WO2019115531A1 - Procédé de fabrication d'inhibiteurs de 11-bêta-hydroxystéroïde déshydrogénase de type 1 - Google Patents

Procédé de fabrication d'inhibiteurs de 11-bêta-hydroxystéroïde déshydrogénase de type 1 Download PDF

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WO2019115531A1
WO2019115531A1 PCT/EP2018/084367 EP2018084367W WO2019115531A1 WO 2019115531 A1 WO2019115531 A1 WO 2019115531A1 EP 2018084367 W EP2018084367 W EP 2018084367W WO 2019115531 A1 WO2019115531 A1 WO 2019115531A1
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compound
formula
range
organic solvent
process according
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PCT/EP2018/084367
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Piero GEOTTI-BIANCHINI
Katalin GYERGYÓI
Marc-Matthias HEIDL
András Szabó
Stefánia SZÜCSNÉ CSERÉPI
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Dsm Ip Assets B.V.
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Priority to CN201880079453.4A priority Critical patent/CN111433189A/zh
Priority to EP18829243.7A priority patent/EP3724166A1/fr
Publication of WO2019115531A1 publication Critical patent/WO2019115531A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention is directed to a process for the manufacture of a compound of formula I
  • Y is CHR 7 , CR 7 R 8 or 0,
  • n 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;
  • step 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)
  • 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 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.
  • the present invention is especially directed to a process for the manufacture of the following compounds (la), (lb) and (lc):
  • 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;
  • 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;
  • R 1 being H, F, Cl, methyl and ethyl, preferably with R 1 being H, F, Cl or methyl.
  • a preferred embodiment of the present invention is a process for the manufacture of a compound of formula (10)
  • step a) with an organic solvent; c) reacting the extracted compound of formula (IVa) in an organic solvent to a compound of formula (Va),
  • step 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)
  • 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.
  • 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.
  • 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.
  • a base is sodium carbonate. Potassium carbonate can also be used.
  • 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 .
  • 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) is the same organic solvent used in step c) and step d).
  • organic solvents that are not miscible with water may be used in step b).
  • 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.
  • 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.
  • 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.
  • 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).
  • an acid is added for neutralizing the base added in step a) to neutralize the base added in step a).
  • these acids are aqueous hydrochloric acid, phosphoric acid, sulfuric acid, hydrogen sulfates such as potassium hydrogen sulfate and methane sulfonic acid.
  • hydrochloric acid in the highest commercially available concentration i.e. 36-37% w/w
  • hydrochloric acid also called ‘fuming hydrochloric acid’
  • the amount of acid depends on the amount of base used before.
  • the pH of the resulting aqueous phase is ⁇ 3.
  • 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.
  • 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.
  • 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) is the same organic solvent as used in step b) and step d). Then no change of the solvent needs to be done.
  • step c also other organic solvents that are aprotic may be used in step c).
  • 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.
  • 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.
  • 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.
  • 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).
  • step c) the acid of formula (IV) is converted in its acyl chloride of formula (V).
  • 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.
  • DMF N,N- dimethylformamide
  • N-formyl azepane any other secondary amide of formic acid.
  • DMF dimethylformamide
  • secondary amides of formic acid are converted into the corresponding
  • 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.
  • 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).
  • 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).
  • 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.
  • 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
  • reaction solvent 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) is the same organic solvent as used in step b) and step c), as no solvent exchange needs to be done.
  • 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.
  • 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.
  • 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) 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.
  • 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.
  • 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.
  • the mixture is warmed up to a temperature up to solvent reflux.
  • 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.
  • the mixture is washed with an acid (preferably 1 N HCl), a strong base (preferably 1% NaOH) and brine (saturated aqueous sodium chloride solution).
  • an acid preferably 1 N HCl
  • a strong base preferably 1% NaOH
  • brine saturated aqueous sodium chloride solution.
  • 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-%
  • 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 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.
  • 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.
  • 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.
  • 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 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.
  • the mixture is washed with an acid (preferably 1 N HCl), a strong base (preferably 1% NaOH) and brine (saturated aqueous sodium chloride solution).
  • an acid preferably 1 N HCl
  • a strong base preferably 1% NaOH
  • brine saturated aqueous sodium chloride solution.
  • 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-%
  • 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.
  • 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.
  • 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.
  • 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.
  • the mixture is washed with a strong base (preferably 1% NaOH), an acid (preferably 1 N HCl), and brine (saturated aqueous sodium chloride solution).
  • a strong base preferably 1% NaOH
  • an acid preferably 1 N HCl
  • brine saturated aqueous sodium chloride solution.
  • 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.
  • 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 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.
  • 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.
  • 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).
  • 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.
  • organic solvent such as AcO/Pr (2 mL/mmol compound (II)
  • 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 activation catalyst dry DMF or N-formylazepane, 0.025-0.05 eq, or Vilsmeier reagent, 0.02 eq
  • SOCl 2 (1 .04-1 .15 eq
  • 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 .
  • 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.
  • Step c 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Step d acylation to the final product under water-free conditions
  • Example 3 Small-scale synthesis with the use of isopropyl acetate as solvent
  • Example 4 Large-scale synthesis with the use of isopropyl acetate as solvent
  • 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.
  • 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
  • Example 6 Large-scale synthesis with the use of isopropyl acetate as solvent and with Vilsmeier reagent as catalyst for step c)
  • 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 d acylation to the final product under Schotten -Baumann conditions
  • Example 7 Large-scale synthesis with the use of isopropyl acetate as solvent and without any catalyst for step c)
  • 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 d acylation to the final product under Schotten -Baumann conditions
  • 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 d acylation to the final product
  • Example 9 Large-scale synthesis with the use of /so-butyl acetate as solvent
  • Step d acylation to the final product.
  • Example 10 Large-scale synthesis with the use of n-butyl acetate as solvent
  • 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.
  • 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.

