WO2017051326A1 - Nouveaux procédés et intermédiaires utiles dans la synthèse d'inhibiteurs d'endopeptidase neutre (nep) - Google Patents

Nouveaux procédés et intermédiaires utiles dans la synthèse d'inhibiteurs d'endopeptidase neutre (nep) Download PDF

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WO2017051326A1
WO2017051326A1 PCT/IB2016/055628 IB2016055628W WO2017051326A1 WO 2017051326 A1 WO2017051326 A1 WO 2017051326A1 IB 2016055628 W IB2016055628 W IB 2016055628W WO 2017051326 A1 WO2017051326 A1 WO 2017051326A1
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formula
compound
alkyl
heterocyclyl
salt
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Benjamin Martin
Gerhard Penn
Berthold Schenkel
Samuel BOURNE
Shing-Hing LAU
Steven Ley
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
    • C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/32—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen
    • C07C45/33—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of CHx-moieties
    • C07C45/34—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of CHx-moieties in unsaturated compounds
    • C07C45/36—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of CHx-moieties in unsaturated compounds in compounds containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/41—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrogenolysis or reduction of carboxylic groups or functional derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2523/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group C07C2521/00
    • C07C2523/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group C07C2521/00 of noble metals
    • C07C2523/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group C07C2521/00 of noble metals of the platinum group metals
    • C07C2523/44—Palladium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C07C2531/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts

Definitions

  • the invention relates to a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors such as sacubitril, and prodrugs thereof.
  • NEP neutral endopeptidase
  • NEP inhibitor prodrug sacubitril (/V-(3-carboxyl-1 -oxopropyl)-(4S)-(p-phenylphenyl- methyl)-4-amino-(2f?)-methyl butanoic acid ethyl ester; lUPAC name 4- ⁇ [(1 S,3f?)-1 -([1 ,1 '- biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino ⁇ -4-oxobutanoic acid) is represented by the following formula (A)
  • Sacubitril together with valsartan a known angiotensin receptor blocker (ARB), forms a sodium salt hydrate complex, known as LCZ696, comprising the anionic forms of sacubitril and valsartan, sodium cations and water molecules in the molar ratio of 1 :1 :3:2.5, respectively (ratio of 6:6:18:15 in the asymmetric unit cell of the solid state crystal) - see also WO 2007/056546 - and which is schematically present in formula (B).
  • ARB angiotensin receptor blocker
  • LCZ696 acts as angiotensin receptor neprilysin inhibitor (ARNI) and is therefore useful particularly in the treatment of hypertention or chronic heart failure. Its utility has been confirmed by clinical trials, e.g. in the landmark PARADIGM-HF trial.
  • ARNI angiotensin receptor neprilysin inhibitor
  • the present invention relates to a novel process for the manufacture of a compound of formula (I), or a salt thereof
  • R is hydrogen or a carboxyl protecting group or C Ce-alkyl, preferably ethyl, and R' and R" are independently of each other hydrogen or a nitrogen protecting group, preferably a hydrogen, a tert-butoxy group or a succinimidyl group,
  • R is hydrogen or a carboxyl protecting group or C Ce-alkyl, preferably ethyl, and R' and R" are independently of each other hydrogen or a nitrogen protecting group, preferably a hydrogen, a tert-butoxy group or a succinimidyl group,
  • the invention also relates to specific process steps useful in the manufacture of the compound of formula (I), as well as to novel intermediates, specific process steps useful in the manufacture of said intermediates, and the use of said intermediates.
  • the present invention relates to the following intermediate compounds
  • R is hydrogen or a carboxyl protecting group or C CValkyl, preferably hydrogen or ethyl, especially of the formula (lla) or a salt thereof
  • R is hydrogen or a carboxyl protecting group or Ci-C 6 -alkyl, preferably hydrogen or ethyl, especially of the formula (Ilia), or a salt thereof,
  • the products of the formula (I) of the process of the present invention as well as the aforementioned intermediates of formula (II), (III) and (IV) can preferably be used in the synthesis (manufacture) of NEP inhibitors or prodrugs thereof, in particular they can be used in the synthesis of NEP inhibitors comprising an y-amino-5-biphenyl-a- methylalkanoic acid, or acid ester, backbone, in particular for the synthesis of the NEP inhibitor prodrug sacubitril.
  • R is hydrogen or a carboxyl protecting group or C Ce-alkyl, preferably ethyl, and R' and R" are independently of each other hydrogen or a nitrogen protecting group, preferably a hydrogen, a tert-butoxy group or a succinimidyl group,
  • Ra is as defined above
  • X is a leaving group, especially halogen
  • R* is a carboxyl protecting group, and, optionally, removing and/or replacing the protecting group R*,
  • R is hydrogen or a carboxyl protecting group or Ci-C 6 -alkyl
  • R is hydrogen or a carboxyl protecting group or C CValkyl, preferably ethyl, and
  • Figure 1 shows some key features of flow chemistry in a typical continuous flow setup which is shown here merely for illustrative purposes, not intending to limit the scope of the invention:
  • an injection loop 1 containing a reagent 1 and an injection loop 2 containing another reagent 2 two reagents are mixed by means e.g. of a T-piece mixer 3, driven by a continuous solvent stream driven by pumps 4.
  • a reaction coil 5 provides residence time (reaction time) and reaction temperature control.
  • QP-TU a thiourea polymer is shown as example
  • An optional Back Pressure Regulator 7 can provide resistence for the pumps to push against.
  • the product(s) 8 are leaving the system.
  • Figure 2 shows a general overview for the manufacture of the Example (2R,4S)-1 , a compound falling under general formula la.
