WO2017051326A1

WO2017051326A1 - New processes and intermediates useful in synthesis of nep inhibitors

Info

Publication number: WO2017051326A1
Application number: PCT/IB2016/055628
Authority: WO
Inventors: Benjamin Martin; Gerhard Penn; Berthold Schenkel; Samuel BOURNE; Shing-Hing LAU; Steven Ley
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2015-09-23
Filing date: 2016-09-21
Publication date: 2017-03-30
Anticipated expiration: 2018-03-23

Abstract

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.

Description

TITLE OF INVENTION

New Processes and Intermediates Useful in Synthesis of NEP Inhibitors

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

The 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)

(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).

(B) Said complex is also referred to by the following chemical names: Trisodium [3-((1 S,3R)-1 - biphenyl-4-ylmethyl-3-ethoxycarbonyl-1 -butylcarbamoyl)propionate-(S)-3'-methyl-2'- (pentanoyl{2"-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] hemipentahydrate or Octadecasodium hexakis(4-{[(1 S,3R)-1 -([1 ,1 '-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4- oxobutyl]amino}-4-oxobutanoate) hexakis(/V-pentanoyl-/V-{[2'-(1 /-/-tetrazol-1 -id-5-yl)[1 ,1 '- biphenyl]-4-yl]methyl}-l-valinate)— water (1/15) (lUPAC nomenclature).

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.

Chemical synthesis routes to prepare NEP inhibitors and their prodrugs, in particular sacu- bitril, and its precursors have been described previously, e.g. in Ksander ef al. J. Med. Chem. 1995, 38, pp.1689-1700; in US patent No 5,217,996 and in the international patent applications WO 2008/031567, WO 2008/083967, WO 2009/090251 , WO 2010/081410, WO 201 1 /035569, WO 201 1 /088797, WO 2012/025501 , WO 2012/025502 and

WO 2014/032627.

However, there is still a need to design a chemical process for the synthesis of sacubitril which is suitable for industrial scale production under economically and environmentally favorable conditions and provides the drug substance in high chemical purity and with high stereo-chemical selectivity.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the manufacture of a compound of formula (I), or a salt thereof

wherein 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,

especially a process for the manufacture of a compound of formula (la), or a salt thereof,

via the corresponding novel sulfinamide compound intermediates.

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.

Accordingly, the present invention relates to the following intermediate compounds

(a) a sulfonamide compound of the formula (II) or a salt thereof

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is tert-butyl or p-tolyl and

R is hydrogen or a carboxyl protecting group or C CValkyl, preferably hydrogen or ethyl, especially of the formula (lla) or a salt thereof

(b) a sulfonamide compound of the formula (III), or a salt thereof

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is tert-butyl or p-tolyl and

R is hydrogen or a carboxyl protecting group or Ci-C₆-alkyl, preferably hydrogen or ethyl, especially of the formula (Ilia), or a salt thereof,

or

(c) a compound of formula (IV) or a salt thereof,

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is tert-butyl or p-tolyl.

especially of the formula (Iva), or a salt thereof

or the enantiomer 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.

Overall, the process of the present invention comprises the following sequence, wherein each synthesis step is also a separate embodiment of the invention:

A process for the manufacture of an intermediate of the formula I, or a salt thereof

comprising

(i) providing an aldehyde of formula VI,

reacting the aldehyde of formula (VI) with a sulfinamide of the formula (VII), or a salt thereof

H₂N

\

Ra (vii)

wherein Ra is Ci-C₆-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂,

to obtain a compound of the formula (IV), or a salt thereof,

wherein Ra is as defined above,

(iii) reacting the obtained compound of formula (IV), or a salt thereof, in the presence of a transition metal under carboxyethoxyallylation conditions with an acrylate compound of the formula V,

wherein X is a leaving group, especially halogen, and R* is a carboxyl protecting group, and, optionally, removing and/or replacing the protecting group R*,

to obtain a sulfinamide compound of the formula (III), or a salt thereof,

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, and

R is hydrogen or a carboxyl protecting group or Ci-C₆-alkyl,

(iv) hydrogenating the obtained sulfinamide compound of the formula (III), or a salt thereof, in the presence of a hydrogenation catalyst to obtain a sulfinamide compound of the formula II, or a salt thereof,

wherein Ra is Ci-C₆-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, and

R is hydrogen or a carboxyl protecting group or C CValkyl, preferably ethyl, and

(v) reacting the obtained sulfinamide compound of the formula (II), or a salt thereof, in the presence of an acyl halide reagent, preferably in the presence of an alcohol of the formula R"'-OH wherein R'" is hydrogen or a carboxy protecting group or C C₆-alkyl, and optionally removing and/or replacing any protecting groups,

to obtain the desired compound of the formula I, or a salt thereof, as defined above. Generally, all processes and process steps of the present invention also allow for and relate to reactions that take place under flow preparation conditions, flow preparation especially relating to continuous flow. BRIEF DESCRIPTION OF THE DRAWINGS

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: Via 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. Via a cartridge 6 containing e.g. polymer supported reagents or scavengers (here QP-TU = a thiourea polymer is shown as example) the resulting mixture is purified. 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.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis of NEP inhibitors

The term "NEP inhibitor" describes a compound which inhibits the activity of the enzyme neutral endopeptidase (NEP, EC 3.4.24.1 1).

The term "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. In a preferred embodiment 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:

especially its calcium salt; and to novel intermediates for said manufacture.

More preferably, 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.

Corresponding process steps for the manufacture of AHU377 are known in the art, e.g. WO2008/083967 describes a method for producing NEP inhibitors or prodrugs thereof, in particular /V-(3-carboxyl-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester, or a salt thereof, via intermediates such as:

- a compound according to formula (2*), or a tautomer, or a salt thereof,

(2*)

wherein R1 is hydrogen or a nitrogen protecting group;

a compound of formula (3*), or a salt thereof,

(3*)

wherein 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,

- a compound of formula (1 d*)

(1 d*)

or a salt thereof.

The conversion of the compound of formula (1 d) into /V-(3-carboxyl-1 -oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester (known in the art as AHU377), or a salt thereof, has been described, for example, in Subsection B-3 in WO 2008/083967.

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

Scheme 5 (page 40) in WO 2008/083967 then leads from the ethyl ester to the calcium salt:

Scheme 5 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. Alternatively, AHU377 can be formed according to the following reaction scheme, according to processes known in the art:

These and other known processes are particular examples for a manufacture of AHU377 or a salt thereof from the compound of formula (I), especially (la), and thus represent a variant for those parts of the invention where the manufacture of AHU377 or related compounds is envisioned or mentioned.

In a following step 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.

Flow Chemistry

Generally, the present invention also allows for and relates to reactions that take place under flow preparation conditions, flow preparation especially relating to continuous flow. Over the last several decades flow chemistry has received a great deal of attention.

Attracted by its promise to revolutionise organic synthesis, many commercial and academic labs have invested a significant amount of time and resources into demonstrating the benefits of flow chemistry. As a result, flow chemistry now has a foothold in almost every area of chemistry, from the production of quantum dots and nanoparticles to the synthesis of active pharmaceutical ingredients (APIs) and complex natural products. Flow chemistry offers significant advantages over traditional batch techniques in many cases.

In recent years, large chemical and pharmaceutical companies have been under growing global and governmental pressure to reduce waste and become more environmentally friendly in their approach to organic synthesis. This has driven much of the industrial investment into methods for continuous manufacturing such as flow chemistry which has the potential to improve the efficiency of many processses, and as a result reduce the costs and environmental impacts associated with them. Key features of flow chemistry

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.

Via 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. Via a cartridge 6 containing e.g. polymer supported reagents or scavengers (here QP-TU = a thiourea polymer is shown as example) the resulting mixture is purified. An optional Back Pressure Regulator 7 can provide resistence for the pumps to push against. The product(s) 8 are leaving the system.

In the context of this invention we will deal with two realms of flow chemistry. In the first instance, 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.

In the second and alternative instance, large stock solutions of reagent can be pumped continuously through the pumps 4 and combined at a T-piece mixer 3 to provide a continuous reaction stream, this is known as continuous flow and is most commonly used for the scale-up of a single compound. The 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. By varying the flow rate through the reactor coil the reaction time can be controlled. Once the reaction leaves the reactor coil it is generally passed through a cartridge of polymer supported reagents 6 which quench, scavenge and purify the stream finally extruded through a back pressure regulator.

In the following, embodiments of the invention amenable to flow chemistry and/or conventional chemistry are described:

Individual Reaction Steps

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

In this reaction, a compound of formula (I) or a salt thereof,

wherein for both formulae (I) and (la) R is hydrogen or a carboxyl protecting group or C-i-C₆- alkyl, preferably hydrogen or 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,

is obtained by a process comprising

reacting a sulfinamide compound of the formula (I I), or a salt thereof,

wherein for both formulae (II) and (Ma) Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, Cs-Cs-cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is butyl, especially tert-butyl, or p-tolyl, and

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,

and optionally removing and/or replacing any protecting groups, to obtain the compound of formula (I).

Suitable acyl halide reagents are for example selected from thionyl chloride, thionyl bromide, PCI₃, PCI5, oxalyl chloride, Me₂C=C(CI)NMe₂, PhCOCI, PBr₃, PBr₅, Ph₃PBr₂, oxalyl bromide or Me₂C=C(Br)NMe₂.

