment, the reducing agent is NaBH4.

[0078] In another particularly preferred embodiment, the reducing agent is LiBH4.

[0079] Those skilled in the art will appreciate that other reducing agents may also be suitable for use in step (i)(c), including, but not limited to, picoline-borane, borazane, and sodium triacetoxyborohydride (STAB).

[0080] In one preferred embodiment, step (i)(c) comprises treating the mixture produced in step (i)(b) (containing the intermediate enamine species) with a reducing agent, e.g., NaBH4 or LiBH4, where the reducing agent is added at a temperature of about 10°C to about 25°C, more preferably about 15°C to about 20°C. Preferably, the resulting mixture is stirred for at least 2 hours, more preferably at least 3 hours, more preferably at least 4 hours, even more preferably at least 5 hours, and even more preferably overnight. The reducing agent (e.g., NaBH4 or LiBH4) is then decomposed by treatment with an acid, preferably HCl, preferably at a temperature of about 10°C to about 20°C, more preferably about 10°C to about 15°C. The aqueous layer is then treated with a base (e.g., K2CO3), and the solid is filtered off and washed with an organic solvent (e.g., dichloromethane). The filtrate is then concentrated, extracted with an organic solvent (e.g., dichloromethane), basified (preferably with KOH) to a pH of approximately 10, and further extracted with an organic solvent (e.g., dichloromethane). The combined organic layers are then dried and concentrated. The crude product can be purified by column chromatography, for example, using basic alumina, to give a solid corresponding to compound XII containing a mixture of cis and trans isomers.

[0081] The process of the present invention provides a method for isolating the trans isomer of compound XII from a mixture of cis and trans isomers. Applicants have discovered that this can be achieved by precipitating the trans isomer of compound XII from a solvent mixture containing the cis and trans isomers. Therefore, the present invention provides: (ii) combining the mixture produced in step (i) with an organic solvent and heating the solvent mixture so produced; (iii) isolating the trans isomer of the compound of formula XII from the solvent mixture produced in step (ii); Further includes:

[0082] In one preferred embodiment, the organic solvent in step (ii) is acetonitrile.

[0083] In one preferred embodiment, step (ii) comprises heating the solvent mixture to dissolve the mixture of cis and trans isomers. Preferably, the mixture is heated to a temperature of at least 40°C, even more preferably at least 50°C, even more preferably at least 60°C, even more preferably at least 70°C, and more preferably at least 80°C. In one preferred embodiment, the mixture is heated to reflux temperature. Preferably, the mixture is heated at reflux temperature for a period of at least 5 minutes, more preferably at least 10 minutes, and even more preferably at least 15 minutes. Upon cooling, the trans isomer precipitates from the solution and can be isolated by filtration (step (iii)). Preferably, the compound The trans isomer of substance XII is a crystalline form.

[0084] Thus, in one preferred embodiment, step (iii) comprises cooling the mixture so that the trans isomer of formula XII precipitates out of solution, filtering the precipitate so formed, and optionally washing and / or drying the precipitate.

[0085] In one preferred embodiment, the precipitate contains less than about 5% cis isomer, more preferably less than about 2%, even more preferably less than about 1%, and even more preferably less than about 0.5% or 0.1% cis isomer.

[0086] Preferably, the precipitate contains 95% or more of the trans isomer, more preferably 98% or more, even more preferably 99% or more, and even more preferably 99.5% or more or 99.9% or more of the trans isomer.

[0087] In one preferred embodiment, the trans isomer of compound XII is substantially the same as the cis isomer. As used herein, "substantially free of cis isomers" means that the cis isomer is 1 This means that it is present at levels such that it is undetectable by 1 H NMR spectroscopy.

[0088] In one preferred embodiment, step (iii) comprises heating the mixture at about 0 to about 15°C, preferably More preferably, it includes a step of cooling to a temperature of about 5 to about 10°C.

[0089] In one preferred embodiment, the method of the present invention involves removing the protecting group PG from compound XII. The method further comprises treating said compound of formula XII with an acid to produce a compound of formula XI (step (iv)). Those skilled in the art will be familiar with the conditions required for the removal of protecting groups. In one preferred embodiment, the method further comprises treating said compound of formula XII with an acid to produce a compound of formula XI (step (iv)). )) Preferably, the acid is a strong acid.

[0090] In one preferred embodiment, the method of the present invention comprises treating a compound of formula XII with concentrated HCl. This step involves removing the protecting group PG by HCl. Those skilled in the art will appreciate that other acids (e.g., trifluoroacetic acid) would also be suitable, and that the choice of acid may depend on the nature of the protecting group. Preferably, the reaction mixture is heated to a temperature of at least 100°C, more preferably at least 105°C, for a period of preferably at least 1 hour. More preferably, the reaction mixture is then heated at a temperature of about 95°C to about 105°C for at least 10 hours, more preferably at least 12 hours, and even more preferably at least 15 hours. Preferably, the reaction mixture is then cooled to a temperature of about 15°C to about 25°C, after which potassium hydroxide is added in portions to achieve a final pH of about 12. The compound of formula XI may then be isolated by conventional methods to yield a low-melting solid shown to be the trans isomer by HRGC.

[0091] Process for preparing compounds of formula II Another aspect of the invention is a method for preparing a compound of formula II, comprising the steps of contacting a compound of formula III with a compound of formula X in N-methylpyrrolidone and isolating the compound of formula II. The present invention relates to a method comprising the steps of:

[0092] [ka] .

[0093] Advantageously, the use of N-methylpyrrolidone as a solvent in this step significantly increases yields: for example, the reaction proceeds in 91% yield when carried out in N-methylpyrrolidone compared to 74% when carried out in a mixture of trifluoroacetic acid and 2,2,2-trifluoroethanol (see WO 2009 / 040556).

