Processes for manufacturing biaryl thioethers

Abstract

The invention provides processes for manufacturing compounds of formula 1a, 1a wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a C1- C4-carbamate; and R2 is a halogen atom selected from F, Cl, and Br. The process according to the invention is particularly suitable for large-scale manufacturing under GMP conditions.

Description

[0001] PROCESSES FOR MANUFACTURING BIARYL THIOETHERS

[0002] Field of the Invention

[0003] The invention relates to processes for manufacturing compounds of formula la, wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci- C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br. The processes according to the invention are particularly suitable for large-scale manufacturing under GMP conditions.

[0004] Background of the Invention 9H-fluoren-9-ylmethyl N-[[2-bromo-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]- carbamate (1) is a crucial building block in the synthesis of the novel macrocyclic peptide antibiotic zosurabalpin (I), as described, for example, in WO2019206853: For marketing products, it is necessary to produce pharmaceuticals in large quantities and according to good manufacturing practice (“GMP”). Hence, high-yielding, cheap, safe, environmentally friendly and reproducible syntheses are of utmost importance.

[0005] WO20 19206853 discloses the laboratory scale synthesis of compound 1 outlined in Scheme 1.

[0006] Scheme 1

[0007] However, it has been found that said laboratory scale synthesis is not suitable for industrial scale manufacturing of compound 1 due to various issues, such as high cost, low yield and use of reagents that are problematic in terms of safety and waste disposal.

[0008] Accordingly, there is a high unmet need for new processes for manufacturing compounds like compound 1.

[0009] Summary of the Invention

[0010] The present invention provides processes for manufacturing compounds of formula la wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci- C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br. The processes according to the invention are superior both in terms of yield and cost efficiency compared to the process for manufacturing compound 1 outlined above, among other advantages.

[0011] One of the key steps of the processes according to the present invention is the reduction of a nitrile of formula 13a wherein one of R1, R2, R3, R4, and R5is a nitrile group; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen; to afford an amine of formula 12a wherein one of R1, R2, R3, R4, and R5is -CH2NH2; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen.

[0012] The key reduction has also been successfully implemented in a continuous flow mode, offering certain advantages over batch mode (as discussed, for example, in Mascia et al., Angew. Chem. Int. Ed. 2013, 52, 12359-12363.).

[0013] Furthermore, some of the steps of the processes according to the invention can be performed without isolating and purifying the intermediates, making the new processes particularly suitable for large-scale manufacturing. Detailed Description of the Invention

[0014] Definitions

[0015] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims and the abstract), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims and the abstract), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0016] The term “protective group” (PG) denotes a group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protective groups can be removed at the appropriate point. Exemplary amino protective groups are Alloc (allyloxycarbonyl), Boc (tert-butoxycarbonyl), Cbz (benzyloxycarbonyl) and Ci-C4-carbamates, such as / -butyl oxy carbonyl. Exemplary protecting groups and their application in organic synthesis are described, for example, in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y, which is included herein by reference in its entirety.

[0017] Manufacturing Processes

[0018] Nitrile Reduction

[0019] One of the key synthetic steps in the processes according to the invention is a particular nitrile reduction with a concomitant disulfide bond reduction.

[0020] Thus, in a first aspect, the present invention provides a process for manufacturing an amine of formula 12a, wherein one of R1, R2, R3, R4, and R5is -CH2NH2; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen; comprising reacting a disulfide of formula 13a, wherein one of R1, R2, R3, R4, and R5is a nitrile group; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen; with a reducing agent, to afford said thiol of formula 12a.

[0021] In a further aspect, the present invention provides a process for manufacturing an amine of formula 12a, wherein one of R1, R2, R3, R4, and R5is -CH2NH2; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen; comprising reacting a disulfide of formula 13a, wherein one of R1, R2, R3, R4, and R5is a nitrile group; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen; with a reducing agent selected from: (i) a preformed mixture of Li AIH4 and H2SO4;

[0022] (ii) a preformed mixture of LiAlFL and AICI3;

[0023] (iii) borane dimethylsulfide complex (BFF-SNfe); and

[0024] (iv) borane-THF complex (BH3-THF); to afford said compound of formula 12a. It was found that free thiols of formula 12c wherein one of R1, R2, R3, R4, and R5is a nitrile group; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen; are unstable under the reaction conditions that are required to reduce the nitrile group to an amino group. By transforming the free thiol 12c to its dimer disulfide 13a prior to the nitrile reduction, as described herein further below, the ensuing nitrile reduction surprisingly produces higher yields and less impurities. In a preferred embodiment, the amine of formula 12a is an amine of formula 12b

[0025] 12b wherein R2is a halogen atom selected from F, Cl, and Br; and the disulfide of formula 13a is a disulfide of formula 13b wherein R2is a halogen atom selected from F, Cl, and Br.

[0026] In a particularly preferred embodiment, the amine of formula 12a is 2-(aminomethyl)-3- bromobenzene-1 -thiol (12) and the disulfide of formula 13a is 2,2'-disulfanediylbis(6-bromobenzonitrile) (13)

[0027] 13

[0028] WO92 / 21668 suggests that LiAllH may be used as a reducing agent for this type of reaction. However, it has now been found that Li AIH4 is not suitable for reducing compounds of formula 13a on an industrial scale, as it leads to the formation of side products, resulting in poor yields and low purities (see Example 10).

[0029] Thus, in one embodiment, said reducing agent is selected from:

[0030] (i) a preformed mixture of LiAlH4 and H2SO4; and

[0031] (ii) a preformed mixture of LiAlH4 and AICI3.

[0032] In one embodiment:

[0033] (i) the molar ratio of LiAlH4 to H2SO4 in said preformed mixture of LiAlH4 and H2SO4 is about 2:1, ±10 mol% of H2SO4, and wherein about 1.5 to about 5 molar equivalents of LiAlH4 are used relative to the disulfide; or

[0034] (ii) about 3.75 molar equivalents of LiAlH4 and about 1.25 molar equivalents of AICI3 are used relative to the disulfide.

[0035] In one embodiment, the reduction is performed at a temperature of about -15 °C to about 0 °C.

[0036] In one embodiment, the reaction mixture is quenched into an acqueous solution of potassium sodium tartrate (“Rochelle salt”) in water.

[0037] In one embodiment, said reducing agent is selected from:

[0038] (i) borane dimethylsulfide complex (BH3-SMe2); and

[0039] (ii) borane-THF complex (BH3-THF).

[0040] In one embodiment, about 3 molar equivalents of borane dimethylsulfide complex or borane-THF complex are used relative to the disulfide. In one embodiment, the borane reduction is performed at a temperature of about 20-25 °C.

[0041] In one embodiment, methanol is added upon completion of the borane reduction.

[0042] In one embodiment, the reduction is performed in THF.

[0043] The process according to the invention is further described in the following numbered clauses:

[0044] Clause 1. The process according to the invention, wherein said reducing agent is selected from:

[0045] (i) a preformed mixture of LiAIF and H2SO4; and

[0046] (ii) a preformed mixture of LiAIF and AICI3.

[0047] Clause 2. The process according to clause 1, wherein:

[0048] (i) the molar ratio of LiAIF to H2SO4 in said preformed mixture of LiAIF and H2SO4 is about 2:1, ±10 mol% of H2SO4, and wherein about 1.5 to about 5 molar equivalents of LiAlFLj are used relative to the disulfide; or

[0049] (ii) about 3.75 molar equivalents of LiAIF and about 1.25 molar equivalents of AICI3 are used relative to the disulfide.

[0050] Clause 3. The process according to clause 1 or 2, wherein the process is performed at a temperature of about -15 °C to about 0 °C.

[0051] Clause 4. The process according to any one of clauses 1 to 3, wherein the reaction mixture is quenched into an acqueous solution of potassium sodium tartrate (“Rochelle salt”) in water.

