Process for manufacturing an antibiotic macrocyclic peptide

Abstract

The invention relates to a novel process for manufacturing 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid (I), or a pharmaceutically acceptable salt thereof. Formula: (I). The invention further relates to certain synthetic intermediates that are useful for the novel process according to the invention, as well as to processes for making those synthetic intermediates. The process according to the invention is particularly suitable for large-scale manufacturing of the compound of formula (I) under GMP conditions.

Description

[0001] PROCESS FOR MANUFACTURING AN ANTIBIOTIC MACROCYCLIC PEPTIDE

[0002] Field of the Invention

[0003] The invention relates to a novel process for manufacturing 4-[(l lS,14S,17S)-14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-( 1 H-indol-3 -ylmethyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I), or a pharmaceutically acceptable salt thereof.

[0004]

[0005] The invention further relates to certain synthetic intermediates that are useful for the novel process according to the invention, as well as to processes for manufacturing them.

[0006] The process according to the invention is particularly suitable for large-scale manufacturing of the compound of formula (I) under GMP conditions.

[0007] Background of the Invention

[0008] The compound of formula (I) is a potent antibiotic with selective action against carbapenem-resistant Acinetobacter baumannii (CRAB), as discussed in Zampaloni et al.. Nature 2024, 625, 566. CRAB has emerged as a major global pathogen with limited treatment options. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years.

[0009] The compound of formula (I) is also known under the INN zosurabalpin (WHO Drug Information, Vol. 36, No. 2, 2022). WO2019206853 discloses a laboratory scale synthesis of zosurabalpin.

[0010] WO2023152347 discloses a large scale synthesis of the compound of formula (la), which is a crucial intermediate in the lab scale synthesis of zosurabalpin disclosed in WO2019206853:

[0011]

[0012] WO2024033278 discloses an improved synthesis of zosurabalpin, starting from the intermediate of formula (la).

[0013] Both WO2019206853 and WO2023152347 also disclose processes for manufacturing an intermediate of formula (lb), which is the ultimate precursor to the intermediate of formula (la).

[0014]

[0015] The processes for manufacturing the intermediate of formula (lb) disclosed in WO2019206853 and WO2023152347 suffer from certain drawbacks that hamper its industrial-scale synthesis, and with that ultimately the industrial-scale synthesis of zosurabalpin, such as low yields, use of hazardous solvents and chemicals, poor atom economy and expensive chemicals, as well as impurities in the final product, in particular potential contamination of the final product with genotoxic dibenzofulvene. Accordingly, there is a high unmet need for a new process for manufacturing the intermediate of formula (lb). Summary of the Invention

[0016] The present invention provides an improved process for manufacturing zosurabalpin, and in particular an improved process for manufacturing the synthetic intermediate of formula (lb), which overcomes the problems outlined above.

[0017]

[0018] As discussed i.a. in WO2019206853, WO2023152347, and WO2024033278, the compound of formula (lb) is a crucial synthetic intermediate in the manufacture of zosurabalpin.

[0019] A key aspect of the present manufacturing process is a novel protective group strategy. More particularly, according to the process of the invention, the Fmoc protected known synthetic intermediate 4 is replaced by the Alloc protected intermediate 1c, leading to improved atom economy and avoiding the formation of stoichiometric amounts of genotoxic dibenzofulvene that is formed upon Fmoc deprotection.

[0020]

[0021] The present invention also provides an improved process for manufacturing zosurabalpin based on synthetic intermediate lb that is readily applicable on an industrial scale under GMP conditions. Finally, the present invention provides certain synthetic intermediates that are useful in the new processes described herein.

[0022] Detailed Description of the Invention

[0023] Definitions

[0024] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims and the abstract), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims and the abstract), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0025] The term “palladium catalyst” as used herein refers to any palladium catalyst that enables the removal of an Alloc protective group from the compound of formula 1c to afford a compound of formula lb. A particular example that can be used for this reaction is Pd(Ph3)4.

[0026] The term “allyl cation scavenger” refers to a reagent used in palladium-catalyzed deallylation reactions (e.g. cleavage of Allyl carbamates or allyl esters) to capture and neutralize the allyl cation (CH2=CH-CH2+) that is released during the deprotection process in order to prevent unwanted side reactions and increase the overall efficiency and selectivity of the deprotection. Some non-limiting examples of allyl cation scavengers include morpholine, A-methylmorpholine, dimethylamine, diethylamine, PPI13, 1,3-dimethylbarbituric acid, and thiosalicylic acid. Preferred, yet non-limiting examples include 1,3-dimethylbarbituric acid, and thiosalicylic acid.

[0027] The term “carboxylic acid” refers to an organic compound having the general formula R-COOH, wherein R is hydrogen, C1-C6-alkyl or phenyl. Non limiting examples of carboxylic acids include acetic acid, formic acid, citric acid, lactic acid, butyric acid and benzoic acid. A preferred, yet non-limiting example is acetic acid.

[0028] The term “salt” as used herein refers to any kind of salts formed by reacting the compounds disclosed herein with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. Where the compounds disclose herein contain a free acidic moiety, salts may also be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.

[0029] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0030] The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

[0031] The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0032]

[0033] Process

[0034] As outlined above, one of the key aspects of the process according to the present invention is that it relies on Alloc protected building block 1c, rather than on Fmoc protected building block 3 described in the prior art. This leads to simpler deprotection, cost saving, as well as lower process mass intensity (“PMF’). In addition, formation of stoichiometric amounts of genotoxic dibenzofulvene that is formed upon Fmoc deprotection and might potentially contaminate the final product is avoided.

[0035] In a first aspect, the present invention provides a process for manufacturing the compound of formula (lb), or a salt thereof,

[0036]

[0037] comprising reacting the compound of formula (1c)

[0038]

[0039] with a palladium catalyst in the presence of an allyl cation scavenger to afford said compound of formula (lb).

[0040] In one embodiment, said palladium catalyst is Pd(Ph3)4.

[0041] In one embodiment, about 0.1 to about 1 mol%, preferably about 0.2 to about 0.5 mol%, more preferably about 0.2 mol% of said palladium catalyst are used relative to the compound of formula (1c).

[0042] In one embodiment, said allyl cation scavenger is selected from 1,3 -dimethylbarbituric acid, thiosalicylic acid and diethylamine.

[0043] In a preferred embodiment, said allyl cation scavenger is selected from 1,3-dimethylbarbituric acid and thiosalicylic acid.

