WO2018041873A1

WO2018041873A1 - Process for the preparation of (6s)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid

Info

Publication number: WO2018041873A1
Application number: PCT/EP2017/071721
Authority: WO
Inventors: Georg WUITSCHIK; Michael MOSCH
Original assignee: F. Hoffmann-La Roche Ag; Hoffmann-La Roche Inc.
Priority date: 2016-09-01
Filing date: 2017-08-30
Publication date: 2018-03-08

Abstract

The present invention relates to a process for synthesizing a compound of formula (la), or pharmaceutically acceptable salt or diastereomer thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.

Description

Process for the preparation of (6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo- 6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid

The present invention relates to a process for the preparation of a compound of formula (la),

wherein R¹ is C_1-6alkyl; R² is

R³ is Ci-₆alkoxyCi_₆alkoxy ; R⁴ is or hydroxy.

Particularly, the present invention relates to a process for the preparation of a compound of formula (I),

or pharmaceutically acceptable salt or enantiomer, or diastereomer thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection. BACKGROUND OF THE INVENTION

The synthetic approach of compounds of formula (la) was disclosed in patent

WO2015113990, however it is not suitable for commercial manufacturing due to the following issues: (a) The overall yield is relatively low. For example, the overall yield of compound (I) according to WO2015113990, for example, is 5.9%. .Specifically, the low yield encountered in the final chiral separation is undesirable, as it more than doubles the volumes and amounts of reagents needed to conduct the synthesis compared to a chiral synthesis.

(b) Critical intermediates, for example, 4-bromo-l-methoxy-2-(3- methoxypropoxy)benzene, l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl-butan-2- amine, N-[l-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-2-methyl-propyl]formamide, ethyl 6-isopropyl- 10-methoxy-9-(3-methoxypropoxy)-2-oxo- 1,6,7, 11b- tetrahydrobenzo[a]quinolizine-3-carboxylate, ethyl 6-isopropyl- 10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate, are isolated in crude form only, thus reducing robustness of the process overall.

(c) column purification is needed for two critical intermediates, for example, l-[4- methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl-butan-2-one, 3-isopropyl-7-methoxy-6-(3- methoxypropoxy)-3,4-dihydroisoquinoline, and 6-isopropyl- 10-methoxy-9-(3-methoxypropoxy)- 2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid, and the final product, racemic version of formula (la).

(d) all intermediates and starting materials are racemic, therefore chiral HPLC, chiral SFC or diastereomeric salt formation is required for chiral purification of the intermediates or final API;

Based on the issues above, one object of the invention therefore is to find an alternative efficient synthetic approach which can be applied on a technical scale and/or result in obtaining the product in a higher yield and/or desired purity. Addressing any one of the issues (a) to (d) mentioned above is also one of the objects of the invention. DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS As used herein, the term "Ci_₆alkyl" signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ie/ -butyl and the like. Particular "Ci_₆alkyl" group is methyl, n-propyl or isopropyl.

The term "Ci_6alkoxy" denotes a group of the formula -O-R', wherein R' is a Ci-6alkyl group. Examples of Ci_₆alkoxy moieties include methoxy, ethoxy, propoxy, isopropoxy and tert- butoxy. Particular "Ci_6alkoxy" group is methoxy or propoxy.

The term "heterocycloalkyl" denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. The term 'W-containing heterocycloalkyl" refers to a "heterocycloalkyl" wherein at least one of the heteroatoms is N. Examples for "N- containing heterocycloalkyl" are aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, l, l-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl.

Particularly 'W-containing heterocycloalkyl" is morpholinyl, piperidinyl, azetidinyl or

pyrrolidinyl.

The term "aryl" denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. Particularly "aryl" is phenyl.

The term "diastereomer" denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.

The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula la and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as /7-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, h., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1. X-ray structure of Example 7.

ABBREVIATIONS

API active pharmaceutical ingredient

D-(+)-DTTA Di-p-toluoyl-D-tartaric acid

L-DTTA Di-p-toluoyl-L-tartaric acid

D-DBTA Dibenzoyl-D-tartaric acid (+)-CSA (lS)-(+)-10-Camphorsulfonic acid

S-BNP (S) (+) 1,1 ' Binaphthyl 2,2 ' diyl hydrogen phosphate

DMAP N,N-dimethylaminopyridine

DMSO Dimethylsulfoxide eq Equivalent IBCF Isobutyl chloroformate

IPA Isopropanol

IP Ac Isopropyl acetate EtOAc or EA ethyl acetate

2-MeTHF 2-Methyltetrahydrofuran

NMM N-methylmorpholine

TEA Triethylamine

DIPEA N,N-Diisopropylethylamine DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

DABCO 1 ,4-diazabicyclo[2.2.2]octane

T3P 2,4,6-Tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide

CDI 1,1 ' -Carbonyldiimidazole

DIC N,N ' -Diisopropylcarbodiimide DCC N,N'-Dicyclohexylcarbodiimide

HATU 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium- hexafluorpho sphate

IBCF Isobutyl chloroformate

MTBE Methyl tert-butyl ether CPME Cyclopentyl methyl ether

TFA Trifluoroacetic acid wt% Weight percentage

PhMe Toluene

RT Room Temperature Mpa Megapascal The present invention provides a process for preparing the compounds of formula (IX) as outlined in the scheme 1 and compounds of formula (la) as outlined in the scheme 2.

Scheme 1

Scheme 2

XIII

la wherein R¹ is C_1-6alkyl; R² is R³ is Ci-₆alkoxyCi_₆alkoxy or C_1-6 alkoxy; R⁴ is Ci_₆alkoxy or hydroxy; R⁵ is

aryl; R⁶ is or Ci-₆alkoxyCi_₆alkyl; or R⁵ and R⁶ together with the nitrogen to which they are attached, form N-containing heterocycloalkyl. Acid is HCl, HBr, HI, H₂SO₄, H₃PO₄, TFA, alkylsulfonic acids such as methanesulfonic acid or trifluoromethanesulfonic acid , aryl sulphonic acids such as benzenesulfonic acid, p- toluenesulfonic acid, 4-nitrophenylsulfonic acid, 4-bromophenylsulfonic acid, D-(+)-DTTA, L-DTTA, L-Tartaric acid, D-DBTA, (+)-CSA, (S)-(+)- 1, 1 '-Binaphthyl-2,2 '-diyl hydrogen phosphate or (R)-(-)- l , l '-Binaphthyl-2,2'-diyl hydrogen phosphate.

1

In another embodiment of this invention, wherein R is isopropyl; R 2 is methoxy; R 3 is 3- methoxypropoxy; R⁴ is ethoxy or hydroxy; R⁵ and R⁶, together with the nitrogen to which they are attached, forms a pyrrolidine ring.