  • Figure 3 shows the Scheme for "Scheme FLOW B", i.e. flow preparation of 4- phenylstyrene.
  • Figure 4 shows the Scheme for "Scheme FLOW C", i.e. flow preparation of 4- (biphenylyl)acetaldehyde 16.
  • Figure 5 shows the Scheme for "Scheme FLOW D", i.e. flow preparation of imine 29.
  • Figure 6 shows the Scheme for "Scheme FLOW E", i.e. flow preparation of acrylic ester (4R)-30).
  • Figure 7 shows the further reactions starting from compound (4R)-30 after hydrolysis of the ethyl group to the acid.
  • NEP inhibitor describes a compound which inhibits the activity of the enzyme neutral endopeptidase (NEP, EC 3.4.24.1 1).
  • prodrug describes a pharmacological substance which is administered in an inactive (or less active) form. Once administered, the prodrug is metabolized in the body in vivo into the active compound.
  • a compound according to formula (la), or salt thereof is further reacted to obtain the NEP inhibitor prodrug sacubitril (N-(3-carboxy-1 -oxopropyl)-(4S)-p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, also known in the art as AHU377) or a salt thereof:
  • AHU377 or its calcium salt can then be used in the manufacture of a complex with valsartan, said complex also known as LCZ696 of formula (B) above, which acts as an angiotensin receptor neprilysin inhibitor which is useful in the treatment of hypertension or chronic heart failure.
  • R1 is hydrogen or a nitrogen protecting group
  • R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, in particular tert-butoxycarbonyl and/or hydrogen, and R5 is hydrogen or C Cy- alkyl; and, in particular,
  • Example 8 of WO 2008/083967 shows the reaction from the free amine - free acid form to an N-protected form:
  • Example 9-1 shows formation of the free ethyl ester with thionyl chloride
  • Example 9-2 provides a way of crystallization of the amino-ethylester.
  • Example 1 in US 5,217,996 shows the manufacture as in step (a) in the scheme above and in Example 4 the direct formation of the sodium salt.
  • AHU377 can be formed according to the following reaction scheme, according to processes known in the art:
  • NEP inhibitor prodrug sacubitril (AHU377) can then be used for the synthesis of the complex LCZ696 comprising sacubitril and valsartan according to the processes depicted in WO 2007/056546.
  • the present invention also allows for and relates to reactions that take place under flow preparation conditions, flow preparation especially relating to continuous flow.
  • flow preparation especially relating to continuous flow.
  • flow chemistry offers significant advantages over traditional batch techniques in many cases.
  • Figure 1 shows some key features of flow chemistry in a typical continuous flow setup which is shown here merely for illustrative purposes, not intending to limit the scope of the invention.
  • reaction coil 5 provides residence time (reaction time) and reaction temperature control.
  • QP-TU a thiourea polymer is shown as example
  • An optional Back Pressure Regulator 7 can provide resistence for the pumps to push against.
  • the product(s) 8 are leaving the system.
  • reagents can be injected into the system via injection loops 1 and 2 and combine at a T-piece mixer 3 to provide a single defined volume of reaction mixture which moves through the system, this is known as a reaction plug and the method is known as plug flow which is used most commonly for optimisations or for producing libraries of compounds.
  • reaction plug or stream is then passed through a length of usually poly-fluorinated tubing known as a 'reactor coil' or "reaction coil” 5 which may be subject to heating or cooling.
  • reaction coil By varying the flow rate through the reactor coil the reaction time can be controlled.
  • reaction A The overall process according to the invention or the manufacture of a compound of the formula (I), especially (la), including a salt and/or an Nitrogen protected variant thereof, as described previously, includes the following reaction steps, each reaction step forming a separate embodiment of the invention: Reaction A
  • R is hydrogen or a carboxyl protecting group or C-i-C 6 - alkyl, preferably hydrogen or ethyl
  • R' and R" are independently of each other hydrogen or a nitrogen protecting group, preferably a hydrogen , a tert-butoxy group or a succinimidyl group,
  • R is hydrogen or a carboxyl protecting group or C CValkyl, preferably hydrogen or ethyl, in the presence of an acyl halide reagent, and preferably in the presence of an alcohol of the formula R"'-OH wherein R'" is hydrogen or a carboxyl protecting group or C Ce-alkyl, especially ethyl, respectively,
  • the reaction preferably takes place in a customary solvent, such as an alcohol, e.g.
  • methanol or ethanol e.g. in the range from 0 to 50°C, e.g. from 10 to 30°C.
  • the reaction can also be led under flow preparation conditions, e.g. using a pump for introducing the acyl halide reagent, and a reaction coil.
  • the obtained compound of formula (I) / (la) can then be transformed via known reaction steps into the desired NEP inhibitor prodrug compounds.
  • the NEP inhibitor prodrug sacubitril (AHU377) can then be used for the synthesis of the complex LCZ696 comprising sacubitril and valsartan according to the processes depicted in WO 2007/056546.
  • a further embodiment of the invention relates to a process for the manufacture of a compound of the formula (II), or a salt thereof
  • R is hydrogen or a carboxyl protecting group or C CValkyl, preferably hydrogen or ethyl, or - if R is other than hydrogen, namely especially C Ce-alkyl, preferably ethyl - of a compound of the formula (I), or a salt thereof
  • R is C Ce-alkyl, preferably hydrogen or ethyl, and R' and R" are both hydrogen,
  • R is hydrogen or a carboxyl protecting group or Ci-C 6 -alkyl, preferably hydrogen or ethyl, in the presence of a hydrogenation catalyst, to obtain the compound of formula (II).
  • the hydrogenation catalyst is a chiral hydrogenation catalyst.
