Patent Publication Number: US-2022234990-A1

Title: Methods of synthesis of (1r,2r,5r)-5-amino-2-methyl-cyclohexanol hydrochloride and intermediates useful therein

Description:
This application is a continuation of U.S. patent application Ser. No. 16/992,219, filed Aug. 13, 2020, which is a continuation of U.S. patent application Ser. No. 16/258,802, filed Jan. 28, 2019, now U.S. Pat. No. 10,774,033, issued Sep. 15, 2020, which is a continuation of U.S. patent application Ser. No. 15/746,853, filed Jan. 23, 2018, now U.S. Pat. No. 10,252,981, issued Apr. 19, 2019, which is a U.S. national stage application of International Patent Application No. PCT/US2016/043511, filed Jul. 22, 2016, which claims the benefit of priority to U.S. Provisional Application Ser. No. 62/196,363, filed Jul. 24, 2015, each of which is incorporated herein by reference in its entirety and for all purposes. 
    
    
     FIELD 
     Provided herein are methods and intermediates for making (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride, which are useful for the preparation of compounds useful for the treatment of a disease, disorder, or condition associated with the JNK pathway. 
     BACKGROUND 
     The connection between abnormal protein phosphorylation and the cause or consequence of diseases has been known for over 20 years. Accordingly, protein kinases have become a very important group of drug targets. (See Cohen,  Nature,  1:309-315 (2002), Gaestel et al.  Curr. Med. Chem.  14: 2214-223 (2007); Grimminger et al.  Nat. Rev. Drug Disc.  9(12):956-970 (2010)). Various protein kinase inhibitors have been used clinically in the treatment of a wide variety of diseases, such as cancer and chronic inflammatory diseases, including rheumatoid arthritis and psoriasis. (See Cohen,  Eur. J. Biochem.,  268:5001-5010 (2001); Protein Kinase Inhibitors for the Treatment of Disease: The Promise and the Problems,  Handbook of Experimental Pharmacology, Springer Berlin Heidelberg,  167 (2005)). 
     JNK is a ubiquitously expressed serine/threonine kinase belonging, together with ERK (extracellular-regulated kinase) and p38, to the family of mitogen-activated protein kinases (MAPKs). (Kyriakis J M,  Sci. STKE  (48):pe1 (2000); Whitmarsh A J, et al.  Sci. STKE  (1):pe1 (1999); Schramek H,  News Physiol. Sci.  17:62-7 (2002); Ichijo H,  Oncogene  18(45):6087-93 (1999)). MAPKs are important mediators of signal transduction from the cell surface to the nucleus, using phosphorylation cascades to generate a coordinated response by a cell to an external stimulus by phosphorylation of selected intracellular proteins, including transcription factors. Additionally, JNK also phosphorylates non-nuclear proteins, for example, IRS-1, and Bcl-2 family members. (Davis R J,  Trends Biochem. Sci.  9(11):470-473 (1994); Seger R et al.,  FASEB J.;  9(9):726-35 (1995); Fanger G R et al.,  Curr. Opin. Genet. Dev.;  7(1):67-74 (1997)). 
     The elucidation of the intricacy of protein kinase pathways and the complexity of the relationship and interaction among and between the various protein kinases and kinase pathways highlights the importance of developing pharmaceutical agents capable of acting as protein kinase modulators, regulators or inhibitors that have beneficial activity on multiple kinases or multiple kinase pathways. The compound chemically named 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (alternatively named 2-[(1,1-dimethylethyl)amino]-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-5-pyrimidinecarboxamide; and referred to herein as “Compound I”), an inhibitor of the JNK pathway, is disclosed in U.S. Patent Application Publication No. 2013/0029987, published on Jan. 31, 2013, International Pub. No. WO 2012/145569 and U.S. patent application Ser. No. 14/608,314, filed Jan. 29, 2015, the entireties of each of which are incorporated by reference herein. Accordingly, there remains a need for new processes for the preparation of Compound I. 
     Citation or identification of any reference in Section 2 of this application is not to be construed as an admission that the reference is prior art to the present application. 
     SUMMARY 
     Provided herein are processes and intermediates useful for the preparation of Compound I: 
     