In a further embodiment of this invention, wherein acid is (S)-(+)- l, l '-Binaphthyl-2,2'-diyl hydrogen phosphate.

The synthesis comprises one or more of the following steps: step a) the formation of N-formylamino acid (IV), o

step b) the formation of amide (VI) via the coupling of carboxylic acid IV and amine

w

or Ci-₆alkoxyCi_₆alkyl, or R⁵ and R⁶ together with the nitrogen to which they are attached, form N-containing heterocycloalkyl; step c) the coupling of a compound of formula (VI) with aryl halide (VII) yielding ketone

wherein R 1 is C_1-6alkyl; R2 is

R 3 is Ci-₆alkoxy or Ci-₆alkoxyCi-₆alkoxy; step d) the formation of a compound of formula (IX) by reduction of a compound of formula (VIII),

wherein R 1 is C_1-6alkyl; R2 is Ci_₆alkoxy; R 3 is Ci_₆alkoxy or Ci-₆alkoxyCi-₆alkoxy; step e) the formation of a compound of formula (X) by cyclisation of a compound of formula (IX),

wherein R 1 is C_1-6alkyl; R2 is C_1-6 alkoxy; R 3 is Ci-₆alkoxy or Ci-₆alkoxyCi_₆alkoxy; step f) the formation of a compound of formula (XII) by reaction with a compound of formula (XI),

wherein R¹ is Ci-₆alkyl; R² is Ci-₆alkoxy; R³ is

or Ci-₆alkoxyCi_₆alkoxy; R⁴ is Ci_₆alkoxy or hydroxy; step g) the formation of a compound of formula (XIII) by oxidation of a compound of formula (XII) and subsequent salt formation with Acid,

wherein R¹ is C_1-6alkyl; R² is

R³ is Ci-₆alkoxy or Ci-₆alkoxyCi_₆alkoxy; R⁴ is Ci_₆alkoxy or hydroxy. Acid is HCl, HBr, HI, H₂SO₄, H₃PO₄, TFA, alkylsulfonic acids such as methane sulfonic acid or trifluoromethanesulfonic acid , aryl sulphonic acids such as

benzenesulfonic acid, p-toluenesulfonic acid, 4-nitrophenylsulfonic acid, 4-bromophenylsulfonic acid, D-(+)-DTTA, L-DTTA, L-Tartaric acid, D-DBTA, (+)-CSA,

(S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate or (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate. step h) the formation of compound of formula (la) via freebasing and optional subsequent transesterification or saponification,

wherein R¹ is C_1-6alkyl; R² is Ci_₆alkoxy; R³ is Ci-₆alkoxy or Ci-₆alkoxyCi-₆alkoxy; R⁴ is Ci_₆alkoxy or hydroxy. Another embodiment of this invention is that compound of formula (la) can also be synthesized in analogy to Scheme 1 with racemic starting material and Scheme 2 without chiral separation step.

A detailed description of present invention of process steps is as following:

Step a) the formation of N-formylamino acid (IV). N-formylamino acid (IV) is synthesized in the presence of formic acid in a suitable solvent.

The conversion as a rule is performed under a heating condition.

The suitable solvent is selected from 2-MeTHF, THF, IP Ac, EA, toluene or DCM, particularly the suitable solvent is toluene.

The reaction temperature is between 20 °C and 130 °C, particularly between 90 °C and 120 °C.

After an appropriate amount of time, usually 8-24 h, the reaction is completed as shown by monitoring with HPLC. The compound of formula (IV) is isolated by filtration of the reaction mixture and isolation of the solid by methods known to the skilled in the art such as by recrystallization from a suitable solvent. The suitable solvent is selected from mixtures n-heptane, n-heptane, cyclohexane, methylcyclohexane, IP AC, THF, 2-MeTHF or EA. Particularly the solvent is a mixture of THF and n-heptane.

Step b) the formation of amide (VI) via the coupling of carboxylic acid IV and amine V.

The amide (VI) is synthesized in the presence of a suitable coupling reagent and a suitable base in a suitable organic solvent. The conversion as a rule is performed under a cooling condition.

The reaction is conducted in a suitable organic solvent, which is selected from 2-MeTHF, THF, IP Ac, EA, toluene, DMF, NMP, ACN or DCM. Particularly, the solvent is THF.

The suitable base is selected from TEA, DIPEA, DBU, DABCO or NMM, particularly the base is NMM.

The suitable coupling reagent is selected from T3P, CDI, DIC, DCC, HATU or IBCF, particularly the coupling reagent is IBCF. The secondary amine of the formula (V) coupling partner is selected from morpholine, piperidine, pyrrolidine or Ν,Ο-dimethylhydroxylamine hydrochloride. Particularly the secondary amine is pyrrolidine.

The reaction is performed at a temperature between -80 °C and 20 °C, particularly between -20 °C and 0 °C.

After an appropriate amount of time, usually 0.5-2 h, the reaction is completed as shown by monitoring with HPLC. The compound of formula (VI) is isolated by addition of an acidic aqueous solution to the reaction mixture. The isolation of the product is carried out by methods known to the skilled in the art such as by extraction.

Step c) the coupling of a compound of formula (VI) with aryl halide (VII) yielding ketone

VIII.

The compound of formula (VIII) is synthesized via the coupling of a compound of formula (VI) with aryl halide (VII) in a suitable solvent using a suitable base, catalyst and metalation reagent. The suitable solvent is selected from 2-MeTHF, THF, MTBE, toluene, CPME or anisol.

Particularly the solvent is THF.

The suitable base is selected from methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, n-hexyl lithium, lithium hydride, sodium hydride, potassium hydride, isopropylmagnesium chloride, or isopropylmagnesium chloride lithium chloride complex.

Particularly the base is methyl lithium, more particularly the base is a solution of methyl lithium in diethoxymethane. The addition rate of the base is controlled while the reaction temperature is between -80 and 20 °C, particularly between -35 and -15 °C.

The suitable catalyst is selected from isopropylmagnesium chloride lithium chloride complex, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium or iodide. Particularly the catalyst is isopropylmagnesium chloride lithium chloride complex. The addition rate of the catalyst is controlled while the reaction temperature is between -80 and 20 °C, particularly between -35 and -15 °C.

The suitable metalation reagent is selected from n-butyl lithium, sec-butyl lithium, tert-butyl lithium, n-hexyl lithium, isopropylmagnesium chloride, isopropylmagnesium chloride or lithium chloride complex. Particularly the metalation reagent is n-butyl lithium, sec-butyl lithium, tert-butyl lithium, n-hexyl lithium. More particularly the metalation reagent is n-butyl lithium. The addition rate of the metalation reagent is controlled while the reaction temperature is between -80 and 20 °C, particularly between -15 and 10 °C.