The reaction preferably takes place in a customary solvent, such as an alcohol, e.g.

methanol or ethanol, and at appropriate temperatures, 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.

As set out above, the obtained compound of formula (I) / (la) can then be transformed via known reaction steps into the desired NEP inhibitor prodrug compounds. And in a following step 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.

Reaction B

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

wherein for both formulae (I) and (la) R is C Ce-alkyl, preferably hydrogen or ethyl, and R' and R" are both hydrogen,

comprising hydrogenating a compound of the formula (III), or a salt thereof,

especially of the formula (Ilia), or a salt thereof

wherein for both formulae (III) and (Ilia) Ra is C Ce-alkyl, C₆-C₁₀-aryl, C₆-C₁₀-aryl-C C₆- alkyl, C₃-C₈-cycloalkyl, Cs-Ce-cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is butyl, especially tert-butyl, or p-tolyl, and

R is hydrogen or a carboxyl protecting group or Ci-C₆-alkyl, preferably hydrogen or ethyl, in the presence of a hydrogenation catalyst, to obtain the compound of formula (II).

In one embodiment, especially for manufacture of a compound of the formula (Ilia), 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 .

In a preferred embodiment, 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. In one embodiment, the hetereo- or homogeneous hydrogenation takes place in the presence of a base, such as amine bases (e.g. triethylamine,

diisopropylethylamine or 1 ,4-diazabicyclo[2.2.2]octane) or alkali metal bases (e.g. LiOH, NaOH or KOH). In one embodiment, 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. In a further embodiment, the hydrogenation, in particular the homogeneous hydrogenation, takes place in the presence of an acid such as methanesulfonic acid or tetrafluoroboric acid.

Generally, 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 hydrogenation is usually performed in a solvent, such as an ether solvent (e.g.

tetrahydrofuran), an ester solvent (e.g. isopropyl acetate) or an alcohol solvent (e.g.

isopropanol, ethanol or methanol).

Generally, 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).

In a preferred embodiment, 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. In preferred embodiments 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. Generally, the organometallic complex, comprises one or more transition metal atoms and suitable achiral ligands.

Suitable achiral ligands for the organometallic complex generally are σ-donor ligands, σ- donor/TT-acceptor ligands or σ,π -donorArr-acceptor ligands. Examples for suitable achiral ligands are among others carbon monoxide, halides (e.g. CI, I or Br), phosphines [e.g. tricyclohexylphosphine (PCy₃)], 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.

Suitable (preferred) chiral ligands are e.g. a Fenphos ligand, a Josiphos ligand, a

Mandyphos ligand, a Walphos ligand, a Taniaphos ligand, a Phospholane ligand, an Atropisomer ligand, a BoPhoz ligand, a QUINAPHOS ligand or mixtures thereof; in particular the chiral ligand is selected from the group consisting of Fenphos ligand, Josiphos ligand, Mandyphos ligand, Walphos ligand, Taniaphos ligand, Phospholane ligand, Atropisomer ligand or mixtures of two or more thereof.

In one embodiment, 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.

Especially preferred is (-)-2,3-Bis[(2R,5R)-2,5-dimethylphospholano]maleic anhydride(1 ,5- cyclooctadiene)rhodium(l) tetrafluoro-borate (CatASium® MRRh).

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.

Reaction C

A further embodiment of the invention relates to a process for the manufacture of a compound of the formula (III), or a salt thereof

especially of the formula (Ilia), or a salt thereof

(Mia), wherein for both formulae (III) and (Ilia) Ra is C Ce-alkyl, C₆-C₁₀-aryl, C₆-C₁₀-aryl-C C₆- alkyl, C₃-C₈-cycloalkyl, Cs-Cs-cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is butyl, especially tert-butyl, or p-tolyl, and

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,

especially of the formula (Iva), or a salt thereof,

Ra (IVa)

or the respective enantiomer thereof;

wherein for both formulae (IV) and (IVa) Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce- alkyl, C₃-C₈-cycloalkyl, Cs-Ce-cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is a bulky moiety, such as a tert-alkyl, e.g. butyl, especially tert-butyl, or an aryl, e.g. p-tolyl, moiety,

in the presence of a transition metal under carboxyethoxyallylation conditions with an acrylate compound of the formula (V)

wherein X is a leaving group, especially halo, and R* is a carboxyl protecting group, and, optionally, removing a protecting group R*, to obtain the compound of the formula (III). In one embodiment, 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. Alternatively, if 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).

As 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.

For the carbethoxyallylation especially 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. In the case of 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]. In the case of zinc, using the S-sulfinly stereochemistry will provide the desirable sS-4R diastereomer [(4R)-5-(4-biphenylyl)-4-[(S)-tert-butylsulfinylamino]-2-methylenepentanoic acid ethyl ester].

Zinc is favourable based e.g. on cost considerations. 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.

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 C₆-C₁₀- aryl-CrCValkyl, e.g. benzyl, or a silyl group SiR7R8R9, wherein R7, R8 and R9 are, independently of each other, C Ce-alkyl or C₆-C₁₀-aryl. Preferred examples for R7, R8 and R9 are methyl, ethyl, isopropyl, t-butyl and phenyl. The carboxyl protecting groups themselves, their introduction reactions, and their removal reactions are described for example in 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,

"Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , in "Methoden der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

For example, an Ci-C₆-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.

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.

Reaction D

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,

especially of the formula (IVa), or a salt thereof,

Ra (IVa)

or the respective enantiomer thereof;

wherein for both formulae (IV) and (IVa) Ra is C CValkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce- alkyl, C₃-C₈-cycloalkyl, Cs-Cs-cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is a bulky moiety, such as a tert-alkyl, e.g. butyl, especially tert-butyl, or an aryl, e.g. p-tolyl, moiety,

comprising reacting an aldehyde of the formula (VI),

with a sulfinamide of the formula (VII),

H

especially of formula (Vila) H_?N

" \

Ra (Vila),

or the enantiomer thereof;

wherein for both formulae (VII) and (Vila) Ra is Ci-C₆-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce- alkyl, C₃-C₈-cycloalkyl, Cs-Ce-cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is a bulky moiety, such as a tert-alkyl, e.g. butyl, especially tert-butyl, or an aryl, e.g. p-tolyl, moiety,

to obtain the compound of formula (IV).

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.

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.

Further Embodiments

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.

Further Reaction Steps for making the compound of formula (VI)

Further embodiments of the present invention relate to the aforementioned reaction sequences wherein the starting compound of formula (VI) is prepared according to one of the following reactions:

Alternative A

The aldehyde of the formula (VI)

wherein 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.

As 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. These and appropriate further reductants and reduction conditions may, e.g., be derived from

"Reductions by the Alumino- and Borohydrides" in Organic Synthesis, 2nd Edition,

Jacqueline Seyden-Penne, 1997, WILEY-VCH. For example, 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.

The carboxylic ester of formula (VIII)

wherein R** is a carboxyl protecting group, especially Ci-C₆-alkyl, is preferably obtained from a hydroxylic acid of the formula (IX)

wherein 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.

Preferably, the hydroxylic acid of the formula (IX)

wherein R** is a carboxyl protecting group, especially C Ce-alkyl,

is obtained from a keto acid of formula (X),

wherein 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

Research & Development 2006, 10, 1032-1053)). 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.

Preferably, the keto acid of the formula (X)

wherein R** is a carboxyl protecting group, especially Ci-C₆-alkyl,

is obtained by reaction of biphenyl of the formula (XI)

with a glyoxylate of formula (XII)

Y-CO-C0₂R** (XII)

wherein Y is a leaving group or OH, especially halogen, and 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 (AICI₃), or alternatively another Lewis acid e.g. selected from the group consisting of other aluminium halides (e.g. AIBr₃); 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 (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.

If needed, Pd/C/H₂ mediated cleavage of any benzylic alcohol group is possible (more typical for industrial purposes), with or without prior activation of the alcohol as a

carbonate/O-acetyl. Other appropriate methods can e.g. be derived from Hydrogenolysis of Benzyl Groups Attached to Oxygen, Nitrogen, or Sulfur, Walter H. Hartung, Robert Simonoff, Published Online: 15 MAR 201 1 DOI: 10.1002/0471264180. or007.05, Copyright © 2004 by Organic Reactions, Inc. Published by John Wiley & Sons, Inc.

Alternative B

The aldehyde of the formula (VI)

can also be prepared from an allyl compound of the formula (XIII)

by anti-Markovnikov Wacker oxidation in the presence of oxygen, a catalyst and water, preferably under flow preparation conditions via a gas reactor, followed by a reactor coil and then a scavenger.

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. As 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)₂PdCI₂, 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,

The allyl compound of the formula (XIII)

can preferably be prepared by ethylene Heck reaction in the presence of a base and catalyst(s) from a compound of the formula (XIV),

wherein 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-Bu₃PH BF₄ and in the presence of a base, such as a tertiary amine, e.g. trimethylamine, triethylamine or N,N-dicyclohexyl-N- methylamine, in the presence of 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.

Preferably, 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.

