Process for the production of (6AR,10AR)-7-propyl-6,6A,7,8,9,10,10A,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-G]quinoline and (4AR,10AR)-1-propyl-1,2,3,4,4A,5,10,10A-octahydro-benzo[G]quinoline-6,7-diol

Abstract

The present invention relates to a compound of formula (Ib) [Formula 1] TIFF2022533155000094.tif55170 (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline having formula (I) [Case 2] TIFF2022533155000095.tif52170 The present invention relates to a novel process for producing (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol having the formula: and salts thereof. Both compounds are used in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease. The present invention also relates to novel intermediate compounds in the process.

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol and (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline and salts thereof, compounds used in the treatment of neurodegenerative diseases and disorders such as Parkinson's disease. The present invention also relates to novel intermediates of said process. [Background technology]

[0002] Parkinson's disease (PD) is a common neurodegenerative disorder that becomes more prevalent with age and affects an estimated 7-10 million people worldwide. Parkinson's disease is a multifaceted disease characterized by both motor and non-motor symptoms. Motor symptoms include resting tremor, bradykinesia / akinesia (slowness and lack of movement), muscular rigidity, postural stability and gait dysfunction, and non-motor symptoms include neuropsychiatric disorders (e.g., depression, psychotic symptoms, anxiety, apathy, mild cognitive impairment and dementia) as well as autonomic and sleep disorders (Poewe et al., Nature Review, (2017) vol3 article 17013:1-21).

[0003] An important hallmark of the pathophysiology of Parkinson's disease is the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta, which provides dopaminergic innervation to the striatum and other brain regions. Such progressive neurodegeneration leads to a decline in striatal levels of dopamine, which ultimately results in a series of changes in the basal ganglia circuitry, ultimately resulting in the four cardinal motor features of Parkinson's disease. The primary targets of dopamine in the striatum consist of medium spiny GABAergic neurons (MSNs) with prominent topographic processes that selectively express D1 or D2 receptors. GABAergic MSNs projecting to the lateral pallidum, also called the striatopallidal "indirect pathway", express D2 receptors (MSN-2). GABAergic-MSNs projecting to the substantia nigra pars reticulata and medial pallidum, also called the striatopallidal "direct pathway", express D1 receptors (MSN-1). Lack of dopamine due to neuronal loss leads to an imbalance in the activity of the two pathways, resulting in a marked decrease in thalamic and cortical output activity and ultimately in motor dysfunction (Gerfen et al, Science (1990) 250:1429-32; Delong, (1990) Trends in Neuroscience 13:281-5; Alexander et Crutcher, (1990) Trends in Neuroscience 13:266-71 and for review see Poewe et al., Nature Review (2017) vol.3 article 17013:1-21).

[0004] The most effective therapeutic strategies available for patients suffering from Parkinson's disease and aiming to control motor symptoms are mainly indirect and direct dopamine agonists. Classical and gold standard therapy includes chronic oral intake of L-3,4-dihydroxyphenylalanine (L-DOPA), which is decarboxylated in the brain to form dopamine. Other approaches include administration of dopamine receptor agonists such as apomorphine, which acts on both D1 and D2 receptor subtypes, or pramipexole, ropinirole, and other agonists that are predominantly directed against the D2 receptor subtype. Due to the activation of both D1 and D2 receptor subtypes and the holistic rebalancing of the indirect-direct pathway (i.e., only D2 agonists reverse the dysfunction of the indirect pathway), acceptable MR (relief of symptoms with movement) is obtained with the use of both L-DOPA and apomorphine.

[0005] L-DOPA and apomorphine, whose structures are shown below, are currently the most effective PD drugs in clinical use. [ka]

[0006] L-DOPA is a prodrug of dopamine and remains the most effective drug in the treatment of motor Parkinson's disease. However, after several years of treatment (i.e., honeymoon period), complications occur due to the inherent progression of the disease (i.e., sustained loss of dopaminergic neurons) and the poor pharmacokinetic (PK) profile of L-DOPA. These complications include 1) dyskinesia, which is an abnormal involuntary movement that occurs during the optimal "timely effect" of the drug, and 2) out-of-phase periods during which the positive effects of L-DOPA gradually decrease and symptoms return or worsen (Sprenger and Poewe, CNS Drugs (2013), 27:259-272).

[0007] Direct dopamine receptor agonists can activate dopamine autoreceptors as well as postsynaptic dopamine receptors located on medium spiny neurons MSN-1 and MSN-2. Apomorphine belongs to a class of dopamine agonists that have a 1,2-dihydroxybenzene (catechol) moiety. When combined with a phenethylamine motif, catecholamines often have low or no oral bioavailability, as is the case with apomorphine. Clinically, apomorphine is used to treat PD, albeit with parenteral delivery (generally intermittent subcutaneous administration or continuous daytime parenteral infusion via pump). For apomorphine, animal studies have shown that transdermal delivery or implantation could provide a potential form of administration. However, when delivery of apomorphine from implants was studied in monkeys (Bibbiani et al., Chase Experimental Neurology (2005), 192:73-78), it was found that in most cases the animals had to be treated with the immunosuppressant dexamethasone to prevent local irritation and other complications after the implant procedure. Alternative delivery strategies for apomorphine therapy in PD, such as inhaled and sublingual formulations, have been extensively explored (see, for example, Grosset et al., Acta Neurol Scand. (2013), 128:166-171 and Hauser et al., Movement Disorders (2016), Vol. 32(9):1367-1372). However, these attempts have not yet been clinically implemented for the treatment of PD.

[0008] An alternative to parenteral formulation of catecholamines involves the use of prodrugs that mask the free catechol hydroxyl group to allow oral administration. However, a known problem with developing prodrugs for clinical use is the difficulty associated with predicting conversion to the parent compound in humans.

[0009] Various ester prodrugs of catecholamines have been reported in the literature, such as N-propyl-noraporphine (NPA) and monopivaloyl esters of apomorphine fully coated for duodenal delivery (WO 02 / 100377) and the diacetyl prodrug of the D1-like agonist Adrogolide, A-86929 (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305-316). Adrogolide undergoes extensive hepatic first-pass metabolism in men after oral administration and, as a result, has low oral bioavailability (about 4%). In PD patients, intravenous (IV) Adrogolide has antiparkinsonian efficacy comparable to L-DOPA (Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305-316).

[0010] In addition to ester prodrugs of catecholamines, an alternative prodrug approach involves masking the two catechol hydroxyl groups as the corresponding methylene-dioxy or diacetaryl derivatives. The principle of this prodrug is described, for example, in Campbell et al., Neuropharmacology (1982); 21(10): 953-961, as well as in U.S. Pat. No. 4,543,256, WO 2009 / 026934 and WO 2009 / 026935.

[0011] Another proposed approach to catecholamine prodrugs is the formation of enone derivatives as proposed, for example, in WO 2001 / 078713 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444. For further examples of catecholamine prodrugs, see, for example, Sozio et al., Exp. Opin. Drug Disc. (2012); 7(5): 385-406.

[0012] The compound (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, hereinafter referred to as Compound (I), is disclosed in WO 2009 / 026934. The trans isomer was previously disclosed in Liu et al., J. Med. Chem. (2006), 49:1494-1498, followed by Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444, with pharmacological data suggesting that the compound has low oral bioavailability in rats. The racemic compound was first disclosed in Cannon et al., J. Heterocyclic Chem. (1980); 17:1633-1636. [ka]

[0013] Compound (I) is a dopamine receptor agonist with mixed D1 and D2 activity. Three prodrug derivatives of Compound (I) are known in the art.

[0014] Liu et al., J. Med. Chem. (2006), 49:1494-1498 and Liu et al., Bioorganic Med. Chem. (2008), 16:3438-3444 disclose an enone derivative of formula (Ia), shown below, which was shown to be converted to the active compound (I) in rats. [ka]

[0015] WO 2009 / 026934 and WO 2009 / 026935 disclose two prodrug derivatives of compound (I), including the compound (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline having the following formula (Ib): [ka]

[0016] The conversion of compound (Ib) to compound (I) in rat and human hepatocytes has been demonstrated in WO 2010 / 097092. Furthermore, the in vivo pharmacology of compounds (Ia) and (Ib) and the active "parent compound" (I) has been tested in various animal models for Parkinson's disease (WO 2010 / 097092). Both compound (I) and compounds (Ia) and (Ib) have been found to be effective, and it has been shown that compounds (Ia) and (Ib) are converted to compound (I) in vivo. All three compounds have been reported to have a longer duration of action than that observed for L-dopa and apomorphine.

[0017] Other prodrugs of compound (I) disclosed in WO 2009 / 026934 and WO 2009 / 026935 are conventional ester prodrugs of formula (Ic): [ka]

[0018] Despite longstanding interest in this field, there remains a clear unmet need for the development of effective, well-tolerated and efficacious drugs for the treatment of PD.

[0019] As a result, there is also a need for processes for producing such drugs, particularly processes that are suitable for large-scale production and that provide high yields of product.

[0020] WO 2009 / 026934 discloses a process for preparing compound (I) and a process for preparing compound (Ib) from compound (I). These processes involve many steps and the use of chiral chromatography to obtain the separate enantiomers and are therefore not optimal for large-scale production.

[0021] Thus, there remains a need for improved processes for the large-scale production of compounds (I) and (Ib). Summary of the Invention

[0022] The inventors of the present invention have developed a novel process for the preparation of (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (compound (I)) and (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline (compound (Ib)). The invented process for the preparation of compound (I) offers several advantages over the process previously described in WO 2009 / 026934, such as: 1) a shorter synthetic route; 2) an improved overall yield of compound (I); 3) the use of resolution via diastereomeric salts instead of resolution by supercritical fluid chromatography (SFC), which is uneconomical and not suitable for large scale production; and 4) a resolution at an earlier stage in the synthetic route instead of the late stage resolution described in WO 2009 / 026934, reducing the amount of reagents / solvents required and the amount of waste produced.

[0023] One aspect of the present invention is a compound represented by the following formula (I): [ka] and salts thereof, with (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol having the following formula (Ib): [ka] The present invention relates to a novel process for the preparation of a compound having the formula:

[0024] Another aspect of the present invention also provides a novel process for preparing (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo[1,2-g]quinoline (Compound (Ib) and salts thereof).

[0025] A further individual aspect relates to novel intermediates of the process.Accordingly, one aspect of the present invention provides a compound of formula (A2) or a salt thereof: [ka]

[0026] Another aspect of the invention provides a compound of formula (A3) or a salt thereof: [ka]

[0027] Yet another aspect of the present invention provides a compound of formula (A4) or a salt thereof: [ka]

[0028] Yet another aspect of the present invention provides a compound of formula (A5) or a salt thereof: [ka]

[0029] Yet another embodiment of the invention provides a compound of formula (a2i) or a salt thereof: [ka]

[0030] Yet another aspect of the invention provides a compound of formula (a2ii) or a salt thereof: [ka]

[0031] definition Compound Reference Reference to Compound (I), Compound (Ib), Compound (A1), Compound (A2), Compound (A3), Compound (A4) or Compound (A5) encompasses the compounds in both dissolved and solid form, including the free substances (zwitterions), salts of the compounds, such as acid addition salts or base addition salts, as well as polymorphic and amorphous forms of the compounds of the invention and their salts. Additionally, the compounds and their salts may potentially exist in unsolvated and solvated forms with solvents such as water, ethanol, etc.

[0032] Sometimes, a specific salt form is indicated for a compound, such as (A2-hemi-L-tartrate) indicating the hemi-L-tartrate salt of compound (A2). Reference to compound Compound (I), Compound (Ib), Compound (A1), Compound (A2), Compound (A3), Compound (A4) or Compound (A5) as the "free base" in the context of the present invention is intended to mean that the compound is not in a salt form.

[0033] Pharmaceutically acceptable salts In the context of this invention, pharma- ceutically acceptable salts are intended to denote non-toxic, ie physiologically acceptable salts.

[0034] The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts, which are salts formed with inorganic and / or organic acids on a nitrogen atom in the parent molecule. The acids may be selected from, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, malonic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, gentisic acid, saccharin, and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalene-2-sulfonic acid, 2-hydroxyethanesulfonic acid, and benzenesulfonic acid.

[0035] Other examples of acids and bases useful for forming pharma- ceutically acceptable salts are described, for example, in Stahl and Wermuth (Eds), Handbook of Pharmaceutical salts. Properties, selection, and use, Wiley-VCH2008.