[0094] Preferably, the reaction mixture is heated to a temperature of at least 110° C., more preferably from about 115° C. to about 125° C. Preferably, the mixture is heated for a period of at least 24 hours, more preferably at least 36 hours. Compound II can be isolated and purified using conventional methods.

[0095] Processes for preparing compounds of formula I Another aspect of the invention is a process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (I) preparing a compound of formula XI by a method as described above in the first aspect of the present invention; (II) contacting said compound of formula XI with a compound of formula II to produce a compound of formula I;

[0096] [ka]

[0097] (III) isolating said compound of formula I; (IV) optionally converting said compound of formula I into its pharmaceutically acceptable salt form; The present invention relates to the method comprising the steps of:

[0098] In one preferred embodiment, the compound of formula XI contains less than about 5% of the cis isomer, more preferably Preferably, it contains less than about 2%, even more preferably less than about 1%, and even more preferably less than about 0.5% or 0.1% of the cis isomer.

[0099] Preferably, the compound of formula XI contains 95% or more of the trans isomer, more preferably 98% or more, even more preferably 99% or more, and even more preferably 99.5% or more or 99.9% or more of the trans isomer.

[0100] In one preferred embodiment, the compound of formula XI is substantially free of cis isomers.

[0101] Advantageously, the applicant has shown that using trans compound XI (rather than a mixture of cis / trans compounds XI) in the conversion of compound II to compound I leads to a dramatic improvement in yield (86% using trans compound XI compared to 18% using a mixture of cis / trans compounds XI as described in WO 2009 / 040556).

[0102] In one preferred embodiment, step (II) is carried out in the presence of an organic solvent, a base, and a coupling reagent. Suitable solvents will be familiar to those skilled in the art and include, for example, dichloromethane and dimethylformamide. Suitable coupling reagents will be familiar to those skilled in the art and include, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). Suitable bases will be familiar to those skilled in the art and include, for example, tertiary aliphatic amine bases. More preferably, the base is N,N-diisopropylethylamine (DIPEA), tri- N Propylamine, and tri- N butylamine. Even more preferably, the base is N,N-diisopropylethylamine (DIPEA).

[0103] In one preferred embodiment, step (II) is carried out in the presence of dichloromethane, N,N-diisopropylethylamine (DIPEA) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU).

[0104] In another preferred embodiment, step (II) is carried out in the presence of DMF, N,N-diisopropylethylamine (DIPEA) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU).

[0105] Preferably, step (II) comprises suspending the compound of formula II in the organic solvent and adding the coupling reagent thereto at a temperature of about 15°C to about 25°C. The base is then added while maintaining the mixture within the same temperature range. Compound XI is then added to the mixture while maintaining the mixture within the same temperature range. The product, compound I, can be isolated using conventional methods.

[0106] More preferably, step (II) comprises suspending the compound of formula II in dichloromethane and adding HBTU thereto at a temperature of about 15°C to about 25°C. DIPEA is then added while maintaining the mixture within the same temperature range. Compound XI is then added to the mixture while maintaining the mixture within the same temperature range. The product, compound I, can be isolated using conventional methods.

[0107] In one preferred embodiment, the method comprises contacting a compound of formula III with a compound of formula X The method further comprises preparing a compound of formula II by

[0108] [ka]

[0109] In one preferred embodiment, the reaction of converting compound III to compound II is carried out by N-methylation. The reaction is carried out in ethyl pyrrolidone. Preferably, the reaction mixture is heated to a temperature of at least 110°C, more preferably from about 115°C to about 125°C. Preferably, the mixture is heated for a period of at least 24 hours, more preferably at least 36 hours. Compound II can be isolated and purified using conventional methods.

[0110] In an alternative preferred embodiment, the reaction of converting compound III to compound II is carried out by triflic acid. Preferably, the reaction is carried out in the presence of trifluoroacetic acid (TFA) and 2,2,2-trifluoroethanol (TFE). This is carried out in the presence of 5 equivalents of TFA relative to the product.

[0111] In one preferred embodiment, the method of the present invention further comprises the step of preparing a compound of formula III by treating a compound of formula IV with MeI.

[0112] [ka]

[0113] Preferably, the reaction is carried out in an organic solvent, more preferably THF, although those skilled in the art will recognize that other solvents may also be suitable.

[0114] In one preferred embodiment, the conversion of compound IV to compound III is carried out using THF and t- Preferably, the reaction is carried out at a temperature below about 10° C., more preferably at a temperature below about 10° C. Preferably, the reaction is carried out at a temperature of about 0 to about 5°C. Preferably, the compound of formula IV is added in portions to a suspension of t-BuOK in THF, followed by the addition of MeI. Preferably, the resulting reaction mixture is stirred at a temperature of about 0 to about 5°C for at least 15 minutes, and then warmed to a temperature of about 20 to about 25°C. Preferably, the mixture is then stirred at a temperature of about 20 to about 25°C for at least 6 hours, more preferably at least 12 hours. Compound III can be isolated and purified using conventional methods.

[0115] In an alternative preferred embodiment, the conversion of compound IV to compound III is carried out using Me in DMF. I and NaH. One skilled in the art will recognize that other conditions and / or reagents for the alkylation step may also be used.

[0116] In one preferred embodiment, the method of the present invention further comprises the step of preparing a compound of formula IV by treating a compound of formula V with Fe powder in the presence of acetic acid.

[0117] [ka]

[0118] In one preferred embodiment, the conversion of compound V to compound IV is carried out at a temperature of about 25 to about 30°C.