[0052] Clause 5. The process according to the invention, wherein said reducing agent is selected from:

[0053] (i) borane dimethylsulfide complex (BH3-SMe2); and

[0054] (ii) borane-THF complex (BH3-THF).

[0055] Clause 6. The process according to clause 5, wherein about 3 molar equivalents of borane dimethylsulfide complex or borane-THF complex are used relative to the disulfide. Clause 7. The process according to clauses 5 or 6, wherein the process is performed at a temperature of about 20-25 °C.

[0056] Clause 8. The process according to any one of clauses 5 to 7, wherein methanol is added upon completion of the reaction.

[0057] Clause 9. The process according to any one of clauses 1 to 8, wherein the process is performed in THF.

[0058] The nitrile reduction of the invention has also been implemented as a continuous flow process (see Example 2), which offers a number of advantages over batch mode manufacturing, such as lower amount of process impurities generated and improved process safety.

[0059] Thus, in one embodiment, the nitrile reduction according to the invention is conducted in a continuous flow reactor, preferably in a plug flow reactor (PFR).

[0060] As outlined above, the nitrile reduction according to the invention is a key synthetic transformation in the manufacture of compounds of formula la, which in turn are important building blocks in the manufacture of macrocyclic peptides like zosurabalpin.

[0061] Thus, in a further aspect, the present invention provides a process for manufacturing a compound of formula la, wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci- C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; comprising the nitrile reduction described herein.

[0062] While various protective groups are suitable for the processes according to the invention, it has been found that replacing the Fmoc protective group that is present in compound 1 (vide supra), with an Alloc protective group has certain advantages, such as improved atom economy and solubility of the respective intermediates in most organic solvents, allowing the use of smaller amounts of solvents. In addition, the Alloc protective group can be removed more conveniently than the Fmoc protective group in the further processing of compounds of formula la to zosurabalpin. In a preferred embodiment, the compound of formula la is prop-2-en-l-yl({2-bromo-6-

[0063] [(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl) carbamate (lb)

[0064] Process for Manufacturing Compounds of Formula la As outlined above, the present invention provides processes for manufacturing compounds of formula la that hinge, i.a., on the particular nitrile reductions described herein.

[0065] A first process according to the invention is described in more detail in the following embodiments, as well as in Examples 1 to 4, 8 and 9:

[0066] A process for manufacturing a compound of formula la, wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; comprising reacting a compound of formula 10 wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; R2is a halogen atom selected from F, Cl, and Br; with 2-chloropyr-3-carbaldehyde (11) in the presence of a base, to afford said compound of formula la.

[0067] In one embodiment, the compound of formula 10 is prop-2-en-l-yl [(2-bromo-6- sulfanylphenyl)methyl]carbamate

[0068] 10a and the compound of formula la is prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb)

[0069] In one embodiment, about 1.5 to about 2.5 molar equivalents, preferably about 1.0 molar equivalents of 2-chloropyr-3-carbaldehyde (11) are used relative to the compound of formula 10. In one embodiment, said base is KHCO3, NaHCCh, K2CO3, or Na2CO3, preferably KHCO3.

[0070] In one embodiment, about 1 molar equivalent of base is used relative to the compound of formula 10.

[0071] In one embodiment, the process is performed in a mixture of THF and water.

[0072] In one embodiment, the process is performed at a temperature of about 20 °C to about 65 °C.

[0073] In one embodiment, the compound of formula 10 is is obtained by protecting the primary amine in a compound of formula 12b

[0074] 12b wherein R2is a halogen atom selected from F, Cl, and Br; with a protecting group PG selected from Fmoc, Alloc, Boc, Cbz, and a C1-C4- carbamate.

[0075] In one embodiment, the compound of formula 12b is 2-(aminomethyl)-3 -bromobenzene- 1- thiol (12) and the primary amine is protected with an Alloc protective group by reacting said 2- (aminomethyl)-3 -bromobenzene- 1 -thiol (12) with allyl chloroformate in the presence of a base, to afford prop-2-en-l-yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate

[0076] (10a)

[0077] 10a

[0078] In one embodiment, about 1.0 to about 1.5 molar equivalents, preferably about 1.1 molar equivalents of allyl chloroformate are used relative to 2-(aminomethyl)-3-bromobenzene- 1 -thiol (12).

[0079] In one embodiment, said base is KHCO3.

[0080] In one embodiment, about 1.5 molar equivalents of base are used relative to 2- (aminomethyl)-3 -bromobenzene- 1 -thiol (12).

[0081] In one embodiment, the process is performed in a mixture of THF and water. In one embodiment, the process is performed at a temperature of about 5 °C to about 40 °C, preferably of about 20 °C to about 25 °C.

[0082] In one embodiment, said compound of formula 10 is not isolated prior to reacting it with 2-chloropyr-3-carbaldehyde (11).

[0083] In one embodiment, said compound of formula 12b is obtained by reacting a disulfide of formula 13b wherein R2is a halogen atom selected from F, Cl, and Br, with a reducing agent, to afford said compound of formula 12b.

[0084] In one embodiment, said reducing agent is selected from: (i) a preformed mixture of Li Al LU and H2SO4;

[0085] (ii) a preformed mixture of LiAlFL and AICI3;

[0086] (iii) borane dimethylsulfide complex (BHs-SMe?); and

[0087] (iv) borane-THF complex (BH3-THF).

[0088] In one embodiment, said reducing agent is selected from:

[0089] (i) a preformed mixture of Li AIH4 and H2SO4; and

[0090] (ii) a preformed mixture of LiAlLL and AICI3.

[0091] In one embodiment:

[0092] (i) the molar ratio of LiAlLL to H2SO4 in said preformed mixture of LiAlLL and H2SO4 is about 2:1, ±10 mol% of H2SO4, and wherein about 1.5 to about 5 molar equivalents of LiAlLL are used relative to disulfide 13b; or

[0093] (ii) about 3.75 molar equivalents of LiAlLL and about 1.25 molar equivalents of AICI3 are used relative to disulfide 13b.

[0094] In one embodiment, the process is performed in THF.

[0095] In one embodiment, the process is performed at a temperature of about -15 °C to about 0 °C.

[0096] In one embodiment, the reaction mixture is quenched into an acqueous solution of potassium sodium tartrate (“Rochelle salt”) in water.

[0097] In one embodiment, the compound of formula 12b is not isolated prior to protecting its primary amine.

[0098] In one embodiment, disulfide 13b is reacted with a preformed mixture of LiAlLL and AICI3, and wherein the process is conducted in a continuous flow reactor, preferably in a plug flow reactor (PFR).

[0099] In one embodiment, said disulfide of formula 13b is 2,2'-disulfanediylbis(6- bromobenzonitrile) (13).

[0100] In one embodiment, wherein said 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) is obtained by heating 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide (DMSO).

[0101] In one embodiment, said heating is heating to about 60 °C to about 70 °C.

[0102] In one embodiment, said 2-bromo-6-sulfanylbenzonitrile (14) is obtained by reacting 2- bromo-6-fluorobenzonitrile (15) with sodium sulfide (Na?S).

[0103] In one embodiment, the sodium sulfide is sodium sulfide nonahydrate.

[0104] In one embodiment, about 1.2 molar equivalents of sodium sulfide are used relative to compound 15.

[0105] In one embodiment, the process is performed in dimethyl sulfoxide (DMSO) or in N- Methyl-2-pyrrolidon (NMP), preferably in DMSO.

[0106] In one embodiment, the process is performed at a temperature of about 0 °C to about 10 °C.

[0107] In one embodiment, said 2-bromo-6-sulfanylbenzonitrile (14) is not isolated prior to heating it in DMSO.