[0036] Compounds (Ib), (A1), (A2), (A3), (A4) and (A5) can be used as intermediates for preparing compound (I), or a pharma- ceutically acceptable salt thereof. Thus, the salt forms of compounds (Ib), (A1), (A2), (A3), (A4) and (A5) are not limited to their pharma- ceutically acceptable salts. However, pharma- ceutically acceptable salts of compounds (Ib), (A1), (A2), (A3), (A4) and (A5) can also be advantageously used in the preparation of compound (I). Thus, in an embodiment of the present invention, the salts of compounds (Ib), (A1), (A2), (A3), (A4) and / or (A5) are pharma- ceutically acceptable salts.

[0037] chemical manufacturing In the context of the present invention, "derived by chemical production" means that the compound is produced by a chemical process ex vivo, such as, but not limited to, one of the processes described in the experimental section of this specification. The terms "production" and "chemical production" are used interchangeably.

[0038] Thus, in an embodiment of the invention, compound (I) is prepared by an ex vivo chemical process.

[0039] In a further embodiment of the invention, compound (Ib) is prepared by an ex vivo chemical process. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Detailed Description of the Invention The present invention relates to a novel method for preparing (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol (compound (I)) via compound (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4',5':5,6]benzo-[1,2-g]quinoline (compound (Ib)). The present invention relates to a novel process for preparing compound (Ib).

[0041] Compound (Ib) is a prodrug of compound (I) and is a dual dopamine agonist with mixed D1 and D2 activity useful for the treatment of neurodegenerative diseases and disorders such as Parkinson's disease. WO 2009 / 026934 discloses a process for the preparation of compound (I) and a further process for the preparation of compound (Ib) from compound (I).

[0042] The present inventors have now discovered a new and improved process for the preparation of both compounds, where compound (Ib) is used as an intermediate in the preparation of compound (I).

[0043] The overall process is briefly illustrated in Scheme 1 below.

[0044] The starting material (A1): tert-butyl 4-(6-chlorobenzo[d][1,3]dioxol-5-yl)-3-oxobutanoate can be prepared using known methods as described by Brueckner and coworkers in Synthesis 2008, 14:2229-2246, or as described below.

[0045] The starting material (a5i): 2-(benzo[d][1,3]dioxol-5-yl)acetonitrile is commercially available.

[0046] Scheme 1: Overall process [ka]

[0047] [Table 1-1]

[0048] [Table 1-2]

[0049] [Table 1-3]

[0050] [Table 1-4]

[0051] [Table 1-5]

[0052] [Table 1-6]

[0053] Process 0) In step 0), the enamine intermediate compound (a2i) is formed. The intermediate compound a2i can be formed using two alternating steps with different starting compounds:

[0054] Step 0 substep (i), ketoester (tert-butyl 4-(6-chlorobenzo[d][1,3]dioxol-5-yl)-3-oxobutanoate) compound (A1) is converted in situ with 3-chloropropan-1-amine using catalytic amount of zinc chloride to enamine intermediate compound (a2i).

[0055] Process 0 substep S1 is an alternative to substep (i) above, in which compound (a6i) is subjected to a Blaise reaction with tert-butyl 2-bromoacetate and zinc, and then treated with acetic acid followed by 3-chloropropan-1-amine hydrochloride to give compound (a2i). In substep S1, compound (a2i) is formed directly and conveniently from compound (a6i).

[0056] In one embodiment of the present invention, sub-step S1 comprises the isolation of compound (a2i).

[0057] Commercially available compound (a5i) is chlorinated with SO2Cl2 to obtain compound (a6i) in high yield. Thus, in a specific embodiment of the present invention, compound (a5i) is chlorinated with SO2Cl2 to obtain compound (a6i). In a more specific embodiment of the present invention, compound (a5i) is chlorinated with SO2Cl2 to obtain compound (a6i), and step 0 substep S1 is subsequently used to obtain compound (a2i).

[0058] Step 0' provides an alternative route to starting compound (A1) from compound (a6i): Commercially available compound (a5i) can be chlorinated with SO2Cl2 to give compound (a6i) in high yield, which can then be converted to either compound (A1) or (a2i) depending on the reaction conditions.

[0059] Compound (a6i) was subjected to a Blaise reaction with tert-butyl 2-bromoacetate and zinc until the formation of compound (A1), which was obtained after aqueous acidic hydrolysis.

[0060] In one embodiment of the present invention, step 0' is used to obtain compound (A1), followed by the formation of compound (a2i) using step 0 substep (i).

[0061] Process 1) In step 1), compound (a2i) is converted to the desired enantiomer compound (A2) or compound (A2-hemi-L-tartrate) by two alternative routes.

[0062] Generally, the presence of primary alkyl chloride and amine functional groups on the same molecule would be expected to promote the alkylation of the amine, which in the present case would lead to the formation of an azetidine. However, it was surprisingly found that compounds (a2ii) and (A2) have good stability, despite the presence of primary alkyl chloride and amine functional groups on the same molecule, since they do not readily form the corresponding azetidines (a3i) or (a3ii), respectively (see below), or self-condense. [ka]

[0063] Step 1, sub-step (ii) followed by sub-step (iii): Furthermore, the inventors have surprisingly found that crude compound (a2ii) in substep (iii) can be resolved via diastereomeric salt formation using L-tartaric acid in a solvent selected from MeOH, EtOH and aqueous mixtures thereof to give resolved amine (A2) as hemi-L-tartrate salt (A2-hemi-L-tartrate salt) in high enantiomeric excess of more than 95%, such as >99.5%, and in high yield. Thus, in one embodiment of the present invention, substep (ii) is used to give compound (a2i), which is then used in substep (iii) to give (A2-hemi-L-tartrate salt).

[0064] In sub-step (ii), the enamine intermediate (a2i) is reduced using, for example, sodium cyanoborohydride (NaBH3CN), sodium triacetoxyborohydride (STAB), 5-ethyl-2-methylpyridine borane (PEMB) or NaBH4 to give the crude product (a2ii). In a specific embodiment of the invention, sub-step (ii) is carried out using sodium cyanoborohydride.

[0065] Alternatively, in process 1 substep (ii), the reduction of compound (a2i) to compound (a2ii) can be carried out using a platinum catalyst (preferably platinum on carbon) in a suitable solvent, such as Me-THF, in the presence of hydrogen.

[0066] In one embodiment of the invention, substep (ii) is carried out using a platinum catalyst at a temperature of about 20 to about 100°C, such as about 50 to about 80°C, for example about 55 to about 65°C, for example about 57°C, or about 58°C, or about 59°C, or about 60°C, or about 61°C, or about 62°C or about 63°C.

[0067] In one embodiment of the invention, substep (ii) is carried out using a platinum catalyst at a pressure of about 2 to about 10 bar, such as about 2 to about 6 bar, such as about 3 to about 5 bar, such as about 4 bar.

[0068] In one embodiment of the present invention, substep (ii) is carried out using a platinum catalyst at a temperature of about 50 to about 80° C. and a pressure of about 2 to about 6 bar.

[0069] In a more particular embodiment of the invention, substep (ii) is carried out using a platinum catalyst at a temperature of about 60° C. and a pressure of about 4 bar.

[0070] In one embodiment of the present invention, compound (a2i) obtained from process 0 sub-step (i) above is subsequently reduced in the same pot using, for example, NaBH3CN, sodium triacetoxyborohydride (STAB), 5-ethyl-2-methylpyridine borane (PEMB) or NaBH4 to give crude product (a2ii).

[0071] In sub-step (iii), compound (a2ii) is resolved in a solvent, such as a solvent selected from MeOH, EtOH and aqueous mixtures thereof, to give the resolved amine (A2) as its hemi-L-tartrate salt (A2-hemi-L-tartrate salt).

[0072] In one embodiment of the present invention, compound (a2i) obtained from process 0 sub-step (i) above is subsequently reduced in the same pot using, for example, NaBH3CN, sodium triacetoxyborohydride (STAB), 5-ethyl-2-methylpyridine borane (PEMB) or NaBH4 to give crude compound (a2ii), which is subsequently resolved in sub-step (iii) to give compound (A2-hemi-L-tartrate).

[0073] In an even more specific embodiment of the present invention, compound (a2i) obtained from step 0 sub-step (i) above is subsequently reduced in the same pot using sodium cyanoborohydride to give crude compound (a2ii), which is subsequently resolved in sub-step (iii) to give compound (A2-hemi-L-tartrate).

[0074] As an alternative to step 1, sub-step (ii) above followed by sub-step (iii), step 1 sub-step (iv) can be used to obtain compound (A2):

[0075] The reduction of compound (a2i) to give compound (A2) in process 1 sub-step (iv) can be carried out using a chiral catalyst containing either rhodium, iridium or ruthenium in the presence of hydrogen gas and a suitable solvent.

[0076] Specifically, asymmetric hydrogenation of compound (a2i) in step 1 substep (iv) is carried out using a catalyst formed from Josiphos SL-J002-2 (cas#277306-29-3) and bis(2,5-norbornadiene)rhodium(I) tetrafluoroborate (cas#36620-11-8) in the presence of hydrogen and 2,2,2-trifluoroethanol as a solvent to give compound (A2) with an enantiomeric excess of 96% and a yield of 93% (based on LC-MS analysis).

[0077] In Scheme 2, a more detailed outline of the sub-steps of step 0) and step 1) is given below.

[0078] Scheme 2: Detailed overview of sub-steps of step 0) and step 1) [ka] In one embodiment of the present invention, step 0 substep S1 is used to obtain compound (a2i), followed by step 1.

[0079] In another more specific embodiment of the present invention, step 0 sub-step S1 is followed by step 1 sub-step (ii) and sub-step (iii) to give compound A2-hemi-L-tartrate.

[0080] In a more specific embodiment of the invention, step 0 sub-step S1 is followed by step 1 sub-step (iv) to give compound (A2).

[0081] In one embodiment of the present invention, step 0' is used to obtain compound (A1).

[0082] Thus, in a more specific embodiment of the invention, step 0' is followed by step 0 sub-step (i) to give compound (a2i), and step 0 sub-step (i) is followed by step 1 sub-step (iv) to give compound (A2).

[0083] In a specific embodiment of the invention, step 0' is used to obtain compound (A1), followed by step 0 substep (i) to obtain compound (a2i), which is then followed by step 0 substep (i) followed by substeps (ii) and (iii) to obtain compound (A2-hemi-L-tartrate).

[0084] In another specific embodiment of the invention, step 0' is followed by step 0 substep (i) to give compound (a2i), and step 0 substep (i) is followed by step 1 substep (iv) to give compound (A2).

[0085] Process 2) In step 2) shown below in Scheme 3, compound (A2) or a salt thereof undergoes further reductive amination with propanal using a reducing agent such as NaBH3CN, sodium triacetoxyborohydride (STAB), borane 5-ethyl-2-methylpyridine borane (PEMB) or a platinum catalyst supported on a support such as carbon and hydrogen in a solvent selected from tetrahydrofuran (THF), isopropanol (IPA) or MeOH to provide compound (A3).

[0086] Scheme 3: Step 2) [ka] In a specific embodiment of the invention, compound (A2-hemi-L-tartrate) is used in step 2 as described herein. Thus, in a more specific embodiment of the invention, step 1 substep (ii) is followed by step 1 substep (iii) to obtain compound (A2-hemi-L-tartrate), which is subsequently used in step 2.

[0087] In an even more specific embodiment of the invention, step 0 substep S1 is followed by step 1 substep (ii) followed by step 1 substep (iii) to obtain the compound (A2-hemi-L-tartrate), which is then used in step 2.

[0088] In a specific embodiment, sodium triacetoxyborohydride (STAB) is used as the reducing agent in step 2.

[0089] In one embodiment of the invention, step 2 is carried out in a solvent selected from the group consisting of tetrahydrofuran (THF), isopropanol (IPA) and MeOH. In a more specific embodiment, step 2 is carried out in THF.

[0090] Process 3) According to step 3) shown below in Scheme 4, compound (A3) is cyclized under basic conditions to give compound (A4), which can be optionally isolated as a hemi-oxalate salt (A4-hemi-oxalate), hydrochloride salt (A4-HCl) or hydrobromide salt (A4-HBr). [ka]

[0091] The reaction takes place in the presence of a strong base, preferably sodium bis(trimethylsilyl)amide (NaHMDS).

[0092] In one embodiment of the invention, step 3 is carried out using a strong base selected from the group consisting of sodium bis(trimethylsilyl)amide (NaHMDS), lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS) and lithium bis(trimethylsilyl)amide (LHMDS). In a specific embodiment of the invention, step 3 is carried out with sodium bis(trimethylsilyl)amide (NaHMDS).

