Process for deprotection of aminoacid derivatives

Abstract

The invention provides a novel process for manufacturing a compound of formula (I) or a salt thereof.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P39648

[0003] PROCESS FOR DEPROTECTION OF AMINO ACID DERIVATIVES

[0004] Field of the Invention

[0005] The invention relates to a novel process for manufacturing a compound of formula (I), or a salt thereof, wherein PG1is amino protective group and PG2is carboxylic acid protective group. The process according to the invention is particularly suitable for large-scale manufacturing under GMP conditions.

[0006] Background of the Invention The compound of formula (la) is a precursor in the synthesis of the antibiotic (Illa):

[0007] Compound (Illa) is a potent antibiotic with selective action against Acinetobacter baumannii. as discussed in WO2019206853. The compound of formula (Illa) is also known under the INN zosurabalpin (WHO Drug Information, Vol. 36, No. 2, 2022).

[0008] CNE / 28.07.2025 For marketing products, it is necessary to produce pharmaceuticals in large quantities and according to good manufacturing practice (“GMP”). Hence, high-yielding, cost-efficient, safe and reproducible syntheses avoiding undesired reactants, reagents, solvents and side products are of importance.

[0009] WO2023152347 discloses a laboratory scale synthesis of the compound of formula (la), via deprotection of the nosyl (Ns) protected amino group, which relies on the use of sodium thiophenolate. Cleavage of the nosyl group from the amine (Ila) generates a desired secondary amine (la), disulfide by-product (1), and SO2 as depicted on the scheme below: sulfide by-product

[0010] However, sodium thiophenolate is an expensive reagent that is also challenging to handle on an instustrial scale due to its air and moisture sensitivity, as well as strong odor. Further disadvantages of the above-mentioned method include the use of the toxic solvent N,N- dimethylformamide (DMF) and utilization of a tedious polish filtration during reaction work up for separation of sulfide by-product (1).

[0011] In summary, said synthesis is not well suited for an industrial scale manufacturing of the compound of formula (la).

[0012] Other common conditions for nosyl deprotection include the use of thiophenol or thioglycolic acid (HSCH2CO2H) in the presence of a base. Thiophenol, a cheaper alternative reagent, would not be a suitable choice due to its pungent and offensive odor, making it difficult to handle on an industrial scale. Additionally, the sulfide generated as a deprotection by-product must be removed prior to product isolation, thus requiring a tedious work up including polish filtration of the reaction mixture. On the other hand, the use of thioglycolic acid as cleaving agent could overcome the problem of troublesome work-up since the cleavage by-product, nitrophenylthioacetic acid, can be separated from the desired product by means of biphasic extractions (basic aqueous wash). However, the problem of handling a reagent with a strong odor remains.

[0013] As a further drawback, deprotection of nosyl group using the above-mentioned reactants leads to the generation of disulfide impurities making isolation of the desired product more challenging.

[0014] Accordingly, there is a need for a new process for manufacturing the compound of formula (la).

[0015] Summary of the Invention

[0016] The present invention provides a solution phase process for manufacturing compound of formula (I), which overcomes the problems outlined above. The present invention also provides use of the new process for the manufacture of the compound of formula (Illa).

[0017] Detailed Description of the Invention

[0018] Definitions

[0019] 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.

[0020] 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 Boc (tert-butoxycarbonyl), benzyl, 4-methoxybenzyl, benzhydryl, Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl), Moz (p- methoxybenzyloxy carbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Teoc (2- (Trimethylsilyl)ethoxycarbonyl), Adoc (adamantoxycarbonyl), formyl, acetyl, and cyclobutoxycarbonyl, particularly Boc and Adoc. In one embodiment the amino protective group is Boc. Exemplary carboxylic acid protective groups are allyl (All), benzyl, ethyl, tert-butyl, and 9-fluorenylmethyl (Fm), particularly All and Fm. In one embodiment the carboxylic acid protective group is All. Exemplary amino and carboxylic acid protective 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.

[0021] The term “salt” as used herein refers to any kind of salts formed by reacting the compounds disclosed herein with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. Where the compounds disclose herein contain a free acidic moiety, salts may also be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.