[0044] 1,3 -dimethylbarbituric acid has surprisingly been found to work particularly well as allyl cation scavenger in that it provides for better control of allylated side products and faster reaction. Moreover, less 1,3-dimethylbarbituric acid is required as allyl cation scavenger than, e.g., di ethylamine as allyl cation scavenger. Thus, in a particularly preferred embodiment, said allyl cation scavenger is 1,3-dimethylbarbituric acid.

[0045] In one embodiment, about 1.0 to about 3.0 equivalents, preferably about 1.0 to about 2.5 equivalents, more preferably about 1.1 equivalents to 2.5 equivalents of said allyl cation scavenger are used relative to the compound of formula (1c).

[0046] In one embodiment, the process is conducted in a solvent selected from an aromatic solvent, an ester solvent, and an ether solvent, preferably in an aromatic solvent. In one embodiment, said aromatic solvent is selected from toluene, xylenes (o-xylene, p-xylene, m-xylene or a mixture thereof), ethylbenzene, anisole, cumene, and cymene, said ester solvent is ethyl acetate and said ether solvent is 2-methyltetrahydrofuran.

[0047] In one embodiment, the process is conducted in toluene.

[0048] In one embodiment, the process is conducted at a temperature of about 0 to about 25 °C, preferably about 10 to about 20 C, more preferably about 10 to about 15 C, most preferably about 10 °C. It has been found that the Alloc deprotection is exothermic and running it at about 10 °C allows for better control than running it at higher temperature. Thus, in a preferred embodiment, the process is conducted at about 10 °C.

[0049] In one embodiment, said compound of formula (1c) is obtained by

[0050] (a) adding K3PO4to a suspension of the hemiphosphate salt 2a

[0051]

[0052] to afford the amine 2 in situ

[0053]

[0054] (b) reacting said amine 2 with aldehyde 3

[0055]

[0056] in the presence of a first carboxylic acid, followed by

[0057] (c) adding a reducing agent and a further carboxylic acid to the reaction mixture obtained from step (b) to afford said compound of formula (1c). In one embodiment, about 0.5 to about 1.5 equivalents, preferably about 0.5 to about 1.0, more preferably about 0.5 to about 0.75 equivalents of K3PO4 are used relative to the aldehyde 3.

[0058] It has surprisingly been found that adding water to K3PO4 in the hemiphosphate salt breaking step (a) above suppresses the formation of certain process impurities. Thus, in one embodiment, about 0 to about 50 equivalents, preferably about 0 to about 23 eq equivalents, more preferably about 3 equivalents of water relative to the aldehyde 3 are added to the reaction mixture in step (a).

[0059] In a preferred embodiment, in step (a), a combination of about 0.5 equivalents of K3PO4 and about 3 equivalents of water are used relative to the aldehyde 3.

[0060] It has further surprisingly been found that, in the absence of water, using a slight excess of K3PO4 in the hemiphosphate salt breaking step (a) above also suppresses the formation of certain process impurities. Thus, in a preferred embodiment, about 0.75 equivalents of K3PO4 are used relative to the aldehyde 3.

[0061] It has further surprisingly been found that, in the absence of water, using about stoichiometric amounts of K3PO4 monohydrate relative to the aldehyde 3 in the hemiphosphate salt breaking step (a) above also suppresses the formation of certain process impurities. Thus, in a preferred embodiment, about 0.5 equivalents of K3PO4 monohydrate are used relative to the aldehyde 3.

[0062] In one embodiment, about 0.5 equivalents of hemiphosphate salt 2a are used relative to the aldehyde 3. It has been found that as little as 0.5 mol% excess of amine 2 can be used relative to the aldehyde 3. Thus, in a preferred embodiment, about 0.5025 equivalents of hemiphosphate salt 2a are used relative to the aldehyde 3.

[0063] In one embodiment, said reducing agent is sodium triacetoxyborohydride or picoline borane, preferably sodium triacetoxyborohydride.

[0064] In a preferred embodiment, said reducing agent is sodium triacetoxyborohydride.

[0065] In one embodiment, about 1.5 to about 2.0 equivalents, preferably about 1.8 equivalents of said reducing agent are used relative to the aldehyde of formula (3). In one embodiment, said first and further carboxylic acids are both acetic acid.

[0066] In one embodiment, about 1.0 to about 1.5 equivalents, preferably about 1.0 equivalents of said first carboxylic acid and about 2.0 to about 5.0 equivalents, preferably about 2.5 to about 4.5 equivalents, more preferably about 3.0 to about 4.0 equivalents, in particular about 4.0 equivalents of said further carboxylic acid are used relative to the aldehyde of formula (3).

[0067] In one embodiment, steps (a) and (b) are performed in a mixture of water and an organic solvent selected from toluene, ethyl acetate and 2-methyltetrahydrofuran, preferably toluene, and wherein step (c) is performed in an organic solvent selected from toluene, ethyl acetate and 2-methyltetrahydrofuran, preferably toluene.

[0068] In a preferred embodiment, steps (a) and (b) are performed in a mixture of water and toluene, and step (c) is performed in toluene. An advantage of using toluene in the imine reduction of step (c) is that the same solvent can be used in the subsequent Alloc deprotection (vide supra).

[0069] In one embodiment, steps (a) and (b) are performed between room temperature and reflux, removing water from the reaction mixture using a Dean-Stark apparatus, and step (c) is performed at about 15 to about 25 °C, preferably at about 20 °C. The choice of temperature in the in situ imine reduction step (c) has surprisingly been found to be important in terms of the formation of impurities. Thus, running step (c) at about 20 °C produces less impurities than running it at, e.g., about 40 °C.

[0070] In a further aspect, the present invention provides a process for manufacturing the compound of formula (la), or a salt thereof,

[0071]

[0072] comprising the process for manufacturing the compound of formula (lb) described herein and further comprising reacting said compound of formula (lb) with a mixture of 2,4,6-trichloro-l,3,5-triazine and A-methylmorpholine to afford said compound of formula (la).

[0073] Using a mixture of 2,4,6-trichloro-l,3,5-triazine and N-methylmorpholine in the ring formation reaction has surprisingly been found to work particularly well, especially on a large scale. Thus, not only is this mixture less dangerous than the explosive reagent HOBt that is described in the prior art for the same reaction, but it has also been found to afford higher yields of macrocycle la with improved impurity profiles.