The reaction is performed at a temperature between -50 °C and 50 °C, particularly between -10 °C and 25 °C.

After an appropriate amount of time, usually 0.5-4 h, the reaction is completed as shown by monitoring with HPLC. The compound of formula (VIII) is isolated by addition of the reaction mixture to an acidic aqueous solution, phase separation, exchange to a solvent suitable for crystallization and isolation of the solid by methods known to the skilled in the art such as by extraction or filtration.

The suitable solvent is selected from n-heptane, n-heptane, cyclohexane,

methylcyclohexane and water. Particularly the solvent is n-heptane.

Step d) the formation of a compound of formula (IX) by reduction of a compound of formula (VIII). The compound of formula (IX) is synthesized in the presence of a suitable catalyst and a reducing agent in a suitable solvent. The conversion as a rule is performed under a heating condition.

The suitable catalyst is selected from a range of Palladium salts, solid supported palladium salts or solid supported palladium. Particularly the catalyst is palladium on charcoal. The suitable reducing agent is selected from hydrogen, a range of formate salts, formic acid, hydrazine or a range of silanes. Particularly the reducing agent is hydrogen, more particularly the reducing agent is hydrogen at a pressure of 20 bar.

The suitable solvent is selected from acetic acid, formic acid, acetic anhydride, TFA, mixtures of protic or aprotic organic solvents with Lewis- or Bronsted acids. Particularly the solvent is acetic acid.

The reaction is performed at a temperature between 15 °C and 120 °C, particularly between 25 °C and 85 °C.

After an appropriate amount of time, usually 2-16 h, the reaction is completed as shown by monitoring with HPLC. The compound of formula (IX) is isolated by separation of the solid supported catalyst, exchange of the reaction solvent to a solvent suitable for crystallization and isolation of the solid by methods known to the skilled in the art such as by extraction or filtration.

The suitable solvent is selected from n-heptane, n-heptane, cyclohexane,

methylcyclohexane or water. Particularly the solvent is water.

Step e) the formation of a compound of formula (X) by cyclisation of a compound of formula (IX).

The compound of formula (X) is synthesized in the presence of a suitable dehydrating reagent in a suitable solvent.

The suitable solvent is selected from THF, 2-MeTHF, cyclopentyl methyl ether, toluene, cyclohexane, methylcyclohexane, chlorobenzene, xylenes or acetonitrile, particularly the solvent is toluene.

The suitable dehydrating reagent is selected from oxalyl chloride, thionyl chloride, iron (III) chloride, aluminum chloride or phosphorous oxychloride, particularly the dehydrating agent is phosphorous oxychloride.

The reaction is performed at a reaction temperature between -10 and 110 °C, particularly between 10 °C and 60 °C.

After an appropriate amount of time, usually 2-5 h, the reaction is completed as shown by monitoring with HPLC. The compound of formula (X) is isolated by quenching the reaction mixture with water and isolation of the solid by methods known to the skilled in the art such as by extraction or precipitation by neutralisation and subsequent filtration.

Step f) the formation of a compound of formula (XII) by reaction of a compound of formula (X) with a compound of formula (XI).

The compound of formula (XII) is synthesized in a suitable solvent followed by a work-up procedure.

The suitable solvent is selected from water, methanol, ethanol, THF, 2-MeTHF or mixtures thereof. Particularly the solvent is a mixture of 2-MeTHF and water.

The reaction is performed at a temperature between 15 °C and 90 °C, particularly between 65 °C and 75 °C. The compound of formula (XII) is isolated through a work-up procedure comprising extraction with a suitable organic.

The suitable organic solvent used in extraction is selected from THF, EA, IP Ac, MTBE and 2-MeTHF. Particularly the organic solvent used in extraction is 2-MeTHF.

Step g) the formation of compound of formula (XIII) by oxidation of a compound of formula (XII) and subsequent salt formation with acid.

Compound of formula (XIII) is synthesized by oxidation with a suitable oxidant in the presence of a suitable base followed by salt formation using a suitable acid in a suitable crystallization solvent. The suitable oxidant is selected from iodine, bromine, chlorine, hydrogen peroxide, oxone or oxygen. Particularly the oxidant is iodine.

The suitable solvent is selected from DCM, THF, 2-MeTHF, EtOAc, DMSO, toluene or water. Particularly the solvent is 2-MeTHF.

The suitable base is selected from TEA, pyridine, DMAP, 2,6-Lutidine, alkali metal carbonates, hydroxides or acetates. Particularly the base is pyridine.

The suitable acid is selected from HC1, HBr, HI, H₂SO₄, H₃PO₄, TFA, alkylsulfonic acids such as methanesulfonic acid or trifluoromethanesulfonic acid, aryl sulphonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, 4-nitrophenylsulfonic acid, 4-bromophenylsulfonic acid, D-(+)-DTTA, L-DTTA, L-Tartaric acid, D-DBTA, (+)-CSA,

(S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate or (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate. Particularly the acid is (S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate.

The addition rate of the oxidant to the reaction mixture containing the base is controlled while the reaction temperature is maintained between 15 °C and 75 °C, particularly between 65 °C and 70 °C.

The amount of base is 1.5-3 eq. of the compound of formula (IX), particularly 2.0-2.5 eq.

After an appropriate amount of time, usually 0.5-2 h, the reaction is complete as shown by HPLC analysis. The compound of formula (XIII) is isolated as a solid upon filtration and the filtrate is further treated by an acid. Step h) the formation of compound of formula (la) via freebasing and optional subsequent transesterification or saponification.

The compound of formula (la) is synthesized in the presence of a suitable reagent in a suitable solvent. The suitable solvent is selected from methanol, ethanol, water, THF, 2-MeTHF, or a mixture of water and methanol, water and ethanol, water and THF or water and 2-MeTHF, particularly the solvent is a mixture of water and 2-MeTHF.

The suitable reagent is selected from alkalimetal hydroxides or carbonates, hydrochloric acid, hydrobromic acid or TFA. Particularly the reagent is sodium hydroxide. The reaction is performed at a temperature between 0 °C and 50 °C, particularly at the temperature between 15 °C and 25 °C.

After an appropriate amount of time, usually 0.5-4 h, the reaction is complete as shown by HPLC analysis. The compound of formula (la) is isolated as a solid upon phase separation and neutralization of the aqueous phase with a suitable acid. The suitable acid is selected from hydrochloric acid, hydrobromic acid, TFA, sulphuric acid or phosphoric acid. Particularly the acid is phosphoric acid.