[0093] Suitable solvents for step 3 are, for example, solvents selected from the group consisting of toluene, THF, and mixtures thereof. In a specific embodiment of the invention, a mixture of toluene and THF is used as the solvent.

[0094] Scheme 4: Step 3) [ka] Generally, the alkylation of esters is disadvantaged by self-condensation (due to the Claisen reaction). A leaving group such as an amine at the β-position is expected to be easily eliminated, leaving an acrylate system. However, the inventors have unexpectedly found that the cyclization of compound (A3) is clean and produces very little self-condensation and / or elimination products, even when the reaction is carried out at a reasonably high temperature of -10°C. Usually, the formation of enolates from esters is carried out at very low temperatures (e.g., -78°C) to avoid side reactions, such as self-condensation (see, for example, Fan et al., Bioorg.Med.Chem.Lett. 2008,18:6236-6239 and Kotsuki et al., J.Org.Chem.1992,57:5036-5040).

[0095] In one embodiment of the present invention, compound (A4) is isolated as the hydrochloride salt compound (A4-HCl).

[0096] Surprisingly, the inventors have found that compound (A4-HCl) can be precipitated as a powder with little or no agglomeration. These qualities further facilitate the process. Compound (A4-HCl) can be obtained by treating compound (A4) with an HCl solution.

[0097] Suitable solvents for precipitating the salt of compound (A4) may be one or more solvents selected from the group consisting of MeTHF, EtOAc, isopropanol, iPrOAc, acetone, toluene, heptane, and mixtures thereof.

[0098] In a specific embodiment of the present invention, a solvent selected from the group consisting of MeTHF, EtOAc, iPrOAc, acetone, toluene, a mixture of isopropanol (iPrOH) and heptane, a mixture of iPrOAc and heptane, and a mixture of acetone and heptane is used for the precipitation of a salt of compound (A4), and more specifically for the precipitation of compound (A4-HCl).

[0099] In a specific embodiment of the present invention, a solvent selected from the group consisting of MeTHF, a mixture of isopropanol (iPrOH) and heptane, a mixture of iPrOAc and heptane, and a mixture of acetone and heptane is used for the precipitation of compound (A4-HCl).

[0100] In a more specific embodiment of the present invention, a mixture of isopropanol and heptane is used to precipitate compound (A4-HCl).

[0101] In a more specific embodiment of the present invention, a mixture of acetone and heptane is used to precipitate compound (A4-HCl).

[0102] If a salt of compound (A4), such as compound (A4-HCl) or compound (A4-hemi-oxalate), is isolated in the process of the invention, compound (A4) may be liberated using a base liberation prior to the commencement of a further synthetic step, such as step 5. Thus, in one embodiment of the invention, the salt of compound (A4) is reacted with a suitable base, such as an aqueous solution of Na2CO3, K2CO3 or ammonia, to obtain a solution of compound (A4) as the free base.

[0103] In a specific embodiment of the present invention, compound (A4-HCl) is reacted with a suitable base, such as an aqueous solution of Na2CO3, K2CO3, or ammonia, to provide compound (A4) as the free base.

[0104] Step 4) In step 4) shown in Scheme 5 below, the intramolecular Friedel-Crafts acylation of compound (A4) produces the tricyclic compound (A5). The Friedel-Crafts acylation is conveniently carried out in chlorobenzene using a mixture of PO and TFA to convert compound (A4) to compound (A5).

[0105] Scheme 5: Step 4) [ka] The inventors have surprisingly found that compound (A5) is stable under acidic conditions or as the acid salt and can be conveniently isolated in high yield as the tosylate salt (see formula (A5-tosylate) below) after careful neutralization of the acidic reaction mixture. [ka]

[0106] In contrast, when compound (A5) is isolated as a free base, it slowly undergoes aromatization by elimination of the amine group to form compound (a4i) (see formula below), among other products. The formation of compound (a4i) from compound (A5) was not observed under acidic conditions, which is unexpected because under acidic conditions the nitrogen atom in compound (A5) is protonated and is expected to be a better leaving group than under neutral or basic conditions. [ka]

[0107] Thus, in one embodiment of the invention, step 4 comprises the isolation of compound (A5) as an acid salt. In a more specific embodiment of the invention, step 4 comprises the isolation of compound (A5-tosylate).

[0108] Step 5) Step 5) shown in Scheme 6 below provides a one-pot hydrodechlorination and ketone reduction of compound (A5), or a salt thereof, in the presence of a palladium catalyst such as Pd / C and hydrogen to produce compound (Ib).

[0109] The high performance of this reaction is unexpected because, in contrast to ketone → alkane reduction, which is promoted by acidic conditions, hydrodechlorination reactions are generally hindered under acidic conditions and instead promoted by basic conditions (Handbook of heterogeneous hydrogenation, S. Nishimura, Wiley 2001).

[0110] Scheme 6: Step 5) [ka] In one embodiment of the present invention, compound (A5) or a salt thereof is used in step 5 to obtain compound (Ib). In another embodiment of the present invention, compound (A5-tosylate) is used in step 5 to obtain compound (Ib).

[0111] Different solvents, particularly alcohol solvents, may be useful for the reaction in step 5. In one embodiment of the invention, an alcohol is used as the solvent in step 5. In a more specific embodiment of the invention, step 5 is carried out using a solvent that is an alcohol selected from the group consisting of MeOH, EtOH, IPA, and 1-propanol. In a more specific embodiment, step 5 is carried out using EtOH as the solvent.

[0112] The hydrogenation reaction in step 5 may be carried out using a palladium catalyst at a temperature in the range of about 20 to about 100°C, for example, about 50 to about 100°C, for example, about 60 to about 80°C, for example, about 65°C, about 67°C, or about 68°C, about 69°C, about 70°C, about 71°C, about 72°C, about 73°C, about 75°C, or about 77°C.

[0113] The hydrogenation reaction in step 5 may be carried out using a palladium catalyst at a pressure in the range of about 2 to about 10 bar, such as about 3 to 6 bar, such as about 3 to about 5 bar, such as about 3.5 bar, or such as about 4 bar, or such as about 4.5 bar.

[0114] In a specific embodiment of the invention, step 5 is carried out using a palladium catalyst such as Pd / Cb at a temperature of about 70° C. and a pressure of about 4 bar.

[0115] Process 6) Finally, step 6) shown in Scheme 7 below provides for the conversion of compound (Ib), or a salt thereof, to compound (I), or a salt thereof, by reaction of compound (Ib) with a Lewis acid or a Brondsted acid selected from the group consisting of BCl3, BBr3 and HBr.

[0116] Scheme 7: Step 6) [ka] In a specific embodiment of the invention, step 6 comprises reacting compound (Ib) with BCl 3 to obtain compound (I) or a salt thereof.

[0117] In another specific embodiment of the present invention, step 6 comprises reacting compound (Ib) as a free base with BCl 3 to obtain compound (I) or a salt thereof.

[0118] If a salt of compound (Ib), such as compound (Ib-L-DTTA), is used as the starting material in step 6, liberation of a base can be used to liberate compound (Ib) prior to the start of a further synthetic step, such as step 6. Thus, in one embodiment of the present invention, a salt of compound (Ib) is reacted with a base, such as an aqueous solution of Na2CO3, K2CO3 or ammonia, to obtain compound (Ib) as the free base.

[0119] In a specific embodiment of the present invention, compound (Ib-L-DTTA) is reacted with a suitable base, such as Na2CO3, K2CO3 or ammonia, to obtain compound (Ib) as the free base.

[0120] In a more specific embodiment of the present invention, step 6 comprises reacting an aqueous solution of Na2CO3, K2CO3 or ammonia with (-)-O,O'-di-p-toluoyl-L-tartrate (L-DTTA) salt, a salt of compound (Ib), to obtain compound (Ib) as a free base, followed by reacting compound (Ib) with BCl3 to obtain compound (I) or a salt thereof, for example, the HCl salt of compound (I).

[0121] Alternative Routes to Obtain Compound (I) The present inventors have also developed an alternative process for the conversion of compound (A6) or compound (A6-tosylate) to enantiopure compound (Ib) in a three-step process, which is obtained as the L-DTTA salt ((-)-O,O'-di-p-toluoyl-L-tartrate salt), as illustrated in Scheme 8 below.

[0122] Scheme 8: Alternative route to obtain compound (I) [ka] Alternative process 5a) In alternative step 5a) in scheme 8 above, compound (A6-tosylate) is converted to the free base using aqueous NaOH in Me-THF, and then reduced to the free base compound (A6) in Me-THF by adding aqueous NaBH4 in 85% yield. The resulting compound (A7) is further reduced to compound (A8) in step 2 by transfer hydrogenation in 90% yield, the reduction being promoted by Pd / C catalyst and formic acid in a mixture of ammonium formate-MeOH-water. Compound (A8) is converted to compound (Ib-L-DTTA salt) in step 3 by first subjecting it to hydrogenation using d / C catalyst and hydrogen gas with added TsOH in IPA, followed by a typical resolution using DTTA in MeOH to obtain compound (Ib-L-DTTA) with an enantiomeric excess of >99%.

[0123] Alternative process 6) Finally, in alternative step 6), compound (Ib-L-DTTA) is converted to the free base of compound (Ib) and the protection of the 1,2-dihydroxy moiety is removed with BCl3 to give the HCl salt of compound (I) after work-up.

[0124] In contrast to this alternative process (including alternative steps 5a, 5b and 6 as shown in Scheme 8), the process including steps 5 and 6 of the present invention (as shown in Schemes 6 and 7) provides a simpler and more efficient process since 1) the resolution via the formation of a diastereomeric salt is carried out at an earlier stage with compound (a2ii) compared to the late resolution of compound (Ib), and 2) the hydrodechlorination and ketone reduction is carried out in a single step from compound (A5) to compound (Ib).

[0125] EMBODIMENTS OF THE PRESENT DISCLOSURE In the following sections further embodiments of the invention are disclosed, a first embodiment denoted E1 and a second embodiment denoted E2.

[0126] E1. The following formula: [ka] Compound (I) having the formula [ka] The process for producing compound (Ib) having the formula:

[0127] E2. Compound (Ib) can be prepared by the following process: Process 0) substep (i) of reacting compound (A1) with 3-chloropropan-1-amine to obtain compound (a2i); or Substep (S1) of reacting compound (a6i) with tert-butyl 2-bromoacetate and zinc to form a mixture, followed by The mixture from substep (S1) is treated with acetic acid, followed by treating said mixture with 3-chloropropan-1-amine hydrochloride to obtain compound (a2i); Process 1) substep (ii) of reducing compound (a2i) obtained in substep (i) or substep (S1) to obtain compound (a2ii); Resolving compound (a2ii) using L-tartaric acid to obtain compound (A2-hemi-L-tartrate, substep (iii); or Following sub-step (i) or sub-step (S1), the reaction is carried out according to the following reaction scheme: [ka] subjecting the obtained compound (a2i) to hydrogenation carried out in the presence of hydrogen and a solvent using a chiral catalyst to obtain compound (A2); The process according to embodiment E1,

[0128] E3. The process according to embodiment E2, wherein compound (a6i) or a salt thereof is prepared by a process comprising reacting compound (a5i) or a salt thereof with a chlorinating agent. [ka]

[0129] E4. The process according to embodiment E3, wherein the chlorinating agent is sulfuryl chloride.

[0130] E5. The process according to any one of embodiments E2 to E4, wherein the reduction in step 1 substep (ii) is carried out in the presence of a reducing agent.

[0131] E6. The process according to any one of embodiments E2-E5, wherein the reducing agent is selected from NaBH3CN, sodium triacetoxyborohydride (STAB), a borane such as 5-ethyl-2-methylpyridine borane (PEMB), and NaBH4.

[0132] E7. The process according to any one of embodiments E2 to E6, wherein the reduction in step 1 substep (ii) is carried out using a platinum catalyst, preferably platinum on carbon.

[0133] E8. The process according to embodiments E1-E4, wherein the chiral catalyst in step 1 substep (iv) is selected from (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene and bis(2,5-norbornadiene)rhodium(I) tetrafluoroborate.

[0134] E9. The process according to claims E1-E4 and E8, wherein the solvent in step 1 substep (iv) is 2,2,2-trifluoroethanol.

[0135] E10. A compound of formula (A2) [ka] Or its salt.