  • the hydrogenation can take place under hydrogenation conditions that are known in the art, preferably in the presence of a chiral hydrogenation catalyst, e.g. selected from those mentioned in WO 2009/090251 .
  • the hydrogenation takes place with hydrogen in the presence of a transition metal catalyst, preferably in the presence of a transition metal catalyst comprising an organometallic complex and a chiral ligand.
  • the reduction may occur under hetereo- or homogeneous hydrogenation conditions, preferably under homogeneous hydrogenation conditions.
  • the hetereo- or homogeneous hydrogenation takes place in the presence of a base, such as amine bases (e.g. triethylamine,
  • the hetereogeneous hydrogenation takes place in the presence of an alkali metal, in particular in an alcohol solvent (e.g. isopropanol, EtOH, MeOH); for example KOH in ethanol.
  • the hydrogenation, in particular the homogeneous hydrogenation takes place in the presence of an acid such as methanesulfonic acid or tetrafluoroboric acid.
  • the heterogenous hydrogenation is carried out in the presence of a transition metal catalyst, wherein the transition metal is selected from group 9 or 10 of the periodic table. Therefore, the transition metal catalyst comprises, for example, Cobalt (Co), Rhodium (Rh), Iridium (Ir), Nickel (Ni), Palladium (Pd) and/or Platinum (Pt).
  • the transition metal catalyst comprises, for example, Cobalt (Co), Rhodium (Rh), Iridium (Ir), Nickel (Ni), Palladium (Pd) and/or Platinum (Pt).
  • the hydrogenation is usually performed in a solvent, such as an ether solvent (e.g.
  • an ester solvent e.g. isopropyl acetate
  • an alcohol solvent e.g.
  • the homogeneous hydrogenation is carried out in the presence of a transition metal catalyst, wherein the transition metal is selected from group 7, 8 or 9 of the periodic table. Therefore, the transition metal catalyst comprises, for example, the transition metal Manganese (Mn), Rhenium (Re), Iron (Fe), Ruthenium (Ru), Osmium (Os), Cobalt (Co), Rhodium (Rh) and/or Iridium (Ir).
  • the transition metal catalyst comprises, for example, the transition metal Manganese (Mn), Rhenium (Re), Iron (Fe), Ruthenium (Ru), Osmium (Os), Cobalt (Co), Rhodium (Rh) and/or Iridium (Ir).
  • the transition metal catalyst comprises an organometallic complex and a chiral ligand.
  • An organometallic complex comprising rhodium is particularly suitable.
  • the organometallic complexes can comprise a single transition metal atom.
  • the complexes can comprise two or more transition metal atoms, optionally comprising a metal-metal bond. In a preferred embodiment two metal atoms are bridged via two halides.
  • the organometallic complex comprises one or more transition metal atoms and suitable achiral ligands.
  • Suitable achiral ligands for the organometallic complex generally are ⁇ -donor ligands, ⁇ - donor/TT-acceptor ligands or ⁇ , ⁇ -donorArr-acceptor ligands.
  • suitable achiral ligands are among others carbon monoxide, halides (e.g. CI, I or Br), phosphines [e.g. tricyclohexylphosphine (PCy 3 )], alkenyls (e.g. cod, nbd, 2-metallyl), alkynyls, aryls (e.g. pyridine, benzene, p-cymene), carbonyls (e.g. acac, trifluoroacetate or dimethylformamide) and mixtures thereof.
  • halides e.g. CI, I or Br
  • phosphines e.g. tricyclohexylphosphine (PCy 3 )]
  • Suitable (preferred) chiral ligands are e.g. a Fenphos ligand, a Josiphos ligand, a
  • the transition metal catalyst comprises a transition metal selected from the group 8 or 9, such as rhodium, ruthenium or iridium and a chiral ligand selected from the group consisting of BoPhoz ligand, BINAP ligand, BINOL ligand, a Phospholane ligand, PhanePhos ligand, P-Phos ligand, QuinaPhos ligand, ProPhos ligand, BDPP ligand, DIOP ligand, DIPAMP ligand, DuanPhos ligand, NorPhos ligand, BINAM ligand, CatAsium ligand, SimplePHOX ligand, PHOX ligand, ChiraPhos ligand, Ferrotane ligand, BPE ligand,
  • TangPhos ligand JafaPhos ligand, DuPhos ligand, Binaphane ligand and mixtures of two or more thereof.
  • the reaction can also be led under flow preparation conditions, e.g. using a pump, an injection loop, a gas reactor for the reaction with hydrogen, a reactor and then a scavenger, e.g. polymer supported thiourea/sulfonic acid.
  • a scavenger e.g. polymer supported thiourea/sulfonic acid.
  • a further embodiment of the invention relates to a process for the manufacture of a compound of the formula (III), or a salt thereof
  • R is hydrogen or a carboxyl protecting group or C CValkyl, preferably hydrogen or ethyl, comprising reacting a compound of the formula (IV), or a salt thereof,
  • the process comprises removing a protecting group R* to give the free acid of the compound of formula (III), especially (Ilia), wherein R is hydrogen, or a salt thereof.
  • R* is other than hydrogen
  • it can be R as defined for a compound of the formula (I) - other than hydrogen - so that the compound of the formula (III), especially (Ilia), is an ester instead of the free acid which, however, is preferably used in the hydrogenation of the compound of formula (III), especially (Ilia), to the compound of formula (II), especially (MA).
  • leaving group X besides halo, especially chloro, iodo or especially bromo, also a sulfonate group, e.g. tosylate or mesylate, or a super leaving group, e.g. triflate, an alkenyl, an aryl triflate or perfluorobutanesulfonyl, is possible.