       
         
         
             
             
         
       
     
     having the name 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, which is useful for the treatment of a disease, disorder, or condition associated with the INK pathway. 
     In particular, provided herein are processes for making a compound of formula (A): 
     
       
         
         
             
             
         
       
     
     having the name (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride. 
     Provided is a method for preparing a compound of formula (A), 
     
       
         
         
             
             
         
       
     
     comprises the steps of:
         (a) contacting a compound of formula (1),       

     
       
         
         
             
             
         
       
     
     with a compound of formula (2), 
     
       
         
         
             
             
         
       
         
         
           
             in the presence of a Lewis Acid in a solvent to provide a compound of formula (3), 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             (b) contacting the compound of formula (3) of step (a) with an aqueous base to provide a compound of formula (4), 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             (c) contacting the compound of formula (4) of step (b) with DMF and a chlorinating agent in an organic solvent, followed by treatment of the resulting acid chloride derivative with aqueous ammonia to provide a compound of formula (5), 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             (d) contacting the compound of formula (5) of step (c) with an aqueous solution of NaOH and NaOCl to provide a compound of formula (6), 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             (e) contacting the compound of formula (6) of step (d) with (+)-dibenzoyl-D-tartaric acid monohydrate in a solvent to provide a compound of formula (7), 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             (f) contacting the compound of formula (7) of step (e) with an aqueous base, followed by treatment of the resulting free base with Boc 2 O in an organic solvent to provide a compound of formula (8), 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             (g) contacting the compound of formula (8) of step (f) with a mixture of a reducing agent, a chiral auxiliary and a Lewis acid in a solvent, followed by treatment with an oxidant in the presence of a base to provide a compound of formula (9), 
           
         
       
    
     
       
         
         
             
             
         
       
     
     and
         (h) contacting the compound of formula (9) of step (g) with a solution of hydrochloric acid in a solvent to provide the compound of formula (A). In one embodiment, the Lewis acid of step (a) is AlCl 3 . In a further embodiment, the solvent of step (a) is DCM. In one embodiment, the base of step (b) is NaOH. In one embodiment, the chlorinating agent of step (c) is SOCl 2 . In a further embodiment, the organic solvent of step (c) is DCM. In one embodiment, the solvent of step (e) is MeOH. In one embodiment, the base of step (f) is NaOH. In a further embodiment, the organic solvent of step (f) is DCM. In one embodiment, the reducing agent of step (g) is NaBH 4 . In a further embodiment, the chiral auxiliary of step (g) is α-pinene. In a particular embodiments, the Lewis acid of step (g) is BF 3 .Et 2 O. In another particular embodiment, the solvent of step (g) is THF. In still another embodiment, the oxidant of step (g) is H 2 O 2 . In a specific embodiment, the base of step (g) is NaOH. In one embodiment, the solvent of step (h) is IPA.       

     In certain aspects, Compound I is useful for inhibiting a kinase in a cell expressing said kinase, for example JNK1 or JNK2. In other aspects, Compound I is useful for treating or preventing a condition treatable or preventable by inhibition of a JNK pathway, as described herein. In another aspect, Compound I is useful for treating or preventing one or more disorders selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection, or lupus. In yet another aspect, Compound I is useful for treating or preventing liver fibrotic disorders, or diabetes and/or metabolic syndrome leading to liver fibrotic disorders, as described herein. 
     The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  depicts a  1 H NMR spectrum of Compound (A) in D 2 O. 
         FIG. 2  depicts an expanded (˜0.2-3.6 ppm)  1 H NMR spectrum of Compound (A) in D 2 O. 
         FIG. 3  depicts a HPLC chromatogram of Compound (A). 
         FIG. 4  depicts a chiral GC chromatogram of Compound (A). 
     