[0136] E11. The compound of embodiment E10 in the form of the hemi-L-tartrate salt shown below. [ka]

[0137] E12. The use of a compound according to any of embodiments E10 and E11 in a process for the manufacture of a compound of formula (I) or a compound of formula (Ib).

[0138] E13. Compound (Ib) can be prepared by the following process: 2) Reacting compound (A2) or compound (A2-hemi-L-tartrate) with propanal in the presence of a reducing agent to obtain the product according to the following reaction scheme a) or b): [ka] The process according to any one of embodiments E1 to E9, wherein compound (A3) is obtained according to the process comprising the steps:

[0139] E14. The process according to embodiment E13, wherein compound (A3) is prepared by reacting compound (A2-hemi-L-tartrate) with propanal in the presence of a reducing agent.

[0140] E15. The process according to embodiment E14, wherein the reducing agent is selected from the group consisting of NaBH3CN, sodium triacetoxyborohydride (STAB), a borane such as 5-ethyl-2-methylpyridine borane (PEMB), and a platinum catalyst, preferably platinum on carbon, together with hydrogen gas.

[0141] E16. The process according to any of embodiments E13 to E15, wherein the reaction is carried out in a solvent selected from, for example, tetrahydrofuran (THF), isopropanol (IPA), or MeOH.

[0142] E17. The following formula (A3) [ka] or a salt thereof.

[0143] E18. The use of a compound according to embodiment E17 in a process for producing a compound of formula (I) or a compound of formula (Ib).

[0144] E19. Compound (Ib) can be prepared by the following process: 3) The following reaction scheme [ka] Compound (A3) is reacted with a strong base according to the formula (A4), Optionally, followed by: [ka] The process according to embodiments E1 to E9, and E13 to E16, wherein the compound (A4) is prepared by a process comprising the step of isolating compound (A4) as the hemi-oxalate salt as shown in

[0145] E20. The process according to embodiment E19, wherein the strong base is sodium bis(trimethylsilyl)amide (NaHMDS).

[0146] E21. The process according to any of embodiments E19 to E20, wherein said reaction of compound (A3) with a base is carried out at a temperature in the range of -20 to -5°C, such as in the range of -15 to -5°C, or for example at a temperature of about -10°C.

[0147] E22. The process according to any of embodiments E19-E21, wherein said compound (A4) is mixed with oxalic acid and isolated as the hemi-oxalate salt.

[0148] E23. The following formula (A4) [ka] or a salt thereof.

[0149] E24. Hemi-oxalate salts shown below [ka] The compound of embodiment E23, wherein the compound has the form:

[0150] E25. The use of a compound according to any of embodiments E23-E24 in a process for the manufacture of a compound of formula (I) or a compound of formula (Ib).

[0151] E26. Compound (Ib) can be prepared by the following process: 4) Intramolecular Friedel-Crafts acylation of compound (A4) is carried out according to the following reaction scheme: [ka] Compound (A5) is obtained according to the following procedure: The process according to embodiments E1 to E9, E13 to E16, E19 to E22, optionally prepared by a process comprising the subsequent step of isolating compound (A5) as a tosylate salt (A5-tosylate). [ka]

[0152] E27. The following formula (A5) [ka] or a salt thereof.

[0153] E28. Tosylate salts as shown below [ka] The compound of embodiment E27 has the form:

[0154] E29. The use of a compound according to any of embodiments E27-E28 in a process for the manufacture of a compound of formula (I) or a compound of compound (Ib).

[0155] E30. Compound (Ib) can be prepared by the following process: 5) According to the following reaction scheme: [ka] The process according to embodiments E1 to E9, E13 to E16, E19 to E22, and E26, which is prepared by a process comprising a step of reducing compound (A5) or a salt thereof to obtain compound (Ib) or a salt thereof.

[0156] E31. The process according to embodiment E30, wherein the reduction is carried out using a palladium catalyst.

[0157] E32. Compound (Ib) can be prepared by the following process: Step 0) according to any one of embodiments E2 to E4 Step 1) according to any of embodiments E2 and E5 to E9, followed by Step 2) according to any of embodiments E13 to E16 The process according to embodiment E1,

[0158] E33. Compound (Ib) can be prepared by the following process: Step 2) according to any of embodiments E13 to E16, followed by Step 3) according to any of embodiments E19 to E22, The process according to any one of embodiments E1 to E7,

[0159] E34. Compound (Ib) can be prepared by the following process: Step 3) according to any of embodiments E19 to E22, followed by Step 4) according to embodiment E26 The process according to any one of embodiments E1-E7, and E11-E13, comprising:

[0160] E35. Compound (Ib) can be prepared by the following process: Step 4) according to any one of embodiments E26, followed by Step 5) according to any of embodiments E30 to E31 The process according to any one of embodiments E1 to E7,

[0161] E36. Compound (Ib) can be prepared by the following process: Step 0) according to any one of embodiments E2 to E4, Step 1) according to any of embodiments E2 and E5 to E9, followed by Step 2) according to any of embodiments E13 to E16, followed by Step 3) according to any of embodiments E19 to E22 The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0162] E37. Compound (Ib) can be prepared by the following process: Step 2) according to any of embodiments E13 to E16, followed by Step 3) according to any of embodiments E19 to E22, followed by Step 4) according to embodiment E26 The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0163] E38. Compound (Ib) can be prepared by the following process: Step 3) according to any of embodiments E19 to E22, followed by Step 4) according to embodiment E26, followed by Step 5) according to any of embodiments E30 to E31 The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0164] E39. Compound (Ib) can be prepared by the following process: Step 0) according to any one of the embodiments E2 to E4, followed by Step 1) according to any of embodiments E2 and E5 to E9, followed by Step 2) according to any of embodiments E13 to E16, followed by Step 3) according to any of embodiments E19 to E22, followed by Step 4) according to embodiment E26 The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0165] E40. Compound (Ib) can be prepared by the following process: Step 2) according to any of embodiments E13 to E16, followed by Step 3) according to any of embodiments E19 to E22, followed by Step 4) according to embodiment E26, followed by Step 5) according to any of embodiments E30 to E31 The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0166] E41. Compound (Ib) can be prepared by the following process: Step 0) according to any one of embodiments E2 to E4, followed by Step 1) according to any of embodiments E2 and E5 to E9, followed by Step 2) according to any of embodiments E13 to E16, followed by Step 3) according to any of embodiments E19 to E22, followed by Step 4) according to embodiment E26, followed by Step 5) according to any of embodiments E30 to E31 The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0167] E42. Compound (I) can be prepared by the following process: 6) Reacting compound (Ib) with a Lewis acid or a Bronsted acid selected from the group consisting of BCl3, BBr3, and HBr to obtain the compound (Ib) according to the following reaction scheme: [ka] The process for the preparation of compound (I) according to any of embodiments E1 to E9, E13 to E16, E19 to E22, E26, and E30 to E31, wherein compound (I) is prepared from compound (Ib) by a step in which compound (I) is obtained according to

[0168] E43. The process according to embodiment E42, wherein step 5) is followed by step 6).

[0169] E44. The process for preparing compound (I) according to any of embodiments E35, E38, and E40-E42, wherein step 5) is followed by step 6.

[0170] E45. A process for the preparation of compound (I) according to any one of embodiments E1-E9, E13-E16, E19-E22, E26, and E30-E31, which is an ex vivo chemical process.

[0171] E46. The following formula (a2i) [ka] or a salt thereof.

[0172] E47. The following formula (a2ii) [ka] or a salt thereof.

[0173] E48. The process according to any one of embodiments E1 to E9, E13 to E16, E19 to E22, E26 and E30 to E45, wherein compound (a2i) is isolated.

[0174] E49. The process according to any one of embodiments E1 to E6, E13 to E16, E19 to E22, E26 and E30 to E45, and E48, wherein the reducing agent used in step 1 substep (ii) is sodium cyanoborohydride.

[0175] E50. The process according to any one of embodiments E1 to E5, E7, E13 to E16, E19 to E22, E26, E30 to E45 and E48 to E49, wherein step 1 substep (ii) is carried out using a platinum catalyst at a temperature of about 20 to about 100°C, such as about 50 to about 80°C, for example about 55 to about 65°C, for example about 57°C, or about 58°C, or about 59°C, or about 60°C, or about 61°C, or about 62°C or about 63°C.

[0176] E51. The process according to any one of embodiments E1 to E5, E7, E13 to E16, E19 to E22, E26, E30 to E45 and E48 to E50, wherein step 1 substep (ii) is carried out using a platinum catalyst at a pressure of from about 2 to about 10 bar, such as from about 2 to about 6 bar, for example from about 3 to about 5 bar, for example about 4 bar.

[0177] E52. The process according to any one of embodiments E1 to E5, E7, E13 to E16, E19 to E22, E26, E30 to E45, and E48 to E51, wherein step 1 substep (ii) is carried out using a platinum catalyst at a temperature of about 50 to about 80° C. and a pressure of about 2 to about 6 bar.

[0178] E53. The process according to any one of embodiments E1 to E5, E7, E13 to E16, E19 to E22, E26, E30 to E45, and E48 to E52, wherein step 1 substep (ii) is carried out using a platinum catalyst at a temperature of about 60° C. and a pressure of about 4 bar.

[0179] E54. The process according to any one of embodiments E1 to E7, E13 to E16, E19 to E22, E26, E30 to E45, and E48 to E53, wherein step 1 substep (iii) is carried out using an alcohol as a solvent, such as a solvent selected from MeOH, EtOH and aqueous mixtures thereof.

[0180] E55. The process according to any one of embodiments E13 to E16, E19 to E22, E26, E32 to E33, E36 to E37, E39 to E45, and E48 to E54, wherein the reducing agent used in step 2 is selected from NaBH3CN, sodium triacetoxyborohydride (STAB), a borane such as 5-ethyl-2-methylpyridine borane (PEMB), and a platinum catalyst, preferably platinum on carbon, together with hydrogen gas.

[0181] E56. The process according to any one of embodiments E13-E16, E19-E22, E26, E32-E33, E36-E37, E39-E45, and E48-E55, wherein the reducing agent used in step 2 is sodium triacetoxyborohydride (STAB).

[0182] E57. The process according to any one of embodiments E13-E16, E19-E22, E26, E32-E33, E36-E37, E39-E45, and E48-E56, wherein step 2 is carried out in a solvent consisting of tetrahydrofuran (THF), isopropanol (IPA) and MeOH.

[0183] E58. The process according to any one of embodiments E13-E16, E19-E22, E26, E32-E33, E36-E37, E39-E45, and E48-E57, wherein step 2 is carried out in THF.

[0184] E59. The process according to any one of embodiments E19-E22, E26, E30-E31, E33-E34, E36-E45, and E48-E58, wherein step 3 is carried out using a strong base selected from the group consisting of sodium bis(trimethylsilyl)amide (NaHMDS), lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), and lithium bis(trimethylsilyl)amide (LHMDS).

[0185] E60. The process according to any one of embodiments E19-E22, E26, E30-E31, E33-E34, E36-E45, and E48-E59, wherein step 3 is carried out using a solvent selected from the group consisting of toluene, THF, and mixtures thereof.

[0186] E61. The process according to any one of embodiments E19 to E21, E26, E30 to E31, E33 to E34, E36 to E45 and E48 to E60, wherein following step 3, compound (A4) is isolated as a salt selected from the group consisting of a hemi-oxalate compound (A4-hemi-oxalate), a hydrochloride compound (A4-HCl) or a hydrobromide compound (A4-HBr).

[0187] E62. The process according to any one of embodiments E19 to E21, E26, E30 to E31, E33 to E34, E36 to E45 and E48 to E61, wherein following step 3, compound (A4) is reacted with HCl solution and the hydrochloride compound (A4-HCl) is isolated.

[0188] E63. The process according to any one of embodiments E19-E22, E26, E30-E31, E33-E34, E36-E45, and E48-E62, wherein following step 3, compound (A4) is isolated using a solvent selected from the group consisting of MeTHF, EtOAc, isopropanol, iPrOAc, acetone, toluene, heptane, and mixtures thereof.

[0189] E64. The process according to any one of embodiments E19-E21, E26, E30-E31, E33-E34, E36-E45, and E48-E63, wherein following step 3, compound (A4-HCl) is isolated using a mixture of isopropanol and heptane.

[0190] E65. The process according to any one of embodiments E19-E21, E26, E30-E31, E33-E34, E36-E45, and E48-E64, wherein following step 3, compound (A4-HCl) is isolated using a mixture of acetone and heptane.