  • a sulfonate group e.g. tosylate or mesylate
  • a super leaving group e.g. triflate, an alkenyl, an aryl triflate or perfluorobutanesulfonyl
  • methyl or ethyl 2-(bromomethyl)acrylate can be used.
  • a preferred transition metal for this reaction is indium (c.f. Haythem K. Dema, Francisco Foubelo and Miguel Yus, Heterocycles, 201 1 , 82, 141 1 ) or zinc (c.f. An Shen, Min Liu, Zhen- Shan Jia, Ming-Hua Xu, and Guo-Qiang Lin, Org. Lett. 2010 , 12, 5154) can be used . Both metals give excellent selectivity but provide opposite diastereomers.
  • Either metal can be used to obtain the desired 4R stereocentre provided the correct corresponding sulfur stereocentre is installed in the previous step.
  • indium using the R-sulfinly stereochemistry will provide the desirable s ?-4R diastereomer [(4R)-5- (4-Biphenylyl)-4-[(R)-tert-butylsulfinylamino]-2-methylenepentanoic acid ethyl ester].
  • the reaction is preferably conducted in an appropriate solvent or solvent mixture, such as an aqueous solvent, especially water and/or an alcohol, such as isopropanol, and preferably in the presence of a salt with an anion corresponding to X, e.g. MX, wherein M is a metal cation and X, is an anion and I is e.g. 1 , 2 or 3, especially with M being an alkaline metal, such as lithium or sodium, and X, being a halogenide anion, e.g. bromide or chloride, e.g. at a temperature in the range from 0 to 50°C, e.g. from 10 to 30°C.
  • an appropriate solvent or solvent mixture such as an aqueous solvent, especially water and/or an alcohol, such as isopropanol
  • a salt with an anion corresponding to X e.g. MX, wherein M is a metal cation and X, is an anion and I is e.g
  • a carboxyl protecting group (e.g. R* here or R** further down in this disclosure) can be any group known in the art, especially C Ce-alkyl, e.g. ethyl, methyl, allyl or tert-butyl, or C 6 -C 10 - aryl-CrCValkyl, e.g. benzyl, or a silyl group SiR7R8R9, wherein R7, R8 and R9 are, independently of each other, C Ce-alkyl or C 6 -C 10 -aryl.
  • Preferred examples for R7, R8 and R9 are methyl, ethyl, isopropyl, t-butyl and phenyl.
  • an Ci-C 6 -alkyl, e.g. ethyl, protecting group R* can be removed by hydrolysis, e.g. in the presence of a base, such as an alkaline metal hydroxide, e.g. lithium hydroxide, in the presence of an appropriate solvent, e.g. a cyclic ether, such as tetrahydrofuran, and water, e.g. at a temperature in the range from 0 to 50 °C, such as from 10 to 30 °C.
  • a base such as an alkaline metal hydroxide, e.g. lithium hydroxide
  • an appropriate solvent e.g. a cyclic ether, such as tetrahydrofuran
  • water e.g. at a temperature in the range from 0 to 50 °C, such as from 10 to 30 °C.
  • the reaction to produce a compound of formula (IV) can also be led under flow preparation conditions, e.g. using a pump, two injection loops (one for each of the compounds of the formula IV/lva and of the formula V), a column with the transition metal followed by a reactor coil, then a scavenger, e.g. polymer supported sulfonic acid/thiourea.
  • flow preparation conditions e.g. using a pump, two injection loops (one for each of the compounds of the formula IV/lva and of the formula V), a column with the transition metal followed by a reactor coil, then a scavenger, e.g. polymer supported sulfonic acid/thiourea.
  • Yet a further embodiment of the invention relates to a process for the manufacture of a compound of the formula (IV), or a salt thereof,
  • This reaction preferably takes place e.g. under the conditions of the Ellman reaction (cf. e.g. F. Chemla, F. Ferreira, J. Org. Chem. 2004, 69, 8244), especially in an appropriate solvent or solvent mixture, e.g. a halogenated hydrocarbon, such as dichloromethane, preferably in the presence of a weakly active acidic catalyst, such as pyridinium p-toluenesulfonate, Ti(OiPr) 4 or Ti(OEt) 4 as Lewis acid (cf. e.g. T. Boultwood, D. P. Affron, A. D. Trowbridge, J. A. Bull, J. Org. Chem. 2013, 78, 6632), for example at a temperature in the range from 0 to 100°C, e.g. from 15 to 70°C.
  • a weakly active acidic catalyst such as pyridinium p-toluenesulfonate
  • the process can also be led under flow preparation conditions, e.g. using a pump, at least one injection loop for each of the compounds of the formula VI and Vll/Vlla, a reaction column (e.g. with a dehydrating agent, such as magnesium sulfate) and a subsequent scavenger, e.g. polymer bound sulfonic acid/benzylamine.
  • a reaction column e.g. with a dehydrating agent, such as magnesium sulfate
  • a subsequent scavenger e.g. polymer bound sulfonic acid/benzylamine.
  • One embodiment of the present invention comprises the reaction sequence comprising the reactions of steps D -> C -> B -> A.
  • One embodiment of the present invention comprises the reaction sequence comprising the reactions of steps C -> B -> A.
  • One embodiment of the present invention comprises the reaction sequence comprising the reactions of steps B -> A.
  • One embodiment of the present invention comprises the reaction sequence comprising the reactions of steps C -> B.
  • One embodiment of the present invention comprises the reaction sequence comprising the reactions of steps D -> C -> B.
  • One embodiment of the present invention comprises the reaction sequence comprising the reactions of steps D -> C.
  • R** is a carboxyl protecting group, especially C Ce-alkyl, such as ethyl, under selective reduction conditions to yield the aldehyde of the formula VI.