Further Reaction Steps for making the compound of formula (VII)

Further embodiments of the present invention relate to the aforementioned reaction sequences wherein the starting compound of formula (VII)

H₂N

\

Ra (vii)

especially of formula (Vila) \

Ra (Vila),

wherein in both formulas (VII) and (Vila) Ra is C Ce-alkyl, C₆-C₁₀-aryl, C₆-C₁₀-aryl-C C₆- alkyl, C₃-C₈-cycloalkyl, Cs-Ce-cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is a bulky moiety, such as a tert-alkyl, e.g. butyl, especially tert-butyl, or an aryl, e.g. p-tolyl, moiety,

can be prepared by (for the manufacture of the compound of formula (Vila) preferably asymmetric) mono-oxidation of a disulfide of the formula XV

wherein both Ra are C Ce-alkyl, C₆-C₁₀-aryl, C₆-C₁₀-aryl-C C₆-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is a bulky moiety, such as a tert-alkyl, e.g. butyl, especially tert-butyl, or an aryl, e.g. p-tolyl, moiety,

followed by amidation of the resulting sulfinyl sulfide compound of the formula (XVI)

Ra

especially of the formula (XVIa)

or the enantiomer thereof;

wherein Ra is as just defined, with a metal amide and subsequent S_N2 attack to yield a thiol of the formula Ra-SH and the compound of the formula (VII), especially (Vila). For synthesis of the compound of the formula (Vi la) via (XVIa), 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

other ligands selected from those of the following formula:

R₂ = t-Bu, i-Pr, Bn, Ph

For example: for = R₂ = t-Bu N-(3,5-di-tert-butylsalicylmethylene)-tert-leucinol

Note: (1 R, 2S)-(+)-cis-aminoindanol gives (SS)-thiosulfinate, which leads to (SS)-sulfinamide and visa versa.

Note: 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.

The resulting sulfinylsulfide compound of the formula (XVI), especially (XVIa), is then reacted under S_N2 substitution with a metal amide, especially an alkaline metal amide, such as lithium amide, in an appropriate solvent or solvent mixture, e.g . in NH₃ 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. Where (appropriate) solvents or solvent mixtures are mentioned above and in any claims (the appropriate being a dispensable feature), apart from the specific solvents mentioned also one or more 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. as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopen- tane, ketones, such as acetone or methylethylketone, or mixtures of these, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning. Where required or desired, water-free or absolute solvents can be used.

Compounds of the invention

The invention also relates to novel compounds mentioned above and below.

It relates especially to a compound of the formula II,

a compound of the formula III,

in particular of the formula Ilia,

particular of the formula IVa

or the enantiomer thereof, as defined above or especially in the examples; or a salt thereof, respectively.

In the aforementioned formulae, the substituents have the following meanings:

R is hydrogen or a carboxyl protecting group or Ci-C₆-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,

Ra is Ci-C₆-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, Cs-Cs-cycloalkyl-Cr C₆-alkyl, heterocyclyl or heterocyclyl-C CValkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably butyl, especially tert-butyl, or p-tolyl.

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. In a following step 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.

The invention, in preferred embodiments, also relates to the subject matter in any of the claims, especially of the dependent claims; the claims are therefore incorporated here by reference.

Definitions

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 C₆-alkyl, preferably Crd-alkyl. The term "C -C₆-" 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, C₃-C₈-cycloalkyl and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

In 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. 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 C₆-C₁₀-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.

In 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.

Unsubstituted or substituted heterocyclyl is a mono- or polycyclic, preferably a mono-, bi- or tricyclic-, most preferably mono-, unsaturated, partially saturated, saturated or aromatic ring system with preferably 3 to 14 (more preferably 5 to 14) ring atoms and with one or more, preferably one to four, heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, such as imizazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyranyl, diazionyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, azepanyl, oxepanyl, thiepanyl, indolyl, isoindoly, quinolinyl, isoquinolinyl, benzazepinyl, carbazolyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolinidyl, thiazolidy, dioxolanyl, dithiolanyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxothiomorpholinyl, dioxothiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, or benzo-fused variants thereof. 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 C₇-alkyl, C Cy-alkoxy,

alkoxy, such as trifluoromethoxy and C Cy-alkoxy-C Cy-alkoxy. When the heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.

In heterocyclylalkyl, the heterocyclyl is preferably as just defined and is attached to an 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. one to three substitutents, the substituents are selected independently from cyano, halo, halo-C C₇alkyl, halo-CrCy-alkyloxy- and CrC₇- alkyloxy. Especially preferred is C Cy-alkylsulfonyl, such as methylsulfonyl, and (phenyl- or naphthy -C Cy-alkylsulfonyl, such as phenylmethanesulfonyl.

In the present application the term "nitrogen protecting group" generally comprises any group which is capable of reversibly protecting a nitrogen functionality, preferably an amino and/or amide functionality. The term "oxygen protecting group" generally comprises any group which is capable of reversibly protecting the oxygen functionality. Preferably 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. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , and in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974.

Preferred nitrogen protecting groups generally comprise:

C Ce-alkyl, preferably C^C^alkyl, more preferably C₁-C₂-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 C₇-alkyl, hydroxy, CrCy-alkoxy, C₂-C₈-alkanoyl-oxy, halogen, nitro, cyano, and CF₃;

aryl-C₁-C₂-alkoxycarbonyl (preferably phenyl-C₁-C₂-alkoxycarbonyl e.g. benzyloxy- carbonyl); C^C^-alkenyloxycarbonyl; C C₆-alkylcarbonyl (eg. acetyl or pivaloyi); C₆-C₁₀- arylcarbonyl; C C₆-alkoxycarbonyl (eg. t-butoxycarbonyl); Ce-C^-aryl-C Ce- alkoxycarbonyl; allyl or cinnamyl; sulfonyl or sulfenyl; succinimidyl group, silyl, e.g. triarylsilyl or trialkylsilyl (eg. triethylsilyl).

Examples of preferred 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. Most preferred nitrogen protecting groups are acetyl, benzyl, benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilyethoxymethyl (SEM), t-butoxycarbonyl (BOC), pyrrolidinylmethyl and pivaloyi.

Examples of more preferred 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. Preferred examples for R7, R8 and R9 are methyl, ethyl, isopropyl, t-butyl and phenyl. Particularly preferred as nitrogen protecting groups are pivaloyi and t-butoxycarbonyl (BOC). In one embodiment, the nitrogen protecting group selected from the group consisting of C C₆-alkyl, which is mono-, di- or tri-substituted by tri-CrCy-alkylsilyl-CrCy-alkoxy, C₆-C₁₀-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, C₂-C₈-alkanoyl-oxy, halogen, nitro, cyano, and CF₃; C₆-Cio-aryl-Ci- C₂-alkoxycarbonyl; C C^-alkenyloxycarbonyl; C Ce-alkylcarbonyl; C₆-C₁₀-arylcarbonyl; C C₆-alkoxycarbonyl; Ce-C^-aryl-C Ce-alkoxycarbonyl; allyl; cinnamyl; sulfonyl; sulfenyl; succinimidyl group; and SiR'R"R"', wherein R', R" and R'" are, independently of each other, CrCy-alkyl, C₆-C₁₀-aryl or phenyl-Ci-C₄-alkyl; wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂.

The following examples serve to illustrate the invention without limiting its scope, while they also represent preferred embodiments.

EXAMPLES

CH₂CI₂, 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 CH₂CI₂, PhMe, MeCN, Et₂0 and MeOH were obtained by distillation over CaH₂. Anhydrous THF was obtained by distillation over LiAIH₄ and CaH₂ with triphenylmethane as an indicator.

¹H NMR spectra were recorded in CDCI₃ or DMSO-d6 on a Bruker Avance DPX-400 (400 MHz), DRX-500 (500 MHz) or DRX-600 (600 MHz) spectrometer with residual CHCI3 (δΗ = 7.26 ppm) or DMSO-d6 (δΗ = 2.50 ppm) as the internal reference. ¹³C NMR spectra were recorded in CDCI₃ or DMSO-d6 on a Bruker Avance DPX-400 (101 MHz), DRX-500 (125 MHz) or DRX-600 (150 MHz) spectrometer with residual CHCI3 (5C = 77.16 ppm) or DMSO- d6 (5C = 39.51 ppm) as the internal reference. COSY, DEPT-135, HMQC and HMBC experiments were used to aid in the assignment of signals. The multiplicity of a signal is indicated as: s - singlet, d - doublet, t - triplet, q - quartet, m - multiplet, br - broad, etc. Coupling constants (J) are quoted in Hz and reported to the nearest 0.1 Hz. The centre of each signal is reported with the exception of multiplets, for which the range of ppm values covered by the signal is reported.

¹H and ¹³C assignments were made according to the arbitrary numbering applied to the following compound figure: Infrared spectra were recorded neat on a Perkin-Elmer Spectrum One FT-IR spectrometer using Universal ATR sampling accessories.

Melting points were determined using an OptiMelt automated melting point system available from Stanford Research Systems calibrated against vanillin (mp 83 °C), phenacetin (mp 136 °C) and caffeine (mp 237 °C).

Optical rotations were measured on a Perkin-Elmer Model 343 digital polarimeter at 24 °C using a sodium halogen lamp (589 nm) as the light source over a path length of 10 cm. [a]_D ²' values are reported in units of 10-1 cm-1 g-1 at concentration (c) in g per 100 ml.

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 (Ε ) 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.