[0022] The term “base”, as used herein, refers to an inorganic or organic base, including but not limited to alkali metal hydroxides, carbonates, phosphates, and alkoxides. Non-limiting examples of bases are Z-BuONa, Z-BuOLi, Z-BuOK, Na2CO3, K3PO4, K2CO3, CS2CO3, LiOH, NaOH, KOH, NaOMe, NaOEt, KOMe, LiOiPr. A preferred example of a base is Z- BuOK. Still another preferred example of a base is K2CO3. The term “aprotic organic solvents” relates to an organic solvent that lacks an acidic proton and is polar. Non-limiting examples of aprotic organic solvents are acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone, N-butylpyrrolidone, dimethylacetamide, ethyl acetate, 2-methyltetrahydrofuran, dimethyl sulfoxide. A preferred example of an aprotic organic solvents is N-butylpyrrolidone.

[0023] The following abbreviations are used in the present text:

[0024] % a / a = assay per assay percent; Adoc = adamantoxycarbonyl; All = allyl; Boc = tertbutoxycarbonyl; °C = degrees Celsius; Cbz = benzyloxycarbonyl, COMU = (l-cyano-2- ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholine-carbenium hexafluorophosphate; Cy2NH: dicyclohexylamine; DCC = Dicyclohexylcarbodiimide; DCM = dichloromethane; DIC = N,N’ -diisopropylcarbodiimide; DMF = N,N- dimethylformamide; DMSO = dimethylsulfoxide; eq = equivalent; EDCI = l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fm = 9-fluorenylmethyl; Fmoc = fluorenylmethoxycarbonyl; g = gram; GMP = good manufacturing practice; Fmoc = fluorenylmethoxycarbonyl; HATU = 2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate; HO At = l-hydroxy-7-azabenzotriazole; HOBt = 1 -Hydroxybenzotriazole; HODhat = 3-hydroxypyrido[3,2-d][l,2,3]triazin-4(3H)-one;

[0025] HOPO = 2-hydroxypyridine-N-oxide; HPLC = high-performance liquid chromatography; Moz = p-methoxybenzyloxy carbonyl; INN = international nonproprietary name; IPC = in process control; KFT = Karl Fischer titration; MeCN = acetonitrile; NBP = N- butylpyrrolidone; Moz = p-methoxybenzyloxy carbonyl; Ns = nosyl; Oxyma = ethyl cyanohydroxyiminoacetate; PG = protective group; T = temperature; T3P = propylphosphonic anhydride; TBTU = N,N,N’,N’-tetramethyl-O-(benzotriazol-l- yl)uranium tetrafluoroborate; THF = tetrahydrofurane; / A1T1NH2 = tert-amylamine; TBME = tert-butyl methyl ether; Z-BuOK = potassium tert-butoxide; Teoc = 2- (trimethylsilyl)ethoxycarbonyl; Troc = 2,2,2-trichloroethoxycarbonyl; V = volume parts (litr per kilogram of input material); mL = milliliter; mmol = millimoles; WHO = World Health Organisation; w. = with; % w / w = weight per weight percent. Manufacturing Process

[0026] In a first aspect, the present invention provides a process for manufacturing a compound of formula (I) or a salt thereof, comprising:

[0027] (a) reacting a compound of formula (II) with N-acetylcysteine in the presence of a first base to form said compound of formula (I), wherein PG1is amino protective group selected from Boc, Adoc, benzhydryl, acetyl, or cyclobutoxycarbonyl; and PG2is a carboxylic acid protective group selected from All, benzyl, ethyl, tertbutyl, or Fm.

[0028] In one embodiment of the process according to the present invention, PG1is Boc or Adoc. In a preferred embodiment of the process according to the present invention, PG1is Boc.

[0029] In one embodiment of the process according to the present invention, PG2is All or Fm.

[0030] In a preferred embodiment of the process according to the present invention, PG2is All.

[0031] In one embodiment of the process according to the present invention, PG1is Boc and PG2is All. In one embodiment of the process according to the present invention, the compound of formula (I) is the compound of formula (la) the compound of formula (II) is the compound of formula (Ila)

[0032] The present invention therefore provides a new method for the nosyl deprotection of nosyl protected compound (II) using N-acetylcystein and less toxic solvent N-butylpyrrolidone. Said method reduces costs and makes the reaction suitable for industrial scale manufacturing. The method is further illustrated by the following reaction scheme: Advantegously, N-acetylcysteine by-product (2) comprising a carboxyl group is water- soluble and can be removed from the reaction mixture by washing with a basic aqueous solution.

[0033] Another advantage of step (a) of the process according to the invention is that it performs very well in N-butylpyrrolidone (NBP), thereby avoiding the use of toxic dimethylformamide (DMF) as described in WO2023152347. This is of particular importance when conducting the reaction on an industrial scale.