EXAMPLES

The invention is illustrated further by the following examples. They should not, however, be construed as limiting the scope of the invention.

GENERAL EXPERIMENTAL CONDITIONS

LC-MS high resolution spectra were recorded with an Agilent LC-system consisting of Agilent 1290 high pressure gradient system, a CTC PAL auto sampler and an Agilent 6520 QTOF. The separation was achieved on a Zorbax Eclipse Plus CI 8 1,7 μιη 2.1x50mm column at 55°C; A=0.02% formic acid in Water; B= acetonitrile with 0.01% formic acid at a flow rate of 0.8 mL/min. gradient: 0 min 5%B, 0.3 min 5%B, 4.5 min 99 %B, 5 min 99%B. The injection volume was 2 μΤ. Ionization was performed in Agilents Multimode source. The mass spectrometer was run in "2 GHz extended dynamic range" mode, resulting in a resolution of about 10 000 at m/z=922. Mass accuracy was ensured by internal drift correction. Mass spectra (MS): generally only ions which indicated the parent mass were reported, and unless otherwise stated the mass ion quoted was the positive mass ion (M+H)+.

NMR Spectra were obtained on a Bruker 600MHz Avance III spectrometer equipped with a 5mm TCI cryoprobe.

All reactions involving air-sensitive reagents were performed under a nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

Example 1

Preparation of (2R)-2-formamido-3-methyl-butanoic acid (Example 1):

The title compound was prepared according to following scheme:

^{1 _a} Example 1

A 5000 L glass-lined reactor was charged with toluene (1601 kg) and D- Valine (155.5 kg, 1325 mol, Compoundl-a) and anhydrous formic acid (91.9 kg) at 20 °C. The reaction mixture was stirred at 96 °C for 18 h. The mixture was cooled to 49 °C and concentrated at reduced pressure until 800-1200 L remained. The mixture was cooled to 24 °C, filtered and the filter cake was rinsed twice with toluene (136 kg each). The filter cake was added to THF (2758 kg) at 15 °C. The mixture was heated to 40 °C and then maintained at this temperature for 2-3 h. The mixture was filtered at 40-44 °C and the filter cake was rinsed twice with THF (276 kg each). The filtrate was concentrated to 400-500 L at 31-49 °C under reduced pressure. At 46-48 °C, n-heptane (528 kg) was added to the mixture and the resulting suspension was stirred for 2 h. The suspension was cooled to 10 °C and stirred for another 4 h at this temperature before it was filtered. The filter cake was washed with heptane (2x105 kg) and dried under reduced pressure to yield Example 1 (138.6 kg, 70.2% yield, 97.4% assay by NMR). 1H NMR (600 MHz,DMSO-d₆) δ ppm 0.87 (dd, J=9.3, 6.9 Hz, 6 H) 1.95 - 2.16 (m, 1 H) 3.89 - 3.94 (m, 1 H), 4.21 (dd, J=8.8, 5.3 Hz, 1 H) 8.07 (s, 1 H) 8.31 (brd, J=8.7 Hz, 1 H) 11.93 - 13.81 (m, 1 H); MS m/e = 146.08151 [M+H] +.

Example 2

N-[(lR)-2-methyl-l-(pyrrolidine-l-carbonyl)propyl]formamide (Example 2):

The title compound was prepared according to following scheme:

Example 1 Example 2 A 3000 L glass-lined reactor was charged with THF (1833 kg),

(2R)-2-formamido-3-methyl-butanoic acid (Example 1, 138 kg), NMM (96.2 kg) and the mixture was stirred at 17-20 °C until all solid was dissolved completely. This solution was added to a solution of IBCF (142 kg) in THF (609 kg) which stirred in a 5000 L glass-lined reactor at -4.7 to -0.6 °C internal temperature. After the addition was finished, the mixture was stirred for 1 h at -1.2 to -0.6 °C. Pyrrolidine (89.2 kg) was added to the mixture at a temperature of -1.2 to 2.1 °C. The mixture was warmed to 10- °C and stirred at 10-20 °C until the reaction was complete (less than 24 h).

The mixture was cooled to 0-10 °C before a solution of sodium chloride (41.5 kg) in a mixture of concentrated hydrochloric acid (9.1 kg) and purified water (414 kg) was added at a speed of 200-300 kg/h in order not to exceed 6.8 °C internal temperature. The mixture was warmed to 15 °C before separation. The aqueous phase was extracted once with toluene (359 kg) and the combined organic phases were washed with a solution of sodium chloride (124 kg) in purified water (414 kg) before they were concentrated under reduced pressure (P<0.08 Mpa) at 18-53 °C until no distillation was observed anymore (200-300 L left). N-heptane (2x282 kg) was added and concentration was continued. The mixture was cooled to 25 °C and water (415 kg) was added. The mixture was stirred for 0.5 h and the phases were separated. The aqueous phase was washed three times with n-heptane (282 kg each) before sodium chloride was added to the aqueous phase. The mixture was stirred until all solids were dissolved and then extracted thrice with Me-THF (359 kg each). The combined organic phases were evaporated under reduced pressure at 21-42 °C until 200-300 L were left. THF (370 kg) was added to mixture and concentration was continued under reduced pressure at 33-43 °C (internal temperature) until no distillate was observed and 200-300 L was left. THF (372.7 kg) was added to the mixture and concentration was continued. After concentration, THF (360.4 kg) was added to the mixture and the mixture was sampled for Karl- Fischer analysis to ensure it was <0.1%. The solution of

Example 2 (491.1 kg, assay 23.9%, purity 95.6%, yield 63.9%) was cooled to 24 °C and was used without further purification in the next step.

A sample of Example 2 was obtained as an oil by evaporation. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (d, J=0.81 Hz, 1 H), 7.98-8.09 (m, 1 H), 6.62 (br d, J=7.25 Hz, 1 H), 4.70 (dd, J=6.72, 9.13 Hz, 1 H), 3.83-4.05 (m, 1 H), 3.65-3.78 (m, 1 H), 3.34-3.60 (m, 3 H), 2.82-2.82 (m, 1 H), 2.32-2.33 (m, 1 H), 1.80-2.10 (m, 6 H), 1.34-1.53 (m, 1 H), 1.26 (s, 1 H), 1.20-1.25 (m, 1 H), 0.99 (d, J=6.72 Hz, 3 H), 0.95 (d, J=6.72 Hz, 3 H); MS m/e = 199.3 [M+H] ⁺.