[0108] In one aspect, the present invention provides a process for manufacturing prop-2-en-l- yl({2-bromo-6-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl) carbamate (lb),

[0109] 1b comprising:

[0110] (a) reacting 2-bromo-6-fluorobenzonitrile (15)

[0111] CN

[0112] Bryl

[0113] 15 with sodium sulfide (Na?S) to afford 2-bromo-6-sulfanylbenzonitrile (14)

[0114] 14

[0115] (b) heating said 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide

[0116] (DMSO) to afford 2,2’-disulfanediylbis(6-bromobenzonitrile) (13)

[0117] 13

[0118] (c) reacting said 2,2’-disulfanediylbis(6-bromobenzonitrile) (13) with a reducing agent to afford 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12) (d) reacting said 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12) with allyl chloroformate in the presence of a base to afford prop-2-en-l-yl [(2-bromo-6- sulfanylphenyl)methyl]carbamate

[0119] Br .

[0120] 10a and

[0121] (e) reacting said prop-2-en-l-yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate (10a) with 2-chloropyr-3-carbaldehyde (11)

[0122] 11 to afford said prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb).

[0123] In one aspect, the present invention provides a process for manufacturing prop-2-en-l- yl({2-bromo-6-[(3-formylpyridin-2-yl)sulfanyl]phenyl(methyl) carbamate (lb), lb which is:

[0124]

[0125] The first process according to the invention outlined above is also described in the following numbered clauses:

[0126] Clause 1. A process for manufacturing a compound of formula la, wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; comprising reacting a compound of formula 10 wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; R2is a halogen atom selected from F, Cl, and Br; with 2-chloropyr-3-carbaldehyde (11) in the presence of a base, to afford said compound of formula la.

[0127] Clause 2. The process according to clause 1, wherein the compound of formula 10 is prop-2-en-l-yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate (10a)

[0128] 10a and the compound of formula la is prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb) lb

[0129] Clause 3. The process according to clause 1 or 2, wherein about 1.5 to about 2.5 molar equivalents, preferably about 1.0 molar equivalents of 2-chloropyr-3-carbaldehyde

[0130] (11) are used relative to the compound of formula 10. Clause 4. The process according to any one of clauses 1 to 3, wherein, said base is KHCO3, NaHCCh, K2CO3, or Na2CO3, preferably KHCO3.

[0131] Clause 5. The process according to any one of clauses 1 to 4, wherein about 1 molar equivalent of base is used relative to the compound of formula 10.

[0132] Clause 6. The process according to any one of clauses 1 to 5, wherein the process is performed in a mixture of THF and water.

[0133] Clause 7. The process according to any one of clauses 1 to 6, wherein the process is performed at a temperature of about 20 °C to about 65 °C.

[0134] Clause 8. The process according to any one of clauses 1 to 7, wherein the compound of formula 10 is is obtained by protecting the primary amine in a compound of formula 12b

[0135] 12b wherein R2is a halogen atom selected from F, Cl, and Br; with a protecting group PG selected from Fmoc, Alloc, Boc, Cbz, and a C1-C4- carbamate.

[0136] Clause 9. The process according to clause 8, wherein the compound of formula 12b is 2- (aminomethyl)-3 -bromobenzene- 1 -thiol (12)

[0137] 12 and the primary amine is protected with an Alloc protective group by reacting said 2- (aminomethyl)-3 -bromobenzene- 1 -thiol (12) with allyl chloroformate in the presence of a base, to afford prop-2-en-l-yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate (10a)

[0138] 10a

[0139] Clause 10. The process according to clause 9, wherein about 1.0 to about 1.5 molar equivalents, preferably about 1.1 molar equivalents of allyl chloroformate are used relative to 2-(aminomethyl)-3-bromobenzene-l-thiol (12).

[0140] Clause 11. The process according to clause 9 or 10, wherein said base is KHCO3.

[0141] Clause 12. The process according to any one of clauses 9 to 11, wherein about 1.5 molar equivalents of base are used relative to 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12).

[0142] Clause 13. The process according to any one of clauses 9 to 12, wherein the process is performed in a mixture of THF and water.

[0143] Clause 14. The process according to any one of clauses 9 to 13, wherein the process is performed at a temperature of about 5 °C to about 40 °C, preferably of about 20 °C to about 25 °C.

[0144] Clause 15. The process according to any one of clauses 9 to 14, wherein said compound of formula 10 is not isolated prior to reacting it with 2-chloropyr-3-carbaldehyde (11).

[0145] Clause 16. The process according to any one of clauses 8 to 15, wherein said compound of formula 12b is obtained by reacting a disulfide of formula 13b wherein R2is a halogen atom selected from F, Cl, and Br, with a reducing agent, to afford said compound of formula 12b.

[0146] Clause 17. The process according to clause 16, wherein said reducing agent is selected from:

[0147] (i) a preformed mixture of LiAIFU and H2SO4;

[0148] (ii) a preformed mixture of LiAIFU and AICI3;

[0149] (iii) borane dimethylsulfide complex (BHs-SMe?); and

[0150] (iv) borane-THF complex (BH3-THF).

[0151] Clause 18. The process according to clause 16, wherein said reducing agent is selected from:

[0152] (i) a preformed mixture of LiAIFU and H2SO4; and

[0153] (ii) a preformed mixture of LiAIFU and AICI3.

[0154] Clause 19. The process according to clause 18, wherein:

[0155] (i) the molar ratio of LiAIFU to H2SO4 in said preformed mixture of LiAIFU and H2SO4 is about 2:1, ±10 mol% of H2SO4, and wherein about 1.5 to about 5 molar equivalents of LiAlFLj are used relative to disulfide 13b; or

[0156] (ii) about 3.75 molar equivalents of LiAIFU and about 1.25 molar equivalents of AICI3 are used relative to disulfide 13b.

[0157] Clause 20. The process according to any one of clauses 16 to 19, wherein the process is performed in THF.

[0158] Clause 21. The process according to any one of clauses 16 to 20, wherein the process is performed at a temperature of about -15 °C to about 0 °C.

[0159] Clause 22. The process according to any one of clauses 18 to 21, wherein the reaction mixture is quenched into an acqueous solution of potassium sodium tartrate (“Rochelle salt”) in water.

[0160] Clause 23. The process according to any one of clauses 16 to 22, wherein the compound of formula 12b is not isolated prior to protecting its primary amine. Clause 24. The process according to any one of clauses 18 to 23, wherein disulfide 13b is reacted with a preformed mixture of LiAIF and AlCh, and wherein the process is conducted in a continuous flow reactor, preferably in a plug flow reactor (PFR).

[0161] Clause 25. The process according to any one of clauses 16 to 24, wherein said disulfide of formula 13b is 2,2'-disulfanediylbis(6-bromobenzonitrile) (13).

[0162] Clause 26. The process according to clause 25, wherein said 2,2'-disulfanediylbis(6- bromobenzonitrile) (13) is obtained by heating 2-bromo-6-sulfanylbenzonitrile (14)

[0163] Clause 27. The process according to clause 26, wherein said heating is heating to about 60 °C to about 70 °C.

[0164] Clause 28. The process according to clause 26 or 27, wherein said 2-bromo-6- sulfanylbenzonitrile (14) is obtained by reacting 2-bromo-6-fluorobenzonitrile (15) with sodium sulfide (Na?S).

[0165] Clause 29. The process according to clause 28, wherein the sodium sulfide is sodium sulfide nonahydrate.

[0166] Clause 30. The process according to clause 28 or 29, wherein about 1.2 molar equivalents of sodium sulfide are used relative to compound 15.