[0119] Preferably, acetic acid is heated to at least 50° C., more preferably at least 60° C., and Fe powder is added thereto. The mixture is then cooled to about 25° C., and compound V is added thereto. Preferably, the resulting mixture is stirred at about 25° C. for a period of at least 6 hours, more preferably at least 12 hours. Compound IV can be isolated and purified using conventional methods.

[0120] In one preferred embodiment, the method of the present invention further comprises the step of preparing a compound of formula V by contacting a compound of formula VI with a compound of formula IX.

[0121] [ka]

[0122] In one preferred embodiment, the reaction of converting compounds VI and IX to compound V is carried out in the presence of a solvent and a base.

[0123] In one preferred embodiment, the reaction of converting compounds VI and IX to compound V is carried out in the presence of acetone and K2CO3. Preferably, the reaction is carried out at a temperature below about 10°C, more preferably below about 5°C.

[0124] Preferably, a solution of compound IX in acetone is cooled to a temperature of about 0° C. to about 5° C., and KCO is added thereto. A solution of compound VI in acetone is then added to the mixture. Compound V can be isolated and purified using conventional methods.

[0125] In one preferred embodiment, the process of the present invention comprises reacting a compound of formula VII in the presence of a reducing agent with cyclopentanone (i.e., in a reductive amination reaction) to prepare a compound of formula VI.

[0126] [ka]

[0127] Preferably, the reaction is carried out in an organic solvent, more preferably dichloromethane. One skilled in the art will recognize that other organic solvents may also be suitable. Preferably, the reducing agent is sodium triacetoxyborohydride (STAB), although one skilled in the art will recognize that other reducing agents may also be suitable. In one preferred embodiment, compound VII is converted to The reaction to convert to compound VI is carried out in the presence of sodium triacetoxyborohydride (STAB) and dichloromethane. Preferably, the reaction is carried out at room temperature. Preferably, the reaction mixture is stirred at about 25° C. for a period of at least 6 hours, more preferably at least 12 hours. Compound VI can be isolated and purified using conventional methods.

[0128] In one preferred embodiment, the process of the present invention involves preparing a compound of formula VII by hydrogenating a compound of formula VIII, preferably in the presence of a solvent and a Raney nickel catalyst. The method further includes the steps of:

[0129] [ka]

[0130] Preferably, the solvent for the hydrogenation reaction is ethanol. Those skilled in the art will recognize that other solvents and / or reaction conditions for the hydrogenation step will also be suitable.

[0131] In one preferred embodiment, the method comprises converting the compound of formula I into its pharmaceutically acceptable salt form. Pharmaceutically acceptable salts of compounds of formula I can be obtained using routine procedures that will be familiar to those skilled in the art.

[0132] As used herein, the term "pharmaceutically acceptable salt" includes suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al., J Pharm Sci, 66, 1-19 (1977). Salts can be prepared, for example, from mineral acids such as sulfuric acid, phosphoric acid, or halogenated acids. with strong inorganic acids such as hydrochloric acid; with strong organic carboxylic acids such as alkanecarboxylic acids of 1 to 4 carbon atoms, unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid; with hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; with amino acids such as aspartic acid or glutamic acid; with benzoic acid; or with organic sulfonic acids such as (C1-C4)-alkyl- or aryl-sulfonic acids, unsubstituted or substituted (e.g., by halogen), such as methane- or p-toluenesulfonic acid. Preferably, the pharmaceutically acceptable salt is an HCl salt.

[0133] Therefore, in one preferred embodiment, the present invention further comprises the step of treating the compound of formula (I) with a suitable acid as described above and isolating the resulting pharmaceutically acceptable salt. Preferably, the reaction occurs in the presence of a suitable solvent, such as ethanol or a mixture of ethanol / THF. Preferably, the pharmaceutically acceptable salt is isolated by filtration and dried in vacuo.

[0134] Another aspect of the invention is a method for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (I') by contacting a compound of formula III with a compound of formula X in N-methylpyrrolidone preparing a compound of formula II and isolating the compound of formula II;

[0135] [ka]

[0136] (II') contacting said compound of formula II with a compound of formula XI to produce a compound of formula I;

[0137] [ka]

[0138] (III') isolating said compound of formula I; (IV') optionally converting said compound of formula I into its pharmaceutically acceptable salt form.

[0139] In one preferred embodiment, the compound of formula XI contains less than about 5% cis isomer, more preferably less than about 2%, even more preferably less than about 1%, and even more preferably less than about 0.5% or 0.1% cis isomer.

[0140] Preferably, the compound of formula XI contains 95% or more of the trans isomer, more preferably 98% or more, even more preferably 99% or more, and even more preferably 99.5% or more or 99.9% or more of the trans isomer.

[0141] In one preferred embodiment, the compound of formula XI is substantially free of cis isomers.

[0142] Another aspect of the invention is a method for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (A) Hydrogenating a compound of formula VIII in the presence of a Raney nickel catalyst to produce a compound of formula VII. and

[0143] [ka]

[0144] (B) contacting said compound of formula VII with cyclopentanone in the presence of a reducing agent to form a compound of formula VI generating a compound;

[0145] [ka]

[0146] (C) contacting said compound of formula VI with a compound of formula IX to produce a compound of formula V;

[0147] [ka]

[0148] (D) treating said compound of formula V with Fe powder in the presence of acetic acid to produce a compound of formula IV;

[0149] [ka]

[0150] (E) treating said compound of formula IV with MeI to produce a compound of formula III;

[0151] [ka]

[0152] (F) contacting said compound of formula III with a compound of formula X to produce a compound of formula II. Pu and,

[0153] [ka]

[0154] (G) contacting said compound of formula II with a compound of formula XI to produce a compound of formula I;

[0155] [ka]

[0156] (H) isolating the compound of formula I; (I) optionally converting said compound of formula I into its pharmaceutically acceptable salt form; The present invention relates to a method, comprising:

[0157] In one preferred embodiment, the compound of formula XI in step (G) contains less than about 5% cis isomer, more preferably less than about 2%, even more preferably less than about 1%, and even more preferably less than about 0.5% or 0.1% cis isomer.