    
    
     DETAILED DESCRIPTION 
     Definitions 
     As used herein, and in the specification and the accompanying claims, the indefinite articles “a” and “an” and the definite article “the” include plural as well as single referents, unless the context clearly indicates otherwise. 
     As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with amounts or weight percents of ingredients of a process, mean an amount or weight percent that is recognized by one of ordinary skill in the art to provide an effect equivalent to that obtained from the specified amount, or weight percent. In certain embodiments, the terms “about” and “approximately,” when used in this context, contemplate an amount or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified amount or weight percent. 
     “JNK” means a protein or an isoform thereof expressed by a JNK1, JNK2, or JNK3 gene (Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J., Sluss, H. K., Derijard, B. and Davis, R. J.  The EMBO J.  15:2760-2770 (1996)). 
     “Treating” as used herein, means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is a condition treatable or preventable by inhibition of a INK pathway, as described herein. In another embodiment, the disorder is selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection, or lupus. In yet another embodiment, the disorder is a liver fibrotic disorder, or diabetes and/or metabolic syndrome leading to liver fibrotic disorders, as described herein. In some embodiments, the disorder is a liver fibrotic disorder, such as non-alcoholic steatohepatitis, steatosis (i.e. fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, or liver fibrosis coincident with chronic or repeated alcohol ingestion (alcoholic hepatitis), with infection (e.g., viral infection such as HCV), with liver transplant, or with drug induced liver injury (e.g., acetaminophen toxicity). In some embodiments, “treating” means an alleviation, in whole or in part, of a disorder, disease or condition, or symptoms associated with diabetes or metabolic syndrome leading to liver fibrotic disorders, such as non-alcoholic steatohepatitis, steatosis (i.e. fatty liver), hepatitis or cirrhosis, or a slowing, or halting of further progression or worsening of those symptoms. In one embodiment, the symptom is jaundice. 
     “Preventing” as used herein, means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject&#39;s risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is a condition treatable or preventable by inhibition of a JNK pathway, as described herein. In another embodiment, the disorder is selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection, or lupus. In one embodiment, the disorder is a liver fibrotic disorder, or diabetes or metabolic syndrome leading to liver fibrotic disorders, as described herein, or symptoms thereof. 
     “Patient” or “subject” is defined herein to include animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quails, or guinea pigs and the like, in one embodiment a mammal, in another embodiment a human. In one embodiment, a subject is a human having or at risk for having interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection, or lupus. In another, a subject is a human having or at risk for having liver fibrotic disorders or diabetes or metabolic syndrome leading to liver fibrotic disorders, or a condition, treatable or preventable by inhibition of a INK pathway, or a symptom thereof. 
     Compound (A) 
     As described in U.S. Patent Application Publication No. 2013/0029987, published on Jan. 31, 2013, International Pub. No. WO 2012/145569 and U.S. patent application Ser. No. 14/608,314, filed Jan. 29, 2015, the entireties of each of which are incorporated by reference herein, compounds of formula I can be prepared as shown in Scheme A. 
     
       
         
         
             
             
         
       
     
     The processes provided herein relate to methods for making a compound of formula (A): 
     
       
         
         
             
             
         
       
     
     having the name (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride, and intermediates useful in said processes. 
     It should be noted that if there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. 
     Methods for Making Compound (A) 
     By way of example and not limitation, the compound of formula (A) can be prepared as outlined in Scheme 1 shown below, as well as in the examples set forth herein. 
     
