inhibitors The present invention is directed to a process for the manufacture of a compound of formula I

wherein Y is CHR ⁷ , CR ⁷ R ⁸ or 0,

n is 0, 1 or 2,

R ¹ and R ² are independently of each other selected from the group consisting of H, F, Cl, methyl and ethyl, and

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and, R ⁸ are independently of each other selected from H or Ci-C ₆ -alkyl;

comprising the following steps:

a) reacting a compound of formula (II) with a compound of formula (III) to a compound of formula (IV) in water in the presence of a base and a catalyst,

b) extracting the compound of formula (IV) from the reaction mixture obtained in step a) with an organic solvent;

c) reacting the extracted compound of formula (IV) in an organic solvent to a compound of formula (V),

d) reacting the compound of formula (V) obtained in step c) with a compound of formula (VI) in an organic solvent to a compound of formula (I)

whereby the organic solvent used in step d) is either a straight or branched C ₃ -alkyl acetate or a straight or branched C ₄ -alkyl acetate or any mixture thereof. The reaction scheme of this process is shown in Fig. 1 .

The synthesis of compounds of formula (I) is already described in WO 2017/012890. The aim of the present invention is, however, to provide a process which is more suitable for large-scale production than the ones mentioned in WO 2017/012890. This object is achieved by the process of the present invention, which does not need chromatographic purification steps and where the work-up is performed at much higher concentration, requiring correspondingly less solvent. Thus, the process of the present invention is also more economic than the ones already known.

The compounds of formula (I) are 1 1 -beta-hydroxysteroid dehydrogenase type 1 inhibitors and can be used to reduce cortisol levels in keratinocytes and to improve dermal collagen content in human skin after exposure to cortisone and UV. Thus, there is a need for a process for their manufacture that is efficient. The present invention is especially directed to a process for the manufacture of the following compounds (la), (lb) and (lc):

with R ¹ and R ² being independently from each other H, F, Cl, methyl or ethyl; preferably with R ¹ and R ² being independently from each other H, F, Cl or methyl;

with R ¹ and R ² being independently from each other H, F, Cl, methyl or ethyl; preferably with R ¹ and R ² being independently from each other H, F, Cl or methyl;

with R ¹ being H, F, Cl, methyl and ethyl, preferably with R ¹ being H, F, Cl or methyl.

Compounds which are preferably manufactured according to the process of the present invention are listed below:

(1 )

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ = H; R ² = F; Y = CHR ⁷ , R ⁷ = CH ₃ , n = 1 ,

R ¹ , R ³ , R ⁵ = H; R ² , R ⁴ , R ⁶ = CH ₃ ; Y = 0; n = 1 .

Of these compounds listed above compounds (3), (9) and (10) are especially preferred. More preferred compounds are compounds (9) and (10) . The most preferred compound is compound (10):

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ = H; Y = CHR ⁷ ; n = 2.

The reaction scheme for its manufacturing process is shown in Fig. 2.

Thus, a preferred embodiment of the present invention is a process for the manufacture of a compound of formula (10)

comprising the following steps:

a) reacting a compound of formula (I la) with a compound of formula (Ilia) to a compound of formula (IVa) in water in the presence of a base and a catalyst;

b) extracting the compound of formula (IVa) from the reaction mixture

obtained in step a) with an organic solvent; c) reacting the extracted compound of formula (IVa) in an organic solvent to a compound of formula (Va),

d) reacting the compound of formula (Va) obtained in step c) with a compound of formula (Via) in an organic solvent to a compound of formula (10)

whereby the organic solvent used in step d) is either a straight or branched C ₃ -alkyl acetate or a straight or branched C ₄ -alkyl acetate or any mixture thereof.

By using an organic solvent in steps b) to d) of the process of the present invention which is either a straight or branched C ₃ -alkyl acetate or a straight or branched C ₄ - alkyl acetate or any mixture thereof the yield for the synthesis of compound (10) could be increased by 9 to 21% compared to the use of ethyl acetate as solvent (see table 0). A similar yield can be expected for the synthesis of the other compounds encompassed by formula (I).

Table 0

Thus, an embodiment of the present invention is a process, wherein the organic solvent used in step b) and/or in step c) is the same organic solvent as used in step d) with the preferences as given above.

A preferred embodiment of the present invention is a process, wherein the organic solvent used in step b) and in step c) is the same organic solvent as used in step d) with the preferences as given above. The steps of the process of the present invention are discussed in further detail below.

Step a)

The reaction of the compound of formula (II) with the compound of formula (III) to the compound of formula (IV) is a so-called Suzuki-Miyaura cross-coupling. The reaction is carried out in water. If water-miscible co-solvents are used, these solvents have to be removed before extractive work-up. Therefore, it is very advantageous not to use water-miscible co-solvents, but to carry out the reaction in water only.

The amount of water used as a solvent is in the range of from 1 to 100 ml. per mmol of compound (II), preferably in the range of from 1 to 50 ml. per mmol of compound (II), more preferably in the range of from 1 to 25 ml. per mmol of compound (II), even more preferably in the range of from 1 to 10 mL per mmol of compound (II), most preferably in the range of from 1 to 5 mL per mmol of compound (II).

Step a) is preferably carried out in the presence of a base and a Pd catalyst. An example of a preferred base is sodium carbonate. Potassium carbonate can also be used.

Examples of catalysts are Pd(EDTA) (EDTA = N,N,N’,N’-ethylenediaminetetraacetic acid) and Pd(PPh ₃ )4, whereby Pd(EDTA) is preferred.

When sodium carbonate is used as base and Pd(EDTA) as catalyst, step a) is carried out at a temperature in the range of from 20 °C to solvent reflux, preferably at a temperature in the range of from 30 °C to solvent reflux, more preferably at a temperature in the range of from 40 °C to solvent reflux, most preferably at a temperature in the range of from 90° C to solvent reflux, and preferably at atmospheric pressure.

The amount of the base, preferably the amount of sodium carbonate, is in the range of from 1 to 10 mol, preferably in the range of from 1 .2 to 4 mol, more preferably in the range of from 1 .5 to 3 mol per mol of compound (II).

The amount of the catalyst, preferably the amount of Pd(EDTA), is in the range of from 0.001 to 10 mol-%, preferably in the range of from 0.005 to 5 mol-%, more preferably in the range of from 0.01 to 1 mol-%, most preferably in the range of from 0.01 to 0.5 mol-%, based on the amount of compound (II).