[0167] Clause 31. The process according to any one of clauses 28 to 30, wherein the process is performed in dimethyl sulfoxide (DMSO) or in N-Methyl-2-pyrrolidon (NMP), preferably in DMSO. Clause 32. The process according to any one of clauses 28 to 31, wherein the process is performed at a temperature of about 0 °C to about 10 °C.

[0168] Clause 33. The process according to any one of clauses 28 to 32, wherein said 2-bromo-6- sulfanylbenzonitrile (14) is not isolated prior to heating it in DMSO.

[0169] Clause 34. A process for manufacturing prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb), comprising:

[0170] (a) reacting 2-bromo-6-fluorobenzonitrile (15) with sodium sulfide (Na?S) to afford 2-bromo-6-sulfanylbenzonitrile (14)

[0171] 14

[0172] (b) heating said 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide

[0173] (DMSO) to afford 2,2'-disulfanediylbis(6-bromobenzonitrile) (13)

[0174] 13

[0175] (c) reacting said 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) with a reducing agent to afford 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12)

[0176] 12

[0177] (d) reacting said 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12) with allyl chloroformate in the presence of a base to afford prop-2-en-l-yl [(2-bromo-6- sulfanylphenyl)methyl]carbamate (10a)

[0178] ^NHAIIoc if Br. ^SH

[0179] 10a and

[0180] (e) reacting said prop-2-en-l-yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate (10a) with 2-chloropyr-3-carbaldehyde (11)

[0181] 11 to afford said prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb).

[0182] Clause 35. A process for manufacturing prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb),

[0183] Further Process for Manufacturing Compounds of Formula 1 a

[0184] In addition to the process for manufacturing compounds of formula la outlined above, the present invention provides a further process for manufacturing compounds of formula la, which is described in the following embodiments, as well as in Examples 5 to 9:

[0185] A process for manufacturing a compound of formula la, wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; comprising reacting a disulfide 16a wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; with HO-CFF-SChNa (Rongalite®) in the presence of a first base, followed by adding a second base and 2-chloropyr-3-carbaldehyde (11) to the reaction mixture to afford said compound of formula la.

[0186] In one embodiment, about 2-3 molar equivalents of HO-CFF-SChNa are used relative to disulfide 16a. In one embodiment, about 2 molar equivalents of compound 11 are used relative to disulfide 16a.

[0187] In one embodiment, said first base and said second base are both K2CO3. In one embodiment, about 2 molar equivalents of first base and about 2 molar equivalents of second base are used relative to compound 16a.

[0188] In one embodiment, the process is performed in THF.

[0189] In one embodiment, the process is performed at a temperature of about 20 °C to about 65 °C.

[0190] In one embodiment, the compound of formula la is prop-2-en-l-yl({2-bromo-6-[(3- formylpyridin-2-yl)sulfanyl]phenyl (methyl) carbamate (lb) and the compound of formula 16a is diprop-2-en-l-yl {disulfanediylbis[(6- bromobenzene-2,l-diyl)methanediyl] (biscarbamate (16)

[0191] 16

[0192] In one embodiment, said disulfide 16a is obtained by (i) reacting a thiol of formula 12b

[0193] 12b wherein R2is a halogen atom selected from F, Cl, and Br; with oxygen to afford a disulfide of formula 17 wherein R2is a halogen atom selected from F, Cl, and Br; followed by (ii) protecting the primary amino groups in the compound of formula 17 with a protecting group PG selected from Fmoc, Alloc, Boc, Cbz, and a C1-C4- carbamate, to afford said disulfide 16a.

[0194] In one embodiment, step (i) is performed in a mixture of acetic acid and water, preferably in a 4:1 (v / v) mixture of acetic acid and water.

[0195] In one embodiment, step (i) is performed at a temperature of about 50-55 °C.

[0196] In one embodiment, in step (i), the compound of formula 12b is 2-(aminomethyl)-3- bromobenzene-1 -thiol (12); and in step (ii), the protecting group PG is Alloc and is introduced by reacting the compound of formula 17, wherein R2is Br, with allyl chloroformate in the presence of a base, to afford diprop-2-en-l-yl {disulfanediylbis[(6- bromobenzene-2,l-diyl)methanediyl]}biscarbamate (16).

[0197] In one embodiment, in step (ii) about 1 molar equivalent of allyl chloroformate is used relative to compound 12.

[0198] In one embodiment, said base in step (ii) is K2CO3.

[0199] In one embodiment, in step (ii), the pH of the reaction mixture is adjusted to about pH 8 to about pH 9 by adding said base prior to adding said allyl chloroformate.

[0200] In one embodiment, step (ii) is performed in a mixture of THF and water.

[0201] In one embodiment, step (ii) is performed at a temperature of about 20 °C to about 30 °C. In one embodiment, said compound of formula 12b is obtained by reacting a disulfide of formula 13b wherein R2is a halogen atom selected from F, Cl, and Br, with a reducing agent, to afford said compound of formula 12b.

[0202] In one embodiment, said reducing agent is selected from:

[0203] (i) a preformed mixture of Li AIH4 and H2SO4;

[0204] (ii) a preformed mixture of LiAILL and AICI3;

[0205] (iii) borane dimethylsulfide complex (BHs-SMe?); and

[0206] (iv) borane-THF complex (BH3-THF).

[0207] In one embodiment, said reducing agent is selected from:

[0208] (i) borane dimethylsulfide complex (BHs-SMe?); and

[0209] (ii) borane-THF complex (BH3-THF).

[0210] In one embodiment, said reducing agent is borane dimethylsulfide complex (BHj-SMe?).

[0211] In one embodiment, about 3 molar equivalents of borane dimethylsulfide complex or borane-THF complex are used relative to disulfide 13b.

[0212] In one embodiment, the reduction is performed in THF.

[0213] In one embodiment, the borane reduction is performed at a temperature of about 20-25 °C.

[0214] In one embodiment, methanol is added upon completion of the borane reduction.

[0215] In one embodiment, said disulfide of formula 13b is 2,2'-disulfanediylbis(6- bromobenzonitrile) (13). In one embodiment, said 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) is obtained by heating 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide (DMSO).

[0216] In one embodiment, said heating is heating to about 60 °C to about 70 °C.

[0217] In one embodiment, said 2-bromo-6-sulfanylbenzonitrile (14) is obtained by reacting 2- bromo-6-fluorobenzonitrile (15) with sodium sulfide (Na?S).

[0218] In one embodiment, the sodium sulfide is sodium sulfide nonahydrate.

[0219] In one embodiment, about 1.2 molar equivalents of sodium sulfide are used relative to compound 15.

[0220] In one embodiment, said reacting 2-bromo-6-fluorobenzonitrile (15) with sodium sulfide is performed in dimethyl sulfoxide (DMSO) or in N-Methyl-2-pyrrolidon (NMP), preferably in DMSO.

[0221] In one embodiment, said reacting 2-bromo-6-fluorobenzonitrile (15) with sodium sulfide is performed at a temperature of about 0 °C to about 10 °C.

[0222] In one embodiment, said 2-bromo-6-sulfanylbenzonitrile (14) is not isolated prior to heating it in DMSO.

[0223] In one aspect, the present invention provides a process for manufacturing prop-2-en-l- yl({2-bromo-6-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl) carbamate (lb), lb comprising:

[0224] (a) reacting 2-bromo-6-fluorobenzonitrile (15) with sodium sulfide (Na?S) to afford 2-bromo-6-sulfanylbenzonitrile (14)

[0225] 14

[0226] (b) heating said 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide (DMSO) to afford 2,2'-disulfanediylbis(6-bromobenzonitrile) (13)

[0227] 13

[0228] (c) reacting said 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) with a reducing agent to afford 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12)

[0229] 12 (d) (i) reacting said 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12) with oxygen; followed by

[0230] (ii) reacting the crude obtained from step (d)(i) with allyl chloroformate in the presence of a base, to afford diprop-2-en-l-yl {disulfanediylbis[(6- bromobenzene-2,l-diyl)methanediyl] (biscarbamate (16)

[0231] .Alloc

[0232] 16 and

[0233] (e) reacting said diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l- diyl)methanediyl] (biscarbamate (16) with HO-CI -SChNa (Rongalite®) in the presence of a first base, followed by adding a second base and 2-chloropyr- 3-carbaldehyde (11)

[0234] 11 to the reaction mixture to afford said prop-2-en-l-yl({2-bromo-6-[(3- formylpyridin-2-yl)sulfanyl]phenyl (methyl) carbamate (lb).