[0158] Preferably, the compound of formula XI in step (G) comprises 95% or more of the trans isomer, more preferably 98% or more, even more preferably 99% or more, and even more preferably 99.5% or more or 99.9% or more of the trans isomer.

[0159] Preferably, the compound of formula XI in step (G) is substantially free of cis isomers.

[0160] Preferred embodiments for steps (A) to (I) of the third aspect are as described above for the second aspect of the invention.

[0161] The present invention is further described by the following non-limiting examples. [Example]

[0162] Abbreviation EtOH ethanol MeOH Methanol EtOAc ethyl acetate DCM dichloromethane DMF Dimethylformamide RT room temperature Et2O diethyl ether MeI methyl iodide t-BuOK Potassium tert-butoxide NMP N-methylpyrrolidone HPLC High Performance Liquid Chromatography HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate DIPEA N,N-Diisopropylethylamine HOBt Hydroxybenzotriazole HRGC High Resolution Gas Chromatography KF Karl Fischer MeCN acetonitrile

[0163] Apparatus and method Solution proton NMR Using a JEOL EX 270MHz spectrometer equipped with an autosampler 1 H NMR spectrum Samples were collected. Samples were dissolved in appropriate deuterated solvents for analysis. Data were acquired using Delta NMR Processing and Control Software version 4.3.

[0164] High-resolution gas chromatography (HRGC) Agilent 6890 Series Gas Chromatograph equipped with a headspace sampler HRGC spectra were obtained by dissolving the sample in methanol. [Example 1]

[0165] Preparation of Compound (I) The free base form of Compound (I) can be prepared according to the synthesis shown in Schemes 1, 2 and 3 below:

[0166] [ka]

[0167] [ka]

[0168] [ka] [Example 1]

[0169] Synthesis of Compound (I) 1.1 Synthesis of Compound (III) (i) Compound VII

[0170] [ka]

[0171] Raney nickel catalyst (200 g, 50% water) was washed with EtOH (3 × 100 ml, solvent decanted). The catalyst was then suspended in ethanol (200 ml). To a suspension of Raney nickel (200 g, 50% suspension in EtOH) in EtOH (3 L) was added ethyl-1-cyanocyclopropanecarboxylate VIII (600 g, 4.3119 mol). The hydrogenation apparatus was purged with N (3 ×) and H (3 ×). The reaction was pressurized with hydrogen to 20 bar and stirred at room temperature overnight. The mixture was filtered through a pad of Celite (500 g) and washed with ethanol (2 × 0.6 L). The filtrate was concentrated. The residue was dissolved in DCM (1.8 L), dried over MgSO, filtered, and concentrated. This gave product VII as a clear oil (yield 580 g, 94%).

[0172] (ii) Compound VI

[0173] [ka]

[0174] Amine VII (800 g, 5.5874 mol) and cyclopentanoic acid in DCM (8 L) To a solution of ethanol (520 ml, 5.867 mol) in 1,2-dichloro-2,4-dichloro-1,4-dichloro-2,5-dichloro-1,6-dichloro-2,6-dichloro-2,7-dichloro-2,7-dichloro-2,8 ... g of product VI (1157 g active (contained 4.3% DCM), 98% yield).

[0175] (iii) Compound V

[0176] [ka]

[0177] A solution of 2,4-dichloro-5-nitropyrimidine IX (1309.4 g, 6.750 mol) in acetone (11.4 L) was cooled to 0-5 °C and KCO (933 g, 6.750 mol) was added. Then, a solution of amine VI (1426.3 g, 6.750 mol) in acetone (2.9 L) was added dropwise over 1.5 h, maintaining the temperature below 5 °C. After 1 h, 1 HNMR analysis showed approximately 6% 2,4-dichloro-5-nitropyrimidine and no compound VI. Compound VI (86 g, 0.407 mol) in acetone (50 ml) was added, and the mixture was stirred at RT for 1 h. The solid was filtered off and washed with acetone (1 L). The filtrate was concentrated at 25 °C (the product polymerizes at higher temperatures), and the residue was dissolved in DCM (8 L), washed with water (2 L), dried over MgSO, filtered, and concentrated at 25 °C. This gave the product as an orange oily solid (2755 g, LC purity 85%). The product was suspended in EtO (475 ml) and stirred at room temperature for 15 min. Heptane (475 ml) was added, and the suspension was stirred at room temperature for 1 h. After that time, the mixture was filtered, and the filter cake was washed with EtO / heptane (1:1, 2 × 950 ml) and dried overnight in a vacuum oven at 25 °C. This gave 1762.2 g of product V as a yellow solid (71% yield, LC purity 96.99%).