The molar ratio of the compound of formula (III) to the compound of formula (II) in its monomeric form is ranging from 1 :1 to 10:1 , preferably from 1 :1 to 5: 1 , more preferably from 1 :1 to 2: 1 , even more preferably from 1 :1 to 1 .5:1 , most preferably from 1 :1 to 1 .2: 1 . Advantageously the compound of formula (III) is used in excess compared to the compound of formula (II).

This step has a very high conversion. Usually the amount of un reacted compound of formula (II) being left after the reaction is < 0.5%, based on the starting amount. Thus, the final product of this step, the compound of formula (IV), is of sufficient purity for the next step and needs not to be purified. Unreacted compound of formula (II) will also be extracted in step b), activated in step c) and form a by product, j.e. the 3-bromobenzoyl derivative of compound (VI), in step d), which cannot be removed by the given extractive work-up. Thus, it is very advantageous that the amount of unreacted compound of formula (II) is so low.

Step b)

It is very advantageous when the organic solvent used in step b) is the same organic solvent used in step c) and step d).

However, also other organic solvents that are not miscible with water may be used in step b). Examples thereof are esters such as ethyl acetate, water-unmiscible alcohols such as 1 -butanol, water-unmiscible ketones such as 2-butanone, and halogenated alkanes such as methylene chloride and chloroform.

Preferably, however, the organic solvent used in step b) is either a straight or branched C ₃ -alkyl acetate or a straight or branched C ₄ -alkyl acetate or any mixture thereof, i.e. n-propyl acetate, n-butyl acetate, /so-propyl acetate, /so-butyl acetate and tert- butyl acetate and any mixture thereof.

More preferably the organic solvent is either /so-propyl acetate or /so-butyl acetate or any mixture thereof, whereby the use of the single solvents and not their mixture is preferred.

Most preferably the organic solvent is /so-propyl acetate.

The amount of solvent used is in the range of from 0.1 to 10 times the amount of water employed in step a), preferably from 0.5 to 7 times the amount of water employed in step a), more preferably from 1 to 5 times the amount of water employed in step a), most preferably from 1 to 3 times the amount of water employed in step a). For neutralizing the base added in step a) an acid is added. Examples of these acids are aqueous hydrochloric acid, phosphoric acid, sulfuric acid, hydrogen sulfates such as potassium hydrogen sulfate and methane sulfonic acid. Aqueous

hydrochloric acid in the highest commercially available concentration, i.e. 36-37% w/w, also called‘fuming hydrochloric acid’, is preferred. The amount of acid depends on the amount of base used before. For the extraction in organic phase to be quantitative, it is necessary that, after acid addition, the pH of the resulting aqueous phase is < 3. Usually an amount of acid in the range of from 2 to 10 mol per mol of base is sufficient, so that at the end of the acid addition the pH of the resulting aqueous phase is < 3.

Usually step b) is carried out by cooling down the reaction mixture obtained in step a) to room temperature, adding the organic solvent and slowly adding the acid under stirring. The aqueous phase is separated, the organic phase is then washed with brine to remove most of the water. Afterwards active charcoal and celite are added to remove the catalyst decomposition by-products. Charcoal and celite are then filtered off and rinsed with the same organic solvent used for the extraction.

A purified organic phase is, thus, obtained. Remaining water is removed by azeotropic distillation followed by distilling off excess organic solvent until preferably the remaining solvent matches the originally added volume. Thus, in a preferred embodiment of the present invention, the amount of solvent for the following step c) is the same amount as added in step b). It is a big advantage of the process of the present invention that isolation of the intermediate, the compound of formula (IV), is not necessary.

Step c)

It is very advantageous when the organic solvent used in step c) is the same organic solvent as used in step b) and step d). Then no change of the solvent needs to be done.

However, also other organic solvents that are aprotic may be used in step c).

Examples thereof are esters such as ethyl acetate, aromatic hydrocarbons such as toluene, nitriles such as acetonitrile, ethers such as tetrahydrofuran, dioxane and 1 ,2-dimethoxyethane, and halogenated alkanes such as methylene chloride and chloroform. Preferably, however, the organic solvent is either a straight or branched C ₃ -alkyl acetate or a straight or branched C ₄ -alkyl acetate or any mixture thereof.

More preferably the organic solvent is either /so-propyl acetate or /so-butyl acetate or any mixture thereof, whereby the use of the single solvents and not their mixture is preferred.

Most preferably the organic solvent is /so-propyl acetate. The amount of solvent used in step c) is in the range of from 0.5 to 5 times the amount of solvent used in step b), preferably from 0.7 to 2 times the amount of solvent used in step b), more preferably from 0.9 to 1 .5 times the amount of solvent used in step b), most preferably from 1 to 1 .2 times the amount of solvent used in step b).

In step c) the acid of formula (IV) is converted in its acyl chloride of formula (V).

Preferably this is done by adding an excess of SOCl ₂ (thionyl chloride), i.e. 1 to 5 equivalents, preferably 1 to 2 equivalents, more preferably 1.04 to 1 .3 equivalents, based on the amount of the compound of formula (IV).

A catalyst can be added together with thionyl chloride to accelerate conversion of the compound of formula (IV) into its acyl chloride of formula (V), such as N,N- dimethylformamide (DMF), N-formyl azepane or any other secondary amide of formic acid. DMF is the preferred catalyst. In the presence of thionyl chloride, secondary amides of formic acid are converted into the corresponding

(chloromethylene)dialkyliminium chlorides, which are also active as catalysts. In particular, in the presence of thionyl chloride, DMF is converted to

(chloromethylene)dimethyliminium chloride (also known as Vilsmeier reagent). The Vilsmeier reagent is commercially available and can be used as a catalyst instead of DMF.

After thionyl chloride addition, the temperature of the reaction mixture is increased from room temperature. If no catalyst was added, the temperature is increased preferably up to a temperature in the range from 40°C to solvent reflux, more preferably from 55°C to solvent reflux, most preferably from 75 °C to solvent reflux.

If a catalyst was added, the temperature is increased preferably to a temperature of up to solvent reflux, more preferably to a temperature in the range of from 45 to 78°C, most preferably to a temperature in the range of from 50 to 60°C. Carrying out step c) in the presence of a catalyst is preferred, since it allows to reach complete activation at lower temperature in the same time or in a shorter time at the same temperature, which is advantageous from an economic point of view (see table 1 below). Examples of the catalyst are secondary amides of formic acid such as N,N-dimethylfomnamide (DMF) or N-formyl azepane or any mixture thereof. DMF is the most preferred catalyst.