       
         
         
             
             
         
       
     
     In one aspect, provided herein are methods for preparing a compound of formula (A): 
     
       
         
         
             
             
         
       
     
     the methods comprising contacting a compound of formula (9): 
     
       
         
         
             
             
         
       
     
     with hydrochloric acid in a solvent. 
     In some embodiments, the solvent is methanol, 2-propanol (IPA), ether or dioxane. In one embodiment, the solvent is 2-propanol (IPA). 
     In some embodiments, the methods further comprise preparing a compound of formula (9): 
     
       
         
         
             
             
         
       
     
     the methods comprising contacting a compound of formula (8): 
     
       
         
         
             
             
         
       
     
     with a mixture of a reducing agent, a chiral auxiliary and a Lewis acid in a solvent, followed by treatment with an oxidant in the presence of a base. 
     In one embodiment, the reducing agent is NaBH 4 . In another embodiment, the chiral auxiliary is α-pinene. In another embodiment, the Lewis acid is BF 3 .Et 2 O. In one embodiment, the solvent is THE or EtOH. In another embodiment, the solvent is THF. In one embodiment, the oxidant is H 2 O 2  or oxone. In another, the oxidant is H 2 O 2 . In one embodiment, the base is NaOH. 
     In some embodiments, the methods further comprise preparing a compound of formula (8): 
     
       
         
         
             
             
         
       
     
     the methods comprising contacting a compound of formula (7): 
     
       
         
         
             
             
         
       
     
     with an aqueous base, followed by treatment of the resulting free base with Boc 2 O in an organic solvent, optionally in the presence of a second base. 
     In one embodiment, the aqueous base is aqueous NaOH. In one embodiment, the organic solvent is DCM or ether. In another embodiment, the organic solvent is DCM. In one embodiment, the second base is triethylamine. 
     In some embodiments, the methods further comprise preparing a compound of formula (7): 
     
       
         
         
             
             
         
       
     
     the methods comprising contacting a compound of formula (6): 
     
       
         
         
             
             
         
       
     
     with (+)-dibenzoyl-D-tartaric acid monohydrate in a solvent. 
     In one embodiment, the solvent is methanol. 
     In some embodiments, the methods further comprise preparing a compound of formula (6): 
     
       
         
         
             
             
         
       
     
     the methods comprising contacting a compound of formula (5): 
     
       
         
         
             
             
         
       
     
     with an aqueous solution of NaOH and NaOCl. 
     In some embodiments, the methods further comprise preparing a compound of formula (5): 
     
       
         
         
             
             
         
       
     
     the methods comprising contacting a compound of formula (4): 
     
       
         
         
             
             
         
       
     
     with DMF and a chlorinating agent in an organic solvent, followed by treatment of the resulting acid chloride derivative with aqueous ammonia. 
     In one embodiment, the chlorinating agent is oxalayl chloride or SOCl 2 . In one embodiment, the chlorinating agent is SOCl 2 . In one embodiment, the organic solvent is DCM. 
     In some embodiments, the methods further comprise preparing a compound of formula (4): 
     
       
         
         
             
             
         
       
     
     the methods comprising contacting a compound of formula (3): 
     
       
         
         
             
             
         
       
     
     with an aqueous base. 
     In one embodiment, the base is LiOH or NaOH. In another embodiment, the base is NaOH. 
     In some embodiments, the methods further comprise preparing a compound of formula (3): 
     
       
         
         
             
             
         
       
     
     the methods comprising contacting a compound of formula (1): 
     
       
         
         
             
             
         
       
     
     with a compound of formula (2): 
     
       
         
         
             
             
         
       
     
     in a solvent, in the presence of a Lewis acid. 
     In one embodiment, the Lewis acid is AlCl 3 . In one embodiment, the solvent is DCM. 
     Intermediates useful in the processes provided herein include: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Utility of Compound I 
     Compound I has utility as a pharmaceutical to treat, prevent or improve conditions in animals or humans. In particular, Compound I is active against protein kinases, particularly JNK1 and/or JNK2. Uses of Compound I are disclosed in U.S. Patent Publication No. 2013/0029987, published Jan. 31, 2013, which is incorporated by reference herein in its entirety. 
     Abbreviations 
     The following abbreviations are used in descriptions and examples: 
     ACN: Acetonitrile 
     Boc: tert-Butoxycarbonyl
 
n-BuOH: n-Butanol
 
DBTA: Dibenzoyl-D-tartaric acid
 
DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene
 
     DCM: Dichloromethane 
     DIPEA: N,N-Diisopropylethylamine 
     DMAc: N,N-Dimethylacetamide 
     DMF: N,N-Dimethylformide 
     DMSO: Dimethylsulfoxide 
     EtOAc: Ethyl acetate 
     EtOH: Ethanol 
     GC: Gas Chromatography 
     IPA: 2-Propanol 
     IPAc: Isopropyl acetate 
     LC: Liquid Chromatography 
     MeOH: Methanol 
     2-MeTHF: 2-Methyl tetrahydrofuran
 