Flow chemistry experiments were performed on a Uniqsis™ FlowSyn and may have been monitored as indicated with a Mettler-Toledo ReactIR 45m diamond or silicon flow cell. All gas-flow reactions were performed with a tube-in-tube gas reactor as described to introduce gases into a continuous flow stream. Omnifit columns were used for the containment of polymer-supported reagent or other solid reagents.

Unless otherwise specified, reagents were obtained from commercial sources and used without further purification.

Abbreviations used:

Aq. Aqueous

BPR back pressure regulator

Brine sodium chloride solution saturated at room temperature

'BuOH tert-butanol

Calcd. Calculated celite Celite®, Diatomaceous earth (IMERYS FILTRATION MINERALS), San Jose,

California, USA)

Cy₂NMe dicyclohexylmethylamine

DABCO 1 ,4-diazabicyclo[2.2.2]octane

DIBAL-H Diisobutylaluminium-hydride

DMF dimethyl formamide

eq. equivalent(s)

ESI Electron Spray lonisation

Et ethyl

Et₂0 diethyl ether

EtOAc ethyl acetate

GC gas chromatography

h hour(s)

HPLC High Performance Liquid Chromatography

HRMS High Resolution Mass Spectrometry

IR Infrared spectroscopy

M molar

Me methyl

MeCN acetonitrile

mL milliliter(s)

mp melting point

NMR Nuclear Magnetic Resonance

PE Petroleum Ether

PEEK polyetheretherketone

PFA perfluoroalkoxy

Ph phenyl

PhMe toluene

'PrOH isopropanol

PPTS pyridinium p-toluene sulfonate

PTFE polytetra fluoroethylene

QP-BZA QuadraPure Macroporous polystyrene supported benzylamine

QP-SA QuadraPure Macroporous polystyrene supported sulfonic acid

QPSA-TU QuadraPure Macroporous polystyrene supported sulfonic acid/thiourea

QP-TU QuadraPure Macroporous polystyrene supported thiourea

(-CH₂NH-C(=S)-NH₂)

rt room temperature (23 °C)

sat. saturated THF tetrahydrofuran

TMSCI Trimethylsilylchloride

t_t retention time (column residence time)

V_max frequency at peak maximum

QuadraPure®: registered trademark of Johnson Matthey Finland Oy, available e.g. from SigmaAldrich.

A general overview for the manufacture of (2R,4S)-1 , a compound falling under general formula la is given in Figure 2.

An adapted protocol was used for the conversion of 17 through to 21 (Takafumi Yamagami, Noriaki Moriyama, Masahiro Kyuhara, Atsushi Moroda, Takeshi Uemura, Hiroaki Matsumae, Yasunori Moritani, and Isao Inoue, Org. Process Res. Dev., 2014, 18 (3), pp 437-445). Example 1 : Ethyl biphenyl-4-yl(hydroxy)acetate (20)

To a suspension of AICI₃ (60.0 g; 450 mmol) in CH₂CI₂ I (400 mL), a solution of biphenyl (46.3 g; 300 mmol) in CH₂CI₂ (200 mL) was added at 0 °C. Ethyl

chloroglyoxylate (53.2 g; 390 mmol) was added to the C₁₆H₁₆0₃ 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 CH₂CI₂ (200 mL), the combined organic layers were washed with saturated aq. NaHC0₃ solution (100 mL) followed by brine (100 mL) then dried with MgS0₄ and concentrated under vacuum.

The residue was dissolved in THF (200 mL) and cooled to 0 °C. A suspension of

NaBH(OAc)₃ (95.4 g; 450 mmol) in THF (200 mL) was slowly added over a period of 10 min. The mixture was stirred for 1 h at 0°C and allowed to warm to room temperature over an additional 1 h. The resulting mixture was washed with brine (100 mL) and partially concentrated under vacuum. The residue was dissolved in EtOAc (300 mL), washed with saturated aq. NaHC0₃ solution (100 mL) followed by brine (100 mL) then dried with MgS0₄ and concentrated under vacuum. Crystallisation from Et₂0/hexane (20:80) yielded title compound 20 as a colourless solid (69.2 g, 270 mmol, 90% yield). Colourless amorphous solid; ¹H NMR (400 MHz, CDCI₃) δ 1 .25 (t, J=7.1 Hz, 3H, H8), 4.12-4.31 (m, 2H, H7), 5.96 (s, 1 H, H5), 7.37 (t, J=7.4 Hz, 1 H, H4'), 7.45 (t, J=7.5 Hz, 2H, H3'), 7.54 (d, J=8.2 Hz, 2H, H3), 7.59 (d, J=7.4 Hz, 2H, H2), 7.62 (d, J=8.2 Hz, 2H, H2'), ¹³C NMR (100 MHz, CDCI₃) δ 14.0 (CH₃, C8), 61 .7 (CH₂, C7), 74.3 (CHOH, C5), 127.1 (2CH, C2'), 127.5 (2CH, C2), 127.6 (CH, C4'), 128.0 (2CH, C3'), 128.8 (2CH, C3), 132.8 (C, C4), 140.3 (C, C1), 142.1 (C, C1 "), 170.3 (C, C6), IR (v_max cnY¹) 2996 (C-H alkyl), 1737 (C=0 ester), 1 177 (C-O ester).

Example 2: Ethyl biphenyl-4-yl(hydroxy)acetate (21)

A reactor was charged with MeCN (200 mL), 20 10 (68.4 g; 267 mmol) and Nal (128 g; 854 mmol).

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 0₁₆Η ₁₆0₂ stirred for 36 h. Upon completion of the reaction (as determined by ¹H NMR), the mixture was quenched with sat. aq. NaHS0₃ until no further effervescence occurred. The resulting solution was extracted with EtOAc (2 ^χ 200 mL). The organic layers were collected, washed with sat. aq. Na₂S₂0₃ (100 mL), brine (100 mL), dried with MgS0₄, filtered and concentrated under vacuum to give the title compound 21 as a yellow oil (55.2 g, 229 mmol, 86% yield). ¹H NMR (400 MHz, CDCI₃) δ 1 .32 (t, J=7.1 Hz, 3H, H8), 3.70 (s, 2H, H5), 4.22 (q, J=7.3 Hz, 2H, H7), 7.38 (t, J=7.4 Hz, 1 H, H4'), 7.41 (d, J=8.1 Hz, 2H, H3), 7.47 (t, J=7.5 Hz, 2H, H3'), 7.61 (d, J=8.2 Hz, 2H, H2), 7.63 (d, J=7.8 Hz, 2H, H2'), ¹³C NMR (100 MHz, CDCI₃) δ 14.2 (CH₃, C8), 41 .1 (CH₂, C5), 60.9 (CH₂, C7), 127.1 (2CH, C2'), 127.3 (CH, C4'), 127.3 (2CH, C2), 128.8 (2CH, C3'), 129.7 (2CH, C3), 133.3 (C, C4), 140.0 (C, C1), 140.8 (C, C1 '), 171 .6 (C, C6), IR (v_max cm^-1) 2980 (C-H alkyl), 1730 (C=0 ester), 1488, 1 151 (C-O ester), HRMS-ESI⁺: m/z [M+H]⁺ Calcd for C₁₆H₁₇0₂:

Expected: 241 .1229. Found: 241 .1221 .

Example 3: (4-Biphenylyl)acetaldehyde (16)

To a stirred solution of 4-biphenylmethylacetate 30 (1 1 .3 g; 47.1 mmol) in toluene (95 mL) at -78 °C, DIBAL-H (56.0 mL of 1 .0 M solution in PhMe, 56.0

mmol) was added via syringe pump at a rate of 1 mL/min. The reaction mixture was then stirred at - 78 °C for 6 h. MeOH (18 mL) was added to quench the reaction at -78 °C. The resulting white emulsion was slowly poured into 3 M HCI (65 mL) over 20 min and the aqueous mixture was then extracted with Et₂0 (3 ^χ 150 mL). The combined organic layers were washed with brine (2 ^χ 100 ml_), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give the crude product. The crude product was purified by recrystallisation with hexane to yield pure (4-biphenylyl)acetaldehyde 16 (9.92 g, 50.5 mmol, 98%) as a colourless amorphous solid; mp 54-58 °C; ¹H NMR (400 MHz, CDCI₃) δ 3.75 (s, 2H, H5), 7.32 (d, J=7.8 Hz, 2H, H3), 7.39 (t, J=7.4 Hz, 1 H, H4'), 7.48 (t, J=7.4 Hz, 2H, H3'), 7.58 (d, J=7.8 Hz, 2H, H2), 7.60 (d, J=7.4 Hz, H2, H2'), 9.81 (t, J=2.5 Hz, 1 H, H6), ¹³C NMR (101 MHz, CDCI₃) δ 50.0 (CH₂, C5), 127.1 (2CH, C3'), 127.4 (CH, C4'), 127.7 (2CH, C2'), 128.9 (2CH, C2), 130.1 (2CH, C3), 130.9 (C, C4), 140.4 (C, C1), 140.6 (C, C1 "), 191 .4 (CHO, C6), IR (v_max cm ¹) 3032 (C=C alkene), 1721 (C=0 aldehyde), 1488 (C=C aromatic), 758 (C=C alkene); HRMS-ESI⁺: m/z [M+H]⁺ Calcd for C₁₄H₁₃0:

Expected: 197.0961 . Found: 197.0958.