[0235] In one aspect, the present invention provides a process for manufacturing prop-2-en-l- yl({2-bromo-6-[(3-formylpyridin-2-yl)sulfanyl]phenyl(methyl) carbamate (lb), which is:

[0236] The further process for manufacturing compounds of formula la outlined above is also described in the following numbered clauses: Clause 1. A process for manufacturing a compound of formula la, wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; comprising reacting a disulfide 16a wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; with HO-CFF-SChNa (Rongalite®) in the presence of a first base, followed by adding a second base and 2-chloropyr-3-carbaldehyde (11) to the reaction mixture to afford said compound of formula la.

[0237] Clause 2. The process according to clause 1, wherein about 2-3 molar equivalents of HO-CFF-SChNa are used relative to disulfide 16a.

[0238] Clause 3. The process according to clauses 1 or 2, wherein about 2 molar equivalents of compound 11 are used relative to disulfide 16a.

[0239] Clause 4. The process according to any one of clauses 1 to 3, wherein said first base and said second base are both K2CO3.

[0240] Clause 5. The process according to any one of clauses 1 to 4, wherein about 2 molar equivalents of first base and about 2 molar equivalents of second base are used relative to compound 16a.

[0241] Clause 6. The process according to any one of clauses 1 to 5, wherein the process is performed in THF. Clause 7. The process according to any one of clauses 1 to 6, wherein the process is performed at a temperature of about 20 °C to about 65 °C.

[0242] Clause 8. The process according to any one of clauses 1 to 7, wherein the compound of formula la is prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb) and the compound of formula 16a is diprop-2-en-l-yl {disulfanediylbis[(6- bromobenzene-2,l-diyl)methanediyl] (biscarbamate (16)

[0243] Alloc

[0244] AHoC

[0245] 16

[0246] Clause 9. The process according to any one of clauses 1 to 8, wherein said disulfide 16a is obtained by (i) reacting a thiol of formula 12b wherein R2is a halogen atom selected from F, Cl, and Br; with oxygen to afford a disulfide of formula 17 wherein R2is a halogen atom selected from F, Cl, and Br; followed by (ii) protecting the primary amino groups in the compound of formula 17 with a protecting group PG selected from Fmoc, Alloc, Boc, Cbz, and a C1-C4- carbamate, to afford said disulfide 16a.

[0247] Clause 10. The process according to clause 9, wherein step (i) is performed in a mixture of acetic acid and water, preferably in a 4:1 (v / v) mixture of acetic acid and water.

[0248] Clause 11. The process according to clause 9 or 10, wherein step (i) is performed at a temperature of about 50-55 °C.

[0249] Clause 12. The process according to any one of clauses 9 to 11, wherein in step (i), the compound of formula 12b is 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12); and in step (ii), the protecting group PG is Alloc and is introduced by reacting the compound of formula 17, wherein R2is Br, with allyl chloroformate in the presence of a base, to afford diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l- diyl)methanediyl] Jbiscarbamate (16).

[0250] Clause 13. The process according to clause 12, wherein in step (ii) about 1 molar equivalent of allyl chloroformate is used relative to compound 12.

[0251] Clause 14. The process according to clause 12 or 13, wherein said base in step (ii) is K2CO3.

[0252] Clause 15. The process according to any one of clauses 12 to 14, wherein in step (ii), the pH of the reaction mixture is adjusted to about pH 8 to about pH 9 by adding said base prior to adding said allyl chloroformate. Clause 16. The process according to any one of clauses 12 to 15, wherein step (ii) is performed in a mixture of THF and water.

[0253] Clause 17. The process according to any one of clauses 12 to 17, wherein step (ii) is performed at a temperature of about 20 °C to about 30 °C.

[0254] Clause 18. The process according to any one of clauses 9 to 17, wherein said compound of formula 12b is obtained by reacting a disulfide of formula 13b wherein R2is a halogen atom selected from F, Cl, and Br, with a reducing agent, to afford said compound of formula 12b.

[0255] Clause 19. The process according to clause 18, wherein said reducing agent is selected from:

[0256] (i) a preformed mixture of LiAIFU and H2SO4;

[0257] (ii) a preformed mixture of LiAIFU and AICI3;

[0258] (v) borane dimethylsulfide complex (BHs-SMe?); and

[0259] (vi) borane-THF complex (BH3-THF).

[0260] Clause 20. The process according to clause 18, wherein said reducing agent is selected from:

[0261] (i) borane dimethylsulfide complex (BFb-SMe?); and

[0262] (ii) borane-THF complex (BH3-THF).

[0263] Clause 21. The process according to clause 20, wherein said reducing agent is borane dimethylsulfide complex (BHj-SMe?). Clause 22. The process according to clause 20, wherein about 3 molar equivalents of borane dimethylsulfide complex or borane-THF complex are used relative to disulfide 13b.

[0264] Clause 23. The process according to any one of clauses 18 to 22, wherein the process is performed in THF.

[0265] Clause 24. The process according to any one of clauses 18 to 23, wherein the process is performed at a temperature of about 20-25 °C.

[0266] Clause 25. The process according to any one of clauses 20 to 24, wherein methanol is added upon completion of the reaction.

[0267] Clause 26. The process according to any one of clauses 18 to 25, wherein said disulfide of formula 13b is 2,2'-disulfanediylbis(6-bromobenzonitrile) (13).

[0268] Clause 27. The process according to clause 26, wherein said 2,2'-disulfanediylbis(6- bromobenzonitrile) (13) is obtained by heating 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide (DMSO).

[0269] Clause 28. The process according to clause 27, wherein said heating is heating to about 60 °C to about 70 °C.

[0270] Clause 29. The process according to clause 27 or 28, wherein said 2-bromo-6- sulfanylbenzonitrile (14) is obtained by reacting 2-bromo-6-fluorobenzonitrile (15) with sodium sulfide (Na?S). Clause 30. The process according to clause 29, wherein the sodium sulfide is sodium sulfide nonahydrate.

[0271] Clause 31. The process according to clause 29 or 30, wherein about 1.2 molar equivalents of sodium sulfide are used relative to compound 15.

[0272] Clause 32. The process according to any one of clauses 29 to 31, wherein the process is performed in dimethyl sulfoxide (DMSO) or in N-Methyl-2-pyrrolidon (NMP), preferably in DMSO.

[0273] Clause 33. The process according to any one of clauses 29 to 32, wherein the process is performed at a temperature of about 0 °C to about 10 °C.

[0274] Clause 34. The process according to any one of clauses 29 to 33, wherein said 2-bromo-6- sulfanylbenzonitrile (14) is not isolated prior to heating it in DMSO.