[0074] In one embodiment, about 1.5 to about 2.5 equivalents, preferably about 2.0 to about 2.5 equivalents, more preferably about 2.25 equivalents of said 2,4,6-trichloro-l,3,5-triazine and about 8.0 to about 12.0 equivalents, preferably about 10.0 to about 12.0 equivalents, more preferably about 12.0 equivalents of said N-methylmorpholine are used relative to the compound of formula (lb).

[0075] In one embodiment, the process is conducted in acetonitrile as a solvent.

[0076] In one embodiment, the process is conducted at a temperature of about -15 to about 0 °C, preferably about -15 to about -5 C, more preferably about -15 to about -10 C, most preferably about -10 °C.

[0077] In a further aspect, the present invention provides a process for manufacturing the compound of formula (Id), or a salt thereof,

[0078]

[0079] comprising the process for manufacturing the compound of formula (la) described herein and further comprising reacting said compound of formula (la) with 4- (methoxycarbonylphenyl)boronic acid 2

[0080]

[0081] in the presence of PdCl2[dtbpf] and potassium carbonate to afford said compound of formula (Id).

[0082] Using potassium carbonate instead of, e.g., potassium phosphate has surprisingly led to an increase in process robustness. Thus, for example, in the presence of potassium carbonate, less catalyst can be used and less boronate 2 decomposition is observed than in the presence of potassium phosphate. Also, the reaction can be run more concentrated (e.g. in 5 vol of solvent, whereas, in the presence of potassium phosphate, the reaction would fail if <10 vol of solvent were used).

[0083] In one embodiment, about 1 to about 3 mol%, preferably about 1.5 to about 2.5 mol%, more preferably about 2 mol% of said PdCl2[dtbpf] and about 1.0 to about 2.5 equivalents, preferably about 1.5 to about 2.0 equivalents, more preferably about 1.5 equivalents of said potassium carbonate and about 1.1 to about 2 equivalents, preferably about 1.1 to about 1.5 equivalents, more preferably about 1.2 equivalents of said boronate 2 are used relative to the compound of formula (Id).

[0084] In one embodiment, the process is conducted in a mixture of toluene and water.

[0085] In one embodiment, the reaction is run in <10 vol of solvent, for example in about 5 vol of solvent.

[0086] In one embodiment, the process is conducted at a temperature of about 75 to about 90 °C, preferably about 80 to about 90 C, more preferably about 85 to about 90 C.

[0087] In one embodiment, upon completion of the reaction, the reaction mixture is extracted with water and the organic phase is treated with ammonium pyrrolidine dithiocarbamate. This has been found to drastically reduce the amount of palladium contamination in the compound of formula (Id).

[0088] In a further aspect, the present invention provides a process for manufacturing the compound of formula (le), or a salt thereof,

[0089]

[0090] comprising the process for manufacturing the compound of formula (Id) described herein and further comprising reacting said compound of formula (Id) with an aqueous solution of sodium hydroxide to afford said compound of formula (le).

[0091] In one embodiment, about 5 to about 8 equivalents, preferably about 6 to about 7 equivalents, more preferably about 7 equivalents of sodium hydroxide are used relative to the compound of formula (Id).

[0092] In one embodiment, said aqueous solution of sodium hydroxide contains about 15% wt / wt of sodium hydroxide.

[0093] In one embodiment, the process is conducted in methanol.

[0094] It has surprisingly been found that the ester hydrolysis is sensitive to the concentration of the reaction mixture and the concentration of the aqueous solution of sodium hydroxide solution that is used. For example, using 15% wt / wt of sodium hydroxide in about 8 vol of methanol affords the compound of formula (le) in yields of about 83-85%, whereas using 7.7% wt / wt of sodium hydroxide in about 12 vol of methanol affords the compound of formula (le) in yields of about 76%. Thus, in a preferred embodiment, said aqueous solution of sodium hydroxide contains about 15% wt / wt of sodium hydroxide and the process is conducted in about 8 vol of methanol.

[0095] In one embodiment, the process is conducted at a temperature of about 30 to about 50 °C, preferably about 35 to about 45 C, more preferably about 40 C.

[0096] In a further aspect, the present invention provides a process for manufacturing the compound of formula (I), or a pharmaceutically acceptable salt thereof,

[0097]

[0098] comprising the process for manufacturing the compound of formula (le) described herein and further comprising reacting said compound of formula (le) with an aqueous solution of hydrochloric acid to afford said compound of formula (I).

[0099] In one embodiment, about 2.0 to about 5.0 equivalents, preferably about 3.0 to about 4.5 equivalents, more preferably about 4.0 equivalents of hydrochloric acid are used relative to the compound of formula (le).

[0100] In one embodiment, said aqueous solution of hydrochloric acid contains about 9% wt / wt of hydrochloric acid.

[0101] In one embodiment, the process is conducted in a mixture of THF and water.

[0102] In one embodiment, the process is conducted at a temperature of about 30 to about 70 °C, preferably about 35 to about 65 °C, more preferably about 40 to about 60 °C, most preferably about 60 °C.

[0103] In a further aspect, the present invention provides a process for manufacturing the compound of formula (I), or a pharmaceutically acceptable salt thereof,

[0104]

[0105] comprising:

[0106] (a) adding K3PO4to a suspension of the hemiphosphate salt 2a

[0107]

[0108] in the presence of a first carboxylic acid, followed by

[0109] (c) adding a reducing agent and a further carboxylic acid to the reaction mixture obtained from step (b) to afford the compound of formula (1c)

[0110]

[0111] (d) reacting said compound of formula (1c) with a palladium catalyst in the presence of an allyl cation scavenger to afford the compound of formula (lb)

[0112]

[0113] (e) reacting said compound of formula (lb) with a mixture of 2,4,6-trichloro- 1,3,5-triazine and N-methylmorpholine to afford the compound of formula (la)

[0114]

[0115] (f) reacting said compound of formula (la) with 4- methoxycarbonylphenyl)boronic acid 2

[0116]

[0117] in the presence of PdCl2[dtbpf] and potassium carbonate to afford the compound of formula (Id)

[0118]

[0119] (g) reacting said compound of formula (Id) with an aqueous solution of sodium hydroxide to afford the compound of formula (le)

[0120]

[0121] (h) reacting said compound of formula (le) with an aqueous solution of hydrochloric acid to afford said compound of formula (I).

[0122] In one embodiment, the process for manufacturing the compound of formula (I) to the invention is:

[0123]

[0124] 1a

[0125]

[0126] In a further aspect, the present invention provides the compound of formula (lb), or a salt thereof, when manufactured according to the processes described herein.