  • selective reductant for use in the selective reduction conditions for example, diisobutyl aluminium hydride (DIBAL-H) which is especially preferred, lithium tri-tert-butoxyaluminium- hydride or aluminium-bis(N-methylpiperazino)hydride may be mentioned.
  • DIBAL-H diisobutyl aluminium hydride
  • lithium tri-tert-butoxyaluminium- hydride or aluminium-bis(N-methylpiperazino)hydride may be mentioned.
  • the reaction can take place in an appropriate solvent or solvent mixture, such as an organic hydrocarbon, e.g. toluene, or a cyclic ether, such as tetrahydrofuran, preferably at low temperatures, e.g. from -100 to 5 °C, e.g. from -78 °C to 0 °C.
  • an appropriate solvent or solvent mixture such as an organic hydrocarbon, e.g. toluene, or a cyclic ether, such as tetrahydrofuran
  • R** is a carboxyl protecting group, especially Ci-C 6 -alkyl, is preferably obtained from a hydroxylic acid of the formula (IX)
  • R** is a carboxyl protecting group, especially C Ce-alkyl, under selective reduction of the hydroxyl group.
  • the selective reduction of the hydroxyl group in a compound of the formula (IX) resulting in a carboxylic acid ester compound of the formula (VIII) can e.g. be effected by using a trialkylsilylhalogenide wherein the halogenide is other than a iodide, e.g. the chloride, via in situ formation of an iodide in the presence of a metal iodide, especially an alkaline metal iodide, such as sodium iodide, in an organic solvent or solvent mixture, e.g. a nitrile, such as acetonitrile, e.g. at temperatures in the range from 10 °C to the reflux temperature of the reaction mixture, e.g. in the range from 40 to 80 °C.
  • a trialkylsilylhalogenide wherein the halogenide is other than a iodide, e.g. the chloride, via in situ formation of an iodide
  • R** is a carboxyl protecting group, especially C Ce-alkyl
  • R** is a carboxyl protecting group, especially C Ce-alkyl, under selective reduction of the keto group to a hydroxyl group.
  • the selective reduction of the keto group in a compound of formula (X) to the hydroxyl group of the compound of the formula IX preferably takes place in the presence of a selective reducing agent, for example using NaBH(OAc) 3 , e.g. in an organic solvent, e.g.
  • a cyclic ester such as tetrahydrofuran; sodium borohydride, for example in water; sodium cyanoborohydride (Book review: Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd Edition, Jacqueline Seyden-Penne, 1997, WILEY-VCH); a metal alkoxide can be used as reagent such as in the Meerwein-Ponndorf-Verley reduction (AI(OiPr) 3 in an appropriate organic solvent, such as isopropanol (for a review see: Organic Process
  • the reaction preferably takes place at a temperature in the range from -20 to 50 °C, e.g. in the range from -10 to 30 °C.
  • keto acid of the formula (X) is N-(2-aminoethyl)-2-aminoethyl keto acid of the formula (X)
  • R** is a carboxyl protecting group, especially Ci-C 6 -alkyl
  • Y is a leaving group or OH, especially halogen
  • R** is a carboxyl protecting group, especially C Ce-alkyl, preferably in the presence of an (especially Lewis) acid.
  • the leaving group (a preferred variant of Y) can be selected from halogeno, e.g. fluoro, chloro, bromo or iodo, especially chloro.
  • As (Lewis) acid especially aluminium trichloride (AICI 3 ), or alternatively another Lewis acid e.g. selected from the group consisting of other aluminium halides (e.g.
  • AIBr 3 titanium tetrabromide; tin tetrachloride; a lanthanide triflate; iron (III) chloride; zinc (II) chloride; a protic acid such as polyphosphoric acid; sulfuric acid; phosphoric acid; and a solid catalyst such as zinc (II) oxide; zinc and zeolites (review on solid catalysts: Giovanni Sartori and Raimondo Maggi, Chem. Rev., 201 1 , 1 1 1 1 (5), 181-214) can be used; or even little or no catalyst (Pearson, D. E.; Buehler, Calvin A. Synthesis (1972), (10), 533-42) can be used.
  • the reaction preferably takes place under reaction conditions known to the person skilled in the art, especially in the presence of an organic solvent or solvent mixture, such as an aliphatic halide solvent, e.g. dichloromethane, at preferred temperatures in the range from - 20 to 50 °C, e.g. at -10 to 10°C.
  • an organic solvent or solvent mixture such as an aliphatic halide solvent, e.g. dichloromethane
  • the reaction in a flow preparation system driven by a pump and using an injection loop preferably takes place at a temperature of 25 to 100 °C, e.g. at 50 to 70 °C, and at an oxygen pressure of e.g. from 2 to 20 bar, e.g. from 6 to 10 bar.
  • scavenger for example polymer bound thiourea may be used.
  • This reaction can preferably take place in an appropriate solvent or solvent mixture, e.g. toluene and tert-butanol, in the presence of water, in the presence of a catalyst, e.g. a palladium catalyst, such as an organopalladium catalyst, e.g. palladium(ll)chloride or (MeCN) 2 PdCI 2 , and of a copper salt, especially a copper (ll)halogenide, such as copper(ll) chloride, preferably at an elevated temperature, e.g. in the range from 25 to 100 °C, such as from 50 to 70°C,
  • a catalyst e.g. a palladium catalyst, such as an organopalladium catalyst, e.g. palladium(ll)chloride or (MeCN) 2 PdCI 2
  • a copper salt especially a copper (ll)halogenide, such as copper(ll) chloride
  • Hal is halo, especially iodo or bromo, preferably under flow preparation conditions.