[0275] Clause 35. A process for manufacturing prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb), comprising:

[0276] (a) reacting 2-bromo-6-fluorobenzonitrile (15)

[0277] 15 with sodium sulfide (Na?S) to afford 2-bromo-6-sulfanylbenzonitrile (14)

[0278] CN

[0279] Br- A ,..SH 14

[0280] (b) heating said 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide

[0281] (DMSO) to afford 2,2'-disulfanediylbis(6-bromobenzonitrile) (13)

[0282] 13

[0283] (c) reacting said 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) with a reducing agent to afford 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12)

[0284] (d) (i) reacting said 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12) with oxygen; followed by

[0285] (ii) reacting the crude obtained from step (d)(i) with allyl chloroformate in the presence of a base, to afford diprop-2-en-l-yl {disulfanediylbis[(6- bromobenzene-2,l-diyl)methanediyl]}biscarbamate (16) f IH Br

[0286] Alloc and

[0287] (e) reacting said diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l- diyl)methanediyl]}biscarbamate (16) with HO-ClHh-SChNa (Rongalite®) in the presence of a first base, followed by adding a second base and 2-chloropyr- 3-carbaldehyde (11) to the reaction mixture to afford said prop-2-en-l-yl({2-bromo-6-[(3- formylpyridin-2-yl)sulfanyl]phenyl (methyl) carbamate (lb).

[0288] Clause 36. A process for manufacturing prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb), lb which is:

[0289]

[0290] Compounds and Synthetic Intermediates

[0291] The present invention also provides certain compounds and synthetic intermediates that may be obtained by the processes according to the invention and / or are useful for carrying out the processes according to the invention. Thus, in one aspect, the present invention provides a compound of formula 13b or 16a

[0292] wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br.

[0293] In one embodiment, the present invention provides a compound of formula 13b wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F and Br.

[0294] In one embodiment, the present invention provides a compound of formula 16a wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br. In a preferred embodiment, the present invention provides a compound of formula 13b or 16a, which is 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) or diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l-diyl)methanediyl] (biscarbamate (16) In a preferred embodiment, the present invention provides a compound of formula 13b which is 2,2'-disulfanediylbis(6-bromobenzonitrile) (13)

[0295] In a preferred embodiment, the present invention provides a compound of formula 16a which is diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l- diyl)methanediyl] (biscarbamate (16)

[0296] Alloc

[0297] Br HN

[0298] Alloc (16).

[0299] In a further aspect, the present invention provides prop-2-en-l-yl({2-bromo-6-[(3- formylpyridin-2-yl)sulfanyl]phenyl (methyl) carbamate (lb);

[0300] In a further aspect, the present invention provides a compound selected from prop-2-en-l- yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate (10a) and 2-(aminomethyl)-3- bromobenzene-1 -thiol (12):

[0301] Examples

[0302] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0303] The following abbreviations are used in the present text: AlCh = alluminium trichloride; Alloc = Allyloxycarbonyl; Boc = tert-butoxycarbonyl; BH3-THF = borane THF complex; BEE-SMe? = borane dimethylsulfide complex; Cbz = benzyloxy carbonyl; DMSO = dimethylsulfoxide; Fmoc = fluorenylmethoxy carbonyl; GMP = Good Manufacturing Practice; LiAlEU = Lithium Alluminium hydride; MTBE = Methyl tert-butyl ether; NMP = N-methyl pyrrolidone; PFR = Plug flow reactor; PG = Protecting group; Rongalite = Sodium hydroxymethanesulfmate; THF = tetrahydrofurane.

[0304] Example 1

[0305] Synthesis of 2-(aminomethyl)-3-bromobenzene-l-thiol (12)

[0306] MF C H Br N S MF: C,H,BrNS

[0307] FW 426 14884 FW: 218.11412

[0308] NU: 424 Da NM: 217 Da Lithium aluminium hydride 2.4M in THF (1113.2 g, 2.93 mol, 5.0 eq) and degassed THF (500 mL) were charged in the reactor and the suspension was cooled to - 12 / - 10 °C. Sulfuric acid (146.8 g, 1.48 mol, 2.5 eq) was dosed over 3 hours keeping T < 0 °C. The suspension of alane was stirred at -15 / -10 °C for 0.5 hour. In a separate reactor the disulfide (13, 250 g, 0.59 mol, 1.0 eq) was suspended in degassed THF (500 mL) and the slurry was cooled to - 15 °C. The alane suspension was dosed over the disulfide keeping the temperature below 0 °C. The dosing reactor was rinsed with degassed THF (500 mL). The orange suspension was stirred at -5 / 0 °C for 30 minutes, warmed to 20 °C in 1 hour, and stirred for additional 2 hours. The reaction mixture was sampled and analyzed by HPLC (the results are reported in Example 10 below). After reaction completion, a solution of 40 wt% of potassium sodium tartrate in water was prepared (4140 g) and then cooled to 5 °C. The reaction mixture was dosed over the quench solution keeping the temperature below 10 °C. The reactor was washed with degassed THF (500 mL). The mixture was agitated at 40 °C, the layers separated. The aqueous layer was back extracted with degassed THF (1250 mL). The mixture was agitated at 40 °C, the layers separated. The combined organics were filtered, and the filtrate was concentrated to approx. 2000 mL. Title compound 12 was isolated as THF solution and used directly in the following step.

[0309] Example 2

[0310] Alternative Synthesis of 2-(aminomethyl)-3-bromobenzene-l-thiol (12) - continuous flow synthesis

[0311] In batch reactor was charged degassed THF (1000 mL), cooled to -5 / 5°C and powdered aluminium trichloride (97.8 g, 0.73 mol, 1.25 eq) was added portion-wise, rinsing with degassed THF (250 ml) and stirred to obtain a clear solution. In a separate reactor, the disulfide (13, 250 g, 0.59 mol, 1.0 eq) was suspended in degassed THF (2000 mL) and stirred to form a slurry. A continuous reactor (PFR) made of two consecutive units comprising a mixing element and tubular reaction coils was set-up and conditioned with THF. Jacket temperature of reactor unit 1 was set to -15 / 0°C while jacket temperature of reaction coil 2 was set to 30 / 40°C. Aluminium chloride stock solution (feedl) was pumped into reactor unit 1 together with lithium aluminium hydride 2.4M in THF (835 g, 2.2 mol, 3.75 eq) adjusting flow rate to obtain 30 sec residence time. Disulfide 13 suspension was pumped into reactor unit 2 and overall flow rate adjusted to obtain 1 min residence time. After reactor stabilization the output clear yellow solution was collected in receiving reactor and stirred at 25 / 35°C for 1 hour. The reaction mixture was sampled and analyzed by HPLC (the results are reported in Example 10 below). After reaction completion, a solution of 40 wt% of potassium sodium tartrate in water was prepared (4140 g) and then cooled to 5 °C. The reaction mixture was dosed over the quench solution keeping the temperature below 10 °C. The reactor was washed with degassed THF (500 mL). The mixture was agitated at 40 °C, the layers separated. The aqueous layer was back extracted with degassed THF (1250 mL). The mixture was agitated at 40 °C, the layers separated. The combined organics were filtered, and the filtrate was concentrated to approx. 2000 mL. Title compound 12 was isolated as THF solution and used directly in the following step.