[0127] In a further aspect, the present invention provides the use of any of the processes described herein in the manufacture of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0128] In a further aspect, the present invention provides the compound of formula (la), or a salt thereof, when manufactured according to the processes described herein.

[0129] In a further aspect, the present invention provides the compound of formula (Id), or a salt thereof, when manufactured according to the processes described herein.

[0130] In a further aspect, the present invention provides the compound of formula (le), or a salt thereof, when manufactured according to the process described herein.

[0131] In a further aspect, the present invention provides the use of the compound of formula (1c) in the manufacture of the compound of formula (lb).

[0132] In a further aspect, the present invention provides the use of the compound of formula (1c) in the manufacture of the compound of formula (I). Examples

[0133] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0134] The following abbreviations are used in the present text:

[0135] Fmoc = Fluoren-9-ylmethoxycybonyl; Alloc = Allyloxycarbonyl; GMP = Good Manufacturing Practices; Pd(PPh3)4 = tetrakis (triphenyl-phosphino) palladium; PPh3 = triphenylphosphine; PMI = Process Mass Intensity; PdCl2[dtbpf] = [1,1 '-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (CAS 95408-45-0); THF = Tetrahydrofuran; TCT = 2,4,6-trichloro-l,3,5-triazine; NMM = A-Methylmorpholine; MeCN = Acetonitrile; MeOH = Methanol; AcOH = Acetic acid; iPrOAc = Isopropyl acetate; HC1 = hydrochloric acid; INN = International Nonproprietary Name; K3PO4 = tripotassium phosphate; K2HPO4 = dipotassium hydrogen phosphate.

[0136] Method for HPLC analysis of Compound 1c

[0137] Column: Agilent BEH C8 150 x 2.1 mm x 1.7um

[0138] Mobile phase A: 5% v / v Acetonitrile in Water

[0139] Mobile Phase B: Acetonitrile

[0140] Mobile Phase C: Acetonitrile / 50 mM ammonium acetate buffer, pH=5.0 (940 ml water, 2.90 ml acetic acid, adjust pH with 25% aq. ammonium hydroxide, add 50 ml Acetonitrile) Column temperature: 20 °C

[0141] Inj. volume: lul

[0142] Sampler temperature: 10 °C

[0143] Detection wavelength: 230 nm

[0144]

[0145]

[0146] Method for HPLC analysis of Compound lb

[0147] Column: Acquity peptide CSH C18 150 x 2.1 mm x 1.7um

[0148] Mobile phase A: 2 ml TFA in Water

[0149] Mobile Phase B: 0.05% TFA in Acetonitrile

[0150] Column temperature: 40 °C

[0151] Inj. volume: 2ul

[0152] Sampler temperature: 10 °C

[0153] Detection wavelength: 230 nm

[0154]

[0155] Method for HPLC analysis of Compound la

[0156] Column: Waters XBridge Phenyl BEH 100 x 4.6 mm x 2.5um

[0157] Mobile phase A: 950 ml water, 50 ml Acetonitrile, 0.05% TFA

[0158] Mobile Phase B: 0.05% TFA in Acetonitrile

[0159] Column temperature: 55 °C

[0160] Inj. volume: 5 ul Sampler temperature: 10 °C

[0161] Detection wavelength: 229 nm

[0162]

[0163] Method for HPLC analysis of Compound Id and le

[0164] Column: Waters XBridge Phenyl BEH 100 x 4.6 mm x 2.5um Mobile phase A: 950 ml water, 50 ml Acetonitrile, 0.05% TFA Mobile Phase B: 0.05% TFA in Acetonitrile

[0165] Column temperature: 55 °C

[0166] Inj. volume: 2 ul

[0167] Sampler temperature: 10 °C

[0168] Detection wavelength: 229 nm

[0169]

[0170] Method for HPLC analysis of Compound I

[0171] Column: Acquity UPLC Peptide CHS C18 100 x 2.1 mm x 1.7 um Mobile phase A: Water + 0.1% TFA

[0172] Mobile Phase B: 0.1% TFA in Acetonitrile

[0173] Column temperature: 40 °C

[0174] Inj. volume: 1.5 ul

[0175] Sampler temperature: 10 °C

[0176] Detection wavelength: 256 nm

[0177]

[0178] Example la

[0179] Preparation of tert-butyl 3-[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[3-bromo-2-[(prop-2-enoxycarbonylamino)methylphenyl ]sulfanylpyridin-3-yl methylamino ]-5-[ ( 2-methylpropan-2-yl)oxycarbonylamino Jpentanoyl amino ]-6-[ (2-methylpropan-2-yl)oxycarbonylamino Jhexanoyl / -methylamino ]-3-oxo-3-prop-2-enoxypropyl indole- 1-carboxylate 1c

[0180] Hydrogen phosphate; [(25)- 1 -[[(25)- 1 -[methyl-[(25)-3 -[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]-1-oxo-1-prop-2-enoxypropan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxy carbonylamino]- l-oxohexan-2-yl]amino]-5-[(2-methylpropan-2-yl)oxycarbonylamino]-l-oxopentan-2-yl]azanium 2a (31.41 g, 18.32 mmol, 0.5025 eq) was suspended in toluene (116 ml). Acetic acid (2.19 g, 36.46 mmol, 1.0 eq), water (1.97 g, 109.38 mmol, 3.0 eq) and tripotassium phosphate (3.89 g, 18.32 mmol, 0.5025 eq) were added. Allyl A-[[2-bromo-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate 3 (1.0 eq) was added and the mixture was distilled azeotropically under reduced pressure, with a Dean-Stark apparatus until the starting materials were consumed. Sodium triacetoxyborohydride (13.91 g, 65.63 mmol, 1.8 eq) and acetic acid (6.57 g, 109.38 mmol, 3.0 eq) were added to the reaction mixture. The reaction was stirred at 20 °C until full conversion. The mixture was extracted with a solution of dipotassium hydrogen phosphate (26.67 g, 153.14 mmol, 4.20 eq) in water (150.0 g) at 40°C. The organic layer was extracted with water (60.0 g). The organic extract was dried azeotropically under reduced pressure. The crude solution was used in the next step without further purification. HPLC: 7c97.49% a / a.