MS: Mass spectrometry
 
MTBE: tert-Butyl methyl ether
 
NMP: N-Methyl-2-pyrrolidone
 
NMR: Nuclear magnetic resonance
 
     OR: Optical Rotation 
     SFC: Supercritical Fluid Chromatography 
     Tf: Triflate or trifluoromethanesulfonyl 
     TFE: 2,2,2-Trifluoroethanol 
     THF: Tetrahydrofuran 
     SYNTHETIC EXAMPLES 
     The following synthetic examples, presented by way of illustration and not limitation, show methods for the preparation of Compound (A). ACD/NAME (Advanced Chemistry Development, Inc., Ontario, Canada) was used to generate names for chemical structures and Chemdraw (Cambridgesoft, Perkin Elmer, Waltham, Mass.) to draw the chemical structures. In certain cases, Chemdraw was used to generate names for chemical structures. 
     Example 1: Synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     Methyl 4-methylcyclohex-3-enecarboxylate (3): To a reactor was added DCM (2.5 L) and methyl acrylate (1) (500.0 g) at 20-25° C. under an atmosphere of nitrogen. After stirring for 5 min., the batch was cooled to 0° C., and isoprene (2) (593.4 g) was added over 5-10 min. After stirring for 5 min. at 25° C., anhydrous AlCl 3  (116.2 g) was added over 60-90 min. while maintaining the temperature between 0-10° C. After stirring at 0-10° C. for 30 min., the batch was gradually warmed to 25° C. and stirred (≥3 h) at that temperature until IPLC indicated &lt;1% unreacted methyl acrylate (1). Upon completion of the reaction, as indicated by HPLC, the batch was cooled to 0° C. and quenched with HCl solution (250 mL conc. HCl and 1750 mL water) over a period of 30-60 min. while keeping the temperature below 10° C. during the quenching period. The batch was allowed to warm up to 25° C., and was filtered through Hyflo to remove the undissolved solid while rinsing the residue with DCM (500 mL). The filtrate was extracted with DCM (1 L), and the combined organic layers were successively washed with 5% aqueous NaHCO 3  (1 L) solution and brine (1 L). DCM was distilled out from the organic fraction at 40-50° C. under atmospheric condition to furnish crude methyl 4-methylcyclohex-3-enecarboxylate (3) as a brown liquid (˜1200 g, quantitative yield, 85.54% purity by HPLC), which was used for the next step without purification. 
     4-Methylcyclohex-3-enecarboxylic acid (4): To a solution of NaOH (290.4 g NaOH in 1800 mL water) in a reactor at 15-20° C. was slowly added 4-methylcyclohex-3-enecarboxylate (3) (1200 g crude material from above; 895.63 g considering 100% yield), while keeping the temperature below 25° C. The batch was gradually warmed to 35-40° C. and the resulting clear solution was stirred (≥2 h) at that temperature until HPLC indicated &lt;1% unreacted intermediate (3). Upon completion of the reaction, as indicated by HPLC, the batch was brought to 25° C. and quenched with water (900 mL). The aqueous mixture containing the product was washed with DCM (2×900 mL). The aqueous layer was cooled to 0-10° C. and acidified with conc. HCl (630 mL) to pH 1-2 while keeping the temperature below 20° C. After stirring the mixture for 10 min. at 20-25° C., the product was extracted from the aqueous layer with DCM (2×900 mL). The combined organic layers were washed with water (900 mL). DCM was distilled out from the organic fraction at 40-45° C. and the resulting solid mass was vacuum dried for 1 h at 40-45° C. to furnish, upon cooling to room temperature, 4-methylcyclohex-3-enecarboxylic acid (4) (707.51 g, 86.90% yield based on HPLC, 85.28% purity by HPLC). The product thus obtained was dissolved in DCM (750 mL) and used for the next step without purification. 