[0034] In one embodiment, the process according to the present invention is performed in a polar aprotic organic solvent.

[0035] In one embodiment, the process according to the present invention is performed in a polar aprotic organic solvent, or in a mixture of aprotic organic solvents.

[0036] In a preferred embodiment, the process according to the present invention is performed in N-butylpyrrolidone (NBP) as a solvent.

[0037] In one embodiment of the process according to the present invention, the first base is alkali metal alkoxide.

[0038] In a preferred embodiment of the process according to the present invention, the first base is alkali metal tert-butoxide.

[0039] In a particularly preferred embodiment of the process according to the present invention, the first base is Z-BuOK.

[0040] It has been found that the introduction of two different bases having different strengths reduces impurity formation during step (a) of the process.

[0041] In one embodiment, the process according to the present invention is performed in the presence of a first base and a second base.

[0042] It is to be understood that the first base and the second base are present in the reaction mixture simultaneously.

[0043] In a preferred embodiment of the process of the present invention, the second base is alkali metal carbonate or alkali metal phosphate. In a particularly preferred embodiment of the process of the present invention, the second base is alkali metal carbonate.

[0044] In a particularly preferred embodiment of the process of the present invention, the second base is K2CO3.

[0045] In one embodiment, >2 equivalents of N-acetylcysteine are used relative to the compound of formula (II) in step (a) of the method according to the invention.

[0046] In a preferred embodiment, 2 equivalents of N-acetylcysteine are used relative to the compound of formula (II) in step (a) of the method according to the invention.

[0047] In one embodiment, >1.9 equivalents of the first base are used relative to the compound of formula (II) in step (a) of the method according to the invention.

[0048] In a preferred embodiment, 1.9 equivalents of the first base are used relative to the compound of formula (II) in step (a) of the method according to the invention.

[0049] In on embodiment, >2 equivalents of the second base are used relative to the compound of formula (II) in step (a) of the method according to the invention.

[0050] In a preferred embodiment, 2 equivalents of the second base are used relative to the compound of formula (II) in step (a) of the method according to the invention.

[0051] In one embodiment, step (a) of the process according to the invention is performed between room temperature and the reflux temperature.

[0052] It is to be understood, that the reflux temperature is determined by the solvent used, and it is approximately equal to the boiling point of that solvent, or to the boiling point of the more volatile component if the mixture of solvents is used.

[0053] In one embodiment, the process according to the present invention is performed at a temperature of 60°C to 110°C.

[0054] In a preferred embodiment, the process according to the present invention is performed at a temperature of 75°C to 80°C.

[0055] In a particularly preferred embodiment, the process according to the present invention is performed at a temperature of 75°C. Advantegously, N-acetylcysteine by-product (2) of step (a) is water-soluble and can be removed from the reaction mixture by washing with a basic aqueous solution.

[0056] In one embodiment, the process for manufacturing a compound of formula (I) or a salt thereof, according to the present invention further comprises:

[0057] (b) diluting the reaction mixture obtained from step (a) with a suitable water immiscible organic solvent;

[0058] (c) quenching the reaction mixture obtained from step (b) with water;

[0059] (d) extracting the compound of formula (I) from the mixture obtained from step

[0060] (c) with a suitable water immiscible organic solvent;

[0061] (e) removing residual water from a combined organic phase obtained from step

[0062] (d);

[0063] (f) concentrating the mixture obtained from step (e);

[0064] (g) filtering the concentrate obtained from step (f).

[0065] In a preferred embodiment, said solvent used in step (b) is toluene.

[0066] In a preferred embodiment, said solvent used in step (d) is toluene.

[0067] In a preferred embodiment, residual water in step (e) is removed by washing combined organic phase obtained from step (c) with saturated aqueous solution of Na2SO4 followed by azeotropic distillation with a suitable organic solvent.

[0068] In a further particularly preferred embodiment, the residual water in step (e) is removed by azeotropic distillation with acetonitrile.

[0069] Advantageously, the compound of formula (I) can be further purified by crystallization with oxalic acid to obtain oxalate salt of the compound of formula (I) with high purity.

[0070] In one embodiment, the process according to the present invention further comprises:

[0071] (h) reacting the compound of formula (I) with oxalic acid to form an oxalate salt of the compound of formula (I). In one embodiment, the present invention provides a manufacturing process as disclosed herein, wherein the process further comprises:

[0072] (i) reacting an oxalate salt of the compound of formula (I) with a suitable base to form the compound of formula (I) as a free base. In a preferred embodiment, step (d) is performed in acetonitrile as a solvent.