[0181] Example lb

[0182] Preparation of tert-butyl 3-[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[3-bromo-2-[(prop-2-enoxycarbonylamino)methylphenyl ]sulfanylpyridin-3-yl methylamino ]-5-[ ( 2-methylpropan-2-yl)oxycarbonylamino Jpentanoyl amino ]-6-[ (2-methylpropan-2-yl)oxycarbonylamino Jhexanoyl / -methylamino ]-3-oxo-3-prop-2-enoxypropyl indole- 1-carboxylate 1c

[0183] Hydrogen phosphate; [(25)- 1 -[[(25)- 1 -[methyl-[(25)-3 -[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]-l-oxo-l-prop-2-enoxypropan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxy carbonylamino]- l-oxohexan-2-yl]amino]-5-[(2-methylpropan-2-yl)oxycarbonylamino]-l-oxopentan-2-yl]azanium 2a (110.2 g, 61.0 mmol, 0.5025 eq) was suspended in toluene (529 ml). Acetic acid (7.3 g, 121.6 mmol, 1.0 eq), and tripotassium phosphate (19.7 g, 92.0 mmol, 0.75 eq) were added. Allyl A-[[2-bromo-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate 3 (50.0 g, 123.0 mmol, 1.0 eq) was added and the mixture was distilled azeotropically under reduced pressure, with a Dean-Stark apparatus until the starting materials were consumed. Sodium triacetoxyborohydride (46.4 g, 219.0 mmol, 1.8 eq) and acetic acid (29.5 g, 491.3 mmol, 4.0 eq) were added to the reaction mixture. The reaction was stirred at 20 °C until full conversion. The mixture was extracted with a solution of dipotassium hydrogen phosphate (26.67 g, 153.14 mmol, 4.20 eq) in water (150.0 g) at 40°C. The organic layer was extracted with water (60.0 g). The organic extract was dried azeotropically under reduced pressure. The crude solution was used in the next step without further purification. HPLC: 1c 96.63% a / a. Example 1c

[0184] Preparation of tert-butyl 3-[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[3-bromo-2-[(prop-2-enoxycarbonylamino)methylphenyl ]sulfanylpyridin-3-yl methylamino ]-5-[ ( 2-methylpropan-2-yl)oxycarbonylamino Jpentanoyl amino ]-6-[ (2-methylpropan-2-yl)oxycarbonylamino Jhexanoyl / -methylamino ]-3-oxo-3-prop-2-enoxypropyl indole- 1-carboxylate 1c

[0185] Hydrogen phosphate; [(25)- 1 -[[(25)- 1 -[methyl-[(25)-3 -[ 1 -[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]-l-oxo-l-prop-2-enoxypropan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxy carbonylamino]- l-oxohexan-2-yl]amino]-5-[(2-methylpropan-2-yl)oxycarbonylamino]-l-oxopentan-2-yl]azanium 2a (3.34 g, 1.85 mmol, 0.5025 eq) was suspended in toluene (9 ml). Acetic acid (0.221 g, 3.68 mmol, 1.0 eq), and tripotassium phosphate monohydrate (0.426 g, 1.85 mmol, 0.5025 eq) were added. Allyl A-[[2-bromo- 6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate 3 (1.50 g, 3.68 mmol, 1.0 eq) was added and the mixture was distilled azeotropically under reduced pressure, with a Dean-Stark apparatus until the starting materials were consumed. Sodium triacetoxyborohydride (1.41 g, 6.63 mmol, 1.8 eq) and acetic acid (0.663 g, 11.05 mmol, 3.0 eq) were added to the reaction mixture. The reaction was stirred at 20 °C until full conversion. The mixture was extracted with a solution of dipotassium hydrogen phosphate (2.69 g, 15.47 mmol, 4.20 eq) in water (15 g) at 40°C. The organic layer was extracted with water (6.0 g). The organic extract was dried azeotropically under reduced pressure. The crude solution was used in the next step without further purification. HPLC: 1c 97.15% a / a.

[0186] Example 2a

[0187] Preparation of (2S)-2-[[(2S)-2-[[ (2S)-2-[[2-[2-(aminomethyl)-3-bromo-phenyl]sulfanyl-3-pyridyl methylamino ]-5-(tert-butoxycarbonylamino)pentanoyl amino ]-6-( tert- butoxycarbonylamino)hexanoyl ]-methyl-amino ]-3-( I -tert-butoxycarbonylindol-3-yl)propanoic acid lb

[0188] To tert-butyl 3-[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[3-bromo-2-[(prop-2- enoxycarbonylamino)methyl]phenyl]sulfanylpyridin-3-yl]methylamino]-5-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]-methylamino]-3-oxo-3-prop-2-enoxypropyl]indole-l- carboxylate 1c solution in toluene (12.4% w / w, 20.19 g, 2.5 g 1c, 2.1 mmol, 1.00 eq) was added thiosalicylic acid (0.808 g, 5.24 mmol, 2.5 eq). The mixture was degassed and a solution of tetrakistriphenylphosphine palladium (12.1 mg, 0.01 mmol, 0.005 eq) dissolved in toluene (1 ml) was added. The mixture was stirred at 20 °C until complete conversion was achieved. The crude (2S)-2-[[(2S)-2-[[(2S)-2-[[2-[2-(aminomethyl)-3-bromo-phenyl]sulfanyl-3-pyridyl]methylamino]-5-(tert-butoxycarbonylamino)pentanoyl]amino]- 6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-(l-tert-butoxycarbonylindol-3-yl)propanoic acid lb solution in toluene was used without further purification in the next step. HPLC: lb 90.72% a / a.

[0189] Example 2b

[0190] Alternative Preparation of (2S)-2-[[(2S)-2-[[(2S)-2-[[2-[2-(aminomethyl)-3-bromo-phenyl sulfanyl-3-pyridyl methylamino ]-5-(tert-butoxycarbonylamino)pentanoyl amino ]- 6-( tert-butoxycarbonylamino)hexanoyl ]-methyl-amino ]-3-( I -tert-butoxycarbonylindol-3-yl)propanoic acid lb

[0191] 1,3 -Dimethylbarbituric acid (6.26 g, 40.11 mmol, 1.1 eq) was dissolved in toluene (94 ml) and degassed. A solution of tetrakistriphenylphosphine palladium (84.3 mg, 0.073 mmol, 0.002 eq) dissolved in toluene (8 ml) was added and the solution was cooled to 10 °C. tertbutyl 3-[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[3-bromo-2-[(prop-2- enoxycarbonylamino)methyl]phenyl]sulfanylpyridin-3-yl]methylamino]-5-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]-methylamino]-3-oxo-3-prop-2-enoxypropyl]indole-l- carboxylate 1c solution in toluene (35.3% w / w, 123.1 g, 43.45 g 1c, 36.46 mmol, 1.00 eq) was added slowly. The mixture was stirred at 10 °C until complete conversion was achieved. The solvent was switched to acetonitrile and the crude lb solution in acetonitrile was used without further purification in the next step. HPLC: lb 96.12% a / a.