     4-Methylcyclohex-3-enecarboxamide (5): To a reactor containing a solution of 4-methylcyclohex-3-enecarboxylic acid (4) in DCM from above (˜1614 g, containing ˜690 g of intermediate (4)) was added DMF (6.9 mL) at 25° C. under an atmosphere of nitrogen. After stirring the reaction for 5 min., thionyl chloride (673.44 g) was added over a period of 30-60 min. while keeping the temperature below 20° C. After stirring for 10 min. at 15-20° C., the reaction was warmed to 25-30° C. and stirred (≥2 h) at that temperature until TLC indicated &lt;2% unreacted intermediate (4). Upon completion of the reaction, as indicated by TLC, the solvents were completely distilled out under vacuum. The resulting mixture was vacuum dried for 30 min. at 35-40° C. and then brought to room temperature. The mass thus obtained was slowly added over a period of 30-60 min. to an ice-cold solution (0-5° C.) of aqueous ammonia (2.76 L) in a separate reactor while keeping the temperature below 10° C. After stirring the reaction mixture for 30 min. at 0-10° C., the resulting residue was filtered off, washed with water, and vacuum dried over air. The product was further dried in an air oven at 45-50° C. and brought to room temperature to furnish 4-methylcyclohex-3-enecarboxamide (5) as an off-white solid (604 g, 88.15% yield based on HPLC, 86.55% purity by HPLC), which was used for the next step without purification. 
     4-Methylcyclohex-3-enamine (6): To a solution of NaOH (481.68 g) and water (2.16 L) in a reactor at −5° C. to 5° C. was added slowly a solution of 10.5% w/w sodium hypochlorite (4587.4 g) under an atmosphere of nitrogen. After stirring for 10 min., 4-methylcyclohex-3-enecarboxamide (5) (600 g) was gradually added in portions at −5° C. to 5° C. The reaction was stirred for 6 h at a temperature below 10° C., gradually warmed to 25° C. and stirred (≥5 h) at that temperature until HPLC indicated &lt;5% unreacted intermediate (5). Upon completion of the reaction, as indicated by HPLC, toluene (1.2 L) was added. The mixture was cooled to 0-5° C. and acidified with conc. HCl (1.5 L) to pH 1-1.5 while keeping the temperature below 20° C. After stirring for 5 min., the organic layer was separated, and the aqueous layer was washed with toluene (1.2 L). The aqueous layer was then cooled to 0-5° C., and basified with aqueous NaOH solution (2.0 kg NaOH and 1340 mL H 2 O) to pH&gt;13 while keeping the temperature below 20° C. The product was extracted with DCM (2×1.5 L), and the combined organic layers were dried over sodium sulfate and filtered. DCM was distilled out from the filtrate at 40-60° C. under atmospheric conditions. The resulting residue was cooled to room temperature to furnish 4-methylcyclohex-3-enamine (6) (377.4 g, 78.74% yield based on HPLC, 85.74% purity by HPLC), which was used for the next step without purification. 
     (R)-4-Methylcyclohex-3-enamine hemi-dibenzoyl-D(+)-tartarate (7): A solution of (+)-dibenzoyl-D-tartaric acid monohydrate (1015.3 g) in methanol (3 L) was gradually brought to reflux. To this refluxing solution was slowly added a solution of 4-methylcyclohex-3-enamine (6) (300 g) in methanol (300 mL) over a period of 60-75 min. The reaction mixture was refluxed for 2 h and then gradually cooled to 25° C. over 4-5 h. After stirring the reaction mixture for an additional 1 h at 25° C., the resulting residue was filtered, washed with methanol, and dried under vacuum for 30 min. Chiral HPLC of the Boc protected product (prepared by converting an aliquot to the Boc derivative) indicated 71.22% of the desired (R)-4-methylcyclohex-3-enamine hemi-dibenzoyl-D(+)-tartarate (7), and 28.72% of the corresponding S-isomer. 
