Process for the preparation of oxetane derivatives

Abstract

The present invention relates to a new process for the preparation of a compound of formula (I) or an acceptable salt thereof (I), at technical scale, as well as novel intermediates thereof.

Description

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

[0002] Case: P39835

[0003] Process for the preparation of oxetane derivatives

[0004] The present invention relates to new processes for the preparation of a compound of formula (I) or a salt thereof

[0005]

[0006] (I)

[0007] which are useful key building block for the synthesis of oral glucagon-like peptide-1 receptor (GLP-1 receptor, or GLP1R) agonists, as well as intermediates thereof and novel salts of the compound of formula (I).

[0008] Diabetes is a serious chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Complications of diabetes include damage to the heart, blood vessels, eyes, kidneys, and nerves. Diabetes can increase risk of heart disease, and stroke. The results include serious effects on quality of life, health, and mortality. WHO Global Report on Diabetes, 2016, World Health Organization.

[0009] The glucagon-like peptide-1 receptor has emerged as a potential target for treating type 2 diabetes. Its ligand, glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion, and increases insulin synthesis among many other effects. Doyle and Egan, 2007, Pharmacol. Ther. 113(3):546-593. GLP-1 is known to delay gastric emptying, suppress food intake, increase satiety, and reduce weight in humans. Shah and Vella, 2014 Rev Endocr Metab Disord. 15(3): 181-187. Activating the GLP-1 receptor has been shown to have beneficial effects on insulin secretion and the maintenance of beta cell glucose sensing, transcription, synthesis, proliferation, and survival. Doyle and Egan, 2007, supra. While the GLP-1 receptor is a promising therapeutic target, only a handful of GLP-1 receptor drugs have been approved to date, and most, or all of these are peptide, or polypeptide drugs.

[0010] There is a need for additional therapies for treating metabolic diseases, and conditions, like type 2 diabetes. Small molecules targeting GLP-1 receptor should provide safe, stable, and easy to administer therapeutics for metabolic diseases, and conditions such as type 2 diabetes and / or obesity. In view of the increasing rise in obesity and the increasing demand for oral weightloss treatments and diabetes treatments, there is a particular need to find novel ways to make high quantities and qualities of the intermediate of formula (I) at a reasonable price.

[0011] The invention thus relates in particular to novel processes with novel intermediates for the preparation of a compound of formula (I), which is a key intermediate in the synthesis of various GLP-1 receptor agonistic oral drugs currently in development, such as for instance danuglipron and CT-996. Some of the known processes to make intermediates of formula (I) rely on ring expansion of an epoxide-containing intermediate and provide generally low to modest yields and often require flash column chromatography for isolation and separation of impurities. Other known processes to make intermediate of formula (I) rely on selective sulfonylation of a diol, followed by a sequence carrying a potentially sensitive azide moiety through several steps. Hence, the present processes have the following particular advantages of giving access to intermediate of formula (I):

[0012] • avoiding low-yielding ring expansion of epoxide-containing compounds;

[0013] • avoiding the use of hazardous epichlorohydrin;

[0014] • avoiding time-consuming flash column chromatography;

[0015] • avoiding the handling of azide-containing intermediates over several steps; and • delivering the product with high purity isolable from the reaction mixtures.

[0016] Overall, the present processes provide easy-to-perform alternatives to the processes known in the art and are generally suitable for a production on technical scale.

[0017] The term "acceptable salt" refers to those salts of the compound as indicated, which retain the properties of the free bases, the free acids or the specifically disclosed salt form, which are not pharmaceutically or otherwise undesirable. In particular, it is to be understood that the term “acceptable salt” as used therein encompasses those salts that provide good crystallization, impurity rejection and / or are stable salts. The salts are formed 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, (-)- dibenzoyl-Z-tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, adipic acid, aspartic acid, pivalic acid, succinic acid, methanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, -toluenesulfonic acid, 1,5-naphthalenedisulfonic acid, salicylic acid, N-acetylcysteine, chlocyphos, 7V-acetylleucine, Mosher’s acid, naproxen, and the like.

[0018] The term "telescoped" refers to a sequence of reactions wherein the applicable intermediate is carried forward from one reaction and used in a subsequent reaction without a full isolation and purification.

[0019] The term “alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. Particular alkyl groups are methyl, ethyl, propyl, isopropyl and n-butyl. More particular alkyl groups are methyl, ethyl, propyl and isopropyl.

[0020] If one of the starting materials, intermediates or final products as described herein contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are for instance tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyl oxy (Cbz) and / ?-methoxybenzyloxy carbonyl (Moz).