[0191] E66. The process according to any one of embodiments E19-E22, E26, E30-E31, E33-E34, E36-E45, and E48-E66, further comprising reacting the isolated salt of compound (A4) with a base to obtain compound (A4) as a free base.

[0192] E67. The process according to any one of embodiments E19-E22, E26, E30-E31, E33-E34, E36-E45, and E48-E66, further comprising reacting a salt of compound (A4) with an aqueous solution of Na2CO3, K2CO3, or ammonia to obtain compound (A4) as the free base.

[0193] E68. The process according to any one of embodiments E19-E22, E26, E30-E31, E34-E35, E37-E45, and E48-E67, further comprising reacting compound (A4-HCl) with an aqueous solution of Na2CO3, K2CO3, or ammonia to obtain compound (A4) as the free base.

[0194] E69. The process according to any one of embodiments E26, E30-E31, E34-E35, E37-E45, and E48-E68, wherein step 4 comprises isolating compound (A5) as an acid salt.

[0195] E70. The process according to any one of embodiments E26, E30-E31, E34-E35, E37-E45, and E48-E69, wherein the Friedel-Crafts acylation in step 4 is carried out using a mixture of P2O5 and TFA in a suitable solvent, such as chlorobenzene.

[0196] E71. The process according to any one of embodiments E30-E31, E35, E38, E40-E45 and E48-E70, wherein compound (A5) or a salt thereof is used in step 5 to obtain compound (Ib).

[0197] E72. The process according to any one of embodiments E30 to E31, E35, E38, E40 to E45 and E48 to E71, wherein compound (A5-tosylate) is used in step 5 to obtain compound (Ib).

[0198] E73. The process according to any one of embodiments E30-E31, E35, E38, E40-E45, and E48-E72, wherein an alcohol solvent is used in step 5.

[0199] E74. The process according to any one of embodiments E30-E31, E35, E38, E40-E45, and E48-E73, wherein a solvent selected from the group consisting of MeOH, EtOH, IPA, and 1-propanol is used in step 5.

[0200] E75. The process according to any one of embodiments E30-E31, E35, E38, E40-E45, and E48-E74, wherein EtOH is used as a solvent in step 5.

[0201] E76. The process according to any one of embodiments E30 to E31, E35, E38, E40 to E45 and E48 to E75, wherein the hydrogenation reaction in step 5 is carried out using a palladium catalyst at a temperature in the range of about 20 to about 100°C, such as about 50 to about 100°C, for example about 60 to about 80°C, for example about 65°C, about 67°C, or about 68°C, about 69°C, about 70°C, about 71°C, about 72°C, about 73°C, about 75°C or about 77°C.

[0202] E77. The process according to any one of embodiments E30 to E31, E35, E38, E40 to E45 and E48 to E76, wherein the hydrogenation reaction in step 5 is carried out using a palladium catalyst at a pressure in the range of from about 2 to about 10 bar, such as from about 3 to 6 bar, for example from about 3 to about 5 bar, such as about 3.5 bar, or such as about 4 bar, or such as about 4.5 bar.

[0203] E78. The process according to any one of embodiments E42 to E45 and E48 to E77, wherein step 6 comprises reacting compound (Ib) with BCl 3 to obtain compound (I) or a salt thereof.

[0204] E79. The process according to any one of embodiments E42 to E45 and E48 to E78, wherein step 6 comprises reacting compound (Ib) as a free base with BCl 3 to obtain compound (I) or a salt thereof.

[0205] E80. The process according to any one of embodiments E42 to E45 and E48 to E79, wherein step 6 comprises reacting a salt of compound (Ib) with a base to obtain compound (Ib) as a free base, and subsequently reacting compound (Ib) with BCl3 to obtain compound (I) or a salt thereof.

[0206] E81. The process according to any one of embodiments E42 to E45 and E48 to E80, wherein step 6 comprises reacting a salt of compound (Ib) with an aqueous solution of Na2CO3, K2CO3 or ammonia to obtain compound (Ib) as a free base, and subsequently reacting compound (Ib) with BCl3 to obtain compound (I) or a salt thereof.

[0207] E82. The process according to any one of embodiments E42 to E45 and E48 to E81, wherein step 6 comprises reacting the (-)-O,O'-di-p-toluoyl-L-tartrate (L-DTTA) salt of compound (Ib) with a base to obtain the free base of compound (Ib), and subsequently reacting compound (Ib) with BCl3 to obtain compound (I) or a salt thereof, such as the HCl salt of compound (I).

[0208] E83. Hydrochloride salts shown below [ka] The compound of embodiment E23, wherein the compound has the form:

[0209] E84. The use of a compound according to any of embodiments E23 and E83 in a process for producing a compound of formula (I) or a compound of formula (Ib).

[0210] E85. The following formula: [ka] Compound (I) having the formula [ka] A process for preparing a compound (Ib) having the formula Compound (Ib) can be prepared by the following process: Process 0) Substep (S1) of reacting compound (a6i) with tert-butyl 2-bromoacetate and zinc to form a mixture, followed by The mixture from substep (S1) is treated with acetic acid, followed by reacting said mixture with 3-chloropropan-1-amine hydrochloride to obtain compound (a2i); Process 1) The compound (a2i) obtained in sub-step (S1) is reduced to obtain compound (a2ii), followed by sub-step (ii). Resolving compound (a2ii) using L-tartaric acid to obtain compound (A2-hemi-L-tartrate), sub-step (iii); by a process comprising the following reaction scheme: [ka] Manufactured in accordance with the process.

[0211] E86. The process according to embodiment E85, wherein compound (a6i) or a salt thereof is prepared by a process comprising reacting compound (a5i) or a salt thereof with a chlorinating agent. [ka]

[0212] E87. The process according to embodiment E86, wherein the chlorinating agent is sulfuryl chloride.

[0213] E88. The process according to any one of embodiments E85 to E87, wherein compound (a2i) is isolated prior to the start of step 1 substep (ii).

[0214] E89. The process according to any one of embodiments E85 to E88, further defined by any one of embodiments E5 to E7, E12 to E16, E19 to E22, E26, E30 to E45, and E48 to E82.

[0215] E90. Compound (A3) can be prepared by the following process: 2) The compound (A2 - hemi-L-tartrate) is reacted with propanal in the presence of a reducing agent to obtain the following reaction scheme b) [ka] A step of obtaining compound (A3) according to the following: The process according to any one of embodiments E85 to E89, comprising:

[0216] All references mentioned in this specification, including publications, patent applications, and patents, are incorporated by reference herein in their entirety and to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety (to the fullest extent permitted by law).

[0217] Headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0218] Description herein of any aspect or embodiments of the invention using terms such as "comprising," "having," "including," or "containing" when referring to one or more elements is intended to provide support for similar aspects or embodiments of the invention that "consist," "consist essentially of," or "substantially comprise" that particular element or elements, unless otherwise specified or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise specified or clearly contradicted by context).

[0219] The use of any and all examples or exemplary terms in this specification (such as "for instance," "for example," "for example," "such as," and "per se") is intended merely to make the invention more clear and does not limit the scope of the invention unless otherwise specified.

[0220] It should be understood that the various aspects, embodiments, implementations, and features of the invention described herein may be claimed separately or in any combination.

[0221] This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

[0222] List of items Some further embodiments of the present invention are disclosed in the following list of items: A first embodiment is denoted as EE1, a second embodiment is denoted as EE2, etc.

[0223] E-E-1. The following formula: [ka] Compound (Ib) having the following reaction scheme: [ka] A process for manufacturing according to the present invention, comprising the steps of: Process 0) substep (i) of reacting compound (A1) with 3-chloropropan-1-amine to obtain compound (a2i); or Substep (S1) of reacting compound (a6i) with tert-butyl 2-bromoacetate and zinc to form a mixture, followed by The mixture from step (S1) is treated with acetic acid, followed by reacting said mixture with 3-chloropropan-1-amine hydrochloride to obtain compound (a2i); Process 1) a substep (ii) of reducing compound (a2i) obtained in process substep (i) or substep (S1) to obtain compound (a2ii), followed by substep (iii) of resolving compound (a2ii) using L-tartaric acid to obtain compound (A2-hemi-L-tartrate); or Substep (i) or substep (S1) is followed by a substep (iv) which comprises subjecting compound (a2i) to hydrogenation carried out using a chiral catalyst in the presence of hydrogen and a solvent to obtain compound (A2); The process includes:

[0224] E-E-2. The process according to embodiment E1, wherein compound (a6i) is prepared by a process comprising reacting compound (a5i) with a chlorinating agent. [ka]

[0225] E-E-3. The process according to embodiment EE2, wherein the chlorinating agent is sulfuryl chloride.

[0226] E-E-4. The process according to any one of embodiments EE1-EE3, wherein the reduction in step 1 substep (ii) is carried out in the presence of a reducing agent.

[0227] EE5. The process according to any one of embodiments EE1-EE4, wherein the reducing agent is selected from NaBH3CN, sodium triacetoxyborohydride (STAB), a borane such as 5-ethyl-2-methylpyridine borane (PEMB), and NaBH4.

[0228] EE6. The process according to any one of embodiments EE1-EE5, wherein the reduction in step 1 substep (ii) is carried out using a platinum catalyst, preferably platinum on carbon.

[0229] EE7. The process according to embodiments EE1-EE3, wherein the chiral catalyst in step 1 substep (iv) is selected from (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene and bis(2,5-norbornadiene)rhodium(I) tetrafluoroborate.

[0230] EE8. The process according to claims EE1-EE3 and EE7, wherein the solvent in process 1 substep (iv) is 2,2,2-trifluoroethanol.

[0231] E-E-9. The following formula (A2) [ka] or a salt thereof.

[0232] E-E-10. Hemi-L-tartrate as shown below [ka] The compound of embodiment E8, wherein the compound has the form:

[0233] E-E-11. Use of a compound according to any of embodiments EE9 and EE10 in a process for producing a compound of formula (I) or a compound of formula (Ib).

[0234] EE12. Compound (Ib) can be prepared by the following process: 2) Reacting compound (A2) or compound (A2-hemi-L-tartrate) with propanal in the presence of a reducing agent to obtain the product according to the following reaction scheme a) or b): [ka] A step of obtaining compound (A3) according to the following: The process according to any one of embodiments EE1-EE8,

[0235] EE13. The process according to embodiment EE12, wherein compound (A3) is prepared by reacting compound (A2-hemi-L-tartrate) with propanal in the presence of a reducing agent.

[0236] EE14. The process according to embodiment EE13, wherein the reducing agent is selected from NaBH3CN, sodium triacetoxyborohydride (STAB), a borane, preferably 5-ethyl-2-methylpyridine borane (PEMB), or hydrogenation over a platinum catalyst, preferably platinum on carbon, and hydrogen gas.

[0237] EE15. The process according to any of embodiments EE12-EE14, wherein the reaction is carried out in a solvent selected from, for example, tetrahydrofuran (THF), isopropanol (IPA), or MeOH.

[0238] EE16. The following formula (A3) [ka] or a salt thereof.

[0239] EE17. Use of a compound according to embodiment EE16 in a process for producing a compound of formula (I) or a compound of formula (Ib).

[0240] EE18. Compound (Ib) can be prepared by the following process: 3) The following reaction scheme [ka] Compound (A3) is reacted with a strong base to give compound (A4), followed by Optionally, compound (A4) may be converted to a hemi-oxalate salt as shown below. [ka] The process according to embodiments E1 to EE8, and EE12 to EE15, wherein the compound is produced by a process comprising isolating the compound as a

[0241] EE19. The process according to embodiment EE16, wherein the strong base is sodium bis(trimethylsilyl)amide (NaHMDS).

[0242] EE20. The process according to any of embodiments EE16-EE17, wherein said reaction of compound (A3) with a base is carried out at a temperature in the range of -20 to -5°C, such as in the range of -15 to -5°C, or such as at a temperature of about -10°C.

[0243] EE21. The process according to any of embodiments EE16-EE18, wherein said compound (A4) is mixed with oxalic acid and isolated as the hemi-oxalate salt.

[0244] EE22. The following formula (A4) [ka] or a salt thereof.

[0245] EE23. Hemi-oxalate salts shown below [ka] The compound of embodiment EE22, wherein the compound has the form:

[0246] EE24. Use of a compound according to any of embodiments EE22-EE23 in a process for producing a compound of formula (I) or a compound of formula (Ib).