Example 3

N-[(lR)-l-[4-methoxy-3-(3-methoxypropoxy)benzoyl]-2-methyl-propyl]formamide

The title compound was prepared according to following scheme:

A 3000 L glass-lined reactor was charged with a solution of

N-[(lR)-2-methyl- l-(pyrrolidine- l-carbonyl)propyl]formamide (68.0 kg, crude Example 2 from last step) in THF (215.4 kg) and a solution of arylbromide 3-a (103.8 kg) in THF (219.6 kg). Upon stirring for 30 min at 18-20 °C, the water content was measured and found to be 0.24%. The mixture was concentrated at 28-43 °C under reduced pressure until 100- 160L mixture remained. The water content was measured and found to be 0.18%. The mixture was

concentrated at 28-43 °C under reduced pressure until 100- 160 L mixture remained. The water content was measured and found to be 0.18%. Dry THF (535.3 kg) was added to the mixture, the water content was measured and found to be 0.05%.

The solution was transferred to a 3000 L titanium reactor and the reactor of origin rinsed with dry THF (60.6 kg) which was combined with the bulk amount. The mixture was cooled to -43 °C before a solution of methyl lithium (3M in diethoxymethane, 111.5 kg) was added at -43 to -32 °C at a rate of 25-45 kg/h while stirring. The mixture was held at -33 to -32 °C for 1.5, before a sample was taken and quenched with a solution of acetic anhydride in THF. The area percentage of Example 2 was 17.8% in HPLC relative to the sum of area percentages of Example 2 and the N-acetyl derivative of Example 2. Isopropylmagnesium chloride lithium chloride complex (1.3M in THF, 134.2 kg) was added at -33 to - 18 °C at a rate of 30 to 50 kg/h. The mixture was warmed to - 15 °C before n-butyl lithium (2.5M in hexanes, 108 kg) was added at a rate of 30-40 kg/h at - 15 to -8.5 °C. The mixture was stirred at -8.9 to -6.7 °C for 4 h 20 min. The reaction mixture was added to a stirred solution of citric acid (108 kg) in purified water

(326 kg at a temperature of 3.7-4.9 °C in a 3000 L glass lined reactor. Upon completion, the mixture was warmed to 15 to 19 °C before separation. Then isopropyl acetate (180 kg) was added to the aqueous phase, and the mixture was stirred for 50 min, settled and separated. The combined organic phases were washed with a solution of sodium chloride (25.5 kg) in purified water (103 kg). The organic phase was filtered over a layer of silica gel (3-5 cm, 13.6 kg) and the filter cake was rinsed with THF (60.5 kg). The solution was concentrated under reduced pressure at a temperature of 14-35 °C until 200-220 L were left, n-heptane (92.5 kg) was added to the mixture at 35-39 °C and the mixture was warmed to 47 °C before more n-heptane (185 kg) was added at a reference rate of 43 kg/h. Stirring was continued at this temperature for 2-6 h. The mixture was cooled to 25 °C at a reference rate of 3-8 °C/h. After stirring for 4 h, the mixture was filtered and the filter cake was rinsed once with n-heptane (92.7 kg), twice with purified water (136 kg each) and rinsed once more with n-heptane (92.1 kg) before drying under reduced pressure and a temperature of 30-40 °C yielding 79.2 kg Example 3 as a light yellow solid (purity: 98.3%, ee: 97.4%, yield: 65.6%). 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 8.32 (s, 1 H), 7.63 (dd, J=8.5, 2.0 Hz, 1 H), 7.54 (d, J=2.0 Hz, 1 H), 6.92 (d, J=8.5 Hz, 1 H), 6.47 (brd, J=8.3 Hz, 1 H), 5.62 (dd, J=9.0, 4.2 Hz, 1 H), 4.18 (t, J=6.5 Hz, 2 H), 3.94 (s, 3 H), 3.58 (t, J=6.1 Hz, 2 H), 3.36 (s, 3 H), 2.18 - 2.26 (m, 1 H), 2.13 (quin, J=6.3 Hz, 2 H), 0.74 - 1.15 (m, 6 H); MS m/e = 324.1822 [M+H] ⁺.

Example 4

N-[(lS)-l-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-2-methyl-propyl]formamide

The title compound was prepared according to following scheme:

Example 3 Example 4

A solution of Example 3 (70.3 kg) in acetic acid (513 kg) was treated three times with active carbon (7.1 kg each) at 45 to 49 °C for 2 h resulting in a solution of 55.4 kg Example 3 in 618 kg acetic acid.

This solution was charged into a 1000 L autoclave, Palladium on charcoal (10wt%., 50% wet, 9.2 kg) was added under nitrogen and then the atmosphere was changed to hydrogen. The pressure was increased to 19-20 bar and the mixture was stirred at 26-30 °C until the pressure stayed constant for 20 h. Additional Palladium on charcoal (10wt%., 50% wet, 2.4 kg) was added after 40 h reaction time and stirring continued for 36 h.

The mixture was heated to 76-78 °C and stirred at a hydrogen pressure of 17-18 bar. After the pressure had been stable for 8 h, the mixture was cooled to 30 °C, the autoclave was vented and the atmosphere was changed back to nitrogen. The mixture was filtered and the filter cake was rinsed twice with acetic acid (56 kg each). The filtrate was transferred into a 1000 L glass-lined reactor and concentrated at 25-51 °C under reduced pressure maintaining constant volume by replacing distillate with purified water. Distillation was continued until 1324 kg purified water had been added. The mixture was cooled to 4.7 °C at a reference rate of

10-15 °C/h. The suspension was stirred at 1.4-4.7 °C and filtered after a sample of the mother liquor indicated product content being less than 0.5wt%. The filter cake was rinsed twice with purified water (110 kg each), swept with nitrogen for 2 h and dried under reduced pressure at 35-44 °C and dried for 15 h at which point residual water and acetic acid content were below 0.5wt% each yielding Example 4 (41.8 kg, yield: 78.3%, purity: 99.1%, ee: 99.8%) as a white solid. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 8.13 (d, J=l . l Hz, 1 H), 7.63 (d,

J=11.8 Hz, 1 H), 6.60 - 6.96 (m, 3 H), 5.05 - 5.77 (m, 1 H), 4.18 (tt, J=9.0, 5.6 Hz, 1 H),

3.95 - 4.11 (m, 2 H), 3.71 - 3.86 (m, 3 H), 3.45 - 3.64 (m, 2 H), 3.12 - 3.32 (m, 1 H), 2.43 - 2.94 (m, 2 H), 2.03 - 2.18 (m, 2 H), 1.66 - 1.95 (m, 2 H), 0.89 - 1.04 (m, 6 H); MS m/e [M+H] ⁺.