[0073] In one embodiment, the present invention provides a process for manufacturing a compound of formula (la): or a salt thereof, comprising: (a) reacting a compound of formula (Ila) with N-acetylcysteine in the presence of t-BuOK and K2CO3 in NBP as a solvent and at a temperature of 75°C to 80°C to form said compound of formula (la).

[0074] In one embodiment, the present invention provides a process for manufacturing a compound of formula (la): or a salt thereof, comprising:

[0075] (a) reacting a compound of formula (Ila) with N-acetylcysteine in the presence of t-BuOK and K2CO3 in N-butylpyrrolidone as a solvent at a temperature of 75°C to 80°C;

[0076] (b) diluting the reaction mixture obtained from step (a) with toluene;

[0077] (c) quenching the reaction mixture obtained from step (b) with water;

[0078] (d) extracting the compound of formula (I) from the mixture obtained from step (c) with toluene;

[0079] (e) removing residual water from a combined organic phase obtained from step (d) by washing said combined organic phase with saturated aqueous solution of Na2SO4 followed by azeotropic distillation with acetonitrile;

[0080] (f) concentrating the mixture obtained from step (e); (g) filtering the concentrate obtained from step (f); said compound of formula (la). Advantageously, the compound of formula (la) can be purified by crystallization with oxalic acid to obtain the compound of formula (Ila) with >99.5 % a / a purity, >99.9 % a / a enantiomeric purity, and >99 % w / w purity.

[0081] In one embodiment, the present invention provides a process for manufacturing a compound of formula (la) as disclosed herein, wherein the process further comprises:

[0082] (h) reacting the compound of formula (la) with oxalic acid in acetonitrile as a solvent to form an oxalate salt of the compound of formula (la).

[0083] In one embodiment, the present invention provides a manufacturing process as disclosed herein, wherein the process further comprises: (i) reacting an oxalate salt of the compound of formula (la) with a suitable base to form the compound of formula (la) as a free base.

[0084] In one embodiment, the process according to the present invention is:

[0085] In a one aspect, the present invention provides a process for manufacturing a compound of formula (Illa) or a salt thereof

[0086] comprising the process according to the present invention.

[0087] In one aspect, the present invention provides the use of the process according to the present invention in the manufacture of the compound of formula (Illa) or a salt thereof.

[0088] In one embodiment, said process for manufacturing the compound of formula (Illa) or a salt thereof, is:

[0089]

[0090] (Villa) wherein step (1) is the process according to the present invention. In a preferred embodiment, the present invention provides a process for manufacturing a compound of formula (Illa), wherein:

[0091] Step (1) is a process according to the present invention as described above;

[0092] Step (2) reacting a secondary amine of formula (la) and a carboxylic acid (IVa) using reagents selected from the mixture of HO At and DIC, or HODhat and DIC, or HOPO and DIC, or HOPO and DCC, or HOPO and EDCI, preferably the mixture of HOPO and DIC.

[0093] Step (3) reacting said compound of formula (Va) with N-acetylcysteine and tAmNH2 to form a compound of formula (Via), followed by washing obtained reaction mixture with a basic aqueous solution, preferably with an aqueous solution of KHCO3 and / or K2CO3.

[0094] Step (4) reacting said compound of formula (Via) with a compound of formula (Vila) in the presence of a carboxylic acid selected from acetic acid and propionic acid, preferably in the presence of acetic acid; and a reducing agent selected from NaBHsCN and NaBH(OAc)3, preferably NaBH(OAc)3; to form a compound of formula (Villa).

[0095] Step (5) (5. a) reacting said compound of formula (Villa) with a transition metal catalyst, preferably (PPhs^Pd, in the presence of a secondary amine, preferably Et2NH, to form a compound of formula (IXa);

[0096] (5.b) adding N-acetylcysteine to the reaction mixture of step (5. a);

[0097] (5.c) adding Cy2NH to the reaction mixture of step (5.b);

[0098] (5.d) distilling off the secondary amine from step (5. a); and

[0099] (5.e) filtering the reaction mixture of step (5.d).

[0100] Step (6) reacting said compound of formula (IXa) with a reagent selected from a mixture of HOBt and EDCI; a mixture of DIC and oxyma; and COMU; preferably a mixture of HOBt and EDCI, to form the compound of formula (X).