     The crude product obtained above (˜645 g) was treated with (+)-dibenzoyl-D-tartaric acid monohydrate (123.1 g) and methanol (3.8 L), and the resulting mixture was refluxed for 2 h, and then gradually cooled to 25° C. over 4-5 h. After stirring the reaction mixture for an additional 1 h at 25° C., the resulting residue was filtered, washed with methanol, and dried under vacuum for 30 min. Chiral HPLC of an aliquot of the product that was converted to the BOC derivative indicated 82.11% of the desired (R)-4-methylcyclohex-3-enamine hemi-dibenzoyl-D(+)-tartarate (7), and 17.82% of the corresponding S-isomer. 
     The crude product obtained above (˜480 g) was treated with (+)-dibenzoyl-D-tartaric acid monohydrate (93.3 g) and methanol (2.9 L), and the resulting mixture was refluxed for 2 h, and then gradually cooled to 25° C. over 4-5 h. After stirring the reaction mixture for an additional 1 h at 25° C., the resulting residue was filtered, washed with methanol, and dried under vacuum for 30 min. The product thus obtained was further dried in air oven at 45-50° C. to furnish (R)-4-methylcyclohex-3-enamine hemi-dibenzoyl-D(+)-tartarate (7) (220.5 g, 28.5% yield, 97.81% purity by GC, melting point range: 205.2-206.3° C., OR: +110.0° (C=1% in acetic acid at 25° C.)); chiral HPLC indicated 86.88% of the desired R-isomer and 13.12% of the corresponding S-isomer. 
     (R)-tert-Butyl (4-methylcyclohex-3-en-1-yl)carbamate (8): To a solution of NaOH (124 g) and water (1200 mL) at 10-20° C. was slowly added (R)-4-methylcyclohex-3-enamine hemi-dibenzoyl-D(+)-tartarate (7) (300 g) while keeping the temperature below 25° C. After stirring the reaction mixture for 15 min., the resulting free base was extracted from the aqueous layer using DCM (2×300 mL, 1×150 mL). The organic layers were combined, and the resulting solution (˜850 mL) was treated with Boc anhydride (236.8 g) at 0-5° C. The reaction mixture was allowed to warm to 25° C., and stirred (≥2 h) at that temperature until HPLC indicated &lt;1% unreacted intermediate (7). Upon completion of the reaction, as indicated by HPLC, water (230 mL) was added, and the mixture was stirred for 10 min. The organic layer was separated and washed with 2% aqueous citric acid solution (230 mL) followed with water (230 mL). DCM was distilled out at 30-40° C. under vacuum, and the resulting pale yellow mass was vacuum dried for 30 min. at 40-45° C. to furnish (R)-tert-butyl (4-methylcyclohex-3-en-1-yl)carbamate (8) (216 g, 98.91% yield based on HPLC, 98.36% purity by HPLC), which contained 14.85% of the corresponding S-isomer as indicated by chiral HPLC. The product thus obtained was taken in THE (437 mL), stirred for 10 min. to obtain a clear solution, and stored under an atmosphere of nitrogen for use in the next step. 
     tert-Butyl ((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)carbamate (9): To a suspension of sodium borohydride (76.97 g) in THE (1290 mL) at 25° C. was slowly added (−)-α-pinene (582.07 g) over a period of 15 min. under an atmosphere of nitrogen. After cooling the reaction mixture to 0-5° C., boron trifluoride etherate (57%, 531.95 g) was added slowly over a period of 30-60 min. The reaction was allowed to warm to 25° C., stirred for 8 h, and then treated with the solution of (R)-tert-butyl (4-methylcyclohex-3-en-1-yl)carbamate (8) in THE prepared above (623 g, containing 215 g of (8)). The resulting reaction mixture was stirred (≥3 h) at 25° C. until HPLC indicated &lt;1% unreacted intermediate (8). After cooling to 0-5° C., the reaction was quenched slowly by adding water over a period of 30-60 min., followed by subsequent addition of aqueous NaOH (244.15 g NaOH and 716 