[0178] (iv) Compound IV

[0179] [ka]

[0180] AcOH (7.6 L) was heated to 60° C. and the heating mantle was removed. Fe powder (431 g, 7.727 mol) was added portionwise over 15 min at 60° C. (no exotherm, slight gas evolution). The mixture was then cooled to 25° C. (ice bath) and compound V (950 g, 2.576 mol) was added portionwise over 3 h (a slight exotherm was observed, ice / The reaction mixture was cooled with water to maintain the reaction temperature at 25-30°C. The reaction mixture was stirred overnight at 25°C. After that time, an LC completion check indicated 82.0% product. The mixture was diluted with water (15.2 L, no exotherm) and the product was filtered off using a filter cloth. The filter cake was washed with water (500 ml) and then treated with saturated aqueous NaHCO3 (2 L, gas evolution). The solid was filtered off (filter paper) and washed with water (3 x 500 ml). The wet cake (1717 g) was combined with three batches of Compound IV prepared by the same method [Batch 1 (950 g) - 1668 g wet, Batch 2 (950 g) - 1701 g wet, Batch 3 (581.1 g) - 1113 g wet] and stirred in water (5 L) at room temperature for 1 hour. The solid was filtered off and dried in a vacuum oven at 50°C for 5 days. This gave 2972.4 g of compound IV as a brown solid (yield approx. 100%, LC purity 94.5%, KF 0.65%, contains Fe salts). The product was used in the next stage without purification.

[0181] (v) Compound III

[0182] [ka]

[0183] Compound IV (2019.1 g total, 1850.0 g active—assuming 100% yield in the previous step) was added portionwise over 10 min to a suspension of t-BuOK (854.3 g) in THF (19.0 L) within the specified temperature range of 0–10 °C. The reaction mixture was stirred for 30 min at 0–10 °C (final temperature 5.47 °C), and then methyl iodide (440 ml) was added dropwise over 23 min while maintaining the temperature within the specified temperature range of 0–5 °C. The mixture was stirred for 15 min at 0–5 °C, then warmed to 20 °C over 2.5 h, and then stirred overnight (12 h) within the specified temperature range of 20–25 °C. A completion analysis by HPLC indicated the reaction was complete (0.5% Compound IV remaining, target <1.0% remaining). The salt was filtered off and washed with THF (1920 mL). The filtrate was concentrated in vacuo and the residue (2321.2 g) was partitioned between DCM (5770 mL) and water (1150 mL). The organic layer was dried over MgSO (426.2 g), filtered, washed with DCM (1000 mL) and concentrated in vacuo. This gave the product as a pale yellow solid (1924.3 g), which was oven-dried at 40° C. for 24 hours to give compound III. Yield=(1502.2 g, 77.5%). Material purity by HPLC 98.48% (0.0% Compound IV).

[0184] 1.2 Synthesis of trans compound XI (i) Synthesis of trans compound XII by reductive amination

[0185] [ka]

[0186] 4-Acetamidocyclohexanone XIII (850 g, 5.477 mol), N-methylpiperazine (729 mL, 6.573 mol), and MeSO3H (28.5 mL, 0.438 mL) in toluene (6.8 L) were heated at reflux using a Dean & Stark separator for 5 h (94 mL of water was collected). Those skilled in the art will recognize that alternative amine protecting groups, such as BOC, Bn2, and the like, can be used with compound XIII. After that time, the mixture was cooled to 50 °C (the mixture solidifies at lower temperatures) and diluted with EtOH (6.8 L). The intermediate enamine was treated in portions with NaBH4 (207.2 g, 5.477 mol) at 15–20 °C and stirred overnight at room temperature. Excess NaBH4 was destroyed with 6 M HCl (4 L) at 10–15 °C. Those skilled in the art will understand that alternative reducing agents, for example, LiBH4 instead of NaBH4, can be used. The layers were separated, and the aqueous layer was treated with K2CO3 (1.2 kg, to achieve pH = 8). The solid was filtered off and washed with DCM (2.5 L, which was used later for extraction). The filtrate was concentrated. The residue was extracted with DCM (2 x 2.5 L), basified with 1.25 M KOH (200 ml, to pH = 10), and extracted with DCM (2.5 L). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product (1020 g) was combined with 3792 g of product from batches 1-3 prepared by the same method and purified on basic alumina (16.5 kg) eluting with 50% heptane / DCM (16 L), 75% heptane / DCM (32 L), DCM (40 L), then 10 L 1% MeOH / DCM to give the product as a white solid (yield 2410 g, 47%; cis:trans ratio 36:64).

[0187] The product was combined with 753.7 g of the cis / trans product, dissolved in MeCN (9.32 L) at reflux, and allowed to cool to RT overnight. The suspension was cooled to 5-10 °C and stirred for 2 h. The precipitate was filtered off, washed with MeCN (1 × 3.1 L, 1 × 2 L, and 1 × 1 L) and sucked dry on the filter. The product was dried at 45 °C overnight. This gave 544.9 g of product trans XII as a white solid (1613.2 g, ca. 25% yield). 1HN Purity exceeds 95% by MR, 1 No cis isomer was detected by 1 H NMR).

[0188] (ii) Compound trans XI

[0189] [ka]

[0190] Concentrated hydrochloric acid (4500 mL) was added to water (2240 ​​mL) over 5 minutes while maintaining the temperature within the specified range of 20-40°C (final temperature 23.83°C). Trans XII (1100.9 g) was added over 4 minutes, and the reaction was then stirred for 10 minutes. The reaction was heated to 95-106°C overnight (17.5 hours), by which time 1 In-process check by H NMR indicated the reaction was complete. The reaction mixture was cooled to within the specified range of 15-25°C over 72 minutes. While maintaining the temperature within the specified range of 20-45°C, solid potassium hydroxide (5890.1 g) was added in portions over approximately 1 hour to give a final pH of 12. The reaction mixture was cooled to within the specified range of 15-25°C over 5 minutes and stirred overnight (17.5 hours) within the specified range of 15-25°C (final temperature 17.97°C). The suspension was filtered, and the filter cake was washed with THF (6120 mL x 3, then 4080 mL). The combined filtrate was returned to the vessel, and the phases were separated. The organic phase was concentrated in vacuo in portions to give 1287.4 g of material. Residual water was removed by azeotroping with toluene (2025 mL, then 2020 mL). The product was then dissolved in DCM (2000 mL), the solid filtered off (to remove a small amount of inorganic material), washed with DCM (200 ml), and the filtrate concentrated in vacuo to give the product as a low melting solid (939.1 g, quantitative yield, active yield ( 1 1 H NMR) 888.4g, 97.9%). 1 4.59% toluene and 0.81% DCM by H NMR, 90.1% trans XI by HRGC.