[0101] Step (7) (7. a) reacting aryl bromide (Xa) with (4-carbomethoxyphenyl)boronic acid (Xia) in the presence of a palladium catalyst, preferably PdC12(dtbpf) and a base, preferably K3PO4 and K2CO3, to afford compound (Xlla); (7.b) adding ammonium pyrrolidinedithiocarbamate or an aqueous solution of A-acetyl cysteine to the reaction mixture of step (7. a);

[0102] (7.c) reacting the reaction mixture of step (7.b) with sodium hydroxide to afford said compound (Xlla); (7.d) crystallizing said compound (Xlla), preferably from a mixture of 1- propanol and acetone.

[0103] Step (8) reacting compound (Xlla) with an acid, preferably with hydrochloric acid, to afford said compound of formula (I).

[0104] In a particularly preferred embodiment, said process for manufacturing the compound of formula (Illa) or a salt thereof, is:

[0105]

[0106] (Villa)

[0107] In more details, the process for manufacturing the compound of formula (Illa) is disclosed in WO2023152347 (steps (2) to (6)) and WO2024033278 (steps (7) and (8)), in particular:

[0108] Step (2) is disclosed in WO2023152347, e.g. on pages 4-6, and in the reference Examples 3 and 4 on pages 34-36; Step (3) is disclosed in WO2023152347, e.g. on page 6-7, and in the reference Examples 7, 8 and 13 on pages 39-41 and 45.

[0109] Step (4) is disclosed in WO2023152347, e.g. on pages 7-8, and in the reference Example 9 on pages 41-42;

[0110] Step (5) is disclosed in WO2023152347, e.g. on pages 9-10, and in the reference Examples 10 and 11 on pages 42-43;

[0111] Step (6) is disclosed in WO2023152347, e.g. on page 10, and in the reference Example 12 on page 43-44;

[0112] Step (7) is disclosed in details in WO 2024033278, e.g. on pages 4-6, 14-16, and in the reference Example 1 on pages 22-23;

[0113] Step (8) is disclosed in WO 2024033278, e.g. on pages 15-16, and in the reference Example la on pages 19-21.

[0114] Examples

[0115] 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.

[0116] Example 1 tert-butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]indole-l-carboxylate (la)

[0117] To a suspension of N-acetylcysteine (60.04 g, 367.9 mmol, 2.0 eq) in deoxygenated N- butylpyrrolidone (7V, 700 mL) solid t-BuOK (39.22 g, 349.5 mmol, 1.9 eq) was charged at 20-25°C. A pink suspension was formed. The resulting suspension was sparged with N2 and stirred at 20-25°C for 30 minutes to obtain a colorless solution. Then, solid K2CO3 (50.85 g, 367.9 mmol, 2.0 eq) was charged and the resulting white suspension was stirred at 20-25°C for 10 minutes. Solid tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2- nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-l-carboxylate (Ila) (100.00 g, 184.0 mmol, 1.0 eq) was charged onto the reaction mixture and the batch temperature was raised up to 75-80°C at l°C / min. A yellowish suspension was obtained which turns orange as the reaction proceeds. Upon reaction completion (checked by HPLC), the reaction mixture was diluted with toluene (4V, 400 mL), cooled to 0-5°C and quenched with H2O (6V, 600 mL). Once water addition was over, the mixture was stirred at 20-25°C for 15 minutes. Then, the layers were separated, and the organic layer was diluted with toluene (5V, 500 mL). The resulting mixture was stirred for minutes at 20-25°C. After this time, the layers were separated, and the aqueous layer was extracted with toluene (1x4V, 400 mL). The organic fractions were joined, washed with Na2SO4 (aq) 15 % w / w (1x3.5 V, 350 mL) and the residual water was removed through azeotropic distillation with MeCN (9 to 14Vxl cycle, KF<0.5 % w / w). Then, the organic fraction was concentrated under reduced pressure to 9V (900 mL) and a clear filtration on sterimatt pad was performed. The filter was washed with MeCN (1x2V, 200 mL) and the resulting orange solution was diluted with MeCN (5V, 500 mL).

[0118] Example la

[0119] A preformed solution of oxalic acid (24.84 g, 275.9 mmol, 1.5 eq) in MeCN (5V, 500 mL) was charged onto tert-butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]indole-l- carboxylate solution over ca 0.5 hours. At the end of the addition, the mixture was cooled to 0-5°C and stirred for 1.5 hours. Upon supernatant check (assay in solution by HPLC <6- 7 g / L), the mixture was filtered, and the cake was washed sequentially with MeCN (1x3 V, 300 mL) and acetone (3x3 V, 300 mL). The resulting solid was then dried at 40°C under reduced pressure for 8.0 hours, tert-butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- propyl] indole- 1 -carboxylate oxalate (lb) was obtained as a white solid with 99.65 % a / a purity, 99.91 % a / a enantiomeric purity and 99.00 % w / w assay in 70% yield.