Example 4: (E)-[2-(4-Biphenylyl)ethylidene](tert-butylsulfinyl)amine ((R_s)-29)

A reactor was charged with CH₂CI₂ (100 ml_), 15 4-biphenylacetaldeyde (42.5 g, 217 mmol), (f?)-fe/?-butanesulfinamide (27.6 g, 228 mmol), pyridinium p-toluenesulfonate (2.7 g, 5 mol%)

and anhydrous MgS0₄ (30.0 g, 255 mmol). The

C₁₈H₂₁ NOS reaction mixture was stirred at room temperature for 5 h and then filtered. The solvent was removed under vacuum to give the title compound (R_s)-29 as a crude orange amorphous solid (64.9 g, 217 mmol, 99% yield) which was used without further purification, mp 48-50 °C; ¹H NMR (400 MHz, CDCI₃) δ 1 .21 (s, 9H, H8), 3.87 (dd, J=15.2, 5.2 Hz, 1 H, H5'), 3.91 (dd, J=15.2, 5.2 Hz, 1 H, H5), 7.31 (d, J=8.0 Hz, 2H, H3), 7.35 (t, J=7.3 Hz, 1 H, H4'), 7.44 (t, J=7.4 Hz, 2H, H3'), 7.58 (d, J=7.8 Hz, 2H, H2), 7.60 (d, J=7.4 Hz, H2, H2'), 8.17 (t, J=5.2 Hz, 1 H, H6), ¹³C NMR (101 MHz, CDCI₃) δ 22.4 (3CH₃, C8), 42.3 (CH₂, C5), 56.9 (C, C7), 127.0 (2CH, C2'), 127.3 (CH, C4'), 127.6 (2CH, C3'), 128.8 (2CH, C2), 129.6 (2CH, C3), 133.8 (C, C4), 140.1 (C, C1), 140.7 (C, C1 '), 167.3 (CH, C6), [a]_D ²⁴ -195.8 (c 1 .0, CHCI₃), 99% e.e., IR (v_max cm ¹) 2960 (C-H alkyl), 2328 (N-S=0 sulfinamide), 1620 (C=N imine), 1487 (C=C aromatic), 1363 (S=0 sulfinyl), 1086, HRMS- ESI⁺: m/z [M+H]⁺ Calcd for C₁₈H₂₂NOS: Expected: 300.1422. Found: 300.1417. Example 5: Ethyl 2-(bromomethyl) acrylate (14)

To a stirred solution of ethyl 2-(hydroxyl-methyl) acrylate (2 g, 15.4 mmol) in diethyl ether (15 mL), at

0 °C phosphorus tribromide (0.51 mL, 5.4 mmol) was

5 added dropwise. The reaction mixture was stirred for 3 h from 0 °C to room temperature. Water (5 mL) was

C₆H₉Br0₂

added and the product was extracted with hexanes (3 ^χ 10 mL). The combined organic layers was washed with brine (2 x 10 mL), dried over anhydrous MgS0₄, filtered and concentrated in vacuo to give 2-(bromomethyl)propenoic acid ethyl ester 14 (2.4 g, 12.3 mmol, 82 %) as a colourless liquid which was used in the next step without further purification. Colourless oil; ¹ H NMR (400 MHz, CDCI₃) δ 1 .30 (t, J=7.2 Hz, 3H, H6), 4.16 (s, 2H, H4), 4.24 (q, J=7.0 Hz, 2H, H5), 5.92 (s, 1 H, H1 '), 6.30 (s, 1 H, H1), ¹³C NMR (101 MHz, CDCI₃) δ 14.1 (CH₃, C6), 29.3 (CH₂, C4), 61 .2 (CH₂, C5), 128.8 (CH₂, C1), 137.6 (C, C2), 164.8 (C, C3), IR (v_max cm ¹) 1718 (C=0 ester), 1628 (C=C alkene), 1 182 (C-O ester), 523 (C-Br), HRMS-ΕΓ: m/z [M+H]⁺ Calcd for C₆H₁₀BrO₂:

Expected: 192.9864. Found: 192.6870.

The starting material ethyl-2-(hydroxyl-methyl)acrylate was prepared as follows:

Ethyl 2-(hydroxyl-methyl) acrylate (28)

¹ 20 To a stirred solution of ethyl acrylate (32 mL,

I 300 mmol) in dioxane:H₂0 (1 :1 (v/v), 100 mL) at room temperature formaldehyde aqueous solution

(37 wt%, 8.2 mL, 100 mmol) and DABCO (1 1 .2 g, 100 mmol) were added, and the reaction mixture

^{6 J} 25 was stirred at room temperature for 48 h. To the reaction mixture sodium chloride (5 g) and diethyl ether (100 mL) were added. The organic layers were separated and then the product was extracted with diethyl ether (3 ^χ 50 mL). The combined organic layers were washed with brine (100 mL), dried over MgS0₄, filtered, and concentrated in vacuo to give the crude product. Purification by silica gel

chromatography (30 % EtOAc-hexane) yielded ethyl 2-(hydroxyl-methyl) acrylate (10.4 g, 80 mmol, 80 %) as a colourless oil. ¹H NMR (400 MHz, CDCI₃) δ 1 .31 (t, J=7.1 Hz, 3H, H6), 2.40 (s, 1 H, OH), 4.24 (q, J=7.1 Hz, 2H, H5), 4.32 (d, J=6.2 Hz, 2H, H4), 5.82 (s, 1 H, H1 '), 6.24 (s, 1 H, H1), ¹³C NMR (101 MHz, CDCI₃) δ 14.0 (CH₃, C6), 60.7 (CH₂, C5), 61 .9 (CH₂, C4), 125.1 (C, C1), 139.7 (C, C2), 166.3 (C, C3), IR (v_max cm ¹) 3414 (O-H, alcohol), 1707 (C=0 ester), 1637 (C=C alkene), 1 153 (C-O ester), 1052 (C-O ester) Example 6: Sufinamide 15:

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. J. Am. Chem. Soc. 2002, 124, 2882). Dropwise addition of hydrogen peroxide over 18 hours and regular monitoring of the reaction by ¹H NMR prevented over-oxidation and 10 98% conversion to the desired mono-oxidised product was achieved. The crude material was then dissolved in THF and added via a dropping funnel to LiNH₂ in NH₃ at -78 °C. Subsequent S_N2 attack at the sulfinyl results in elimination of fe/ -butylthiol and inversion of the stereochemistry to provide enantiopure sulfinamide 15 in 48% yield, after

recrystallisation.

UNH₂, NH₃

G

Fe(N0₃)₃ .9H₂0 i!

H₂N"^S'''f-Bu

recrystallization

48% yield

15

Scheme Batch 2: Synthesis of Sulfinamide 15

Example 7: (4R)-5-(4-Biphenylyl)-4-[(R)-tert-butylsulfinylamino]-2-methylenepentanoic acid ethyl ester ({4R)-30) A mixture of (£)-[2-(4-biphenylyl)ethylidene](tert- butylsulfinyl)amine (2.0 g, 6.7 mmol), 2-(bromomethyl)- propenoic acid ethyl ester (1 .2 ml_, 8.7 mmol) and indium powder (3.1 g, 26.7 mmol) in a saturated aqueous NaBr solution (87 ml_) was stirred for 36 h at room temperature. The resulting mixture was extracted

with EtOAc (3 ^χ 20 ml_), dried over anhydrous MgS0₄, filtered and the solvent was removed under vacuum to

C24H31 O3S

give crude product. Purification by silica gel chromatography (40% EtOAc-hexane) yielded (4R)-5-(4-biphenylyl)-4-[(R)-tert- butylsulfinylamino]-2-methylenepentanoic acid ethyl ester (4R)-30 (1 .9 g, 4.88 mmol, 73%) as a viscous yellow oil. ¹H NMR (400 MHz, CDCI₃) δ 1 .08 (s, 9H, H16), 1 .27 (t, J=7.2 Hz, 3H, H18), 2.63 (m, 2H, H3), 2.82 (dd, J=14.0, 6.4 Hz, 1 H, H5") 2.90 (dd, J=14.0, 7.2 Hz, 1 H, H5), 3.71 (d, J=5.5 Hz, 1 H, NH), 3.76 (m, 1 H, H4), 4.19 (q, 2H, H17), 5.67 (s, 1 H, H14"), 6.31 (s, 1 H, H14), 7.24 (d, J=8.0 Hz, 2H, H7), 7.29 (t, J=7.2 Hz, 1 H, H13), 7.39 (t, J=7.5 Hz, 2H, H12), 7.49 (d, J=8.0 Hz, 2H, H8), 7.54 (d, J=7.6 Hz, H2, H1 1), ¹³C NMR (101 MHz, CDCI₃) δ 14.2 (CH₃, C18), 22.6 (3CH₃, C16), 38.0 (CH₂, C3), 41 .9 (CH₂, C5), 55.8 (CH, C4), 56.8 (C, C15), 61 .0 (CH₂, C17), 126.9 (2CH, C1 1), 127.0 (CH₂, C14), 127.2 (CH, C13), 128.5 (2CH, C8), 128.8 (2CH, C12), 130.03 (2CH, C7), 137.1 (C, C2), 137.3 (C, C6), 139.3 (C, C9), 140.8 (C, C10), 167.4 (C, C1), IR (v_max cm ¹) 2980 (C-H alkyl), 1710 (C=0 ester), 1629 (C=C alkenyl), 1487 (C=C aromatic), 1 180 (C-O ester), 1049 (S=0 sulfinyl); [a]_D ²⁴ - 19.3 (c 1 .0, CHCI₃), HRMS-ΕΓ: m/z [M+H]⁺ Calcd for C₂₄H₃₂N0₃S: Expected: 414.2103. Found: 414.2097. HPLC 98% ee Daicel Chiralpak AD-H column, 90:10

hexanes/isopropanol; 0.9 mL/min, 254 nm; t_R, (R) = 12.4 min; t_R, (S) = 17.0 min.