  • the reaction can, for example, be conducted with ethylene in the presence of a Pd catalyst, especially palladium chloride or more especially an organopalladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or palladium(ll)acetate (Pd(OAc) 2 ), preferably in the presence of a ligand, such as triphenylphosphine or t-Bu 3 PH BF 4 and in the presence of a base, such as a tertiary amine, e.g.
  • trimethylamine triethylamine or N,N-dicyclohexyl-N- methylamine
  • an appropriate solvent or solvent mixture such as toluene, methanol or a mixture thereof, preferably at an elevated temperature, e.g. in the range from 50 to 150 °C, e.g. from 100 to 140°C.
  • the reaction is conducted under flow preparation conditions, using a pump, an injection loop, a gas reactor (administering an ethylene pressure of 2 to 30, e.g. 10 to 20 bar) and subsequently a scavenger, e.g. polymer bound thiourea/sulfonic acid.
  • a gas reactor administering an ethylene pressure of 2 to 30, e.g. 10 to 20 bar
  • a scavenger e.g. polymer bound thiourea/sulfonic acid.
  • Ra is as just defined, with a metal amide and subsequent S N 2 attack to yield a thiol of the formula Ra-SH and the compound of the formula (VII), especially (Vila).
  • the asymmetric mono- oxidation is preferably conducted in the presence of a chiral ligand , e.g. a benzo- cyclopentanolimine such as (1 S,2R)-1 -[(2-Hydroxy-3,5-di-tert-butyl-benzylidene)-amino]- indan-2-ol of the formula
  • R 2 t-Bu, i-Pr, Bn, Ph
  • N-(3,5-di-tert-butylsalicylmethylene)-(S)-tert-leucinol gives (RS)-thiosulfinate, which leads to (RS)-sulfinamide and visa versa.
  • the mono-oxidation is preferably achieved with a peroxide, especially hydrogen peroxide, in an appropriate solvent, such as a ketone, e.g. acetone, e.g. under conditions described by Ellman et al. (cf. D. J. Weix, J. A. Ellman, Org. Lett. 2003, 5, 131 7) in the presence of a vanadyl complex, especially vanadyl-Jb/ ' s-acetylacetonate, in an appropriate solvent or solvent mixture, e.g. a ketone, such as acetone, preferably at lower temperatures e.g. in the range from -20 to 20 °C, e.g . from -5 to 5 °C.
  • a peroxide especially hydrogen peroxide
  • an appropriate solvent such as a ketone, e.g. acetone
  • the resulting sulfinylsulfide compound of the formula (XVI), especially (XVIa), is then reacted under S N 2 substitution with a metal amide, especially an alkaline metal amide, such as lithium amide, in an appropriate solvent or solvent mixture, e.g . in NH 3 in a cyclic ether, such as tetrahydrofuran , preferably at low temperatures, e.g. in the range from -100 to 0 °C, e.g. from -80 to -50°C, resulting in the sulfinamide of the formula VI I, especially Vila.
  • a metal amide especially an alkaline metal amide, such as lithium amide
  • solvents from the following group may be used: water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1 - or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, e.g.
  • esters such as lower alkyl-lower alkanoates, for example ethyl acetate
  • ethers such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane
  • liquid aromatic hydrocarbons such as benzene or toluene
  • the invention also relates to novel compounds mentioned above and below.
  • R is hydrogen or a carboxyl protecting group or Ci-C 6 -alkyl, preferably hydrogen or ethyl, R' and R" are independently of each other hydrogen or a nitrogen protecting group, preferably a hydrogen, a tert-butoxy group or a succinimidyl group,
  • the products of the formula (I) of the process of the present invention as well as the aforementioned intermediates of formula (II), (III) and (IV) can preferably be used in the synthesis (manufacture) of NEP inhibitors or prodrugs thereof, in particular they can be used in the synthesis of NEP inhibitors comprising an y-amino-5-biphenyl-a- methylalkanoic acid, or acid ester, backbone, in particular for the synthesis of the NEP inhibitor prodrug sacubitril.
  • NEP inhibitor prodrug sacubitril (AHU377) can then be used for the synthesis of the complex LCZ696 comprising sacubitril and valsartan according to the processes depicted in WO 2007/056546.
  • Alkyl being a radical or part of a radical is a straight or branch (one or, if desired and possible, more times) carbon chain, and is especially C C 6 -alkyl, preferably Crd-alkyl.
  • C -C 6 - defines a moiety with up to and including maximally 7, especially up to and including maximally 4, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon.
  • Cycloalkyl is, for example, C 3 -C 8 -cycloalkyl and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.
  • cycloalkylalkyl the cycloalkyl is e.g. as defined for cycloalkyl and is attached to an alkyl as defined for alkyl, e.g. Cs-Cs-cycloalkyl-CrCe-alkyl.
  • alkyl e.g. Cs-Cs-cycloalkyl-CrCe-alkyl.
  • An example is cyclopropylmethyl or cyclohexylmethyl.
  • Alkoxy is, for example, CrC alkoxy and is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and also includes corresponding pentyloxy, hexyloxy and heptyloxy radicals.
  • C ⁇ C ⁇ alkoxy is preferred.
  • Aryl being a radical or part of a radical is, for example C 6 -C 10 -aryl, and is, preferably a mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 10 carbon atoms, preferably phenyl, napthenyl or fluorenyl and which can be unsubstituted or substituted, by one or more substituents independently selected from for example, C Cy- alkyl, CrCy-alkoxy-CrCy-alkyl or CrCy-alkoxy.
  • Aryloxy refers to a Aryl-O- wherein aryl is as defined above.
  • arylalkyl the aryl moiety is e.g. as defined for aryl and attached to an alkyl as defined for alkyl; e.g. Ce-C ⁇ -aryl-C Ce-alkyl. Examples are benzyl or 1 -phenylethyl.