Claims

CLAIMS1. A process for manufacturing a compound of formula (I)or a salt thereof, comprising: (a) reacting a compound of formula (II)with N-acetylcysteine in the presence of a first base to form said compound of formula (I), wherein PG1is amino protective group selected from Boc, Adoc, benzhydryl, acetyl, or cyclobutoxycarbonyl ; and PG2is a carboxylic acid protective group selected from All, benzyl, ethyl, tertbutyl, or Fm.

2. The process according to claim 1, wherein PG1is Boc.

3. The process according to claim 1 or 2, wherein PG2is All.

4. The process according to claim 1, wherein the compound of formula (I) is the compound of formula (la)the compound of formula (II) is the compound of formula (Ila)5. The process according to any one of claims 1 to 4, wherein the process is performed in a polar aprotic organic solvent.

6. The process according to any one of claims 1 to 5, wherein the process is performed in N-butylpyrrolidone as a solvent.

7. The process according to any one of claims 1 to 6 wherein the first base is alkali metal alkoxide.

8. The process according to any one of claims 1 to 7, wherein the first base is Z-BuOK.

9. The process according to any one of claims 1 to 8, wherein the process is performed in the presence of a first base and a second base.

10. The process according to claim 9, wherein the second base is alkali metal carbonate or alkali metal phosphate.

11. The process according to claim 9 to 10, wherein the second base is K2CO3.

12. The process according to claim 6, wherein the process is performed at a temperature of 60°C to 110°C.

13. The process according to claim 6, wherein the process is performed at a temperature of 75°C to 80°C.

14. The process according to any one of claims 1 to 13, wherein the process further comprises:(b) diluting the reaction mixture obtained from step (a) with a suitable water immiscible organic solvent;(c) quenching the reaction mixture obtained from step (b) with water;(d) extracting the compound of formula (I) from the mixture obtained from step (c) with a suitable water immiscible organic solvent;(e) removing residual water from a combined organic phase obtained from step (d);(f) concentrating the mixture obtained from step (e);(g) filtering the concentrate obtained from step (f).

15. The process according to any one of claims 1 to 14, wherein the process further comprises:(h) reacting the compound of formula (I) with oxalic acid to form an oxalate salt of the compound of formula (I).

16. The process according to claim 15 wherein the process further comprises:(i) reacting an oxalate salt of the compound of formula (I) with a suitable base to form the compound of formula (I) as a free base.

17. The process according to claim 16, wherein step (i) is performed in acetonitrile as a solvent.

18. The process for manufacturing a compound of formula (la)or a salt thereof, comprising:(a) reacting a compound of formula (Ila)with N-acetylcysteine in the presence of t-BuOK and K2CO3 in N-butylpyrrolidone as a solvent at a temperature of 75°C to 80°C;(b) diluting the reaction mixture obtained from step (a) with toluene;(c) quenching the reaction mixture obtained from step (b) with water;(d) extracting the compound of formula (la) from the mixture obtained from step (c) with toluene;(e) removing residual water from a combined organic phase obtained from step (d) by washing said combined organic phase with saturated aqueous solution of Na2SO4 followed by azeotropic distillation with acetonitrile;(f) concentrating the mixture obtained from step (e); (g) filtering the concentrate obtained from step (f); to form said compound of formula (la).

19. The process according to claim 18, wherein the process further comprises:(h) reacting the compound of formula (la) with oxalic acid in acetonitrile as a solvent to form an oxalate salt of the compound of formula (la).

20. The process according to claim 19, wherein the process further comprises:(i) reacting an oxalate salt of the compound of formula (la) with a suitable base to form the compound of formula (la) as a free base.

21. A process for manufacturing a compound of formula (Illa)or a salt thereof, comprising a process according to any one of claims 1 to 20.

22. Use of the process according to any one of claims 1 to 20 in the manufacture of a compound of formula (Illa)or a salt thereof.

23. The process according to claim 21, which is:and wherein step (1) is the process according to any one of claims 4 to 14, 16 to 18, or 20.

24. The invention as described hereinbefore.

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