[0192] Example 3

[0193] Preparation of tert-butyl 3-[[(l lS,14S,17S)-22-bromo-14-[4-(tert- butoxycarbonylaminofbutyl ]-ll-[3-( tert-butoxycarbonylamino)propyl -l 6-methyl- 12, 15, 18-trioxo-2-thia-4, 10, 13, 16, 19-pentazatricyclo [ 19.4.0.03,8]pentacosa- 1(25), 3, 5, 7,21,23-hexaen-17-yl]methyl]indole-l-carboxylate la 2,4,6-Trichloro-l,3,5-triazine (15.13 g, 82.03 mmol, 2.25 eq) was dissolved in acetonitrile (370 ml). The solution was cooled to 10 °C. N-Methylmorpholine (44.26 g, 437.5 mmol, 12.0 eq) was added at 10 °C. The resulting mixture was cooled to -10 °C. A solution of (2S)-2-[[(2S)-2-[[(2S)-2-[[2-[2-(aminomethyl)-3-bromo-phenyl]sulfanyl-3-pyridyl]methylamino]-5-(tert-butoxycarbonylamino)pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-(l-tert-butoxycarbonylindol-3-yl)propanoic acid lb in acetonitrile (353.0 g, 11.0% w / w, 38.94 g lb, 1.0 eq) was added at -10 °C in 4 hours. The mixture was stirred until reaction completion. The mixture was warmed up to 5 °C and extracted with a solution of ammonium chloride (9.74 g, 183.1 mmol, 5.0 eq) in water (184 ml). The organic phase was concentrated and diluted with ethyl acetate. The solution was extracted with water (156 ml) three times. The organic phase was concentrated under reduced pressure, then the solvent was swapped to acetonitrile, tert-butyl 3-[[(llS,14S,17S)-22-bromo-14-[4-(tert-butoxycarbonylamino)butyl]-ll-[3-(tert-butoxycarbonylamino)propyl]-16-methyl- 12.15.18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- l(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-l-carboxylate la was crystallized from acetonitrile, isolated by filtration and dried under reduced pressure, tert-butyl 3-[[(115,14£,175)-22-bromo-14-[4-(tert-butoxycarbonylamino)butyl]-ll-[3-(tert-butoxycarbonylamino)propyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-l-carboxylate la: 28.2 g. Yield: 73.7% mol / mol (overall from 3). HPLC: la 99.23% a / a.

[0194] Example 4

[0195] Preparation of tert-butyl 3-[[(l lS,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-l 1-[ 3-(tert-butoxycarbonylamino)propyl ]-22-( 4-methoxycarbonylphenyl)-16-methyl- 12.15.18-trioxo-2-thia-4, 10, 13, 16, 19-pentazatricyclo [ 19.4.0.03,8]pentacosa-1(25), 3, 5, 7,21,23-hexaen-17-yl]methyl]indole-l-carboxylate Id

[0196] tert-butyl 3-[[(l 15',145',175)-22-bromo-14-[4-(tert-butoxycarbonylamino)butyl]-l l-[3-(tert-butoxycarbonylamino)propyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-l-carboxylate la (20.0 g, 19.05 mmol, 1.0 eq), 4-(methoxycarbonylphenyl)boronic acid 2 (4.11 g, 22.85 mmol, 1.2 eq) and potassium carbonate (3.95 g, 28.57 mmol, 1.5 eq) were suspended in toluene (100 ml). The mixture was heated to 85-90°C. PdCl2[dtbpf] (248 mg, 0.309 mmol, 0.02 eq) was added to the mixture. Water (8.6 g, 476.14 mmol, 25 eq) was added in 1-6 hours, and the mixture was stirred until complete conversion. The mixture was extracted with water (30 ml), and the organic phase was treated with ammonium pyrrolidine dithiocarbamate (0.939 g, 5.71 mmol, 0.30 eq). The resulting suspension was filtered, and the clear filtrate was extracted twice with water (30 ml ) and treated with active charcoal (1.0 g). The suspension was filtered to remove the charcoal, and the filter residue was rinsed with toluene (40 ml). The solvent was swapped to methanol, and the crude methanolic solution of tert-butyl 3-[[(115,145,175)-14-[4-(tert-butoxycarbonylamino)butyl]-ll-[3-(tert-butoxycarbonylamino)propyl]-22-(4-methoxycarbonylphenyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-l-carboxylate Id was used in the following step without further purification. HPLC: Id 94.44% a / a.

[0197] Example 5

[0198] Preparation of 4-[ ( 1 IS, 14S, 17S)-14-[ 4-(tert-butoxycarbonylamino)butyl -ll-[ 3-( tert-butoxycarbonylamino)propyl]-17-(lH-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10, 13,16, 19 -pentazatricyclo [ 19.4.0.03,8]pentacosa-l(25), 3,5, 7,21,23-hexaen-22-yl]benzoic acid le

[0199] The methanolic solution of crude tert-butyl 3-[[(l 15, 145, 175)-14-[4-(tert-butoxycarbonylamino)butyl]-ll-[3-(tert-butoxycarbonylamino)propyl]-22-(4-methoxycarbonylphenyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-l-carboxylate Id was heated to 40°C, and 15% w / w aq. NaOH (35.53 g, 133.32 mmol, 7.00 eq) was added to the solution. The resulting mixture was stirred at 40°C until complete conversion. A 35% w / w aqueous solution of citric acid (26.15 g, 47.61 mmol, 2.5 eq) was added to the mixture and methanol was evaporated under reduced pressure. Isopropyl acetate (140 ml) was added to the residue. The aqueous phase was discarded, and the organic phase was extracted twice with water (30 ml). The organic layer was concentrated under reduced pressure and the solvent was swapped to 1 -propanol. The product was crystallized by addition of acetone. The wet solid was suspended in acetone (100 ml) and stirred at 35 °C for 1 hour, then the solids were collected by suction filtration and rinsed with acetone. The wet solids were dried under reduced pressure. 4-[(l 15, 145, 175)- 14- [4- (terLbutoxycarbonylamino)butyl]-ll-[3-(terLbutoxycarbonylamino)propyl]-17-(U / -indol- 3 -ylmethyl)- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3,5,7,21,23-hexaen-22-yl]benzoic acid le: 15.95 g. Yield: 84.5% mol / mol. HPLC: le: 99.87% a / a.