Example 8: (4R)-5-(4-Biphenylyl)-4-[(R)-tert-butylsulfinylamino]-2-methylenepentanoic acid ((4R)-3)

To a stirred solution of (4R)-5-(4-biphenylyl)-4-[(R)- tert-butylsulfinylamino]-2-methylenepentanoic acid 30 ethyl ester (200 mg, 0.5 mmol) in H₂0:THF (1 :1 , 2.5 ml_), at 0 °C lithium hydroxide monohydrate (120 , mg, 5.0 mmol) was added. The reaction mixture was ' stirred at room temperature for 12 h. The reaction was quenched by addition of phosphoric acid (85%

35 v/v) until pH 3-4 was obtained. Et₂0 (10 ml_) was

C22H27^NC½S added and the aqueous layer removed. The remaining organic layer was washed with brine (5 ml_), dried with MgS0₄ and the solvent removed under vacuum. The residue was dissolved in the minimum amount of CH₂CI₂ followed by slow addition of hexane to crystallise (4R)-5-(4-biphenylyl)-4-[(R)-tert- butylsulfinylamino]-2-methylenepentanoic acid (185 mg, 0.49 mmol, 98 %) (4R)-3 as a white amorphous solid; mp 136-137 °C; ¹H NMR (400 MHz, CDCI₃) δ 1 .19 (s, 9H, H16), 2.52 (dd, J=14.3, 9.2 Hz, 1 H, H3'), 2.58 (dd, J=14.2, 3.6 Hz, 1 H, H3), 2.78 (dd, J=13.8, 7.5 Hz, 1 H, H5'), 2.97 (dd, J=13.8, 6.6 Hz, 1 H, H5), 3.77 (m, 1 H, H4), 4.87 (s, 1 H, NH), 5.64 (s, 1 H, H14'), 6.34 (s, 1 H, H14), 7.27 (d, J=7.8 Hz, 2H, H7), 7.34 (t, J=7.4 Hz, 1 H, H13), 7.43 (t, J=7.6 Hz, 2H, H12), 7.53 (d, J=8.1 Hz, 2H, H8), 7.58 (d, J=7.2 Hz, 2H, H1 1), ¹³C NMR (101 MHz, CDCI₃) δ 22.8 (3CH₃, C16), 37.3 (CH₂, C3), 42.6 (CH₂, C5), 56.2 (C, C15), 57.5 (CH, C4), 127.0 (2CH, C1 1), 127.1 (2CH, C8), 127.2 (CH, C13), 128.7 (2CH, C12), 129.2 (CH₂, C14), 130.0 (2CH, C7), 137.1 (C, C6), 137.5 (CCH₂, C2), 139.4 (C, C9), 140.8 (C, C10), 170.1 (C, C1), IR (Vmax cm ¹) 2963 (C-H alkyl), 1694 (C=0 ester), 1627 (C=C alkenyl), 1487 (C=C aromatic), 1 185 (C-O ester), 1007 (S=0 sulfinyl), [a]_D ²³ -70.3 (c 1 .0, CHCI₃), HRMS- El⁺: m/z [M+H]⁺ Calcd for C₂₂H₂₈N0₃S: Expected: 386.1790. Found: 386.1780. HPLC 97 % ee Daicel Chiralpak AD-H column, 90:10 hexanes/isopropanol; 0.75 mL/min, 254 nm; t_R, (R) = 16.9 min; t_R, (S) = 8.8 min. The other diastereomers could not be observed above baseline noise.

Example 9: (2R, 4S)-5-(4-Biphenylyl)-4-[(R)-tert-butylsulfinylamino]-2-methylpentanoic acid ((2R,4S)-2)

C22H29NO3S (0.1 mol%), diisopropylethylamine (0.03 ml_, 194 vmol,

0.9 eq) and 'PrOH (0.72 ml_) at room temperature. The reactor was purged with H₂ (20 bar) three times. The reaction mixture was stirred at room temperature under H₂ (20 bar) for 20 h. After venting the H₂ gas, the reaction mixture was filtered through celite and the solvent was removed in vacuo to yield crude product. Purification by recrystallization in hexane gave (2R, 4S)-5-(4-biphenylyl)-4-[(f?)-tert-butylsulfinylamino]-2-methylpentanoic acid (2R,4S)-2 (72 mg, 194 vmol, 90 %). Colourless amorphous solid; mp 151 -152 °C; ¹H NMR (400 MHz, CDCI₃) δ 1 .10 (s, 9H, H16), 1 .23 (d, J=6.8 Hz, 3H, H14), 1 .58 (ddd, J=14.4, 10.3, 4.0 Hz, 1 H, H3'), 2.07 (ddd, J = 14.4, 10.7, 3.6 Hz, 1 H, H3), 2.74 (dd, J=13.8, 8.2 Hz, 1 H, H5'), 2.81 -2.89 (m, 1 H, H2), 2.93 (dd, J=13.8, 5.1 Hz, 1 H, H5), 3.37 (d, J=7.5 Hz, 1 H, NH), 3.66 (m, 1 H, H4), 7.22 (d, J=8.1 Hz, 2H, H7), 7.34 (t, J=7.4 Hz, 1 H, H13), 7.43 (t, J=7.7 Hz, 2H, H12), 7.52 (d, J=8.1 Hz, 2H, H8), 7.56 (d, J=7.1 Hz, 2H, H1 1 ), ¹³C NMR (101 MHz, CDCI₃) δ 18.1 (CH₃, C14), 22.7 (3CH₃, C16), 36.5 (CH₂, C3), 41 .2 (CH₂, C5), 43.2 (CH, C2), 56.2 (CH, C4), 57.2 (C, C15), 127.0 (2CH, C1 1), 127.1 (2CH, C8), 127.2 (2CH, C12), 128.8 (CH, C13), 130.1 (2CH, C7), 136.7 (C, C6), 139.5 (C, C9), 140.8 (C, C10), 171 .8 (C, C1), IR (v_max cm ¹) 3264 (N-H sulfinamide), 2920 (C-H alkyl), 1708 (C=0 acid), 1206 (S=0 sulfinyl), 1006, [a]_D ²⁰ (c 1 .0, CHCI₃) -15.8, HRMS-EI⁺: m/z [M+H]⁺ Calcd for C22H30NO3S: Expected: 388.1946. Found: 388.1958.

Example 10: (2R, 4S)-5-(4-Biphenylyl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride ((2R, 4S)1)

To a stirred solution of (2R, 4S)-5-(4-biphenylyl)-4-

[(R)-tert-butylsulfinylamino]-2-methylpentanoic acid (50 mg, 134 vmol) in absolute ethanol (0.4 ml_), at 0 °C thionylchloride (20 μΙ_, 268 μηιοΓ) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction was evaporated to dryness to furnish (2R, 4S)-5-(4-biphenylyl)-4-amino-2-

methylpentanoic acid ethyl ester hydrochloride (2R, 4S)1 as a white solid (45 mg, 130 vmol, 99%). Colourless amorphous solid; ¹H NMR (600 MHz, DMSO-c/₆) δ 1 .06 (d, J=7.1 Hz, 3H, H14), 1 .09 (t, J=7.1 Hz, 3H, H16), 1 .58 (ddd,

J=13.8, 8.1 , 5.4 Hz, 1 H, H3'), 1 .85 (ddd, J=14.3, 9.1 , 5.0 Hz, 1 H, H3), 2.69-2.76 (m, 1 H, H2), 2.80 (dd, J=13.8, 8.1 Hz, 1 H, H5'), 3.03 (dd, J=13.8, 5.5 Hz, 1 H, H5), 3.35-3.41 (m, 1 H, H4), 3.98 (q, J=7.1 Hz, 2H, H15), 7.35 (d, J=8.0 Hz, 2H, H7), 7.35 (t, J=7.4 Hz, 1 H, H13), 7.46 (t, J=7.7 Hz, 2H, H12), 7.64 (dd, J=7.8 Hz, 2H, H8), 7.66 (d, J=7.8 Hz, 2H, H1 1 ), 8.16 (br. s, 3H, NH₃), ¹³C NMR (151 MHz, DMSO-c/₆) δ 13.9 (CH₃, C16), 17.5 (CH₃, C14), 35.0 (CH, C2), 35.5 (CH₂, C3), 38.1 (CH₂, C5), 50.4 (CH, C4), 60.1 (CH₂, C15), 126.5 (2CH, C8), 126.8 (2CH, C1 1), 127.4 (CH, C13), 128.9 (2CH, C12), 130.0 (2CH, C7), 135.5 (C, C6), 138.7 (C, C9), 139.7 (C, C10), 174.7 (C, C1), HRMS-ESI⁺: m/z [M+H]⁺ Calcd for C₂oH26N0₂: Expected: 312.1964. Found: 312.1967. HPLC (Chiralpak AD-H, 250mm, 4.6 mm I.D., 5.0 urn; isocratic n-Hexane/ethanol/methanol/triethylamine 80/10/10/0.2; 40°C; 0.8 ml/min; 254 nm; run time 23 mins) (2R,4S)-1 (97.07%) and isomers, (2S,4R)-1 (0.21 %), (2S,4S)-1

(2.32%) and (2R,4R)-1 (0.40%). Flow Synthesis - Results and Discussion

Investigations into the flow route were carried out in parallel to the investigations into a batch route. Attention was focused on the Zn-mediated route to AHU377 as this route allowed for ample material to be put aside for flow optimisations.