  • a heterocyclyl roup is unsubstituted or substituted by one or more, e.g. up to three, substitutents preferably independently selected from the group consisting of halo, C Cy-alkyl, halo-C C 7 -alkyl, C Cy-alkoxy,
  • heterocyclyl such as trifluoromethoxy and C Cy-alkoxy-C Cy-alkoxy.
  • heteroaryl When the heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.
  • heterocyclylalkyl the heterocyclyl is preferably as just defined and is attached to an alkyl as defined for alkyl.
  • alkyl as defined for alkyl. Examples are imidazolylmethyl, pyridylmethyl or piperidinylmethyl.
  • Sulfonyl is (unsubstituted or substituted) C Cy-alkylsulfonyl, such as methylsulfonyl, (unsubstituted or substituted) phenyl- or naphthyl-CrCy-alkylsulfonyl, such as phenyl- methanesulfonyl, or (unsubstituted or substituted) phenyl-or naphthyl-sulfonyl; wherein if more than one substituent is present, e.g.
  • the substituents are selected independently from cyano, halo, halo-C C 7 alkyl, halo-CrCy-alkyloxy- and CrC 7 - alkyloxy.
  • C Cy-alkylsulfonyl such as methylsulfonyl
  • phenyl- or naphthy -C Cy-alkylsulfonyl such as phenylmethanesulfonyl.
  • nitrogen protecting group generally comprises any group which is capable of reversibly protecting a nitrogen functionality, preferably an amino and/or amide functionality.
  • oxygen protecting group generally comprises any group which is capable of reversibly protecting the oxygen functionality.
  • the nitrogen protecting group is an amine protecting group and/or an amide protecting group.
  • Suitable nitrogen protecting groups are conventionally used in peptide chemistry and are described e.g. in the relevant chapters of standard reference works such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.
  • Preferred nitrogen protecting groups generally comprise:
  • C Ce-alkyl preferably C ⁇ C ⁇ alkyl, more preferably C 1 -C 2 -alkyl, most preferably C alkyl which is optionally mono-, di- or tri-substituted by trialkylsilylC Cy-alkoxy (eg. trimethylsilyethoxy) aryl, preferably phenyl, or an heterocyclic group, preferably pyrrolidinyl, wherein the aryl ring or the heterocyclic group is unsubstituted or substituted by one or more, e.g. two or three, residues, e.g. selected from the group consisting of C C 7 -alkyl, hydroxy, CrCy-alkoxy, C 2 -C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ;
  • aryl-C 1 -C 2 -alkoxycarbonyl (preferably phenyl-C 1 -C 2 -alkoxycarbonyl e.g. benzyloxy- carbonyl); C ⁇ C ⁇ -alkenyloxycarbonyl; C C 6 -alkylcarbonyl (eg. acetyl or pivaloyi); C 6 -C 10 - arylcarbonyl; C C 6 -alkoxycarbonyl (eg.
  • nitrogen protecting groups are acetyl, benzyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbony (Fmoc), benzyloxymethyl (BOM), pivaloyl-oxy-methyl (POM), trichloroethxoycarbonyl (Troc), 1 - adamantyloxycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl, tert.-butyl-dimethylsilyl, triethylsilyl (TES), triisopropylsilyl, trimethylsilyethoxymethyl (SEM), t-butoxycarbonyl (BOC), t-butyl, 1 -methyl-1 ,1 -dimethylbenzyl, (phenyl)methylbenzene, pyrridinyl and pivaloyi.
  • nitrogen protecting groups are acetyl, benzyl, benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilyethoxymethyl (SEM), t-butoxycarbonyl (BOC), pyrrolidinylmethyl and pivaloyi.
  • nitrogen protecting groups are pivaloyi, pyrrolidinylmethyl, t- butoxycarbonyl, benzyl and silyl groups, particularly silyl groups according to the formula SiR7R8R9, wherein R7, R8 and R9 are, independently of each other, alkyl or aryl.
  • R7, R8 and R9 are methyl, ethyl, isopropyl, t-butyl and phenyl.
  • Particularly preferred as nitrogen protecting groups are pivaloyi and t-butoxycarbonyl (BOC).
  • the nitrogen protecting group selected from the group consisting of C C 6 -alkyl, which is mono-, di- or tri-substituted by tri-CrCy-alkylsilyl-CrCy-alkoxy, C 6 -C 10 -aryl, or an heterocyclic group, wherein the aryl ring or the heterocyclic group is unsubstituted or substituted by one, two or three residues selected from the group consisting of C Cy-alkyl, hydroxyl, CrCy-alkoxy, C 2 -C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ; C 6 -Cio-aryl-Ci- C 2 -alkoxycarbonyl; C C ⁇ -alkenyloxycarbonyl; C Ce-alkylcarbonyl; C 6 -C 10 -arylcarbonyl; C C 6 -alkoxycarbonyl; Ce-C ⁇ -aryl-C
  • CH 2 CI 2 , EtOAc, n-hexane, acetone and PE (distillate fraction 40-60 °C) were obtained as laboratory reagent grade solvents from Fisher scientific and distilled before use.
  • Anhydrous CH 2 CI 2 , PhMe, MeCN, Et 2 0 and MeOH were obtained by distillation over CaH 2 .
  • Anhydrous THF was obtained by distillation over LiAIH 4 and CaH 2 with triphenylmethane as an indicator.
  • High resolution mass spectrometry was performed on a Waters Micromass LCT Premier spectrometer using time of flight analysis with positive electrospray ionisation (EST) or negative electrospray ionisation (EST), an ABI/MDS Sciex Q-STAR Pulsar with ESI+, or a Bruker BioApex II 4.7e FTICR utilising either ESI + or a positive electron ionisation ( ⁇ ) source equipped with a direct insertion probe. All reported values are within ⁇ 5 ppm of the calculated value.