Example 5

(3S)-3-isopropyl-7-methoxy-6-(3-methoxypropoxy)-3,4-dihydroisoquinoline

The title compound was prepared according to following scheme:

Example 4 Example 5

A 1000 L glass-lined reactor was charged with toluene (241 kg) and POCI₃ (26.2 kg). N- [( 1 S)- 1 -[[4-methoxy-3-(3-methoxypropoxy)phenyl] methyl] -2-methyl-propyl] formamide (35.2 kg) was added at 15-30 °C in 5 portions under vigorous stirring at intervals of 40-60 min. Stirring was continued at 21 to 24 °C for at least 4.25 h. The mixture was heated to 45 °C and stirred at this temperature for 1.5 h. The mixture was cooled to 25 °C and transferred into a 2000 L glass-lined reactor containing purified water (87.5 kg) and ice (87.5 kg) maintaining an internal temperature of 15-19 °C. The mixture was warmed to 23 °C and n- heptane (71.5 kg) as added. The mixture was stirred for 3 h, settled and phases separated. A solution of hydrochloric acid (14.7kg) in purified water (87.5kg) was added to the organic phase. The mixture was stirred for lh, settled and phases separated. The combined aqueous phases were transferred into a 500 L glass lined reactor and cooled to 8.8 °C. At this temperature, a solution of sodium hydroxide (61.3 kg) in purified water (143 kg) was added at a reference rate of 10-16 kg/h until a pH of 9 was reached. Stirring was continued for 5 h and then the mixture was filtered and the filter cake was washed with purified water until the filtrate showed no precipitation when treated with aqueous barium hydroxide solution. The filter cake was dried under reduced pressure at a temperature of less than 35 °C until the water content of the product was less than 0.5wt to yield Example 5 (26.8 kg, purity: 98.8%, ee: 99.3%, yield: 79.7%) as an off-white solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.21 (d, J=2.9 Hz, 1 H), 7.03 (s, 1 H), 6.86 (s, 1 H), 4.04 (t, J=6.4 Hz, 2 H), 3.76 (s, 3 H), 3.46 (t, J=6.2 Hz, 2 H), 3.24 (s, 3 H), 3.05 (dtd, J=14.7, 5.7, 5.7, 3.0 Hz, 1 H), 2.60 (dd, J=16.0, 5.6 Hz, 1 H), 2.34 - 2.42 (m, 1 H), 1.95 (quin, J=6.3 Hz, 2 H), 1.88 (dq, J=13.1, 6.6 Hz, 1 H), 0.99 (dd, J=16.4, 6.7 Hz, 6 H); MS m/e = 292.1916 [M+H] ⁺.

Example 6 ethyl

(6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydro-5H-benzo[a]quinoli zin-5-ium-3-carboxylate (S)-(+)-l,l '-binaphthyl-2,2'-diyl hydrogenphosphate

2-methyltetrahydrofurane solvate

The title compound was prepared according to following scheme:

Example 6

A 2.5 L glass sulphonation flask equipped with mechanical stirrer, cooler, thermometer and nitrogen bubbler was charged with (3S)-3-isopropyl-7-methoxy-6-(3-methoxypropoxy)-3,4-dihydroisoquinoline (100 g, 0.343 mol, Example 5) and sodium chloride (100 g). Water (600 g) was added at 20 °C. The reaction mixture was heated to 70-75 °C and a mixture of ethyl 2-ethoxymethylene)acetoacetate (83.1 g, 0.446 mol, 6-a) and 2-MeTHF (100 mL) was added within 30 min. Stirring was continued at 70-75 °C for 2 h. The mixture was cooled to 20 °C and diluted with 2-MeTHF (250 mL). Phases were separated and the aqueous phase was extracted with 2-MeTHF (200 mL). The combined organic phases were concentrated under reduced pressure at 45-50 °C until no more solvent was distilled over. 2-MeTHF (600 mL) was added and 300 mL solvent was distilled off at a pressure of 450 mbar and a bath temperature of 65 °C. 2-MeTHF (250 mL). Then pyridine (57 g, 0.721 mol) was added and the mixture was heated to 65-70 °C. After that, a solution of iodine (87.1 g, 0.343 mol) in 2-MeTHF (150 mL) was added during 60 min. The mixture was stirred at 65-70 °C for 3 h. The mixture was cooled to 10-15 °C, stirred for 30 min and filtered. The filter cake was washed with 2-MeTHF (4x50 mL) and the combined filtrates were added to a suspension of (S)-(+)-l,r-Binaphthyl-2,2'-diyl hydrogenphosphate (110 g, S-BNP) in 2-MeTHF (450 mL) at 20 °C. The mixture was stirred for 14 h, filtered, and the filter cake was washed with 2-MeTHF (5x200 mL) and dried under reduced pressure at 60-65 °C to yield Example 6 (222 g, 74.9% as an off-white solid with residual pyridinium hydroiodide, which was used without further purification. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 8.53 - 8.70 (m, 2 H), 8.11 (tt, J=7.8, 1.6 Hz, 1 H), 8.03 (brs, 1 H), 7.87 (dd,J=13.8, 8.5 Hz, 6 H), 7.60 (dd, J=7.7, 6.5 Hz, 1 H), 7.55 (d, J=9.0 Hz, 4 H), 7.39 (t, J=7.5 Hz, 3 H), 7.34 (d, J=8.6 Hz, 3 H), 7.19 - 7.25 (m, 3 H), 6.69 (s, 1 H), 4.38 - 4.53 (m, 2 H), 4.13 - 4.26 (m, 3 H), 3.85 - 3.98 (m, 5 H), 3.71 (td, J=8.1, 6.4 Hz, 1 H), 3.52 - 3.62 (m, 2 H), 3.32 - 3.42 (m, 4 H), 3.00 (d,J=16.5 Hz, 1 H), 2.13 (quin, J=6.2 Hz, 2 H), 1.77 - 2.03 (m, 5 H), 1.34 - 1.49 (m, 4 H), 1.23 (d, J=6.0 Hz, 4 H), 0.92 (d, J=6.6 Hz, 3 H), 0.77 (d, J=6.7 Hz, 3 H); MS m/e = 429.2144 [M+H] ⁺.