The following table 1 shows a comparison of the activation kinetics with DMF (0.025 eq), N-formylazepane (0.05 eq) and no catalyst. Tests were run using the same amount of compound (IVa) (10 mmol), at the same temperature (55°C) and concentration in AcO/Pr (20 ml_), and with the same amounts of SOCl ₂ (0.84 ml_, 1 1.5 mmol, 1.15 eq, plus 0.22 ml_, 3.0 mmol, 0.30 eq, after 110 minutes).

Table 1

Step c) is preferably carried out at atmospheric pressure under light stream of inert gas to remove S0 ₂ and HCl formed upon activation, thus shifting the equilibrium to the products.

After complete activation, i.e. formation of the acyl chloride of formula (V), excess thionyl chloride is removed, either by stripping the mixture under inert gas at a temperature above the boiling point of thionyl chloride, preferably at a

temperature in the range of from 80° C to solvent reflux, or by stirring the resulting reaction mixture under moderate vacuum or both. The vacuum must be such that the reaction solvent does not boil; for instance, for /so-propyl acetate it is preferably in the range of from 0.5 to 0.7 bar at 45 °C.

Step d)

It is very advantageous when the organic solvent used in step d) is the same organic solvent as used in step b) and step c), as no solvent exchange needs to be done.

As outlined before, the organic solvent in step d) is either a straight or branched C ₃ -alkyl acetate or a straight or branched C ₄ -alkyl acetate or any mixture thereof.

Preferably the organic solvent is either /so-propyl acetate or /so-butyl acetate or any mixture thereof, whereby the use of the single solvents and not their mixture is preferred.

More preferably the organic solvent is /so-propyl acetate. The amount of solvent used in step d) is in the range of from 0.5 to 10 times the amount of solvent used in step b), preferably from 0.7 to 5 times the amount of solvent used in step b), most preferably from 0.9 to 2 times the amount of solvent used in step b). Step d) can be performed either under water-free conditions (method A) or under Schotten-Baumann conditions, both by adding compound (VI) and an aqueous base to the acyl chloride (V) (method B) or by adding the acyl chloride to the biphasic mixture of compound (VI) and an aqueous base (method C). Step d) - Method A

In step d), the compound of formula (V) is advantageously used as the mixture obtained in step c), /.e. compound of formula (V) with a certain amount of organic solvent, and preferably brought to a temperature in the range of from -15°C to 10°C, more preferably to a temperature in the range of from -10°C to 5°C. Then the compound of formula (VI), diluted with an organic solvent, preferably diluted with the same organic solvent as used in step c), is added to this mixture. Preferably the molar ratio of the compound of the formula (VI) to the compound of the formula (V) is in the range of from 2:1 to 4:1 , more preferably in the range of from 2.1 :1 to 2.3:1.

After completion of the addition the mixture is warmed up to a temperature up to solvent reflux. Preferably the temperature is in the range of from 10°C to solvent reflux, more preferably at a temperature in the range of from 10°C to 70 °C, most preferably at a temperature in the range of from 20 °C to 50 °C.

After the reaction, the mixture is washed with an acid (preferably 1 N HCl), a strong base (preferably 1% NaOH) and brine (saturated aqueous sodium chloride solution). To remove residual boronic acid, i.e. the compound of formula (III), from the organic phase by quantitatively converting it into its salt, the basic washing phase must have a pH > 1 1. This can be achieved by using a diluted solution of a strong base, like sodium or potassium hydroxide, whereby aqueous 1 weight-%

NaOH is preferred.

Then celite, activated charcoal and sodium sulfate are added. The temperature is increased under stirring to a range of from 40 to 80°C, then the mixture is cooled down to room temperature and filtered. The solvent is removed and the residue dried.

Step d) - Method B

The compound of formula (V) is advantageously used as the mixture obtained in step c), i.e. compound of formula (V) with a certain amount of organic solvent, and preferably brought to a temperature in the range of from -15°C to 10° C, more preferably to a temperature in the range of from -10°C to 5°C.

Then the compound of formula (VI), diluted with an organic solvent, preferably diluted with the same organic solvent as used in step c), and a basic aqueous solution are added to this mixture. Preferably the molar ratio of the compound of the formula (VI) to the compound of the formula (V) is in the range of from 1 :1 to 2:1 , more preferably in the range of from 1 :1 to 1.2:1 . The base used can be freely chosen among inorganic bases. Sodium carbonate or potassium carbonate are preferred, sodium carbonate is the most preferred. Preferably the amount of base used is in the range of from 1 to 5 mol per mol of compound of formula (V), more preferably in the range of from 1 to 2 mol per mol of compound of formula (V).

After completion of the addition the mixture is warmed up to a temperature in the range of from 10°C to solvent reflux, preferably at a temperature in the range of from 25 ° C to 40° C.

After the reaction, the mixture is washed with an acid (preferably 1 N HCl), a strong base (preferably 1% NaOH) and brine (saturated aqueous sodium chloride solution). To remove residual boronic acid, i.e. the compound of formula (III), from the organic phase by quantitatively converting it into its salt, the basic washing phase must have a pH > 11 . This can be achieved by using a diluted solution of a strong base, like sodium or potassium hydroxide, whereby aqueous 1 weight-%

NaOH is preferred. Then celite, activated charcoal and sodium sulfate are added. The temperature is increased under stirring to a range of from 40 to 80°C, then the mixture is cooled down to room temperature and filtered. The solvent is removed and the residue dried. Step d) - Method C

A biphasic mixture of the compound of formula (VI), diluted in an organic solvent, preferably in the organic solvent used for step c), and a basic aqueous solution are brought to a temperature in the range of from -15°C to 10°C, preferably from -10°C to 5°C.

Preferably the molar ratio of the compound of the formula (VI) to the compound of the formula (V) is in the range of from 1 :1 to 2: 1 , more preferably in the range of from 1 :1 to 1 .2:1. The base used can be freely chosen among inorganic bases. Sodium carbonate or potassium carbonate are preferred, sodium carbonate is the most preferred. Preferably the amount of base used is in the range of from 1 to 5 mol per mol of compound of formula (V), more preferably in the range of from 1 to 2 mol per mol of compound of formula (V). The compound of formula (V) is advantageously used as the mixture obtained in step c), i.e. the compound of formula (V) with a certain amount of organic solvent, and preferably brought to a temperature in the range of from -15°C to 10°C, more preferably to a temperature in the range of from -10°C to 5°C. This solution is added dropwise to the biphasic mixture described above. At the end of the addition, the temperature is increased to a temperature in the range of from 10°C to solvent reflux, preferably at a temperature in the range of from 25 °C to 40 °C.