[0247] EE25. Compound (Ib) can be prepared by the following process: 4) Intramolecular Friedel-Crafts acylation of compound (A4) is carried out to obtain the compound (A4) according to the following reaction scheme: [ka] Compound (A5) is obtained according to the following procedure, Optionally, as a tosylate salt (A5-tosylate), [ka] The process according to embodiments EE1-EE8, EE12-EE15, EE18-EE21, wherein the compound (A5) is produced by a process comprising isolating compound (A5).

[0248] EE26. The following formula (A5) [ka] or a salt thereof.

[0249] EE27. Tosylate salts as shown below [ka] The compound of embodiment EE26, wherein the compound has the form:

[0250] EE28. The use of a compound according to any of embodiments EE26-EE27 in a process for producing a compound of formula (I) or a compound of formula (Ib).

[0251] EE29. Compound (Ib) can be prepared by the following process: 5) Compound (A5) or a salt thereof is reduced to obtain a compound according to the following reaction scheme: [ka] The process according to embodiments EE1 to EE8, EE12 to EE15, EE18 to EE21, and EE25, wherein compound (Ib) or a salt thereof is obtained according to

[0252] EE30. The process according to embodiment EE29, wherein the reduction is carried out using a palladium catalyst.

[0253] EE31. Compound (Ib) can be prepared by the following process: Step 0 according to any of the embodiments EE1 to EE3); followed by Step 1 according to embodiments EE1 and EE4 to EE8; followed by Step 2 according to any of embodiments EE12 to EE15); The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0254] EE32. Compound (Ib) can be prepared by the following process: Step 2 according to any of embodiments EE12 to EE15); followed by Step 3 according to any of embodiments EE18 to EE21); The process according to any of embodiments EE1-EE8,

[0255] EE33. Compound (Ib) can be prepared by the following process: Step 3 according to any of the embodiments EE18 to EE21); followed by Step 4 according to embodiment EE25); The process according to any one of embodiments EE1-EE8, and EE12-EE15,

[0256] EE34. Compound (Ib) can be prepared by the following process: Step 4 according to any one of embodiments EE25; followed by Step 5 according to any of embodiments EE29 to EE30); The process according to any one of embodiments EE1-EE8,

[0257] EE35. Compound (Ib) can be prepared by the following process: Step 0 according to any of the embodiments EE1 to EE3); followed by Step 1 according to any of embodiments EE1 and EE4 to EE8); followed by Step 2 according to any of embodiments EE12 to EE15); followed by Step 3 according to any of embodiments EE18 to EE21); The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0258] EE36. Compound (Ib) can be prepared by the following process: Step 2 according to any of embodiments EE12 to EE15); followed by Step 3 according to any of the embodiments EE18 to EE21); followed by Step 4 according to embodiment EE25); The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0259] EE37. Compound (Ib) can be prepared by the following process: Step 3 according to any of the embodiments EE18 to EE21); followed by Step 4 according to embodiment EE25; followed by Step 5 according to any of embodiments EE29 to EE30); The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0260] EE38. Compound (Ib) can be prepared by the following process: Step 1 according to any of embodiments EE1 and EE4 to EE8); followed by Step 2 according to any of embodiments EE12 to EE15); followed by Step 3 according to any of the embodiments EE18 to EE21); followed by Step 4 according to any one of embodiments EE25); The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0261] EE39. Compound (Ib) can be prepared by the following process: Step 2 according to any of embodiments EE12 to EE15); followed by Step 3 according to any of the embodiments EE18 to EE21); followed by Step 4 according to embodiment EE25; followed by Step 5 according to any of embodiments EE29 to EE30); The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0262] EE40. Compound (Ib) can be prepared by the following process: Step 0 according to any of the embodiments EE1 to EE3); followed by Step 1 according to any of embodiments EE1 and EE4 to EE8); followed by Step 2 according to any of embodiments EE12 to EE15); followed by Step 3 according to any of the embodiments EE18 to EE21); followed by Step 4 according to embodiment EE25; followed by Step 5 according to any of embodiments EE29 to EE30); The process according to embodiment 1, wherein the composition is produced by a process comprising:

[0263] EE41. The process for preparing compound (I) according to any of embodiments EE1-EE8, EE12-EE15, EE18-EE21, EE25, EE29-EE30, and EE32-EE40, wherein compound (I) is prepared from compound (Ib) by the following steps:

[0264] EE42. A process for producing compound (Ib) according to any one of embodiments EE1-EE8, EE12-EE15, EE18-EE21, EE25, EE29-EE30, and EE32-EE40, which is an ex vivo chemical process.

[0265] EE43. A process for producing compound (Ib) according to any one of embodiments EE1-EE8, EE12-EE15, EE18-EE21, EE25, EE29-EE30, and EE31-EE42, as further defined by any one of embodiments E48-E82 and E85-E90.

[0266] EE44. The following formula: [ka] A process for producing a compound (Ib) having the formula Compound (Ib) can be prepared by the following process: Process 0) Substep (S1) of reacting compound (a6i) with tert-butyl 2-bromoacetate and zinc to form a mixture, followed by The mixture from substep (S1) is treated with acetic acid, followed by reacting said mixture with 3-chloropropan-1-amine hydrochloride to obtain compound (a2i); Process 1) Substep (ii) of reducing compound (a2i) obtained in substep (S1) to obtain compound (a2ii), followed by substep (iii) of resolving compound (a2ii) using L-tartaric acid to obtain compound (A2-hemi-L-tartrate); by a process comprising the following reaction scheme; [ka] Manufactured in accordance with the process.

[0267] EE45. The process according to embodiment EE44, wherein compound (a6i) or a salt thereof is prepared by a process comprising reacting compound (a5i) or a salt thereof with a chlorinating agent. [ka]

[0268] EE46. The process according to embodiment EE45, wherein the chlorinating agent is sulfuryl chloride.

[0269] EE47. The process according to any one of embodiments EE44 to E46, wherein compound (a2i) is isolated prior to the start of step 1 substep (ii).

[0270] EE48. The process according to any one of embodiments EE44 to EE47, further defined by any one of embodiments E5 to E7, E12 to E16, E19 to E22, E26, E30 to E45, and E48 to E82.

[0271] EE49. Compound (A3) can be prepared by the following process: 2) The compound (A2-hemi-L-tartrate) is reacted with propanal in the presence of a reducing agent to obtain the following reaction scheme b): [ka] The process according to any one of embodiments EE44 to EE48, wherein compound (A3) is obtained according to the process comprising the steps of:

[0272] Experimental Section Abbreviation: DCM: dichloromethane DEA: Diethylamine ee: enantiomeric excess EtOAc: ethyl acetate IPA: Isopropanol iPrOAc: isopropyl acetate iPrOH: Isopropanol Me-THF: 2-methyltetrahydrofuran NaHMDS: Sodium bis(trimethylsilyl)amide Pd / C: Palladium on carbon PEMB: 5-ethyl-2-methylpyridine borane STAB: Sodium triacetoxyborohydride TFA: Trifluoroacetic acid THF: tetrahydrofuran Me-THF: 2-methyltetrahydrofuran TsOH: p-toluenesulfonic acid v / v: volume / volume w / w: weight / weight

[0273] NMR method QNMR(600MHz): 1) Relaxation delay: 40 seconds 2) Acquisition time 3.76 seconds 3) Time Domain 64k 4) Size 32k 5) Dummy scan 4 6) Scan 8 7) Pulse 30 degrees

[0274] LC-MS and HPLC methods LC-MS analytical data was obtained using the methods identified below.

[0275] LC-MS Method: LC-MS was performed on a Waters Aquity UPLC-MS system consisting of a column manager, a binary solvent manager, a sample organizer, a PDA detector (operated at 254 nM), an ELS detector and a TQ-MS equipped with an APPI source operated in positive ion mode. LC conditions: The column was an Acquity UPLC BEH C18 1.7 μm; 2.1×150 mm operated at 60° C. using a binary gradient of 0.6 ml / min consisting of water+0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5)+0.05% trifluoroacetic acid.

[0276] Gradient (Linear): 0.00 minutes 10%B 3.00 minutes 100%B 3.60 minutes 10%B Total execution time: 3.6 minutes

[0277] Chiral HPLC Method: Chiral HPLC was performed on a Merck Hitachi 7000 series HPLC consisting of a pump, interface, programmable autosampler, column oven and UV detector operating at 220 nm. The column was a Chiralpak AD-H 5 μm; 4.6×250 mm operated at 30° C., with an eluent flow rate of 1.0 mL / min consisting of hexane / IPA / DEA (90 / 10 / 0.1) (v / v) and a total run time of 20 min. EXAMPLES

[0278] Example 1: Preparation of Compounds (a2i), (a2ii) and (A2-hemi-L-tartrate) (Step 0 Substep (i) Followed by Step 1 Substeps (ii) and (iii)) A mixture of 3-chloropropan-1-amine hydrochloride (24.9 g, 192 mmol), compound (A1) (20.0 g, 63.9 mmol), zinc chloride, sodium acetate (17.3 g, 211 mmol) and sodium sulfate (4.54 g, 32.0 mmol) in Me-THF (1.7 ml, 3.20 mmol, 1.9 M) was stirred overnight.

[0279] A solution of sodium cyanoborohydride (5.22 g, 83 mmol) in Me-THF (50 mL) was then added slowly at room temperature and the mixture was stirred at 40 °C for 4 h. The mixture was cooled to room temperature and added slowly to a stirred mixture of saturated aqueous NH4Cl (100 mL) and water (100 mL). The mixture was stirred at room temperature for 15 min. The organic phase was separated and washed with a mixture of saturated aqueous NH4Cl and water (100 mL, 1:1 (v / v)) and then washed twice with saturated aqueous NaHCO3 (2 x 100 mL). The organic phase was washed with brine (100 mL), dried over MgSO4, filtered and coevaporated to dryness with MeOH in several rounds to give crude compound (a2ii) (27.7 g) as an oil.

[0280] To a solution of crude compound (a2ii) in MeOH (150 mL) was added a solution of L-tartaric acid (5.32 g, 35.5 mmol) in MeOH (43 mL) with stirring at reflux. The mixture was cooled slowly to room temperature overnight with stirring and seeding (ca. 20 mg) just under reflux. The resulting suspension was filtered, and the filter cake was washed with MeOH (20 mL) and dried in a vacuum oven at 40° C. to give compound (A2-hemi-L-tartrate) (11.3 g, 38%) as a solid, with a S:R ratio of compound (A2) of 1:161 (99.4% ee) by chiral HPLC analysis. LC-MS:RT=2.22min,[M+H] + =390.0m / z. 1 H NMR(600MHz,DMSO-d6)δ 7.03(s,1H),6.95(s,1H),6.04(dd,J=1.0,1.0Hz,2H),4.12(s,2H,L-tartaric acid) ,3.66(t,J=6.5Hz,2H),3.21(quintet,J=8.0Hz,1H),2.91(dd,J=6.0,13.5Hz, 1H),2.75(t,J=7.0Hz,2H),2.62(dd,J=8.5,13.5Hz,1H),2.31(dd,J=7.0, 15.5Hz, 1H), 2.26 (dd, J=7.0, 15.5Hz, 1H), 1.82-1.86 (m, 2H), 1.36 (s, 9H).

[0281] Example 2: Production of compound (A3) (Step 2) A mixture of compound (A2-hemi-L-tartrate) (400 mg, 0.43 mmol), propanal (80 μL, 1.12 mol), acetic acid (49 μL, 0.86 mmol) and THF (4.0 mL) was stirred for 30 min. STAB (182 mg, 0.86 mmol) was then added. The reaction mixture was stirred at room temperature for 3.5 h. A saturated aqueous solution of NaHCO3 (4 mL) was added and the mixture was extracted with toluene. The organic extract was dried over MgSO4, filtered and evaporated to dryness to give crude compound (A3) (167 mg, 90%) as a solid. LC-MS:RT=2.46min,[M+H] + =432.3m / z. 1H NMR(600MHz,CDCl3)δ 6.80(s,1H),6.62(s,1H),5.94(s,2H),3.49-3.55(m,2H),3.35-3.39(m,1 H),2.90(dd,J=3.5,13.5Hz,1H),2.61-2.63(m,2H),2.52(dd,J=9.0,13.5H z,1H),2.36-2.45(m,3H),2.16(dd,J=5.5,14.5Hz,1H),1.86-1.92(m,1H) ,1.76-1.83(m,1H),1.39-1.49(m,2H),1.41(s,9H),0.86(t,J=7.5Hz,3H).