Example 7 Preparation of

(6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine- 3-carboxylic acid monohydrate (Example 7):

The title compound was prepared according to following scheme:

Example 7

A 1.5 L sulpho nation flask equipped with mechanical stirrer, thermometer and nitrogen bubbler was charged at 15-25 °C with ethyl

(6S)-6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydro-5H-benzo[a]quinolizin- 5-ium-3-carboxylate (S)-(+)- 1 , 1 '-binaphthyl-2,2'-diyl hydrogenphosphate

2-methyltetrahydrofurane solvate (200 g, Example 6) and 2-MeTHF (700 mL), followed by TEA (43 mL). The suspension was stirred at 20 °C for 60 min before it was filtered. The filter cake was washed with 2-MeTHF (200 mL) and the combined filtrates was concentrated to 290 mL under reduced pressure at 55-60 °C. The solution was cooled to 20 °C and a solution of aqueous sodium hydroxide (32wt , 48.2 g) and purified water (500 g) was added. The mixture was stirred at 20 °C for 4 h, and phases were separated. The aqueous phase was washed with 2-MeTHF (2x200 mL). Ethanol (134 mL) was added to the aqueous phase. Aqueous phosphoric acid (20% wt) was added at 20 °C until the pH of the solution reached 7.5-7.7 at which point seed crystals (Example 7, 100 mg) were added. Addition of aqueous phosphoric acid (20% wt) was continued until a pH of 4-4.5 was reached. The resulting suspension was stirred for at least 1 h before it was filtered. Then the filter cake was washed with water (600 mL) and dried at ambient pressure and 15-25 °C to give Example 7 as an off-white powder (68.1 g, yield: 70.1%, purity: >99.9%, ee: 100%). 1H NMR 600 MHz, CHLOROFORM-d) δ ppm 8.48 (s, 1 H), 7.17 (s, 1 H), 7.07 (s, 1 H), 6.77 (s, 1 H), 4.13 - 4.25 (m, 2 H), 3.92 (s, 3 H), 3.89 (dd, J=9.5, 5.0 Hz, 1 H), 3.52 - 3.61 (m, 2 H), 3.29 - 3.39 (m, 4 H), 3.06 (d, J=16.1 Hz, 1 H), 2.14 (quin, J=6.2 Hz, 2 H),

1.72 - 1.86 (m, 1 H), 0.94 (d, J=6.6 Hz, 3 H), 0.82 (d, J=6.7 Hz, 3 H); MS m/e = 402.1908 [M+H]

+

Example 8 Comparative study According to the synthetic procedure disclosed in WO2015 1 1 990, the overall yield was

5.9% with the details below:

Xantphos, AA4 AA1 AA2 t-BuONa, THF

Compound (I) was prepared starting from compound AAl according to the above scheme: alkylation of phenol AAl gave bromide AA2, which underwent Pd catalyzed coupling reaction with ketone AA3 to afford intermediate AA4. Reductive amination and formylation gave formamide AA6, which was treated with POCI₃ to give the dihydroisoquinoline AA7.

Dihydroisoquinoline AA7 reacted with compound AA8 followed by p-chloranil to give ester AA10. After hydro lyzation and chiral separation, the final compound was obtained.

Table 1 Yield of Each Step from Example 1 to Example 7

According to the synthetic route of this invention, the overall yield is 9.6%. The Yield overall yield for the new process is calculated as follows: achieved Example 1 70.2%

Example 2 63.9%

Example 3 65.6%

Example 4 78.3%

Example 5 79.7%

Example 6 74.9%

Example 7 70.1%

The overall yield in the longest linear sequence is thus calculated as the product of the individual step yields as shown in Table 1 and found to be 9.6%.

In addition, the process of this invention, compared to the one disclosed in WO2015113990, shows advantages from the following aspects:

(a) The overall yield is increased from 5.9% to 9.6%. Specifically, the low yield

encountered in the final chiral separation is undesirable, as it more than doubles the volumes and amounts of reagents needed to conduct the synthesis compared to a chiral synthesis.

(b) The number of intermediates which are isolated in crude form only is reduced from 4 to 2, thus increasing the robustness of the process overall: Example 2 and 6-b.

(c) column purification is not needed for any intermediates and not the final product

(d) D- Valine (1-a) is employed as chiral starting material, thus all intermediates are chiral. Therefore chiral HPLC, chiral SFC or diastereomeric salt formation can be avoided.

Claims

1. A process for the preparation of a compound of formula (la),

wherein

R¹ is Ci_₆alkyl;

R is Ci_₆alkoxy;

R is Ci_₆alkoxy or Ci-₆alkoxyCi_₆alkoxy;

R⁴ is Ci_₆alkoxy or hydroxy;

or pharmaceutically acceptable salt or diastereomer thereof; comprising one or more of the following steps:

step a) formation of N-formylamino acid (IV),

wherein R¹ is C_1-6alkyl; step b) formation of amide (VI) via coupling of carboxylic acid IV and amine

(VI), wherein R¹ is C_1-6alkyl; R⁵ is

or Ci-₆alkoxyCi_₆alkyl, or R⁵ and R⁶ together with the nitrogen to which they are attached, form N-containing heterocycloalkyl; step c) coupling of a compound of formula (VI) with aryl halide (VII) yielding ketone (VIII),

1 2 3

wherein R is Ci-₆alkyl; R is Ci-₆alkoxy; R is Ci-₆alkoxy or Ci_₆alkoxyCi_₆aIkoxy; step d) formation of a compound of formula (IX) by reduction of a compound of formula (VIII),

1 2 3

wherein R is Ci_₆alkyl; R is Ci-₆alkoxy; R is Ci-₆alkoxy or Ci_₆alkoxyCi_₆aIkoxy; step e) formation of a compound of formula (X) cyclisation of a compound of formula (IX),

1 2 3

wherein R is Ci_₆alkyl; R is C_1-6 alkoxy; R is Ci-₆alkoxy or Ci_₆alkoxyCi_₆alkoxy; step f) formation of a compound of formula (XII) by reaction with a compound of formula

(xi),

wherein R¹ is C_1-6alkyl; R² is Ci_₆alkoxy; R³ is Ci_₆alkoxy or Ci_₆alkoxyCi-₆alkoxy; R⁴ is Ci-₆alkoxy or hydroxy; step g) formation of compound of formula (XIII) by oxidation of a compound of formula (XII) and subsequent salt formation with Acid,

wherein R¹ is C_1-6alkyl; R² is Ci_₆alkoxy; R³ is Ci_₆alkoxy or Ci_₆alkoxyCi-₆alkoxy; R⁴ is Ci-₆alkoxy or hydroxy; step h) formation of a compound of formula (la) via freebasing and optional subsequent transesterification or saponification,

wherein R¹ is C_1-6alkyl; R² is Ci_₆alkoxy; R³ is Ci_₆alkoxy or Ci_₆alkoxyCi_₆alkoxy; R⁴ is Ci_₆alkoxy or hydroxy.

2. A process according to claim 1, wherein R¹ is isopropyl; R² is methoxy; R³ is 3- methoxypropoxy; R⁴ is ethoxy or hydroxy; R⁵ and R⁶, together with the nitrogen to which they are attached, form a pyrrolidine ring.

3. A process according to claim 1 for the synthesis of formula (I),

or pharmaceutically acceptable salt or enantiomer, or diastereomer thereof.