mL water) and a solution of 48% hydrogen peroxide (432.36 g). The reaction mixture was gradually warmed to 25° C. and stirred for 3 h, after which a solution of sodium thiosulfate (75 g sodium thiosulfate and 75 mL water) was added. After stirring for 30 min., a solution of citric acid (254 g of citric acid and 860 mL water) was added, and the mixture was stirred for an additional 30 min. after which ethyl acetate was added (1290 mL). After stirring for 10 min., the organic layer was separated and the aqueous fraction was extracted with ethyl acetate (2×430 mL). The organic layers were combined and the solvent was distilled out at 40-50° C. under vacuum. The resulting mass was vacuum dried for 1 h to afford quantitative yield of tert-butyl ((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)carbamate (9) (858 g crude), which was used for the next step without purification. 
     (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (A): A mixture of tert-butyl ((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)carbamate (9) from above (853 g, containing 233 g of (9)) and IPA-HCl (14% w/w solution; 699 mL) was stirred (≥2 h) at 25° C. until HPLC indicated &lt;1% unreacted intermediate (9). The solvent was distilled out at 40-60° C. under vacuum. Fresh IPA (233 mL) was added at 40-45° C. and the solvent was again distilled out at 40-60° C. under vacuum. After degassing for 30 min. at 40-60° C., the resulting mass was treated with fresh IPA (699 mL) and the mixture was stirred under nitrogen at 30-35° C. for 30 min. and then at 0-5° C. for an additional 30 min. The solid product was filtered at 0-5° C. and washed with chilled IPA. The resulting product was dried under vacuum at 40-60° C. to afford ˜70 g crude product, which contained ˜96.49% of the desired RRR-isomer as indicated by chiral GC (other isomers were present as impurities in the amount of 2.06% (SSS isomer), 0.18% (SRR isomer), and 1.26% (RSS isomer)). IPA (3 L) was added and the resulting slurry was refluxed for 30 min. The mixture was gradually cooled to 70-75° C., and the undissolved impurity was filtered off and washed with IPA (140 mL). The solvent was distilled out at 40-60° C. to afford a white mass which was gradually cooled to 25° C. and then treated with water (31.5 mL) and acetonitrile (31.5 mL). The resulting mixture was heated at 75-80° C. for 10 min. to obtain a clear solution, which was then treated slowly with acetonitrile (574 mL) at 75-80° C. over a period of 1 h. After stirring for 15 min. at 75-80° C., the resulting mass was cooled to 0-5° C. over 2-3 h and stirred at that temperature for 30 min. The product was filtered under nitrogen at 0-5° C., and the solid cake was washed with chilled acetonitrile (70 mL) and dried under vacuum to afford the desired RRR isomer. The above process of precipitating the desired product out of a mixture of water and acetonitrile by addition of acetonitrile at 75-80° C. was repeated until chiral-GC indicated the presence of no more than 0.5% of any other single isomer (SSS, SRR and RSS isomer). The product thus obtained was further dried under vacuum at 40-60° C. to afford (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (A) as a white solid (63 g, 37.4% yield, 100% purity by HPLC, melting point range: 244.0-245.5° C., SOR: −31.2° (C=1% in MeOH at 25° C.)); chiral GC indicated 99.83% of the desired RRR-isomer and 0.17% of the corresponding SSS-isomer.  1 H-NMR (D 2 O) (400 MHz): δ 3.18-3.08 (m, 2H), 2.15-2.12 (m, 1H), 1.86-1.83 (m, 1H), 1.72-1.68 (m, 1H), 1.32-1.16 (m, 3H), 1.02-0.91 (m, 1H), 0.86-0.85 (d, 3H, J=6.4 Hz) 
     A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.