[0191] 1.3 Alternative synthesis of trans compound XI Alternatively, the reductive amination step can be carried out as follows:

[0192] [ka]

[0193] Boc-4-aminocyclohexanone (20 g, 93.8 mmol) was added to the flask at RT under N, followed by N-methylpiperazine (13 mL, 117.2 mmol), methanesulfonic acid (0.5 mL, 7.7 mmol), and toluene (140 mL). The slurry was heated to reflux in a Dean-Stark setup over 30 min [no exotherm observed upon warming] to produce a light brown solution. The solution was stirred at 110-115 °C for 6 h to remove HO, at which point 1 H NMR showed 83% enamine. The solution was cooled to 50 °C over 20 min (using an ice / water bath) and EtOH (100 mL) was added. The solution was then further cooled to 20 °C over 20 min and LiBH (2 M in THF, 100 mL, 200.0 mmol) was added dropwise over 30 min (an exotherm of 20-27 °C and significant off-gassing was observed). The reaction was stirred at RT for 18 h. At this point, 1H NMR showed less than 5% enamine. The reaction was quenched via the dropwise addition of 6 M HCl (approximately 150 mL, 900.0 mmol) over 15 min until a pH of 2 was observed [exotherm 20-25 °C and slight off-gassing]. The phases were separated and the organic layer was removed. The aqueous was then basified via the addition of K2CO3(s) (30 g, 217.1 mmol) over 15 min until a pH of 8 was reached [exotherm 20-28 °C and significant off-gassing]. The slurry was filtered and the filtrate reduced in vacuo to give a pale brown oil. The filter cake was washed with DCM (2 × 80 mL). The brown oil was partitioned between DCM from the filter cake washes and 2 M NaOH (20 mL). The aqueous was removed and extracted with DCM (90 mL). The combined DCM extracts were dried (MgSO4), filtered, and reduced in vacuo to give a pale orange oil. The oil was azeotroped with MeCN (100 mL) to give 23 g of a beige solid (82% crude yield). 1 H NMR indicated a trans to cis ratio of approximately 75 / 25 and an overall purity of approximately 50%. An 11 g portion of the solid was slurried in MeCN (55 mL), heated to 70° C. (a solution formed at 67° C.), and then cooled to RT over 1 h. The slurry was stirred at RT for 18 h. The slurry was filtered, washed (MeCN, 5 mL), and dried in vacuo to give 1,2-dichloro-2,4 ... 1 This gave 4.3 g of the trans Boc-protected product (32% yield) as a white powder with 95% purity by 1 H NMR.

[0194] The trans Boc-protected product was then deprotected to yield trans XI by treatment with concentrated HCl under the same conditions described above in section 1.2(ii).

[0195] 1.4 Synthesis of Compound I (i) Compound II

[0196] [ka]

[0197] Compound III (1490.6 g active, 1492.7 g total) in NMP (2960 mL) A solution of 115-125°C (898.9 g) and Compound X (898.9 g) was heated within the specified range of 115-125°C over 51 minutes, then heated within the range of 115-125°C for 36 hours. The batch was cooled with stirring for 4 hours, after which time it was allowed to cool without stirring (when cooled, the batch contains a significant amount of solids that do not easily stir). After standing for approximately 29 hours, the batch was warmed to 52°C, allowing the batch to be sampled as a mobile, homogeneous suspension. Analysis by HPLC indicated the reaction was complete (83.35% Compound II present, target GT 75%). The batch was cooled to 20°C and the mixture was diluted with water for pouring (6000 mL). A moderate exotherm was observed, causing the batch to warm to 26.8°C. External cooling was applied, and the batch was then stirred for 40 minutes within the specified range of 10-25°C. The product was filtered, washed with water for pouring (2 x 1500 mL), sucked dry, and oven-dried within the specified range of 45-55°C for 18-20 hours, by which time the product in each of the three oven-drying trays showed a water content of 10% (by KF analysis). To remove unreacted Compound III, the crude product (2212.7 g) was dissolved in toluene (6 The solids were slurried in toluene (1520 mL) at 10-25°C (final temperature 18.3°C) for 74 minutes. The solids were filtered, washed with toluene (1520 mL), and oven-dried for 17 hours within the specified range of 45-55°C. In-process analysis of the solids in each of the three oven-dried trays was 0.21-0.35% Compound III (target LT 0.5%) by HPLC; 1 H NMR showed 1.56-1.85% NMP (target NMT 2.5%), and toluene 1 Not detected by H NMR (Result FOI). The solid was then packaged. Yield 1905.8 g (89.7% yield). Purity by HPLC 93.16% (0.30% Compound III).