[0200] Example 6

[0201] Preparation of 4-[ ( 1 IS, 14S, 17S)-14-(4-aminobutyl)-l l-( 3-aminopropyl)-l 7-(lH-indol-3-ylmethyl)-16-methyl-12, 15, 18-trioxo-2-thia-4,10, 13,16, 19-pentazatricyclo[19.4.0.03,8]pentacosa-l(25),3,5, 7,21,23-hexaen-22-yl]benzoic acid (I)

[0202] 4-[(115',145',175)-14-[4-(tert-butoxycarbonylamino)butyl]-ll-[3-(tert-butoxycarbonylamino)propyl]- 17-( lH-indol-3 -ylmethyl)- 12,15,18-trioxo- 16-methyl-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-l(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (le) (10 g, 10.1 mmol, 1 eq), tetrahydrofuran (27 ml), and water (16 mL) were charged into a 250 mL four-necked reaction vessel and stirred at 60°C. A solution of HC125% (5.89 g, 40.4 mmol, 4.0 eq.) and water (10 mL) was added within 60 minutes at 60°C. The addition funnel was rinsed with water (2.5 mL) and the reaction mixture was stirred at 60°C for 4 hours. Following basic workup and crystallization at pH 10, the title compound (I) was obtained as a white powder (7.57 g, 95%).

Claims

CLAIMS1. A compound, which is tert-butyl 3-[(25)-3-allyloxy-2-[[(25)-2-[[(25)-2-[[2-[2- [(allyloxycarbonylamino)methyl]-3-bromo-phenyl]sulfanyl-3-pyridyl]methylamino]- 5-(tert-butoxycarbonylamino)pentanoyl]amino]-6-(tert- butoxycarbonylamino)hexanoyl]-methyl-amino]-3-oxo-propyl]indole-l-carboxylate (1c), or a salt thereof2. A process for manufacturing the compound of formula (lb), or a salt thereof,comprising reacting the compound of formula (1c)with a palladium catalyst in the presence of an allyl cation scavenger to afford said compound of formula (lb).

3. The process according to claim 2, wherein said palladium catalyst is Pd(Ph3)4.

4. The process according to claim 2 or 3, wherein about 0.1 to about 1 mol%, preferably about 0.2 to about 0.5 mol%, more preferably about 0.2 mol% of said palladium catalyst are used relative to the compound of formula (1c).

5. The process according to any one of claims 2 to 4, wherein said allyl cation scavenger is selected from 1,3-dimethylbarbituric acid, thiosalicylic acid and diethylamine.

6. The process according to any one of claims 2 to 5, wherein about 1.0 to about 3.0 equivalents, preferably about 1.0 to about 2.5 equivalents, more preferably about 1.1 equivalents to 2.5 equivalents of said allyl cation scavenger are used relative to the compound of formula (1c).

7. The process according to any one of claims 2 to 6, wherein the process is conducted in a solvent selected from an aromatic solvent, an ester solvent, and an ether solvent, preferably in an aromatic solvent.

8. The process according to claim 7, wherein said aromatic solvent is selected from toluene, xylenes (o-xylene, / ?-xylene, m-xylene or a mixture thereof), ethylbenzene, anisole, cumene, and cymene, said ester solvent is ethyl acetate and said ether solvent is 2-methyltetrahydrofurane.

9. The process according to claim 7, wherein the process is conducted in toluene.

10. The process according to any one of claims 2 to 9, wherein the process is conducted at a temperature of about 0 to about 25 °C, preferably about 10 to about 20 C, more preferably about 10 to about 15 C, most preferably about 10 °C.

11. The process according to any one of claims 2 to 10, wherein said compound of formula (1c) is obtained by(a) adding K3PO4to a suspension of the hemiphosphate salt 2ain the presence of a first carboxylic acid, followed by(c) adding a reducing agent and a further carboxylic acid to the reaction mixture obtained from step (b) to afford said compound of formula (1c).

12. The process according to claim 11, wherein about 0.5 to about 1.5 equivalents, preferably about 0.5 to about 1.0, more preferably about 0.5 to about 0.75 equivalents of K3PO4 are used relative to the hemiphosphate salt 2a.

13. The process according to claim 11 or 12, wherein about 0 to about 50 equivalents, preferably about 0 to about 23 eq equivalents, more preferably about 3 equivalents of water relative to the aldehyde 3 are added to the reaction mixture in step (a).

14. The process according to claim 11 or 12, wherein said K3PO4 is K3PO4 monohydrate.

15. The process according to any one of claims 11 to 14, wherein about 0.5 equivalents of hemiphosphate salt 2a are used relative to the aldehyde 3.

16. The process according to any one of claims 11 to 15, wherein said reducing agent is sodium triacetoxyborohydride or picoline borane, preferably sodiumtriacetoxyborohydride.

17. The process according to any one of claims 11 to 16, wherein about 1.5 to about 2.0 equivalents, preferably about 1.8 equivalents of said reducing agent are used relative to the aldehyde of formula (3).

18. The process according to any one of claims 11 to 17, wherein said first and further carboxylic acids are both acetic acid.

19. The process according to any one of claims 11 to 18, wherein about 1.0 to about 1.5 equivalents, preferably about 1.0 equivalents of said first carboxylic acid and about 2.0 to about 5.0 equivalents, preferably about 2.5 to about 4.5 equivalents, more preferably about 3.0 to about 4.0 equivalents, in particular about 4.0 equivalents of said further carboxylic acid are used relative to the aldehyde of formula (3).

20. The process according to any one of claims 11 to 19, wherein steps (a) and (b) are performed in a mixture of water and an organic solvent selected from toluene, ethyl acetate and 2-methyltetrahydrofurane, preferably toluene, and wherein step (c) is performed in an organic solvent selected from toluene, ethyl acetate and 2- methyltetrahydrofurane, preferably toluene.

21. The process according to any one of claims 11 to 20, wherein steps (a) and (b) are performed between room temperature and reflux, removing water from the reaction mixture using a Dean-Stark apparatus, and wherein step (c) is performed at about 15 to about 25 °C, preferably at about 20 °C.