After the reaction, the mixture is washed with a strong base (preferably 1% NaOH), an acid (preferably 1 N HCl), and brine (saturated aqueous sodium chloride solution). To remove residual boronic acid, i.e. the compound of formula (III), from the organic phase by quantitatively converting it into its salt, the basic washing phase must have a pH > 1 1. This can be achieved by using a diluted solution of a strong base, like sodium or potassium hydroxide; 1% aqueous NaOH is preferred. Then celite, activated charcoal and sodium sulfate are added. The temperature is increased under stirring to a range of from 40 to 80° C, then the mixture is cooled down to room temperature and filtered. The solvent is removed and the residue dried.

The invention is now further illustrated in the following non-limiting examples.

Examples

The following abbreviations have been used: AcO/Bu iso- butyl acetate

AcOnBu n-butyl acetate

AcOEt ethyl acetate

AcO/Pr iso- propyl acetate

AcOnPr n-propyl acetate d day

DMF N,N-dimethylformamide

EDTA N,N,N’,N’-ethylenediaminetetraacetic acid

eq equivalent

h hour

MeCN acetonitrile

MeOH methanol

MS molecular sieves

meq milliequivalent

min minute

rpm runs per minute

TFA trifluoroacetic acid

UPLC ultra-high performance liquid chromatography

V/V volume over volume

Reagents, instruments and analytical methods

The 10 mM Pd(EDTA) catalytic mixture used for the Suzuki-Miyaura cross-coupling reactions was prepared as described by D.N. Korolev and N.A. Bumagin in Tetrahedron Lett. 2005, 46, 5751 from palladium(ll) chloride, N,N,N’,N’-ethylenediaminetetraacetic acid disodium salt dihydrate and sodium carbonate. milli H ₂ 0 was used. Water-free DMF (on molecular sieves) was used as activation catalyst for acyl chloride formation. N-formylazepane was prepared by refluxing azepane with an excess formic acid overnight in dry toluene, as described for other formic acid amides by Y. Motoyama et al. in J. Am. Chem. Soc., 127, 13150 (2005) in the supplementary information, and purified by Kugelrohr destination. All other reagents were purchased in synthesis grade or higher quality and used as received.

Due to the well-known equilibrium between phenylboronic acid and its cyclotriboronic anhydride, the actual equivalent weight of the reagent is lower than its molecular mass in monomeric form, so that apparent sub-stoichiometric amounts can achieve full conversion of the cross-coupling partner. As the monomer/trimer ratio varies from batch to batch, depending on the production conditions, and over time, due to exposition to ambient moisture, preliminary small-scale cross-coupling trials were employed shortly before the syntheses to ascertain the optimal stoichiometry.

Air- and moisture-sensitive reactions were performed under Ar. Analytical chromatograms were measured on a Waters Acquity Ultra-high Performance Liquid Chromatography (UPLC), equipped with an Acquity HSS T3 100 A, 1 .8 pm 2.1 x50 mm ² analytical column and a PDA detector operating in the 200-400 nm wavelength range. H ₂ 0 + 0.02% TFA (A phase) and MeCN + 0.02% TFA (B phase) were used as eluents, with a flow of 0.5 mL/min.

UPLC quantification of the hydrolysis-prone acyl chloride (compound V) of the intermediate (compound IV) for in-process control analyses in steps c) and d) was achieved by quantitative conversion to the corresponding methyl ester through dilution of samples in water-free MeOH and heating to reflux for a few seconds.

General procedure

Step a): Suzuki-Miyaura cross-coupling

A 0.5 M solution of compound (II) such as 3-bromobenzoic acid in 1 M Na ₂ C03 _(aq) is prepared using degassed H ₂ 0. Compound (III) such as phenylboronic acid (0.88-1 .05 eq) is added under an inert atmosphere and the mixture is heated to 50 ° C under stirring until dissolution. 0.25-0.8 meq 10 mM Pd(EDTA) catalyst mixture are added dropwise over 2-10 min. The mixture is heated until gentle reflux and stirred until UPLC analyses show <0.5% remaining compound (II).

Step b): Work-up: Extraction

After cooling to room temperature, organic solvent such as AcO/Pr (2 mL/mmol compound (II)) is added, then aqueous acid such as fuming HCl acid is added dropwise under stirring until pH<3 is reached. Phases are separated (if the organic layer is turbid, it is heated to 40-50° C until a clear solution results), then the organic layer is washed with brine (saturated aqueous sodium chloride solution). Celite and Na ₂ S0 ₄ are added under stirring to facilitate separation of catalyst by-products, then the mixture is filtered, e.g. on a sintered glass filter, and rinsed with the organic solvent such as AcO/Pr. Mother liquors and rinsing solutions are pooled and concentrated to the initial volume of the organic solvent.

Step c): Activation of the intermediate as acyl chloride

Using an activation catalyst

The mixture from Step b) is set under an inert atmosphere, the activation catalyst (dry DMF or N-formylazepane, 0.025-0.05 eq, or Vilsmeier reagent, 0.02 eq) and a small excess of SOCl ₂ (1 .04-1 .15 eq) are added under stirring at room temperature. After 5 min, the mixture is heated to 55-60°C with formation of a clear solution and stirred until UPLC analyses show either < 5% non-activated intermediate (compound (IV)) or plateauing of conversion with > 5% remaining intermediate (compound (IV)), in which case further SOCl ₂ is added in amounts corresponding to the residual intermediate (compound (IV)) and activation is prolonged accordingly. The mixture is then first heated to 80°C and stirred for 0.5 h while stripping under Ar, then cooled to 45°C and stirred for 0.8-1 .5 h under moderate vacuum (-0.5 bar) to remove most formed HCl and excess SOCl ₂ .