[0312] Example 3

[0313] Synthesis of prop-2-en-l-yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate (10a)

[0314] Potassium bicarbonate (176.2 g, 1.77 mol, 3.0 eq) and degassed water (1250 mL) were added to the THF solution of amine 12 of the previous step and pH was monitored (expected 10 / 11). The biphasic mixture was stirred at 20 / 25 °C and allyl chloroformate (141.4 g, 1.18 mol, 2.0 eq) as THF solution (degassed, 500 mL) was dosed at the same temperature. The mixture was stirred at the same temperature for 16 hours. After reaction completion, the reaction mixture was progressed without isolation to the following step. Example 4

[0315] Synthesis of prop-2-en-l-yl ({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl}methyl)carbamate (lb)

[0316] A solution of potassium bicarbonate (117.5 g, 1.18 mol, 2.0 eq) in degassed water (375 mL) was added to the reaction mixture comprising compound 10a from the previous step (Example 3) at 20 °C. pH was monitored (expected 8). The reaction mixture was warmed to 40 °C, and a solution of 2-chloropyr-3-carbaldehyde (11, 149.5 g, 1.06 mol, 1.8 eq) in degassed THF (625 mL) was added. The mixture was warmed at 65 °C and stirred for 3 hours. After reaction completion, the mixture was cooled to 40 °C and toluene (1250 mL) was added. The mixture was agitated at 40 °C, the layers separated. The aqueous layer was back extracted with toluene (1250 mL) at 40 °C. The organic layers were combined and washed with water (1250 mL) at 40 °C. The mixture was agitated at 40 °C, the layers separated. The organics were concentrated under reduced pressure to approx. 500 mL. Toluene (1750 mL) was added, and the mixture was sampled for water content. Then, the reaction mixture was filtered keeping the temperature above 40 °C, the filter was washed with toluene (1000 mL), and the filtrate was concentrated under reduced pressure to approx. 500 mL. The residue was warmed to 50 °C and then cooled to 45 °C. MTBE (750 mL) was dosed at 45 °C in 1 hour. The slurry was aged at the same temperature for 30 minutes and then cooled to 0 °C in 5 hours. The precipitate was filtered and washed with cold MTBE (500 mL). The solid was washed again with cold MTBE (500 mL). The solid was dried at 40 °C. Title compound lb was isolated as a brownish solid (308.6 g, 64.6% molar yield for 3 steps).

[0317] Example 5

[0318] Synthesis of 2-(aminomethyl)-3-bromobenzene-l-thiol (12)

[0319] MF: C14H6Br2N2S2MF: C7H8BrNS

[0320] FW: 426.14884 FW: 218.11412

[0321] NM: 424 Da NM: 217 Da

[0322] Disulfide 2,2'-disulfanediylbis(6-bromobenzonitrile) (13, 50 g, 0.12 mol, 1.0 eq) was suspended in deoxygenated THF (500 mL) at 20 / 22°C. Under nitrogen blanket, boron dimethylsulfide complex (26.7 g, 0.35 mol, 3.0eq) was added over 30 minutes, the dropping funnel was rinsed forward with further THF (25 mL). The orange mixture was stirred at 20 / 22 °C for 2 hours. After reaction completion, the mixture was cooled to 0 / 5°C and methanol (455 mL, 11.26 mol, 16.0 eq) was charged keeping internal temperature < 10°C (ca. 1 hour addition time, hydrogen gas evolution). The resulting mixture was allowed to reach 20 / 22°C and concentrated to residue (dimethylsulfide, trimethylborate distillation). THF (200 mL) was added to the residue, the resulting suspension was stirred at 20 / 22°C for 16 hours and then filtered. The wet product was rinsed with THF (25 mL) and dried at 40°C under vacuum. 2-(aminomethyl)-3 -bromobenzene- 1 -thiol 12 was isolated as a pale solid (37.0 g, 71% molar yield).

[0323] Example 6

[0324] Synthesis of diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l- diyl)methanediyl]}biscarbamate (16)

[0325] 2-(Aminomethyl)-3 -bromobenzene- 1 -thiol (12, 37 g, 0.17 mol, 1.0 eq) was suspended in an acetic acid (296 mL) / Water (74 mL) mixture. The suspension was heated to 50 / 55°C and a clear solution was obtained. The solution was stirred at the given temperature under air blanket for 36 hours. The mixture was cooled to 20 / 22°C. Water (185 mL) was added and the solution was concentrated under vacuum to ca. 185 mL. Water (185 mL) was added, the mixture concentrated under vacuum to ca. 185 mL. Water (185 mL) was added, the mixture concentrated under vacuum to ca. 185 mL. pH was adjusted to 8-9 upon addition of solid potassium carbonate (ca. 50 g). THF (520 mL) was added to the mixture. Allyl chloroformate (20.5 g, 0.17 mol, 1.0 eq) was added keeping temperature < 30°C (30 minutes addition time). The mixture was stirred at 20 / 22°C for 1 hour. After reaction completion layers were separated. Aqueous layer was further extracted with THF (3x75 mL). The joined organic fractions were washed with water (110 mL). The organic fraction was concentrated to ca. 110 mL. Toluene (185 mL) was added, the mixture was concentrated to ca. 110 mL. Toluene (185 mL) was added, the mixture was concentrated to ca. 110 mL. Heptane (110 mL) was added at 20 / 22°C over 30 minutes. The resulting suspension was stirred at 20 / 22°C for ca. 2 hours, and then cooled to 0 / 5°C and stirred for further 14 hours. The suspension was filtered, the wet product rinsed with heptane (75 mL) and dried at 48°C under vacuum for 16 hours. Diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l- diyl)methanediyl]}biscarbamate (16) was isolated as a pale solid (32.1 g, 61% molar yield).

[0326] Example 7

[0327] Synthesis of prop-2-en-l-yl ({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl}methyl)carbamate (lb)

[0328] Disulfide diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2, 1- diyl)methanediyl]}biscarbamate (16, 30.0 g, 0.050 mol, 1.0 eq) was dissolved in THF (210 mL). A solution of potassium carbonate (13.8 g, 0.10 mol, 2.0 eq) in water (150 mL) was added followed by solid Rongalite (23.0 g, 0.15 mol, 3.0 eq) and the mixture was stirred at 60 / 65°C for 1 hour. After reaction completion, the mixture was cooled to 20 / 25°C. Solid potassium carbonate (13.8 g, 0.10 mol, 2.0 eq) and 2-chloropyr-3-carbaldehyde (11, 14.1 g, 1.0 mol, 2.0 eq) were added. The mixture was stirred at 60 / 65°C for 1 hour. After reaction completion, the mixture was cooled to 20 / 22°C. The layers were separated, and the organic phase was concentrated to ca. 60 mL under vacuum. Toluene was added (90 mL) and the solution was concentrated to ca. 60 mL. Dilution / concentration was repeated for a total of three times. The concentrated solution was heated to 30 / 35°C, methyl tert-butyl ether (256 mL) was added over 30 minutes. The suspension was cooled to 0 / 5°C, stirred for 2 hours and then filtered. The wet product was washed twice with methyl tert-butyl ether (30 mL) and dried at 40°C under vacuum for 16 hours. Prop-2-en-l-yl ({2-bromo-6-[(3- formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate (lb) was isolated as a pale solid (31.2 g, 77% molar yield).

[0329] Preparation of precursors

[0330] Example 8

[0331] Synthesis of 2-bromo-6-sulfanylbenzonitrile (15)

[0332] Sodium sulfide nonahydrate (2162 g, 9.0 mol, 1.2 eq) was suspended in DMSO (7.5 L) at 20 °C. The suspension was stirred for 2 hours and then cooled to 0 / 5 °C. To this suspension was dropwise added a solution of 2-bromo-6-fluorobenzonitrile (14, 1500 g, 7.5 mol, 1.0 eq) in DMSO (3 L) keeping T < 10 °C. The yellow mixture was stirred at 10 °C for 20 hours. After reaction completion, water (15 L) was added. Then, 20 wt% HC1 (1920 g) was dropwise added to pH 2-3. Ethyl acetate (12 L) was added. The mixture was agitated for 15 minutes, the layers separated. The aqueous layer was back extracted with ethyl acetate (12 L). The mixture was agitated for 15 minutes, the layers separated. The aqueous layer was back extracted with ethyl acetate (12 L). The mixture was agitated for 15 minutes, the layers separated. The organics were combined, and water (10 L) was added. The mixture was agitated for 15 minutes, the layers separated. The organic layer was concentrated under reduced pressure and directly used without further purification in the next step. Example 9

[0333] Synthesis of 2,2'-disulfanediylbis(6-bromobenzonitrile) (13)

[0334] To the crude mixture of Example 8 comprising 2-bromo-6-sulfanylbenzonitrile (15) at 10 °C was charged DMSO (6 L). Distillation proceeded to remove ethyl acetate. The mixture was warmed to 60 °C and stirred for 2 hours. After reaction completion, the slurry was cooled to 20 °C, filtered, and washed with water (3 L). The wet cake was washed again with water (3 L). The wet solid was charged in the reactor. Ethyl acetate (7.5 L) was added, and the mixture was heated to 70 °C for 5 hours. Then, the slurry was cooled to 20 / 25 °C and stirred for 10 hours. The slurry was filtered and the solid was dried at 40 °C. Title compound 13 was isolated as yellowish solid (1228 g, 76.8% molar yield for 2 steps). 'H-NMR (400 MHz, DMSO-t / e): 5 = 7.65 (t, J= 8.1 Hz, 2H), 7.82 (dd, J= 8.1, 1.0 Hz, 2H), 7.89 (dd, J= 8.1, 1.0 Hz, 2H).13C-NMR (100 MHz, DMSO-< 5 = 115.5, 116.0, 125.9, 130.7, 133.6, 135.7,

[0335] 141.6.