4. A process according to any one of claims 1, 2 and 3, characterized in that the formation of the N-formylamino acid (IV) in step a) is performed in the presence of formic acid in a solvent under a heating condition, wherein the solvent is selected from 2-MeTHF, THF, IP Ac, EA, toluene or DCM, particularly the solvent is toluene.

5. A process according claim 4, wherein the reaction temperature is between 20 °C and 130 °C, particularly between 90 °C and 120 °C.

6. A process according to any one of claims 1 to 5, characterized in that the formation of amide (VI) via the coupling of carboxylic acid IV and amine V in step b) is performed in the presence of a coupling reagent and a base in an organic solvent under a cooling condition, wherein the amine V is selected from morpholine, piperidine, pyrrolidine or Ν,Ο-dimethylhydroxylamine hydrochloride, particularly the amine V is pyrrolidine.

7. A process according to claim 6, wherein the coupling reagent is selected from T3P, CDI, DIC, DCC, HATU or IBCF, particularly the coupling reagent is IBCF.

8. A process according to claim 6 or 7, wherein the base is selected from TEA, DIPEA, DBU, DABCO or NMM, particularly the base is NMM.

9. A process according to any one of claims 6 to 8, wherein the organic solvent is selected from 2-MeTHF, THF, IP Ac, EA, toluene, DMF, NMP, ACN or DCM, particularly, the organic solvent is THF.

10. A process according to any one of claims 1 to 9, characterized in that the coupling of the compound of formula (VI) with aryl halide (VII) in step c) is performed in a solvent in the presence of a base, a catalyst and a metalation reagent, wherein the solvent is selected from 2-MeTHF, THF, MTBE, toluene, CPME, or anisol, particularly the solvent is THF.

11. A process according to claim 10, wherein the base is selected from methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, n-hexyl lithium, lithium hydride, sodium hydride, potassium hydride, isopropylmagnesium chloride or isopropylmagnesium chloride lithium chloride complex; particularly the base is methyl lithium, more particularly the base is a solution of methyl lithium in diethoxymethane.

12. A process according to claim 10 or 11, wherein the catalyst is selected from

isopropylmagnesium chloride lithium chloride complex, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide; particularly the catalyst is isopropylmagnesium chloride lithium chloride complex.

13. A process according to any one of claims 10 to 12, wherein the metalation reagent is selected from n-butyl lithium, sec-butyl lithium, tert-butyl lithium n-hexyl lithium, isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex; particularly the metalation reagent is n-butyl lithium, sec-butyl lithium, tert-butyl lithium n-hexyl lithium, more particularly the metalation reagent is n-butyl lithium.

14. A process according to any one of claims 10 to 13, wherein the reaction is performed at a temperature between -50 °C and 50 °C, particularly between -35 °C and 25 °C.

15. A process according to any one of claims 1 to 14, characterized in that the formation of the compound of formula (IX) by reduction of the compound of formula (VIII) in step d) is performed in the presence of a catalyst and a reducing agent in a solvent under a heating condition, wherein the catalyst is selected from a range of palladium salts, solid supported palladium salts or solid supported palladium, particularly the catalyst is palladium on charcoal.

16. A process according to claim 15, wherein the reducing agent is selected from hydrogen, a range of formate salts, formic acid, hydrazine and a range of silanes, particularly the reducing agent is hydrogen, more particularly the reducing agent is hydrogen at a pressure of 20 bar.

17. A process according to claim 15 or 16, wherein the solvent is selected from acetic acid, formic acid, acetic anhydride, TFA, mixtures of protic or aprotic organic solvents with Lewis- or Bronsted acids, particularly the solvent is acetic acid.

18. A process according to any one of claims 1 to 17, characterized in that the formation of the compound of formula (X) by cyclisation of the compound of formula (IX) in step e) is performed in the presence of a dehydrating reagent in a solvent, wherein the dehydrating reagent is selected from oxalyl chloride, thionyl chloride, iron (III) chloride, aluminum chloride or phosphorous oxychloride, particularly the dehydrating agent is phosphorous oxychloride.

19. A process according to claim 18, wherein the solvent is selected from THF, 2-MeTHF, cyclopentyl methyl ether, toluene, cyclohexane, methylcyclohexane, chlorobenzene, xylenes or acetonitrile, particularly the solvent is toluene.

20. A process according to any one of claims 1 to 19, characterized in that the formation of the compound of formula (XII) by reaction of the compound of formula (X) with a compound of formula (XI) in step f) is performed in a solvent followed by a work-up procedure, wherein the solvent is selected from water, methanol, ethanol, THF, 2-MeTHF or mixtures thereof, particularly the solvent is a mixture of 2-MeTHF and water.

21. A process according to any one of claims 1 to 20, characterized in that the formation of compound of formula (XIII) in step g) is performed by oxidation of the compound of formula (XII) in the presence of an oxidant and a base, and subsequent salt formation with acid in the presence of a solvent, wherein the oxidant is selected from iodine, bromine, chlorine, hydrogen peroxide, oxone and oxygen, particularly the oxidant is iodine.

22. A process according to claim 21, wherein the solvent used in the oxidation and salt formation is selected from DCM, THF, 2-MeTHF, EtOAc, DMSO, toluene and water, particularly the solvent is 2-MeTHF.

23. A process according to claim 21 or 22, wherein the base is selected from TEA, pyridine, DMAP, 2,6-Lutidine, alkali metal carbonates, hydroxides or acetates. Particularly the base is pyridine.

24. A process according to any one of claims 21 to 23, wherein the amount of base is 1.5-3 eq. of the compound of formula (IX), particularly 2.0-2.5 eq.

25. A process according to any one of claims 21 to 24, wherein the acid is selected from HC1, HBr, HI, H₂SO₄, H₃PO₄, TFA, methane sulfonic acid, trifluoromethanesulfonic acid ,

(S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate and (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate, particularly the acid is (S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate.

26. A process according to any one of claims 1 to 25, characterized in that the formation of compound of formula (la) in step h) is performed by freebasing in the presence of a reagent in a solvent and optional subsequent transesterification or saponification, wherein the solvent is selected from methanol, ethanol, THF, 2-MeTHF, water and mixtures thereof, particularly the solvent is a mixture of water and 2-MeTHF.

27. A process according to claim 26, wherein the reagent is selected from alkalimetal hydroxides or carbonates, hydrochloric acid, hydrobromic acid and TFA, particularly the reagent is sodium hydroxide.

28. A process according to any one of claims 26 to 27, wherein the reaction is performed at a temperature between 0 °C and 50 °C, particularly between 15 °C and 25 °C.