As set out at the beginning the advances in gas-flow methodology could be utilised in the flow assisted API synthesis.

Proposed Flow Route

It was envisaged that by substituting biphenyl 17 from the batch route for 4-iodobiphenyl 33 it will be possible to apply both the ethylene Heck methodology and anti-Markovnikov Wacker oxidation methodology in the flow synthesis of AHU377 intermediate (2R,4S)-1 . It is expected that the same end-game approach used in the batch synthesis can be easily modified for flow mode, while key building block, acetaldehyde 16 may be prepared in two steps from iodide 33 via an ethylene Heck coupling followed by aerobic anti-Markovnikov Wacker oxidation.

enantioseiective meiai '-mediated

hydrogenation carbethoxyallyiation

3 key building blocks

kov tion

Commercially

available

Scheme FLOW A: Retrosynthetic flow approach to (2R,4S)-1 Synthesis of (4-biphenyl)acetaldehyde 16

Pleasingly, it was found that 4-iodobiphenyl 33 could be transformed into 4-phenylstyrene 32 in quantitative yield (Scheme FLOW B, see Figure 3). Solid supported scavengers QP-TU and QP-SA were employed to remove both palladium and base from the reaction stream respectively, after which removal of the solvent provided 32 which was used directly in the next step without further purification. The corresponding Scheme ("Flow B", flow preparation of 4-phenylstyrene)) is shown in Figure 3.

Using conditions for an anti-Markovnikov Wacker oxidation of styrenes, 4-phenylstyrene 32 could then be oxidised to acetaldehyde 16 (Fig. 4 = "Scheme FLOW C: Preparation of 4- (biphenylyl)acetaldehyde 16). Full conversion of the starting material was achieved with a 86% selectivity for the desired compound over formation of the corresponding benzaldehyde and methyl ketone by-products. Crystallization of the sulfite aldehyde adduct was investigated as a means of purification but mass recovery was very low (<20%). Therefore, column chromatography was necessary to provide pure 16 in 80% yield.

As shown in Fig. 5 ("Scheme Flow D"; flow preparation of imine 29), condensation of acetaldehyde 16 with sulfinamide 15 in the presence of PPTS (5 mol%) and MgS0₄ took several hours to reach completion in batch mode. However, we found that by flowing the reaction mixture through a column of MgS0₄ heated to 70 °C followed by QP-SA and QP- BZA, to scavenge PPTS and the small excess of sulfinamide 15, full conversion to imine 29 could be achieved in less than 10 minutes. It was also possible to apply the same solvent system as that used in the previous oxidation step, potentially allowing for the two steps to be telescoped together into a single multistep process if an in-line purification method for imine 29 could be found.

The key Reformatsky-type carbethoxyallylation reaction was also successfully transferred to flow mode (Fig. 6; "Scheme Flow E", flow preparation of acrylic ester (4R)-30). The reaction mixture containing imine 29, bromide 14 and LiCI as additive, was passed through a column containing activated zinc dust. A residence time of <5 minutes through the zinc column followed by quenching with polymer supported reagents never resulted in more than 95% conversion of imine 29. However, the addition of a 10 mL reaction coil maintained at room temperature after the zinc column extended the residence time by approximately 30 minutes resulting in full conversion of the imine. Initially, DMF was used as the solvent of choice but in our efforts to telescope the reaction with the previous imine formation we discovered that the Zn-mediated carbethoxyallylation also proceeded in 'PrOH or 'BuOH with similar conversions, this would allow the process to be telescoped with the previous 2 steps in the synthesis. Several unknown by-products were formed and analysis of the crude material revealed it to be roughly 80% pure, containing exclusively the (S_s,4R)-30 diastereomer. Purification of the crude material by column chromatography provided the desired product as a yellow oil in 70% yield.

To our knowledge this is the first example of a Reformatsky-type reaction performed in continuous flow. There are clear benefits to running this reaction in flow; the reaction is run as a slurry in batch and requires slow addition of the bromide due to the exothermic formation of the organozinc. In flow, we were able to observe efficient dissipation of heat away from the narrow zinc packed column when reagents were combined in a 1 :1 .2 ratio with reaction times of less than 30 minutes, compared to several hours in batch.

Following development of the flow carbethoxyallylation it was our intention to perform the hydrolysis in batch so that we could quickly move onto the hydrogenation of (4R)-3 in flow using the tube-in-tube reactor.

The following steps as shown in Fig. 7 describe the further reactions starting from compound (4R)-30 after hydrolysis of the ethyl group to the acid:

(Note: The ethyl is removed by hydrolysis before the hydrogenation so that hydrogenation can be performed on the free acid (better selectivity). After hydrogenation, the ethyl ester is reformed and concomitant sulfinyl deprotection provides the final desired compound HCI salt.)

This work has demonstrated the potential benefits of a flow approach towards the synthesis of AHU377 and LCZ696.

In detail, reactions were as follows:

Example 10: 4-Phenylstyrene (32)

4-lodobiphenyl (1 .5 mmol), Cy₂NMe (1 .2 eq), Pd(OAc)₂ (1 mol%), ⁱBuPH BF₄ (2 mol%) were dissolved in PhMe/MeOH (5 ml_, 9:1 ). The reaction mixture was injected into a Uniqsis™ Flowsyn reactor (Uniqsis Ltd. Shepreth, Cambridgeshire, UK) via a 5 ml_ PEEK injection loop. 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

°C; ¹H NMR (400 H6a), 5.81 (d,

1 1 .0 Hz, 1 H, H5),

C1 H1 12 5 7.36 (t, J=7.5 Hz, 1 H, H4'), 7.45 (t, J=7.5 Hz, 2H, H3'),

7.50 (d, J=8.2 Hz, 2H, H3), 7.59 (d, J=8.0 Hz, 2H, H2), 7.62 (d, J=7.8 Hz, 2H, H2'), ¹³C NMR (101 MHz, CDCI₃) δ 1 13.8 (CH₂, C6), 126.6 (2CH, C3), 126.9 (2CH, C2'), 127.2 (2CH, C2), 127.3 (CH, C4'), 128.7 (2CH, C3'), 136.4 (C, C5), 136.6 (C, C4), 140.5 (C, C1 ), 140.7 (C, C1 '), IR (Vmax Cm ¹) 3034 (C-H aromatic), 1626 (C=C alkenyl), 1483 (C=C aromatic), HRMS- El⁺: m/z [M+H]⁺ Calcd for C₁₄H₁₃: Expected: 181 .1012. Found: 181 .1012.

Example 1 1 : (4-Biphenyl)acetaldehyde (16)

4-phenylstyrene (0.4 mmol) was dissolved in PhMe/'BuOH (1 :6, 2 mL, 0.2 M) and loaded into injection loop A (2 mL). (MeCN)₂PdCI₂ (5 mol%), CuCI₂ (5 mol%) and H₂0 (1 .4 eq) were dissolved in PhMe/'BuOH (1 :6, 2 mL) and loaded into injection loop B (2 mL). The reagents were then both pumped using a Uniqsis™ Flowsyn reactor via the 2 mL PEEK injection loops A and B at a combined flow rate of 0.5 mL/min (using PhMe/'BuOH (1 :6) as stock solvent). The combined reagent stream was then pumped through a tube-in-tube gas reactor (1 .5 m AF-2400) pressurised with pure 0₂ (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

(containing the reaction plug and any dispersion) was collected into a vial (flushed with nitrogen) and a sample taken for GC analysis. The solvent was removed under vacuum and the crude residue purified by column chromatography to provide (4-biphenyl)acetaldehyde as a colourless crystalline solid (63 mg, 0.32 mmol, 80% yield).