Without activation catalyst

The mixture from Step b) is set under an inert atmosphere, a small excess of SOCl ₂ (1 .15-1 .3 eq) is added under stirring at room temperature. After 5 min, the mixture is heated to 55-80°C with formation of a clear solution and stirred until UPLC analyses show either < 5% non-activated intermediate (compound (IV)) or plateauing of conversion with > 5% remaining intermediate (compound (IV)), in which case further SOCl ₂ is added in amounts corresponding to the residual intermediate (compound (IV)) and activation is prolonged accordingly. The mixture is then first heated to 85°C and stirred for 0.5 h while stripping under Ar, then cooled to 45°C and stirred for 0.8-1 .5 h under moderate vacuum (-0.5 bar) to remove most formed HCl and excess SOCl ₂ . Step d), method A: acylation to the final product under water-free conditions

The mixture from Step c ) is cooled to 0°C and stirred under an inert atmosphere. Compound (VI) such as azepane (2.1 -2.3 eq) is diluted in organic solvent such as AcO/Pr (1 : 1 to 2:3 V/V) and added dropwise to the mixture along the walls of the reaction vessel under intense stirring over 20-40 min, resulting in a thick suspension. After completion of the addition, the mixture is warmed slightly above room temperature (30-50° C) and stirring continues until UPLC analyses either show < 1 % remaining acyl chloride (compound (V)) or plateauing of conversion with > 1 % remaining acyl chloride (compound (V)), in which case further compound (VI) such as azepane is added in double molar amounts compared to the remaining acyl chloride (compound (V)) and the reaction is prolonged accordingly. The mixture is then washed with 1 N HCl, aqueous 1 weight-% NaOH (basic washing is repeated until no more intermediate (compound (V)) and no more excess compound (III) from step a) such as phenyl boronic acid are detected in the organic layer) and with brine. Celite, activated charcoal and Na ₂ S0 ₄ are added to the organic layer, the mixture is first stirred above room temperature (40-80° C), then allowed to stand at room temperature, finally filtered on a silica gel pad, which is rinsed with several portions of organic solvent such as AcO/Pr. Solvents are removed under reduced pressure and the residue is dried 4-7 d in the drying cabinet at 40 °C.

Step d), method B: acylation to the final product under Schotten-Baumann conditions adding the amine to the acyl chloride

The mixture from Step c) is cooled to 0° C under an inert atmosphere. Compound (VI) such as azepane (1 .02-1 .05 eq) diluted 2:3 V/V in organic solvent such as AcO/Pr and a 1 -2 M Na ₂ C03 _(aq) solution (1 .1 -1 .2 eq) are simultaneously added dropwise along the reaction vessel walls to the stirred solution over 20-40 min. After completion of the addition, the pH of the aqueous phase is checked, if pH<8 further Na ₂ C03 ₍ aq ₎ solution is added in small portions under stirring until pH>8. The mixture is allowed to come back to room temperature and stirred until UPLC analyses either show < 1 % remaining acyl chloride (compound (V)) or plateauing of conversion with > 1 % remaining acyl chloride (compound (V)), in which case further compound (VI) such as azepane is added in amounts corresponding to the remaining acyl chloride (compound (V)) and the reaction is prolonged accordingly. Phases are separated, the organic layer is washed with aqueous 1 weight-% NaOH (basic washing is repeated until no more intermediate (compound (V)) and no more excess compound (III) from step a) such as phenyl boronic acid are detected in the organic layer), 1 N HCl and with brine. Celite, activated charcoal and Na ₂ S0 ₄ are added to the organic layer, the mixture is first stirred above room temperature (40-80° C), then allowed to stand at room temperature, finally filtered on a silica gel pad, which is rinsed with several portions of organic solvent such as AcO/Pr. Solvents are removed under reduced pressure and the residue is dried 4-7 d in the drying cabinet at 40 °C. Step d), method C: acylation to the final product under Schotten-Baumann conditions adding the acyl chloride to the biphasic mixture of amine and aqueous inorganic base

Compound (VI) such as azepane (1 .02-1 .05 eq) diluted 1 :4 V/V in the organic solvent such as AcO/Pr and a 1 -2 M aqueous Na ₂ C0 ₃ solution (1 .1 -1 .2 eq) are mixed and cooled to 0°C under an inert atmosphere. The mixture from step c) is cooled to 0°C under an inert atmosphere and added dropwise to the biphasic mixture above over 20-60 min with vigorous stirring. After completion of the addition, the mixture is allowed to come back to room temperature. After C0 ₂ evolution ceases, the pH of the aqueous layer is checked: if the pH is <7 further Na ₂ C03 _(aq) solution is added in small portions under stirring until the pH is >7.

The mixture is stirred at room temperature or slightly above (25-40° C) until UPLC analyses either show < 1% remaining acyl chloride (compound (V)) or plateauing of conversion with > 1% remaining acyl chloride (compound (V)), in which case further compound (VI) such as azepane is added in amounts corresponding to the remaining acyl chloride (compound (V)) and the reaction is prolonged accordingly.

Phases are separated, the organic layer is washed with aqueous 1 weight-% NaOH (basic washing is repeated until no more intermediate (compound (IV)) and no more excess compound (III) such as phenyl boronic acid from step a) are detected in the organic layer), 1 N HCl and brine. Celite, activated charcoal and Na ₂ S0 ₄ are added to the organic layer, the mixture is first stirred above room temperature (40-80° C), then allowed to stand at room temperature, finally filtered on a silica gel pad, which is rinsed with several portions of organic solvent such as AcO/Pr. Solvents are removed under reduced pressure and the residue is dried 4-7 d in the drying cabinet at 40°C. Example 1 : Small-scale synthesis with the use of isopropyl acetate as solvent

Step a): Suzuki-Miyaura cross-coupling

Performed according to the general procedure employing 4.10 g 3-bromobenzoic acid (20 mmol), 4.28 g Na ₂ C0 ₃ (40 mmol, 2.0 eq), 2.44 g phenylboronic acid (19.6 mmol, 0.98 eq) and 1 .6 ml. 10 mM Pd(EDTA) catalytic mixture (0.016 mmol, 0.8 meq). UPLC analyses showed < 0.3% remaining 3-bromobenzoic acid.

Step b): work-up

Performed according to the general procedure employing 40 ml. of /so-propyl acetate. 5.2 ml. of 37% aqueous HCl (62 mmol; 3.1 eq.) were necessary for acidification to pH < 3.

Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure using 0.08 ml. DMF (-1 mmol, 0.05 eq) and 1 .52 ml. SOCl ₂ (20.6 mmol, 1 .04 eq). UPLC analyses showed < 2% non -activated intermediate.