[0198] (ii) Compound I

[0199] [ka]

[0200] To a suspension of Compound II (1869.8 g active, 1896.5 g total) in DCM (18640 mL) was added HBTU (1801.9 g), rinsing with DCM (20 mL) within the specified range of 15-25 °C. DIPEA (1500 mL) was then added dropwise within the specified range of 15-25 °C. The reaction mixture was stirred within the specified range of 15-25 °C for 31 minutes, by which time analysis by TLC indicated complete consumption of Compound II. Trans Compound XI (905.1 g) was added in portions over 30 minutes, while maintaining the temperature within the specified range of 15-25 °C. The reaction mixture was stirred within the specified range of 15-25 °C for 69 minutes. The batch was then sampled, and analysis by HPLC indicated 0.02% Compound II remaining (target LT 0.5%). To remove HOBt, the mixture was washed with NaOH solution (9440 mL, then 9400 mL, then 9420 mL, 0.4 M NaOH) and water (9400 mL). After the final wash, in-process analysis showed 0.05% HOBt by HPLC (target LT 1%). It was noted that a significant amount of solid had precipitated in the organic layer. The organic layer could not be immediately dried with MgSO because solid would have been lost during filtration. The suspension in the organic phase was filtered, and the filter cake was washed with DCM (500 mL). The filtrate was then dried with MgSO (1284.3 g), filtered, and washed with DCM (1500 mL). The organics were then concentrated in vacuo at 40 °C. The filtered solids were then added to give 3489.9 g of solid. The crude product (in six flasks) was evaporated from EtOAc (6500 mL total). The product was returned to the 50 L vessel, slurried in EtOAc (8500 mL) within the specified range of 10-25° C. for 36 minutes, filtered, washed with EtOAc (2160 mL, then 2150 mL), and dried within the specified range of 45-55° C. for 64.5 hours. This gave 2475.3 g of product ( 10% EtOAc, 10.6% DCM by HNMR. The product was dissolved in MeOH (5980 mL) within the specified range of 60-70°C (final temperature 62.7°C). The solution was immediately polish filtered into a 50 L vessel (final temperature 54.17°C). The solution was warmed to the specified range of 60-70°C (final temperature 60.3°C). Water (5760 mL) was added dropwise over 39 minutes while maintaining the temperature within the specified range of 60-70°C. The mixture was stirred within the specified range of 60-70°C for 10 minutes, then cooled to 25°C over 123 minutes. After stirring for 21 min within the specified range of 15-25 °C (final temperature 19.16 °C), the suspension was filtered, washed with a 1:1 solution of MeOH in water (2880 mL, then 2700 mL) for irrigation, sucked dry on the filter, and oven-dried for 19.5 h within the specified range of 45-55 °C to give 2076.3 g (78.8% yield) of product. Purity by HPLC: 96.43% (0.33% compound I cis, 0.01% compound II, 0.01% HOBt, specification NLT 95.0%); 2.75% water by KF.

[0201] Comparative Example (according to WO 2009 / 040556) (i) 4-(4-methylpiperazin-1-yl)cyclohexanamine N-benzyloxycarbonyl-4-aminocyclohexanone (1 mmol) was added to a reaction tube containing THF (5 mL), N-methylpiperazine, acetic acid, and sodium triacetoxyborohydride. The reaction was stirred at ambient temperature for 20 hours. The reaction was quenched with NaHCO3 solution (2 mL) and then acidified to pH 2 with 1N HCl solution. After washing the mixture with EtOAc, the aqueous layer was separated and basified to pH 10 with 2N NaOH solution. The product was extracted into EtOAc, which was washed with saturated NaCl, dried (MgSO4), and evaporated under reduced pressure. The product so produced was dissolved in methanol to a concentration of 0.05 M. A total hydrogen molar ratio was calculated using an H-Cube™ (ThalesNano Inc.) flow reactor. Hydrogenation was carried out at a flow rate of 1 mL / min over a 10% Pd / C catalyst heated for 5-60°C under reduced pressure. Concentration under reduced pressure provided 4-(4-methylpiperazin-1-yl)cyclohexanamine.

[0202] (ii) Compound I Compound III (66mg, 0.15mmol, 1eq), DIPEA (52μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) in 1 mL After adding DMF and stirring the resulting solution at room temperature for 20 minutes, 4-(4-methylpiperazin-1-yl)cyclohexanamine (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL) was added. The reaction mixture was then stirred at room temperature for 2 hours and then purified by preparative RP-HPLC-MS to give compound I (17 mg, 18%) as a white solid.

[0203] Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

Claims

1. To prepare a compound of formula (XII) (wherein PG is a protecting group) or a compound of formula (XI), 1. A method for producing a medicament for use in a medical device, comprising: 【Chemical 1】 (i) treating a compound of formula XIII (wherein PG is a protecting group) with N-methylpiperazine to produce a compound of formula XII, wherein said compound of formula XII is in the form of a mixture of cis and trans isomers; (ii) combining the mixture produced in step (i) with an organic solvent and heating the solvent mixture so produced; (iii) isolating the trans isomer of the compound of formula XII from the solvent mixture produced in step (ii); (iv) optionally treating the trans isomer of the compound of formula XII with an acid to give a compound of formula XI and isolating said compound of formula XI. The method comprising:

2. PG is acetyl, tert-butoxycarbonyl (BOC) and dibenzyl (Bn ２ 2. The method of claim 1, wherein the compound is selected from the group consisting of:

3. 3. The method of claim 1, wherein the protecting group PG is acetyl.

4. The method according to claim 1 or 2, wherein the protecting group PG is tert-butoxycarbonyl (BOC).

5. The protecting group PG is dibenzyl (Bn ２ 3. The method according to claim 1 or 2, wherein

6. Step (i) (a) forming a mixture comprising a compound of Formula XIII, N-methylpiperazine, a solvent, and an acid, and heating the mixture; (b) cooling the mixture obtained in step (a) and diluting with a solvent; (d) treating the mixture obtained in step (b) with a reducing agent; (e) isolating the compound of formula XII as a mixture of cis and trans isomers; The method according to any one of claims 1 to 5, comprising:

7. The reducing agent in step (d) is NaBH ４ The method of claim 6, wherein

8. The reducing agent in step (d) is LiBH ４ The method of claim 6, wherein

9. 9. The method according to any one of claims 6 to 8, wherein the solvent in step (i)(a) is toluene and the acid is a sulfonic acid selected from benzenesulfonic acid, para-toluenesulfonic acid and methanesulfonic acid, more preferably methanesulfonic acid.