Abstract

La présente invention concerne un procédé de fabrication d'un composé de formule (I) dans laquelle Y est CHR7, CR7R8 ou O, n vaut 0, 1 ou 2, R1 et R2 sont indépendamment l'un de l'autre choisis dans le groupe constitué par H, F, Cl, méthyle et éthyle, et R3, R4, R5, R6, R7 et R8 sont indépendamment l'un de l'autre choisis parmi H ou un alkyle en C1-C6. Les composés de formule (I) sont des inhibiteurs de 11-bêta-hydroxystéroïde déshydrogénase de type 1 et peuvent être utilisés pour réduire les taux de cortisol dans les kératinocytes et pour améliorer la teneur en collagène dermique dans la peau humaine après exposition à la cortisone et aux UV.
PCT/EP2018/084367 2017-12-12 2018-12-11 Procédé de fabrication d'inhibiteurs de 11-bêta-hydroxystéroïde déshydrogénase de type 1 WO2019115531A1 (fr)

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CN201880079453.4A CN111433189A (zh) 2017-12-12 2018-12-11 制造11-β-羟基类固醇脱氢酶1型抑制剂的方法
EP18829243.7A EP3724166A1 (fr) 2017-12-12 2018-12-11 Procédé de fabrication d'inhibiteurs de 11-bêta-hydroxystéroïde déshydrogénase de type 1

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Citations (1)

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WO2017012890A1 (fr) 2015-07-23 2017-01-26 Dsm Ip Assets B.V. Nouveaux inhibiteurs sélectifs de la 11-bêta-hydroxystéroïde déshydrogénase de type 1

Patent Citations (1)

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WO2017012890A1 (fr) 2015-07-23 2017-01-26 Dsm Ip Assets B.V. Nouveaux inhibiteurs sélectifs de la 11-bêta-hydroxystéroïde déshydrogénase de type 1

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