Step d ): acylation to the final product under water-free conditions

Performed according to method A of the general procedure using 4.8 mL azepane (42 mmol, 2.12 eq) in 5 mL AcO/Pr. UPLC analyses showed < 0.5% remaining acyl chloride. After work-up, solvent removal under reduced pressure and drying for 4 d, 5.236 g product of 98.8% UPLC purity were obtained as an oil (92.6% yield).

Example 2: Large-scale synthesis with the use of isopropyl acetate as solvent Step a): Suzuki-Miyaura cross-coupling

Performed according to the general procedure, employing 60.92 g 3-bromobenzoic acid (300 mmol), 64.1 g Na ₂ C0 ₃ (602 mmol, 2.01 eq), 33.2 g phenylboronic acid (267 mmol, 0.89 eq) and 12 mL 10 mM Pd(EDTA) catalyst mixture (0.12 mmol, 0.4 meq). UPLC analyses showed < 0.2% remaining 3-bromobenzoic acid.

Step b): work-up

Performed according to the general procedure employing 600 mL of /so-propyl acetate. 76 mL 37% HCl (910 mmol, 3.03 eq) were necessary for acidification to pH<3. Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure using 0.58 ml. DMF (7.5 mmol, 0.025 eq) and 25.2 ml. SOCl ₂ (342 mmol, 1 .14 eq). UPLC analyses showed < 4% non-activated intermediate.

Step d): acylation to the final product under water-free conditions

Performed according to method A of the general procedure using 78.5 ml. azepane (690 mmol, 2.30 eq) diluted in 120 ml. AcO/Pr. As UPLC analyses showed still about 1% unconverted acyl chloride after conversion plateaued, further 0.7 mL azepane

(6.1 mmol, 0.02 eq) diluted in 10 mL AcO/Pr were added dropwise and the mixture was stirred further at room temperature until UPLC analyses showed complete conversion. After work-up, solvent removal under reduced pressure and drying for 7 d, 79.80 g product of 98.9% UPLC purity were obtained as a semi-solid mass containing large crystals (92.3% yield).

Example 3: Small-scale synthesis with the use of isopropyl acetate as solvent

Step a): Suzuki-Miyaura cross-coupling

Performed according to the general procedure employing 14.36 g 3-bromobenzoic acid (70 mmol), 14.95 g Na ₂ C0 ₃ (140 mmol, 2.0 eq), 7.66 g phenylboronic acid (61 .6 mmol, 0.88 eq) and 2.8 mL 10 mL Pd(EDTA) catalytic mixture (0.028 mmol, 0.4 meq). UPLC analyses showed < 0.2% remaining 3-bromobenzoic acid.

Step b): work-up

Performed according to the general procedure employing 140 mL of /so-propyl acetate. 17.8 mL 37% HCl (213 mmol, 3.05 eq) were necessary for acidification to pH<3.

Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure employing 0.16 mL DMF (2.1 mmol, 0.03 eq) and 5.7 mL SOCl ₂ (77 mmol, 1 .1 eq). UPLC analyses showed < 3.5% non- activated intermediate.

Step d): acylation to the final product under Schotten -Baumann conditions Performed according to method B of the general procedure employing 8.4 mL azepane (73.8 mmol, 1 .05 eq) diluted in 12.6 mL AcO/Pr and 8.94 g Na ₂ C0 ₃ (83.9 mmol, 1 .2 eq) in 84 mL H ₂ 0 (1 M solution), after completion of the addition pH 8. UPLC analyses showed < 0.5% remaining acyl chloride. After work-up, solvent removal and drying for 4 d, 19.084 g product of 98.4% UPLC purity were obtained as a semi-solid mass containing large crystals (95.2% yield).

Example 4: Large-scale synthesis with the use of isopropyl acetate as solvent

Step a): Suzuki-Miyaura cross-coupling

The reaction was performed according to the general procedure employing 82.05 g 3-bromobenzoic acid (400 mmol), 85.3 g Na ₂ C03 (800 mmol, 2.0 eq), 43.80 g phenylboronic acid (352 mmol, 0.88 eq) and 10 mL 10 mM Pd(EDTA) catalyst mixture (0.10 mmol, 0.25 meq). UPLC analyses showed < 0.3% remaining 3-bromobenzoic acid. At this point, the mixture was cooled to room temperature and divided in four equal portions.

Step b): work-up

One of the four portions was worked up according to the general procedure employing 200 mL AcO/Pr. 25.5 mL 37% HCl (305 mmol, 3.0 eq) were necessary for acidification to pH<3.

Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure employing 0.20 mL DMF (2.6 mmol, 0.025 eq) and 8.5 mL SOCl ₂ (1 15 mmol, 1 .15 eq). UPLC analyses showed < 5% non- activated intermediate.

Step d): acylation to the final product under Schotten -Baumann conditions

Performed according to method C of the general procedure employing 12 mL azepane (105 mmol, 1 .05 eq) diluted in 48 mL AcO/Pr and 12.78 g Na ₂ C0 ₃ (120 mmol, 1 .2 eq) in 120 mL H ₂ 0 (1 M solution), after C0 ₂ evolution stopped pH 8. UPLC analyses showed < 1% remaining acyl chloride. After work-up, solvent removal and drying for 6 d, 27.183 g product of 99.5% UPLC purity were obtained as a semi solid mass containing large crystals (95.8% yield). Example 5: Small-scale synthesis with the use of isopropyl acetate as solvent and with N-formylazepane as catalyst for step c)

Step a): Suzuki-Miyaura cross-coupling

The reaction was performed according to the general procedure employing 4.102 g 3-bromobenzoic acid (20 mmol), 4.27 g Na ₂ C0 ₃ (40 mmol, 2.0 eq), 2.19 g phenylboronic acid (17.6 mmol, 0.88 eq) and 0.8 ml. 10 mM Pd(EDTA) catalyst mixture (0.08 mmol, 0.4 meq). UPLC analyses showed < 0.2% remaining 3-bromobenzoic acid. Step b): work-up

Performed according to the general procedure employing 40 ml. AcO/Pr und 5.0 mL 37% HCl (60 mmol, 3.0 eq) were necessary for acidification to pH < 3. After work-up, filtration and concentration back to the original volume, the mixture was divided in two equal portions.