10. The method according to any one of claims 1 to 9, wherein the organic solvent in step (ii) is acetonitrile.

11. The method of any preceding claim, wherein step (ii) comprises heating the solvent mixture.

12. 12. The method of any of claims 1 to 11, wherein step (iii) comprises cooling the mixture so that the compound of formula XII precipitates from solution, filtering the precipitate so formed, and optionally washing and / or drying said precipitate.

13. Step (iii) is performed by heating the mixture at a temperature of from 0 to about 15°C, more preferably from about 5 to about 10°C. The method of any one of claims 1 to 12, comprising the step of cooling to

14. The method according to any one of claims 1 to 13, wherein the compound of formula XII obtained in step (iii) is substantially free of cis isomers.

15. 10. The method of claim 1, further comprising treating a compound of formula XII with an acid to produce a compound of formula XI.

15. The method according to any one of 14.

16. 16. The method of claim 15, comprising treating the compound of formula XII with concentrated HCl.

17. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (I) preparing a compound of formula XI by a method according to any one of claims 1 to 16; (II) contacting said compound of formula XI with a compound of formula II to produce a compound of formula I. 【Chemistry 2】 and, (III) isolating said compound of formula I; (IV) optionally converting said compound of formula I into its pharmaceutically acceptable salt form; The method comprising:

18. 18. The method of claim 17, wherein the compound of formula XI is substantially free of cis isomers.

19. 19. The method of claim 17 or 18, wherein step (II) is carried out in the presence of dichloromethane, N,N-diisopropylethylamine (DIPEA), and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU).

20. a compound of formula II by a reaction comprising contacting a compound of formula III with a compound of formula X Preparation steps: 【Chemistry 3】 The method of any of claims 17 to 19, further comprising:

21. 21. The method of claim 20, wherein the reaction is carried out in N-methylpyrrolidone and the reaction mixture is heated to a temperature of at least 110°C, more preferably from about 115°C to about 125°C.

22. A compound of formula III is prepared by a reaction comprising treating a compound of formula IV with MeI. Steps 【Chemistry 4】 22. The method of claim 20 or 21, further comprising:

23. 23. The process of claim 22, wherein the reaction is carried out in the presence of t-BuOK and THF, preferably the reaction is carried out at a temperature below about 10°C, more preferably at a temperature of about 0 to about 5°C.

24. Preparing a compound of formula IV by a reaction comprising treating a compound of formula V with Fe powder in the presence of acetic acid: 【Chemistry 5】 24. The method of claim 22 or 23, further comprising:

25. 25. The method of claim 24, wherein the reaction is carried out at a temperature of about 25 to about 30°C.

26. Preparing a compound of formula V by a reaction comprising contacting a compound of formula VI with a compound of formula IX: 【Chemistry 6】 26. The method of claim 24 or 25, further comprising:

27. The reaction is ２ CO ３ 27. The method of claim 26, wherein the method is carried out in the presence of at a temperature preferably below about 10°C, more preferably below about 5°C.

28. a reaction comprising contacting a compound of formula VII with cyclopentanone in the presence of a reducing agent. Preparing a compound of formula VI by: 【Chemistry 7】 28. The method of claim 26 or 27, further comprising:

29. 29. The method of claim 28, wherein the reaction is carried out in the presence of sodium triacetoxyborohydride (STAB) and dichloromethane.

30. The compound of formula VIII is hydrogenated in the presence of a solvent and a Raney nickel catalyst to give the compound of formula VII.

2. Preparing a compound of formula: 【Chemistry 8】 30. The method of claim 28 or 29, further comprising:

31. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (A) Hydrogenating a compound of formula VIII in the presence of a Raney nickel catalyst to produce a compound of formula VII. Steps to complete 【Chemistry 9】 and, (B) contacting said compound of formula VII with cyclopentanone to produce a compound of formula VI. Tep 【Chemistry 10】 and, (C) contacting said compound of formula VI with a compound of formula IX to produce a compound of formula V 【Chemistry 11】 and, (D) treating said compound of formula V with Fe powder in the presence of acetic acid to produce a compound of formula IV 【Chemistry 12】 and, (E) treating said compound of formula IV with MeI to produce a compound of formula III 【Chemistry 13】 and, (F) contacting said compound of formula III with a compound of formula X to produce a compound of formula II. P 【Chemistry 14】 and, (G) contacting said compound of formula II with a compound of formula XI to produce a compound of formula I, preferably wherein said compound of formula XI is substantially free of cis isomers. 【Chemistry 15】 and, (H) isolating said compound of formula I; (I) optionally converting said compound of formula I into its pharmaceutically acceptable salt form; The method comprising:

32. 32. The method of claim 31, wherein the compound of formula XI is prepared by the method of any of claims 1 to 16.

33. A process for preparing a compound of formula II, comprising: contacting a compound of formula III with a compound of formula X in N-methylpyrrolidone; and isolating said compound of formula II: 【Chemistry 16】 The method comprising:

34. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising: (I') preparing a compound of formula II by the method of claim 33; (II') contacting said compound of formula II with a compound of formula XI to produce a compound of formula I; (III') isolating said compound of formula I; (IV') optionally converting said compound of formula I into its pharmaceutically acceptable salt form. 【Chemistry 17】

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