22. A process for manufacturing the compound of formula (la), or a salt thereof,comprising the process for manufacturing the compound of formula (lb) according to any one of claims 2 to 20 and further comprising reacting said compound of formula (lb) with a mixture of 2,4,6-trichloro-l,3,5-triazine and N- methylmorpholine to afford said compound of formula (la).

23. The process according to claim 22, wherein about 1.5 to about 2.5 equivalents, preferably about 2.0 to about 2.5 equivalents, more preferably about 2.25 equivalents of said 2,4,6-trichloro-l,3,5-triazine and about 8.0 to about 12.0 equivalents, preferably about 10.0 to about 12.0 equivalents, more preferably about 12.0 equivalents of said N-methylmorpholine are used relative to the compound of formula (lb).

24. The process according to any one of claims 22 or 23, wherein the process is conducted in acetonitrile as a solvent.

25. The process according to any one of claims 22 to 24, wherein the process is conducted at a temperature of about -15 to about 0 °C, preferably about -15 to about -5 C, more preferably about -15 to about -10 C, most preferably about -10 °C.

26. A process for manufacturing the compound of formula (Id), or a salt thereof,comprising the process for manufacturing the compound of formula (la) according any one of claims 21 to 25 and further comprising reacting said compound of formula (la) with 4-(methoxycarbonylphenyl)boronic acid 2in the presence of PdCl2[dtbpf] and potassium carbonate to afford said compound of formula (Id).

27. The process according to claim 26, wherein about 1 to about 3 mol%, preferably about 1.5 to about 2.5 mol%, more preferably about 2 mol% of said PdCl2[dtbpf] and about 1.0 to about 2.5 equivalents, preferably about 1.5 to about 2.0 equivalents, more preferably about 1.5 equivalents of said potassium carbonate and about 1.1 to about 2 equivalents, preferably about 1.1 to about 1.5 equivalents, more preferably about 1.2 equivalents of said boronate 2 are used relative to the compound of formula (Id).

28. The process according to any one of claims 26 or 27, wherein the process is conducted in a mixture of toluene and water.

29. The process according to any one of claims 26 to 28, wherein the process is conducted at a temperature of about 75 to about 90 °C, preferably about 80 to about 90 C, more preferably about 85 to about 90 C.

30. The process according to any one of claims 26 to 29, wherein, upon completion of the reaction, the reaction mixture is extracted with water and the organic phase is treated with ammonium pyrrolidine dithiocarbamate.

31. A process for manufacturing the compound of formula (le), or a salt thereof,comprising the process for manufacturing the compound of formula (Id) according to any one of claims 26 to 30 and further comprising reacting said compound of formula (Id) with an aqueous solution of sodium hydroxide to afford said compound of formula (le).

32. The process according to claim 31, wherein about 5 to about 8 equivalents, preferably about 6 to about 7 equivalents, more preferably about 7 equivalents of sodium hydroxide are used relative to the compound of formula (Id).

33. The process according to any one of claims 31 or 32, wherein said aqueous solution of sodium hydroxide contains about 15% wt / wt of sodium hydroxide.

34. The process according to any one of claims 31 to 33, wherein the process is conducted in methanol.

35. The process according to any one of claims 31 to 34, wherein the process is conducted at a temperature of about 30 to about 50 °C, preferably about 35 to about 45 C, more preferably about 40 C.

36. A process for manufacturing the compound of formula (I), or a pharmaceutically acceptable salt thereof,comprising the process for manufacturing the compound of formula (le) according to any one of claims 31 to 35 and further comprising reacting said compound of formula (le) with an aqueous solution of hydrochloric acid to afford said compound of formula (I).

37. The process according to claim 36, wherein about 2.0 to about 5.0 equivalents, preferably about 3.0 to about 4.5 equivalents, more preferably about 4.0 equivalents of hydrochloric acid are used relative to the compound of formula (le).

38. The process according to any one of claims 36 or 37, wherein said aqueous solution of hydrochloric acid contains about 9% wt / wt of hydrochloric acid.

39. The process according to any one of claims 36 to 38, wherein the process is conducted in a mixture of THF and water.

40. The process according to any one of claims 36 to 39, wherein the process is conducted at a temperature of about 30 to about 70 °C, preferably about 35 to about 65 °C, more preferably about 40 to about 60 °C, most preferably about 60 °C.

41. A process for manufacturing the compound of formula (I), or a pharmaceutically acceptable salt thereof,comprising:(a) adding K3PO4to a suspension of the hemiphosphate salt 2ato afford the amine 2(b) reacting said amine 2 with aldehyde 3in the presence of a first carboxylic acid, followed by(c) adding a reducing agent and a further carboxylic acid to the reaction mixture obtained from step (b) to afford the compound of formula (1c)(d) reacting said compound of formula (1c) with a palladium catalyst in the presence of an allyl cation scavenger to afford the compound of formula (lb)(e) reacting said compound of formula (lb) with a mixture of 2,4,6-trichloro- 1,3,5-triazine and N-methylmorpholine to afford the compound of formula (la)(f) reacting said compound of formula (la) with 4- methoxycarbonylphenyl)boronic acid 2in the presence of PdCl2[dtbpf] and potassium carbonate to afford the compound of formula (Id)(g) reacting said compound of formula (Id) with an aqueous solution of sodium hydroxide to afford the compound of formula (le)(h) reacting said compound of formula (le) with an aqueous solution of hydrochloric acid to afford said compound of formula (I).

42. The process according to claim 41, which is:

43. The compound of formula (lb), or a salt thereof, when manufactured according to the process of any one of claims 2 to 21.

44. Use of the process according to any one of claims 2 to 21 in the manufacture of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

45. The compound of formula (la), or a salt thereof, when manufactured according to the process of any one of claims 22 to 25.

46. Use of the process according to any one of claims 22 to 25 in the manufacture of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

47. The compound of formula (Id), or a salt thereof, when manufactured according to the process of any one of claims 26 to 30.

48. Use of the process according to any one of claims 26 to 30 in the manufacture of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

49. The compound of formula (le), or a salt thereof, when manufactured according to the process of any one of claims 31 to 35.

50. Use of the process according to any one of claims 31 to 35 in the manufacture of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

51. The compound of formula (I), or a pharmaceutically acceptable salt thereof, when manufactured according to the process of any one of claims 36 to 42.

52. Use of the compound of formula (1c) according to claim 1 in the manufacture of the compound of formula (lb).

53. Use of the compound of formula (1c) according to claim 1 in the manufacture of the compound of formula (I).

54. The invention as described hereinbefore.

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