Step c): activation of the intermediate as acyl chloride

One of the two portions was activated according to the general procedure employing 63 mg N-formyl azepane (0.5 mmol, 0.05 eq) and 0.84 mL SOCl ₂ (11 .5 mmol, 1 .15 eq). As UPLC analyses showed plateauing of activation at about 25% non-activated intermediate, further 0.22 mL SOCl ₂ (3.0 mmol, 0.30 eq) were added and the mixture was stirred further until UPLC analyses showed -5% non-activated intermediate.

Step d ): acylation to the final product under Schotten -Baumann conditions

Performed according to method B of the general procedure employing 1 .2 mL azepane (10.5 mmol, 1 .05 eq) diluted in 1 .8 mL AcO/Pr and 1 .272 g Na ₂ C0 ₃ (12 mmol, 1 .2 eq) in 6 mL H ₂ 0 (2 M solution), after C0 ₂ evolution stopped pH 8. UPLC analyses showed < 1 % remaining acyl chloride. After work-up, solvent removal and drying for 2 d, 2.685 g product of 98.8% UPLC purity were obtained as an oil (94.5% yield).

Example 6: Large-scale synthesis with the use of isopropyl acetate as solvent and with Vilsmeier reagent as catalyst for step c)

Step a): Suzuki-Miyaura cross-coupling The reaction was performed according to the general procedure employing 82.05 g 3-bromobenzoic acid (400 mmol), 85.3 g Na ₂ C0 ₃ (800 mmol, 2.0 eq), 43.80 g phenylboronic acid (352 mmol, 0.88 eq) and 10 ml. 10 mM Pd(EDTA) catalyst mixture (0.10 mmol, 0.25 meq). UPLC analyses showed <0.3% remaining 3-bromobenzoic acid. At this point, the mixture was cooled to room temperature and divided in four equal portions.

Step b): work-up

One of the four portions was worked up according to the general procedure employing 200 ml. AcO/Pr. 25.1 ml. 37% HCl (301 mmol, 3.0 eq) were necessary for acidification to pH < 3.

Step c): activation of the intermediate as acyl chloride

One of the two portions was activated according to the general procedure employing 263 mg (chloromethylene)dimethyliminium chloride (Vilsmeier reagent, 2.0 mmol, 0.02 eq) and 8.5 ml. SOCl ₂ (1 1.5 mmol, 1 .15 eq). UPLC analyses showed <2 % non-activated intermediate.

Step d ): acylation to the final product under Schotten -Baumann conditions

Performed according to method B of the general procedure employing 12 mL azepane (105 mmol, 1 .05 eq) diluted in 18 mL AcO/Pr and 12.78 g Na ₂ C0 ₃ (120 mmol, 1 .2 eq) in 100 mL H ₂ 0 (1 .2 M solution), after C0 ₂ evolution stopped pH 7, therefore further 0.64 g Na ₂ C0 ₃ (6 mmol, 0.06 eq) were added and pH > 8 was found. UPLC analyses showed < 1% remaining acyl chloride. After work-up, solvent removal and drying for 6 d, 27.63 g product of 99.1% UPLC purity were obtained as an oil (95.7% yield).

Example 7: Large-scale synthesis with the use of isopropyl acetate as solvent and without any catalyst for step c)

Step a): Suzuki-Miyaura cross-coupling

The reaction was performed according to the general procedure employing 82.05 g 3-bromobenzoic acid (400 mmol), 85.3 g Na ₂ C0 ₃ (800 mmol, 2.0 eq), 43.80 g phenylboronic acid (352 mmol, 0.88 eq) and 10 mL 10 mM Pd(EDTA) catalyst mixture (0.10 mmol, 0.25 meq). UPLC analyses showed <0.3% remaining 3-bromobenzoic acid. At this point, the mixture was cooled to room temperature and divided in four equal portions.

Step b): work-up

One of the four portions was worked up according to the general procedure employing 200 ml. AcO/Pr. 25.5 ml. 37% HCl (305 mmol, 3.0 eq) were necessary for acidification to pH < 3.

Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure employing 9.2 ml. SOCl ₂ (125 mmol, 1 .15 eq). As UPLC analyses showed plateauing of conversion at about 17% non- activated intermediate, further 1 .2 ml. SOCl ₂ (16 mmol, 0.16 eq) were added and the mixture was stirred further until UPLC analyses showed 5% non-activated intermediate.

Step d ): acylation to the final product under Schotten -Baumann conditions

Performed according to method B of the general procedure employing 12 mL azepane (105 mmol, 1 .05 eq) diluted in 18 mL AcO/Pr and 12.78 g Na ₂ C0 ₃ (120 mmol, 1.2 eq) in 100 mL H ₂ 0 (1 .2 M solution), after C0 ₂ evolution stopped pH 6 was found, therefore further 3.72 g Na ₂ C03 (35 mmol, 0.35 eq) were added in portions until pH > 8 was obtained. UPLC analyses showed <1% remaining acyl chloride. After work-up, solvent removal and drying for 6 d, 26.052 g product of 99.2% UPLC purity were obtained as a semi-solid mass containing large crystals (91 .8% yield).

Examples 8-1 1

The syntheses were performed following the general procedure, but using acetic acid esters other than AcO/Pr as organic solvents. As the reaction yielding the intermediate in the first step is performed under purely aqueous conditions, while an organic solvent is added only for work-up, a large amount of intermediate was prepared in a single batch, then divided in four portions and worked up using different solvents in the different examples, as described below.

Example 8: Large-scale synthesis with the use of n-propyl acetate as solvent Step a): Suzuki-Miyaura cross-coupling

The reaction was performed according to the general procedure employing 82.05 g 3-bromobenzoic acid (400 mmol), 85.3 g Na ₂ C0 ₃ (800 mmol, 2.0 eq), 43.80 g phenylboronic acid (352 mmol, 0.88 eq) and 12 ml. 10 mM Pd(EDTA) catalyst mixture (0.12 mmol, 0.3 meq). UPLC analyses showed < 0.5% remaining 3-bromobenzoic acid. At this point, the mixture was cooled to room temperature and divided in four equal portions.

Step b): work-up

One of the four portions was worked up according to the general procedure, but replacing AcO/Pr with the same amount of AcOnPr (200 ml_). 25.5 ml. 37% HCl (305 mmol, 3.0 eq) were necessary for acidification to pH < 3.

Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure employing 0.20 ml. dry DMF (2.6 mmol, 0.026 eq) and 8.5 ml. SOCl ₂ (1 15 mmol, 1 .15 eq). UPLC analyses showed < 5% non -activated intermediate.