Example 12: (E)-[2-(4-Biphenylyl)ethylidene](tert-butylsulfinyl)amine ((S_s)-29)

(4-Biphenyl)acetaldehyde (392 mg, 2 mmol) was dissolved in PhMe/'BuOH (1 :9, 2 mL, 1 M) and loaded into injection loop A (2 mL). (S)-fe/?-butylsulfinamide (266 mg, 2.2 mmol, 1 .1 eq) and PPTS (5 mol%) dissolved in PhMe/'BuOH (1 :6, 2 mL) and loaded into injection loop B (2 mL). The reagents are pumped using a Uniqsis™ 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 MgS0₄ (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

(£)-[2-(4-Biphenylyl)ethylidene](tert-butylsulfinyl)amine (S_s)-29as an orange amorphous solid (595 mg, 2.0 mmol, 99%). Example 1 3: (4R)-5-(4-biphenylyl)-4-[(S)-tert-butylsulfinylamino]-2-methylenepentanoic acid ethyl ester (30)

(£)-[2-(4-Biphenylyl)ethylidene](tert-butylsulfinyl)amine (595 mg, 2 mmol) dissolved in 'PrOH (2 mL, 1 M) and loaded into injection loop A (2 mL). (460 mg, 2.4 mmol, 1 .2 eq) and LiCI (4 eq) dissolved in 'PrOH (2 mL) and loaded into injection loop B (2 mL). The reagents were pumped using a Uniqsis™ Flowsyn reactor via the 2 mL PEEK injection loops A and B at a combined flow rate of 0.2 mL/min (using 'PrOH as stock solvent). The combined reagent stream then flowed through an Omnifit column (3 mm i.d . χ 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. Purification of the crude residue by column chromatography provided (4R)-5-(4-biphenylyl)-4-[(S)-tert-butylsulfinylamino]-2-methylenepentanoic acid ethyl ester 30 as a colourless oil (579 mg , 1 .4 mmol, 70%).

Claims

Claims:

comprising reacting a sulfinamide compound of the formula (II), or a salt thereof,

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is butyl, especially tert-butyl, or p-tolyl, and R is as defined for a compound of the formula (I),

in the presence of an acyl halide reagent, preferably in the presence of an alcohol of the formula R"'-OH wherein R'" is hydrogen or a carboxyl protecting group or Ci-C₆-alkyl, and optionally removing and/or replacing any protecting groups,

to obtain the compound of formula (I).

2. The process according to claim 1 , wherein the compound of the formula I is a compound of the formula la, or a salt thereof

(|a)

and the sulfinamide compound of formula II is a compound of the formula lla, or a salt thereof

3. A process for the manufacture of a sulfinamide compound of the formula (II) or a salt thereof,

wherein Ra is Ci-C₆-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is butyl, especially tert-butyl, or p-tolyl and R is hydrogen or a carboxyl protecting group or C CValkyl, preferably hydrogen or ethyl, comprising hydrogenating a compound of the formula (III), or a salt thereof,

wherein R and Ra are defined as for the compound of formula (II), in the presence of a hydrogenation catalyst,

to obtain the compound of formula (II).

4. The process according to claim 3, wherein the compound of formula II is of the formula Ma, or a salt thereof,

and wherein the compound of the formula (III) is a compound of the formula (Ilia), or a salt thereof

and wherein the hydrogenation catalyst is a chiral hydrogenation catalyst.

5. The process according to claim 1 or 2, wherein the starting sulfinamide compound of formula (II) or (Ma) is obtained according to the process of claim 3 or 4.

6. A process for the manufacture of a compound of the formula (III), or a salt thereof,

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is butyl, especially tert-butyl, or p-tolyl and 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,

Ra (IV)

wherein Ra is as defined for a compound of the formula III,

in the presence of a transition metal under carboxyethoxyallylation conditions with an acrylate compound of the formula (V),

wherein X is a leaving group, especially halogen, and R* is a carboxyl protecting group, and, optionally, removing a protecting group R*,

to obtain the compound of formula (III).

7. The process according to claim 6, wherein the compound of the formula (III) is a compound of the formula (Ilia), or a salt thereof

and the compound of the formula (IV) is a compound of the formula (Iva), or a salt thereof

or the enantiomer thereof.

8. The process according to claim 3 or 4, wherein the starting compound of formula (III) or (Ilia) is obtained according to the process of claim 6 or 7.

5 9. The process according to claim 1 or 2, wherein the starting sulfinamide compound of formula (II) or (Ma) is obtained according to the process of claim 3 or 4, and the starting compound of formula (III) or (Ilia) in claim 3 or 4 is obtained according to the process of claim 6 or 7.

10 10. A process for the manufacture of a compound of the formula (IV), or a salt thereof,

"Ra (IV)

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 15 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is butyl, especially tert-butyl, or p-tolyl, comprising reacting an aldehyde

with a sulfinamide of the formula (VII),

H₂N

\

20 Ra (vii)

wherein Ra is as defined for a compound of the formula (IV),

to obtain the compound of formula (IV).

1 1 . The process according to claim 10, wherein the compound of the formula (IV) is of 25 formula (IVa), or a salt thereof,

or the enantiomer thereof, and

the sulfinamide of formula (VII) is of the formula (Vila),

H

5 or the enantiomer thereof.

12. The process according to claim 6 or 7, wherein the starting compound of formula (IV) or (IVa) is obtained according to the process of claim 10 or 1 1 .

10 13. The process according to claim 3 or 4, wherein the starting compound of formula (III) or (Ilia) is obtained according to the process of claim 6 or 7, and the starting compound of formula (IV) or (IVa) in claim 6 or 7 is obtained according to the process of claim 10 or 1 1 .

14. The process according to claim 1 or 2, wherein the starting sulfinamide compound of 15 formula (II) or (Ma) is obtained according to the process of claim 3 or 4, and the starting compound of formula (III) or (Ilia) in claim 3 or 4 is obtained according to the process of claim 6 or 7, and the starting compound of formula (IV) or (IVa) in claim 6 or 7 is obtained according to the process of claim 10 or 1 1 .

20 15. The process according to any one of claims 10 to 14, wherein the aldehyde of

formula (VI)

is prepared by a process comprising

(i) treating a biphenyl of the formula (XI)

with a glyoxylate of formula (XII)

Y-CO-C0₂R** (XII)

wherein Y is a leaving group, especially halogen, and R** is a carboxyl protecting group, especially C C₆-alkyl, preferably ethyl,

in the presence of an acid, preferably a Lewis acid,

to obtain a keto acid of the formul

wherein R** is a carboxyl protecting group, especially C Ce-alkyl, preferably ethyl;

(ii) treating the obtained keto acid of the formula (X) under selective reduction of the keto group to a hydroxyl group to obtain a hydroxylic acid of the formula (IX)

wherein R** is a carboxyl protecting group, especially C Ce-alkyl, preferably ethyl,

(iii) treating the obtained hydroxylic acid of the formula (IX) under selective reduction of the hydroxyl group to obtain a carboxylic acid ester of formula (VIII)

(VIII)

wherein R** is a carboxyl protecting group, especially C Ce-alkyl, preferably ethyl, and (iv) treating the obtained carboxylic acid ester of formula (VIII) under selective reduction conditions to obtain the desired compound of formula (VI).

16. The process according to any one of claims 10 to 14, wherein the aldehyde of formula (VI)

is prepared by a process comprising

(i) reacting a compound of the formula (XIV)

wherein Hal is halo, especially iodo or bromo,

in an ethylene Heck reaction to obtain a compound of the formula (XIII)

and

(ii) treating the obtained compound of the formula (XIII) via anti-Markovnikov Wacker oxidation in the presence of a catalyst, preferably under flow preparation conditions, to obtain the compound of formula (VI).

17. A process according to any one of claims 10 to 16, wherein the sulfinimide compound of the formula (VII)

H₂N

\

Ra (Vii)

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂,

is prepared by a process comprising

(i) a mono-oxidation of a disulfide of the formula (XV)

Ra— S

\

Ra (XV),

wherein both Ra are defined as above for a compound of the formula (VII), (ii) followed by amidation of the resulting sulfinyl sulfide compound of the formula (XVI)

with a metal amide and subsequent S_N2 attack to yield a thiol of the formula Ra-SH and the compound of the formula VII.

5

18. A process according to claims 17, wherein the compound of formula (VII) is of formula (Vila)

or the enantiomer thereof; and

10 the compound of formula (XVI) is of formula (XVIa)

Ra— s

\

0^{X Ra} XVIa

or the enantiomer thereof,

and the mono-oxidation in step (i) is an asymmetric mono-oxidation.

15 19. The process according to any one of claims 1 to 18, wherein the process steps individually or all together are carried out under flow preparation conditions.

A sulfinamide compound selected from the group consisting of

compound of the formula (II) or a salt thereof

20

(ii)

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-C Ce-alkyl, heterocyclyl or heterocyclyl-C Ce-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen,

25 oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is tert-butyl or p-tolyl and

5

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, 10 oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is tert-butyl or p-tolyl and

R is hydrogen or a carboxyl protecting group or C CValkyl, preferably hydrogen or ethyl, especially of the formula Ilia, or a salt thereof,

15 21 . A compound of formula (IV) or a salt thereof,

wherein Ra is C Ce-alkyl, C₆-C₁₀-aryl, Ce-C^-aryl-C Ce-alkyl, C₃-C₈-cycloalkyl, C₃-C₈- cycloalkyl-CrCe-alkyl, heterocyclyl or heterocyclyl-CrCe-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0)₂, preferably Ra is tert-butyl or p-tolyl.

especially of the formula IVa,

or the enantiomer thereof.

22. Use of a compound of formula (II), (III) or (IV) or a salt thereof, according to claim 20 or 21 in the synthesis of the NEP-inhibitor /V-(3-carboxy-1 -oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid or a salt thereof, or the NEP inhibitor prodrug /V-(3-carboxyl-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methyl butanoic acid ethyl ester or a salt thereof.

23. A process for preparing /V-(3-carboxyl-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methyl butanoic acid, or a salt thereof, or N-(3-carboxyl-1 -oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester, or a salt thereof comprising the manufacture of a compound, or a salt thereof, as defined in claim 20 or 21 .