[0336] Example 10

[0337] Comparative Example Using LiAlH4 as a reducing agent

[0338] The disulfide (13, 10 g, 0.02 mol, 1.0 eq) was suspended in degassed THF (10 mL) and the slurry was stirred at 10-15 °C. Lithium aluminium hydride 2.4M in THF (44.5 g, 0.12 mol, 5.0 eq) was dosed over the disulfide suspension keeping the temperature at 20-25 °C. The dosing reactor was rinsed with degassed THF (20 mL). The orange suspension was stirred for an additional 2 hours. The reaction mixture was sampled for conversion. Due to incomplete conversion and low purity (see table below), the reaction mixture was discarded.

[0339] A comparative overview of the reduction methods described in Examples 1, 2 and 10 is provided in the table below. “Des-Br impurity” refers to 2-(aminomethyl)benzenethiol (18). The HPLC method that was used to produce the data shown in the table below is described in Example 11.

[0340] 18

[0341] Example 11 The HPLC method that was used for in-process controls in Examples 1, 2, and 10 is described as follows:

Claims

CLAIMS1. A process for manufacturing a compound of formula 12a,wherein one of R1, R2, R3, R4, and R5is -CH2NH2; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen; comprising reacting a disulfide of formula 13a,wherein one of R1, R2, R3, R4, and R5is a nitrile group; one of R1, R2, R3, R4, and R5is a halogen atom selected from F, Cl, and Br; and three of R1, R2, R3, R4, and R5are hydrogen; with a reducing agent selected from:(i) a preformed mixture of Li AIH4 and H2SO4;(ii) a preformed mixture of LiAlFL and AICI3; (iii) borane dimethylsulfide complex (BH3-SMe2); and(iv) borane-THF complex (BH3-THF); to afford said compound of formula 12a.

2. The process according to claim 1, wherein the compound of formula 12a is a compound of formula 12bwherein R2is a halogen atom selected from F, Cl, and Br; and wherein the disulfide of formula 13a is a disulfide of formula 13bwherein R2is a halogen atom selected from F, Cl, and Br.

3. A process for manufacturing a compound of formula la,wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; comprising the process according to any one of claims 1 or 2.

4. A process for manufacturing a compound of formula la,wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; comprising reacting a compound of formula 10wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; R2is a halogen atom selected from F, Cl, and Br; with 2-chloropyr-3-carbaldehyde (11)in the presence of a base, to afford said compound of formula la.

5. The process according to claim 4, wherein the compound of formula 10 is obtained by protecting the primary amine in a compound of formula 12b12b wherein R2is a halogen atom selected from F, Cl, and Br; with a protecting group PG selected from Fmoc, Alloc, Boc, Cbz, and a C1-C4- carbamate.

6. A process for manufacturing a compound of formula la,wherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; comprising reacting a disulfide 16awherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br; with HO-CFF-SChNa (Rongalite®) in the presence of a first base, followed by adding a second base and 2-chloropyr-3-carbaldehyde (11)11 to the reaction mixture to afford said compound of formula la.

7. The process according to claim 6, wherein said disulfide 16a is obtained by (i) reacting a thiol of formula 12b12b wherein R2is a halogen atom selected from F, Cl, and Br; with oxygen to afford a disulfide of formula 17wherein R2is a halogen atom selected from F, Cl, and Br; followed by (ii) protecting the primary amino groups in the compound of formula 17 with a protecting group PG selected from Fmoc, Alloc, Boc, Cbz, and a C1-C4- carbamate, to afford said disulfide 16a.

8. The process according to claim 5 or 7, wherein said thiol of formula 12b is obtained by the process according to any one of claims 1 or 2.

9. A process for manufacturing prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb),lb comprising:(a) reacting 2-bromo-6-fluorobenzonitrile (15)with sodium sulfide (Na2S) to afford 2-bromo-6-sulfanylbenzonitrile (14)(b) heating said 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide (DMSO) to afford 2,2'-disulfanediylbis(6-bromobenzonitrile) (13)13 (c) reacting said 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) with a reducing agent to afford 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12)(d) reacting said 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12) with allyl chloroformate in the presence of a base to afford prop-2-en-l-yl [(2-bromo-6- sulfanylphenyl)methyl]carbamate (10a)10aand(e) reacting said prop-2-en-l-yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate(10a) with 2-chloropyr-3-carbaldehyde (11)to afford said prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb).

10. A process for manufacturing prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2- yl)sulfanyl]phenyl (methyl) carbamate (lb),comprising:(a) reacting 2-bromo-6-fluorobenzonitrile (15)with sodium sulfide (Na?S) to afford 2-bromo-6-sulfanylbenzonitrile (14)14(b) heating said 2-bromo-6-sulfanylbenzonitrile (14) in dimethyl sulfoxide(DMSO) to afford 2,2'-disulfanediylbis(6-bromobenzonitrile) (13)13(c) reacting said 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) with a reducing agent to afford 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12)12(d) (i) reacting said 2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12) with oxygen; followed by(ii) reacting the crude obtained from step (d)(i) with allyl chloroformate in the presence of a base, to afford diprop-2-en-l-yl {disulfanediylbis[(6- bromobenzene-2,l-diyl)methanediyl]}biscarbamate (16)J 1H Br Alloc ’’16 and(e) reacting said diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l- diyl)methanediyl]}biscarbamate (16) with HO-ClHh-SChNa (Rongalite®) in the presence of a first base, followed by adding a second base and 2-chloropyr- 3-carbaldehyde (11)11 to the reaction mixture to afford said prop-2-en-l-yl({2-bromo-6-[(3- formylpyridin-2-yl)sulfanyl]phenyl (methyl) carbamate (lb).

11. A compound of formula 13bwherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F and Br.

12. A compound of formula 16awherein PG is an amino protective group selected from Fmoc, Alloc, Boc, Cbz, and a Ci-C4-carbamate; and R2is a halogen atom selected from F, Cl, and Br.

13. The compound of formula 13b according to claim 11 or the compound of formula 16a according to claim 12, which is 2,2'-disulfanediylbis(6-bromobenzonitrile) (13) or diprop-2-en-l-yl {disulfanediylbis[(6-bromobenzene-2,l- diyl)methanediyl] (biscarbamate (16)14. Prop-2-en-l-yl({2-bromo-6-[(3-formylpyridin-2-yl)sulfanyl]phenyl (methyl) carbamate (lb);15. A compound selected from: prop-2-en-l-yl [(2-bromo-6-sulfanylphenyl)methyl]carbamate (10a); and2-(aminomethyl)-3 -bromobenzene- 1 -thiol (12)

Images