[0282] Example 3: Preparation of compound (A4) (Step 3). To a solution of compound (A3) (40.0 g, 92.5 mmol) and toluene (311 mL) at -10°C, a solution of NaHMDS in THF (93.2 mL, 185 mmol, 2 M) was added over a period of 7.5 minutes. A slight increase in temperature was observed. The reaction mixture was stirred at -10°C for 50 minutes. The temperature was then increased to 5°C and maintained overnight. The reaction mixture was then brought to room temperature and an aqueous solution of NaCl (160 g, 5% (w / w)) was added over a period of 5 minutes. The organic phase was separated and evaporated to dryness in vacuum. The residue was stripped with acetone (200 mL) and the residue was mixed with acetone and oxalic acid (8.30 g, 92.2 mmol) and stirred at room temperature overnight. The mixture was then cooled in an ice bath for 1 hour and filtered. The filter cake was washed twice with cold acetone (2×50 mL), crushed and dried in vacuum at 50° C. to give compound (A4-hemi-oxalate) (35.0 g, 78%) as a powder, predominantly as the cis isomer. 1 Determined by 1 H NMR analysis. LC-MS:RT=0.61min,[M+H] + =396.3m / z. 1H NMR(600MHz,DMSO-d6)δ 7.07(s,1H),7.03(s,1H),6.06(s,2H),3.73(br s,1H),2.99-3.16(m,2H),2.73-2.90(m,4H),2.43(br s,1H),1.88-1.96(m,1H),1.60-1.80(m,3H),1.45-1.56(m,2H),1.35(s,9H),0.81(t,J=7.5Hz,3H).

[0283] Example 4: Production of compound (A5) (Step 4) Free basing of compound (A4-hemi-oxalate): A mixture of compound (A4-hemi-oxalate) (1000 g, 2.06 mol), heptane (8 L), water (6 L) and aqueous ammonia (500 mL, 6.76 mol, 25% (w / w)) was stirred at 35-45° C. for 4 h. The organic phase was separated and concentrated to 1-2 L by distillation at >95° C. Then, chlorobenzene (1.0 L) was added and the mixture was concentrated to 1.5-2.0 L by distillation in vacuum to obtain a solution of compound (A4) as the free base.

[0284] Formation of compound (A5): To a stirred mixture of P2O5 (30 g, 211 mmol) and chlorobenzene (200 mL), trifluoroacetic acid (50.0 mL, 650 mmol) was added over 5 to 15 minutes at 15 to 30° C. The resulting mixture was stirred at room temperature for 30 minutes.

[0285] A solution of compound (A4) as the free base in chlorobenzene (see above, corresponding to 50 g (103 mmol) of compound (A4-hemi-oxalate)) was then added over 10-30 min at 25-45 °C. The resulting mixture was stirred at 35-40 °C for 3 h and then at room temperature overnight. To the reaction mixture was added IPA (125 mL) at room temperature and the mixture was stirred at 40-45 °C for 2 h and then at room temperature overnight. To a stirred mixture of aqueous ammonia (150 mL, 2.00 mol, 25% (w / w)) and water (1.0 L) the mixture was added over 5-10 min at 5-10 °C. The mixture was stirred at 35-45 °C for 10 min. The organic phase was separated and the aqueous phase was extracted with chlorobenzene (100 mL). To the combined stirred organic phase was added a solution of TsOH-HO (23.6 g, 124 mmol) in IPA (150 mL). The mixture was concentrated in vacuum at 50-70 °C on a rotary evaporator to a volume of about 50 mL. IPA (100 mL) was added and the mixture was again concentrated in vacuum at a rotary evaporator to a volume of about 50 mL. IPA (125 mL) was added and the mixture was stirred at room temperature to allow precipitation. The formed suspension was cooled to 5 °C and filtered. The filter cake was washed twice with cold IPA (2 × 20 mL, 5 °C) and dried in a vacuum oven at 50 °C to give compound (A5-tosylate) (35.6 g, 70%) as a powder. LC-MS:RT=1.62min,[M+H] + =322.2m / z. 1 H NMR(600MHz,DMSO-d6)δ 9.65(br s,1H),7.46-7.48(m,2H),7.45(s,1H),7.09-7.11(m,2H),6.23(d,J=5.5Hz,1H),6.21(d, J=5.5Hz,1H),3.67-3.74(m,1H),3.56(dd,J=4.5,16Hz,2H),3.31-3.39(m,1H),3.06-3.1 4(m,1H),2.93-3.03(m,1H),2.83-2.93(m,2H),2.27(s,3H),2.18-2.24(m,1H),1.91-1.9 8(m,1H),1.70-1.84(m,2H),1.61-1.70(m,1H),1.41-1.50(m,1H),0.96(t,J=7.5Hz,3H).

[0286] Example 5: Production of compound (Ib) (Step 5) A mixture of compound (A5-tosylate) (5.00 g, 10.1 mmol), 5% Pd / C (561 mg, 0.101 mmol, Johnson Matthey type 424) and EtOH (50 mL) was hydrogenated at 4 bar hydrogen and 70° C. for 48 h. The reaction mixture was filtered through Arbocell BC200 and the filtrate was coevaporated several times with toluene. The resulting solution was washed with dilute aqueous ammonia (10% (w / w)), then with brine, dried over MgSO4, filtered and evaporated to dryness to give compound (Ib) (2.59 g) as a solid. LC-MS:RT=1.95min,[M+H] + =274.3m / z. 1 H NMR(600MHz,CDCl3)δ 6.63(d,J=8.0Hz,1H),6.59(d,J=8.0Hz,1H),5.92(d,J=1.5Hz,1H),5.89(d,J=1.5Hz,1H),3.15(dd,J=5. 0,16.0Hz,1H),2.97-3.00(m,1H),2.82(dd,J=5.0,17.0Hz,1H),2.73(ddd,J=5.5,10.5,13.5Hz,1H),2.56 (dd,J=11.0,15.5Hz,1H),2.49(ddd,J=5.5,10.5,13.5Hz,1H),2.21-2.30(m,1H),2.18(dt,J=5.0,10.5H z,1H),1.87-1.92(m,1H),1.58-1.72(m,2H),1.42-1.58(m,1H),1.06-1.15(m,1H),0.89(t,J=7.5Hz,3H).

[0287] Example 6: Preparation of Compound (I) from Compound (Ib) (Step 6) A 2 L three-neck flask equipped with a mechanical overhead stirrer was charged with the (-)-O,O'-di-p-toluoyl-L-tartrate (L-DTTA) salt of compound (Ib) (242 g, 367 mmol), toluene (1250 mL), water (375 mL) and 25% aqueous ammonia (100 mL, 1340 mmol). The mixture was stirred at 20-25 °C for 50 min before phase separation. The organic phase was washed with a mixture of water (170 mL) and 25% aqueous ammonia (35 mL, 470 mmol). The separated organic phase was concentrated to near dryness under vacuum at 50 °C. The residue was concentrated to near dryness three times successively with toluene (3 x 250 mL) under vacuum at 50 °C. The residue was dissolved and transferred to a 4 L three-neck flask containing toluene (1200 mL). The solution was cooled to 4°C and for 25 min, and BCl3 in toluene (800 mL, 800 mmol, 1M) was added. The reaction mixture was stirred at 0-5°C for 3 h. After an additional 1.8 h at 0-5°C, methanol (500 mL) was added to quench the reaction mixture for 20 min. The resulting mixture was heated at 55°C overnight, then heated to reflux and 500 mL of solvent was removed by distillation. Methanol (500 mL) was added, the mixture was heated to reflux and 500 mL of solvent was removed by distillation. IPA (500 mL) was added, the mixture was heated to reflux and 500 mL of solvent was removed by distillation. IPA (1200 mL) was added and the mixture was heated to 75°C for 1.5 h. The suspension was cooled to 20°C in 1.5 h, and then the product was removed by filtration. The filter cake was washed twice with IPA / toluene (1:1, 2 x 200 mL). Drying under vacuum at 50° C. gave the HCl salt of compound (I) (105 g, 96%) as a solid. 1H NMR(600MHz,DMSO-d6)δ 6.53(d,J=8.0Hz,1H),6.37(d,J=8.0Hz,1H),3.01(dd,J=4.5,15.0Hz,1H),2.89(app d,J=11.0Hz,1H),2.79(dd,J=5.0,17.5Hz,1H),2.65-2.70(m,1H),2.36( dd,J=11.0,15.5Hz,1H),2.25-2.30(m,1H),2.12(dt,J=2.5,12.0Hz,1H), 1.99-2.05(m,2H),1.79-1.84(m,1H),1.58-1.63(m,1H),1.49-1.57(m,1H ),1.35-1.47(m,3H),1.05(dq,J=4.0,13.0Hz,1H),0.84(t,J=7.5Hz,3H).

[0288] Example 7: Preparation of compound (A2-hemi-L-tartrate) from compound (a2i) (step 1, substep (ii) using Pt catalyst, and step 1, substep iii) A mixture of compound (a2i) (12.4 g, 32.0 mmol) and platinum on carbon (Johnson Matthey type 128M; 4.88% Pt; 52.6% (w / w) water; 2.16 g, 0.256 mmol) in Me-THF (31 mL) was hydrogenated at 60° C. and 4 bar of hydrogen for 24 h. The reaction mixture was filtered and evaporated to dryness to give crude compound (a2ii). To crude compound (a2ii) in MeOH (67 mL) was added a solution of L-tartaric acid (2.40 g, 16.0 mmol) in MeOH (20 mL) slowly at reflux with stirring. The mixture was cooled slowly to room temperature overnight with stirring and seeded at about 62° C. (about 20 mg of pure compound (A2-hemi-L-tartrate)). The resulting suspension was filtered, and the filter cake was washed with MeOH (10 mL) and dried in a vacuum oven at 40° C. to give compound (A2-hemi-L-tartrate) (4.90 g, 33%) as a white solid, having an enantiomeric excess of compound (A2) of 99.2% according to chiral HPLC analysis.

[0289] Example 8: Preparation of compound (A1) from compound (a6i) (Substep 0') To vigorously stirred zinc powder (Umicore) (2.84 g, 43.5 mmol) in THF (15.0 mL) was added methanesulfonic acid (83 μL, 1.28 mmol) and the mixture was stirred at reflux for 30 min. Then a solution of compound (a6i) (5.00 g, 25.6 mmol) in THF (15.0 mL) was added, followed by dropwise addition of tert-butyl 2-bromoacetate (6.48 g, 33.2 mmol) over 1 h 40 min at reflux. The mixture was stirred at reflux for 1 h, then the heat was removed and the stirred reaction mixture was cooled to room temperature overnight. To a 0° C. aqueous HCl solution (38 mL, 76 mmol, 2.0 M) was added the reaction mixture with stirring. The resulting mixture was concentrated under vacuum to remove most of the THF, then cooled in an ice-water bath with vigorously stirring and seeded with a pure sample of compound (A1). The formed suspension was filtered cold (approximately 5° C.), the filter cake was washed with a water:THF (10:1) mixture and dried overnight in a vacuum oven at 40° C. to give compound (A1) (7.72 g, 97%) as a slightly yellowish solid. LC-MS (Method: 555) RT = 2.84 and 3.41 min (the two peaks are the keto and enol tautomers of compound (A1)) 1 H NMR(600MHz,DMSO-d6)δ 7.07(s,1H),6.89(s,1H),6.06(s,2H),3.90(s,2H),3.53(s,2H),1.41(s,9H).

[0290] Example 9: Preparation of compound (a2i) from compound (a6i) (Step 0, Substep S1) A mixture of zinc powder (Umicore) (10.0 g, 153 mmol) and methanesulfonic acid (332 μL, 5.11 mmol) in THF (60 mL) was heated at reflux with stirring for 30 min.

[0291] A solution of compound (a6i) (20.0 g, 102 mmol) in THF (60 mL) was added. Then tert-butyl 2-bromoacetate (25.9 g, 133 mmol) was added slowly at reflux over 2 hours. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature.

[0292] The reaction mixture was filtered from excess zinc and cooled in an ice-water bath. Then, with stirring, acetic acid (7.6 mL, 133 mmol) was added slowly. The mixture was coevaporated several times with MeOH to remove THF via the THF-MeOH azeotrope. This resulted in a suspension to which a solution of 3-chloropropan-1-amine hydrochloride (33.2 g, 256 mmol) in MeOH (50 mL) was added. The mixture was stirred overnight at room temperature. The mixture was filtered, the filter cake was washed with a little MeOH and dried in a vacuum oven at 40° C. to give compound (a2i) (32.0 g, 81%) as a white solid. LC-MS (Method: 555) RT = 2.84 and 3.41 min (the two peaks seen due to hydrolysis of compound (a2i) to compound (A1) are the keto and enol tautomers of compound (A1) by LC-MS analysis). 1 H NMR(600MHz,DMSO-d6)δ 8.57(t,J=6.5Hz,1H),7.10(s,1H),6.89(s,1H),6.08(s,2H),3.85(s,1H),3.67(t,J =6.5Hz,2H),3.58(s,2H),3.33(q,J=6.5Hz,2H),1.95(q,J=6.5Hz,2H),1.36(s,9H).