Step d ): acylation to the final product

Performed according to method B of the general procedure replacing AcO/Pr with the same amounts of AcOnPr. 12 mL azepane (105 mmol, 1 .05 eq) diluted in 18 mL AcOnPr and 12.78 g Na ₂ C0 ₃ (120 mmol, 1 .2 eq) in 60 mL H ₂ 0 (2 M solution) were employed, after completion of the addition pH 8. UPLC analyses showed no remaining acyl chloride. After work-up, solvent removal and drying for 5 d, 24.070 g product of 98.4% UPLC purity were obtained as an oil (83.9% yield).

Example 9: Large-scale synthesis with the use of /so-butyl acetate as solvent

Step a): Suzuki-Miyaura cross-coupling.

The reaction was performed according to the general procedure employing 82.05 g 3-bromobenzoic acid (400 mmol), 85.3 g Na ₂ C0 ₃ (800 mmol, 2.0 eq), 43.80 g phenylboronic acid (352 mmol, 0.88 eq) and 12 mL 10 mM Pd(EDTA) catalyst mixture (0.12 mmol, 0.3 meq). UPLC analyses showed < 0.5% remaining 3-bromobenzoic acid. At this point, the mixture was cooled to room temperature and divided in four equal portions. Step b): work-up

One of the four portions was worked up according to the general procedure, but replacing AcO/Pr with the same amount of AcO/Bu (200 ml_). 25.5 ml. 37% HCl (305 mmol, 3.0 eq) were necessary for acidification to pH < 3.

Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure employing 0.20 ml. DMF (2.6 mmol, 0.026 eq) and 8.5 ml. SOCl ₂ (1 15 mmol, 1 .15 eq). UPLC analyses showed < 5% non- activated intermediate.

Step d ): acylation to the final product.

Performed according to method B of the general procedure replacing AcO/Pr with the same amounts of AcO/Bu. 12 ml. azepane (105 mmol, 1 .05 eq) diluted in 18 mL AcO/Bu and 12.78 g Na ₂ C0 ₃ (120 mmol, 1 .2 eq) in 60 mL H ₂ 0 (2 M solution) were employed, after completion of the addition pH 8. As UPLC analyses showed still -1% unreacted acyl chloride after conversion plateaued, further 0.23 mL azepane (2 mmol, 0.02 eq) were added and stirred at room temperature until UPLC analyses showed no remaining acyl chloride. After work-up, solvent removal and drying for 6 d, 26.385 g product of 98.1% UPLC purity were obtained as an oil (91.7% yield).

Example 10: Large-scale synthesis with the use of n-butyl acetate as solvent

Step a): Suzuki-Miyaura cross-coupling

The reaction was performed according to the general procedure employing 82.05 g 3-bromobenzoic acid (400 mmol), 85.3 g Na ₂ C0 ₃ (800 mmol, 2.0 eq), 43.80 g phenylboronic acid (352 mmol, 0.88 eq) and 12 mL 10 mM Pd(EDTA) catalyst mixture (0.12 mmol, 0.3 meq). UPLC analyses showed < 0.5% remaining 3-bromobenzoic acid. At this point, the mixture was cooled to room temperature and divided in four equal portions.

Step b): work-up

One of the four portions was worked up according to the general procedure, but replacing AcO/Pr with the same amount of AcOnBu (200 mL). 25.5 mL 37% HCl (305 mmol, 3.0 eq) were necessary for acidification to pH<3. Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure employing 0.20 ml. DMF (2.6 mmol, 0.026 eq) and 8.5 ml. SOCl ₂ (1 15 mmol, 1 .15 eq). UPLC analyses showed < 4% non- activated intermediate.

Step d): acylation to the final product

Performed according to method B of the general procedure replacing AcO/Pr with the same amounts of AcOnBu. 12 ml. azepane (105 mmol, 1 .05 eq) diluted in 18 mL AcOnBu and 12.78 g Na ₂ C0 ₃ (120 mmol, 1 .2 eq) in 60 mL H ₂ 0 (2 M solution) were employed, after completion of the addition pH > 8. UPLC analyses showed no remaining acyl chloride. After work-up, solvent removal and drying for 6 d, 25.351 g product of 97.8% UPLC purity were obtained as an oil (87.4% yield). Example 1 1 : Comparative example: Use of ethyl acetate as solvent

Step a): Suzuki-Miyaura cross-coupling

The reaction was performed according to the general procedure employing 82.05 g 3-bromobenzoic acid (400 mmol), 85.3 g Na ₂ C0 ₃ (800 mmol, 2.0 eq), 43.80 g phenylboronic acid (352 mmol, 0.88 eq) and 12 mL 10 mM Pd(EDTA) catalyst mixture (0.12 mmol, 0.3 meq). UPLC analyses showed <0.5% remaining 3-bromobenzoic acid. At this point, the mixture was cooled to room temperature and divided in four equal portions.

Step b): work-up

One of the four portions was worked up according to the general procedure, but replacing AcO/Pr with the same amount of AcOEt (200 mL). 25 mL 37% HCl (300 mmol, 3.0 eq) were necessary for acidification to pH<3.

Step c): activation of the intermediate as acyl chloride

Performed according to the general procedure employing 0.20 mL DMF (2.6 mmol, 0.026 eq) and 8.5 mL SOCl ₂ (1 15 mmol, 1 .15 eq). As UPLC analyses showed that activation plateaued at about 45% non-activated intermediate, further 4.8 mL SOCl ₂ (65 mmol, 0.65 eq) were added and the mixture was stirred further until UPLC analyses showed -5% non-activated intermediate. Step d ): acylation to the final product under Schotten -Baumann conditions

Performed according to method B of the general procedure replacing AcO/Pr with the same amounts of AcOEt. 12 ml. azepane (105 mmol, 1 .05 eq) diluted in 18 mL AcOEt and 12.78 g Na ₂ C0 ₃ (120 mmol, 1 .2 eq) in 60 mL H ₂ 0 (2 M solution) were employed. After completion of the addition pH 5 was found, therefore further 14.91 g Na ₂ C03 (140 mmol, 1 .4 eq) were added in portions until pH>8 was obtained. UPLC analyses showed no remaining acyl chloride. After work-up, solvent removal and drying for 5 d, 21 .41 g product of 98.5% UPLC purity were obtained as an oil (74.7% yield).