  • TLC was performed on 0.25 mm thickness plates pre-coated with Merck Kieselgel 60 F254 silica gel and were visualised using ultra-violet radiation (254 nm) and by oxidative staining with aqueous acidic ammonium molybdate(VII) or aqueous basic potassium permanganate solution.
  • Flash column chromatography was carried out manually using Breckland 60 (0.040 - 0.063 mm) silica gel.
  • QuadraPure® registered trademark of Johnson Matthey Finland Oy, available e.g. from SigmaAldrich.
  • chloroglyoxylate (53.2 g; 390 mmol) was added to the C 16 H 16 0 3 20 mixture dropwise over a period of 0.5 h. After complete addition, the mixture was stirred at 0 °C for 1 h and allowed to warm to room temperature over an additional 3 h. The reaction was cooled to 0°C followed by the slow addition of water ( ⁇ 50 mL), maintaining the temperature below 20 °C. Once a colour change from dark red to light yellow was observed, water (300 mL) was added in one portion. The aqueous layer was separated and extracted with CH 2 CI 2 (200 mL), the combined organic layers were washed with saturated aq. NaHC0 3 solution (100 mL) followed by brine (100 mL) then dried with MgS0 4 and concentrated under vacuum.
  • TMSCI (135 mL; 1068 mmol) was added to the mixture dropwise over a period of 0.5 h. Following addition, the mixture was heated to 60 °C and 0 16 ⁇ 16 0 2 stirred for 36 h. Upon completion of the reaction (as determined by 1 H NMR), the mixture was quenched with sat. aq. NaHS0 3 until no further effervescence occurred. The resulting solution was extracted with EtOAc (2 ⁇ 200 mL). The organic layers were collected, washed with sat. aq.
  • Chiral sulfinamide 15 was prepared on multi-gram scale using methodology developed by Ellman and co-workers (cf. D. J. Weix, J. A. Ellman, Org. Lett. 2003, 5, 1317).
  • Asymmetric mono-oxidation of di-fe/ -butyl disulfide 22 to give sulfinyl sulfide 23 was achieved using 5 hydrogen peroxide in acetone at 0 °C with vanadyl Jb/ ' s-acetylacetonate and chiral ligand 24
  • Ligand was prepared from the corresponding 3,5-di-tert-butylsalicylaldehyde and (1 S,2R)-1 - amino-2-indanol (purchased from Sigma Aldrich) according to (Ruck, Rebecca T.; Jacobsen, Eric N.
  • Example 7 (4R)-5-(4-Biphenylyl)-4-[(R)-tert-butylsulfinylamino]-2-methylenepentanoic acid ethyl ester ( ⁇ 4R)-30)
  • the resulting mixture was extracted with EtOAc (3 ⁇ 20 ml_), dried over anhydrous MgS0 4 , filtered and the solvent was removed under vacuum to
  • the reaction plug was pumped at 1 .0 mL/min (using PhMe/MeOH (9:1 ) as stock solvent) through a tube-in-tube gas reactor (1 .5 m AF2400 obtained from Biogeneral Inc.: http://www.biogeneral.com/teflon.html) pressurised with ethylene (15 bar) followed by a 20 mL PTFE reaction coil at 120 °C.
  • the exiting reaction stream was passed through an Omnifit column ( Kinesis Ltd., St. Neots, Cambridgeshire, UK) containing a mixture of QP-TU and QP-SA followed by a BPR (20 bar).
  • a fraction (containing the reaction plug and any dispersion) was collected and flushed with argon.
  • the solvent was removed from the product fraction under vacuum to provide 4-phenylstyrene as a colourless solid (268 mg, 1 .5 mmol, 99%). colourless
  • the combined reagent stream was then pumped through a tube-in-tube gas reactor (1 .5 m AF-2400) pressurised with pure 0 2 (8 bar) followed by a 30 mL stainless steel reaction coil at 60 °C (residence time: 60 min).
  • the exiting product stream then passed through an Omnifit column containing QP-TU and a BPR (15 bar). A 6 mL fraction
  • the reagents are pumped using a UniqsisTM Flowsyn reactor via the 2 mL PEEK injection loops A and B at a combined flow rate of 0.3 mL/min (using PhMe/'BuOH (1 :6) as stock solvent).
  • the combined reagent stream then flow through an Omnifit column containing MgS0 4 (6 g) heated to 70 °C, followed by a column containing a mixture of QP- SA and QP-BZA, followed by a BPR (4 bar).
  • a 6 mL fraction (containing the reaction plug and any dispersion) is collected and the solvent removed under vacuum to provide
  • the combined reagent stream then flowed through an Omnifit column (3 mm i.d . ⁇ 100 mm) containing activated zinc dust (1 .35 g) followed by a PFA reactor coil (1 0 mL).
  • the output stream was then passed through a column containing QP-SA and QP-TU , followed by a BPR (4 bar).
  • a 6 mL fraction (containing the reaction plug and any dispersion) was collected and the solvent removed under vacuum.

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Abstract

L'invention concerne un nouveau procédé, de nouvelles étapes de procédé et de nouveaux intermédiaires utiles dans la synthèse de composés pharmaceutiquement actifs, en particulier des inhibiteurs d'endopeptidase neutre (NEP), tel que le sacubitril, et des promédicaments de ceux-ci.
PCT/IB2016/055628 2015-09-23 2016-09-21 Nouveaux procédés et intermédiaires utiles dans la synthèse d'inhibiteurs d'endopeptidase neutre (nep) WO2017051326A1 (fr)

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