[0293] Example 10: Preparation of compound (a6i) from compound (a5i) To a vigorously stirred mixture of compound (a5i) (30.0 g, 186 mmol) and n-heptane (200 mL) at 0° C. was added sulfuryl chloride (17.4 ml, 214 mmol). The cooling was removed and the mixture was allowed to warm to room temperature with vigorously stirring. The mixture was stirred at room temperature for 4 hours. The formed suspension was filtered and the precipitate was washed with heptane and dried in vacuum at 40° C. to give compound (a6i) (33.4 g, 92%) as a white solid. LC-MS (Method: 555) RT=2.28 min, [M+H] + =195.1m / z. 1 H NMR(600MHz,CDCl3)δ 6.95(s,1H),6.88(s,1H),6.02(s,2H),3.74(s,2H).

[0294] Example 11: Large-Scale Preparation of Compound A4-HCl from Compound A2-Hemi-L-Tartrate (Steps 2 and 3) To a cold slurry containing compound (A2-hemi-L-tartrate salt) (750 g, 805.9 mmol, 1 equiv.) and sodium triacetoxyborohydride (597.8 g, 2820 mmol, 3.5 equiv.) in THF (3750 mL, 5 volumes) at 10° C. was added a cold (10° C.) solution of propionaldehyde (121.7 g, 150.2 mL, 2100 mmol, 2.6 equiv.) in THF (1500 mL, 2 volumes) over the course of 30 minutes. Glacial acetic acid (169.4 g, 161.5 mL, 2820 mmol, 3.5 equiv.) was then added over the course of 5 minutes at 21° C. and the reaction mixture was stirred at 23° C. overnight. Then 10% of the volume was distilled off under vacuum at 25° C. before adding water (2250 mL, 3 vol) and the solution was stirred at 22° C. for 1 h. Toluene (2250 mL, 3 vol) was then added followed by 25% ammonia (880 mL, 1176 mmol, 14.6 eq) until pH 8 and the solution was stirred at 22° C. for 1 h before the two phases were separated. The aqueous phase was separated with toluene (2250 mL, 3 vol) and the combined organic phase was washed with 7.5% brine (1500 mL, 2 vol). The organic solution was completely concentrated under reduced pressure at 65° C. to give crude compound (A3) (696.9 g, 100%, HPLC 98.4 area %, RT 14.96 min) as an oil.

[0295] To the crude compound (A3) (696.6 g, 805.9 mmol), toluene (6000 mL, 8 volumes) was added and the solution was cooled to 0° C. before 1 m NaHMDS in THF (3380 mL, 3380 mmol, 2.1 equiv.) was added over the course of 100 min, the temperature of the mixture not exceeding 5° C. The reaction mixture was stirred at 2° C. for 3.5 h before the solution was warmed to 20° C. over the course of 13 min. 5% brine (3750 mL, 5 volumes) was then added to quench the reaction mixture and the mixture was stirred for 10 min before the two phases were separated. The organic phase was washed successively with 10% acetic acid (2310 mL, 4030 mmol, 2.5 equiv.) and water (3750 mL, 5 volumes) before the organic phase was completely concentrated under reduced pressure at 60° C. Isopropanol (2250 mL, 3 vol) was then added and the organic phase was again concentrated completely under reduced pressure at 60° C. Subsequently, isopropanol (750 mL, 1 vol) was added and the solution was transferred to a premixed solution of isopropanol (750 mL, 1 vol), heptane (6000 mL, 8 vol) and acetyl chloride (229.2 mL, 3220 mmol, 2 equiv.) (premixed at 22° C.-1 hr) and precipitation was observed. The mixture was stirred at 20° C. for 1 hr before cooling the slurry to 4° C. over 30 min and stirring at this temperature for 80 min. The product was then removed by filtration and the filter cake was washed with cold (4° C.) heptane (750 mL, 1 vol). The wet product was dried under vacuum at 50° C. overnight. This gave compound (A4-HCl) (555.1 g, 80%) as a white powder. HPLC purity: 99.3 area%, 99.2w / w%. 1H NMR(400MHz,CDCl3)δ 12.50(s,1H),7.05(s,1H),6.82(s,1H),5.99(m,2H),3.87(dd,J=15.8,6.7Hz,1H),3.65 (m,1H),3.45(m,1H),3.20(ddd,J=11.0,9.7,4.4Hz,1H),3.08(tdd,J=12.7,4.9,2.5Hz,1 H),2.92(m,2H),2.77(tdd,J=12.0,8.5,3.1Hz,1H),2.49(m,1H),2.21(m,1H),1.84(m,2 H),1.66(dtd,J=13.5,11.7,4.0Hz,1H),1.52(m,1H),1.39(s,9H),0.77(t,J=7.3Hz,3H).

[0296] Reference List U.S. Pat. No. 4,543,256 International Publication No. 2001 / 078713 Brochure International Publication No. 02 / 100377 Brochure International Publication No. 2009 / 026934, Brochure International Publication No. 2009 / 026935 Brochure International Publication No. 2010 / 097092 Brochure Alexander et Crutcher,(1990)Trends in Neuroscience 13:266-71; Bibbiani et al.,Chase Experimental Neurology(2005),192:73-78; Brueckner and co-workers in Synthesis 2008,14:2229-2246; Campbell et al., Neuropharmacology(1982);21(10):953-961; Cannon et al., J. Heterocyclic Chem. (1980);17:1633-1636; Delong, (1990)Trends in Neuroscience 13:281-5; Fan et al., Bioorg. Med. Chem. Lett. 2008, 18: 6236 - 6239; Gerfen et al, Science (1990) 250: 1429 - 32; Giardina and Williams; CNS Drug Reviews (2001), Vol. 7(3): 305 - 316); Grosset et al., Acta Neurol Scand. (2013), 128: 166 - 171; Hauser et al., Movement Disorders (2016), Vol. 32(9): 1367 - 1372; Kotsuki et al., J. Org. Chem. 1992, 57: 5036 - 5040); Liu et al., J. Med. Chem. (2006), 49: 1494 - 1498; Liu et al., Bioorganic Med. Chem. (2008), 16: 3438 - 3444; S. Nishimura, Wiley 2001, Handbook of heterogeneous hydrogenation; Poewe et al., Nature Review, (2017) vol 3 article 17013: 1 - 21; Sprenger and Poewe, CNS Drugs (2013), 27: 259 - 272; Sozio et al., Exp. Opin. Drug Disc. (2012); 7(5): 385 - 406; Stahl and Wermuth (Eds) “Handbook of Pharmaceutical salts. Properties, selection, and use”, Wiley - VCH, 2008; The present invention may include the following aspects. [1] The following formula:

Chem.

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[10] The following formula (A3)

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[11] Compound (Ib) can be prepared by the following process: 3) Reacting compound (A3) with a strong base to obtain the compound represented by the following reaction scheme:

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[12] A4 is the HCl salt shown below.

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[13] The following formula (A4)

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[14] Compound (Ib) can be prepared by the following process: 4) Intramolecular Friedel-Crafts acylation of compound (A4) is carried out to obtain the compound (A4) according to the following reaction scheme:

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[15] The following formula (A5)

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[16] Compound (Ib) can be prepared by the following process: 5) Compound (A5) or a salt thereof is reduced to obtain a compound according to the following reaction scheme:

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[17] Compound (I) can be prepared by the following process: 6) BCl 3 , BBr 3 and HBr, to react compound (Ib) with a Lewis acid or Bronsted acid selected from the group consisting of

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[18] The following formula (a2i)

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[19] The following formula (a2ii)

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Claims

1. The following formula (A2) 【Chemistry 4】 or a salt thereof.

2. The following formula (A3) 【Chemistry 6】 or a salt thereof.

3. The following formula (A4) 【Chemistry 9】 or a salt thereof.

4. The following formula (A5) 【Chemistry 11】 or a salt thereof.

5. 5) The following reaction scheme 【Chemistry 12】 A process for producing compound (Ib) or a salt thereof, comprising a step of reducing compound (A5) or a salt thereof to obtain compound (Ib) or a salt thereof according to the formula:

6. A process for producing compound (I) or a salt thereof, comprising the steps of: 5) The reaction scheme below 【Chemistry 12】 to obtain compound (Ib) or a salt thereof; and 6) The reaction scheme below 【Chemistry 13】 reacting compound (Ib) with a Lewis acid or a Bronsted acid selected from the group consisting of BCl 3 , BBr 3 and HBr according to the formula (3) to obtain compound (I) or a salt thereof; The process includes:

7. Step 6 is reacting compound (Ib) with BCl ３ to obtain compound (I) or a salt thereof.

8. Step 6 is reacting a salt of compound (Ib) with a base to obtain compound (Ib) as a free base, followed by reacting compound (Ib) with BCl ３ to obtain compound (I) or a salt thereof.

9. Step 6 is to convert the salt of compound (Ib) into Na ２ CO ３ , K ２ CO ３ or with an aqueous solution of ammonia to obtain compound (Ib) as a free base, which can then be reacted with BCl ３ to obtain compound (I) or a salt thereof.

10. Step 6 is reacting the (-)-O,O'-di-p-toluoyl-L-tartrate (L-DTTA salt) of compound (Ib) with a base to obtain the free base of compound (Ib), followed by annealing compound (Ib) with BCl. ３ to obtain compound (I) or a salt thereof.

11. The process of any one of claims 6 and 8 to 10, wherein step 6 comprises reacting the (-)-O,O'-di-p-toluoyl-L-tartrate salt (L-DTTA salt) of compound (Ib) with a base to obtain the free base of compound (Ib), and subsequently reacting compound (Ib) with BCl 3 to obtain the HCl salt of compound (I).

12. Compound (A5-tosylate) The process according to any one of claims 6 to 11, wherein in step 5, 13. The process of claim 6, wherein an alcohol solvent is used in step 5.

14. The process of claim 6, wherein a solvent selected from the group consisting of MeOH, EtOH, IPA and 1-propanol is used in step 5.

15. The process of claim 6, wherein EtOH is used as the solvent in step 5.

16. The process of claim 6, wherein step 5 is carried out using a palladium catalyst at a temperature in the range of 50°C to 100°C.

17. The process of claim 6, wherein step 5 is carried out using a palladium catalyst at a pressure in the range of 3 bar to 6 bar.

18. The process of claim 17, 4) The following reaction scheme 【Chemistry 10】 Intramolecular Friedel-Crafts acylation of compound (A4) to give compound (A5), followed by Optionally, isolating compound (A5) or a salt thereof. The process of any one of claims 6 to 17, further comprising:

19. The process of claim 18, 3) The following reaction scheme 【Chemistry 7】 Compound (A3) is reacted with a strong base to give compound (A4), followed by Optionally, isolating compound (A4) or a salt thereof.

20. The process of claim 18, further comprising:

20. The process of claim 19, 2) The following reaction scheme a) or b): 【Chemistry 5】 reacting compound (A2) or compound (A2-hemi-L-tartrate) with propanal in the presence of a reducing agent to obtain compound (A3) according to the procedure described above.

20. The process of claim 19, further comprising:

21. The following reaction scheme: According to the following steps: Process 0) Substep (i) of reacting compound (A1) with 3-chloropropan-1-amine to obtain compound (a2i); or substep (S1) of reacting compound (a6i) with tert-butyl 2-bromoacetate and zinc to form a mixture, followed by treating said mixture with acetic acid, followed by reacting said mixture with 3-chloropropan-1-amine hydrochloride to obtain compound (a2i); Process 1) Substep (ii) of reducing compound (a2i) obtained in substep (i) or substep (S1) to obtain compound (a2ii), followed by Substep (iii) of resolving compound (a2ii) using L-tartaric acid to obtain compound (A2-hemi-L-tartrate).

21. The process of claim 20, further comprising:

22. The following formula (a2i) 【Chemistry 14】 or a salt thereof.

23. The following formula (a2ii) 【Chemistry 15】 or a salt thereof.

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