[0021] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes can be made and equivalents can be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention.

[0022] Specifically numbered aspects of the invention are:

[0023] 1. A process comprising the reaction of a compound of formula (1-4)

[0024]

[0025] with a suitable reduction agent like H2, Red-Al, LiBH4, LiAlH4, NaBH4, BH3. THF or Et2SiH2, preferably Red-Al, LiBH4or NaBH4, and most preferably Red-Al or LiBH4, in presence of a suitable solvent like THF, 2-Me-THF, CPME, TBME, toluene, methanol or ethanol or a mixture thereof, preferably THF, 2-Me-THF or CPME containing some methanol, and most preferably THF or a mixture of THF and MeOH, and optionally in presence of a suitable additive and / or a suitable catalyst like NiCl6.6H2O, NiCl2, CoCl2, ZnCl2, B(OMe)3, B(OEt)3or Ti(OiPr)4, Ni, Pd / C, PtO2, preferably ZnCl2, in order to arrive at a compound of formula (I)

[0026] P"'y^^NH2

[0027]

[0028] (I)

[0029] or an acceptable salt thereof like A-acetylleucine, chlocyphos, Mosher’s acid, naproxen, 1,5 -naphthalenedi sulfonic acid, oxalic acid or / ?-toluenesulfonic acid, preferably 1,5-naphthalenedi sulfonic acid, oxalic acid or / ?-toluenesulfonic acid, and most preferably oxalic acid or / ?-toluenesulfonic acid.

[0030] A process according to embodiment 1 further comprising the following preceding step: the reaction of a compound of formula (1-3)

[0031] O

[0032] P" T^NH2

[0033]

[0034] (1-3)

[0035] in presence of a suitable solvent like dichloromethane, ethyl acetate, THF or 2-Me-THF, preferably dichloromethane or ethyl acetate, and most preferably dichloromethane, a suitable base like pyridine, triethylamine or diisopropylethylamine, preferably pyridine or triethylamine, and most preferably pyridine, and a suitable dehydrating agent like trifluoroacetic anhydride, trichloroacetyl chloride or Burgess reagent, preferably trifluoroacetic anhydride or trichloroacetyl chloride, in order to arrive at a compound of formula (1-4) A process according to embodiment 2 further comprising the following preceding step: the reaction of a compound of formula (1-2)

[0036] O

[0037]

[0038] (1-2)

[0039] in presence of a suitable solvent like MeOH, EtOH, zPrOH, THF, 2-Me-THF, TBME or CPME, preferably MeOH or EtOH, and most preferably MeOH, and either (i) NH3 or (ii) a suitable ammonium salt with a suitable base, preferably NH3, in order to arrive at a compound of formula (1-3)

[0040]

[0041] (i-3);

[0042] wherein in the above reaction R is alkyl; preferably R is, ethyl, propyl or isopropyl, more preferably isopropyl.

[0043] A process according to embodiment 3 further comprising the following preceding step: the reaction of a compound of formula (I-1)

[0044] o

[0045]

[0046] with a suitable hydrolase (e.g. a suitable lipase, esterase, protease, peptidase or acylase) with esterase activity and in presence of

[0047] • a suitable buffer selected from potassium phosphate, sodium phosphate, Tris-HCl, sodium acetate, MES, HEPES and PIPES, preferably the buffer is potassium phosphate;

[0048] • optionally a suitable co-solvent selected from TBME, 2-Me-THF, THF, CPME, toluene, anisole, n-heptane, cyclohexane, preferably the co-solvent is 2-MeTHF; and

[0049] • optionally a suitable additive such as for instance (NH₄)₂SO₄U

[0050] in order to arrive at a compound of formula (1-2)

[0051]

[0052] (1-2),

[0053] in the above reaction the R is alkyl, in particular ethyl, propyl and isopropyl, and the hydrolase is preferably one of the Amano proteases CES P-1 or P6 SD.

[0054] A process according to embodiment 1 further comprising the following preceding step: the reaction of a compound of formula (1-6)

[0055]

[0056] in presence of a suitable solvent, preferably water, a suitable buffer like Tris-HCl, sodium acetate, MES, PIPES, MOPS, phosphate buffer, or HEPES, or the like, a suitable nitrilase or nitrile hydratase and optionally a suitable co-solvent like THF, 2-Me-THF, DMSO, EtOAc, iPrOAc, heptane, toluene, MTBE, CPME, alcohols, or the like, in order to arrive at a compound of formula (1-4)

[0057]

[0058] (1-4).

[0059] A process according to embodiment 5 further comprising the following preceding step: the reaction of a compound of formula (1-5)

[0060]

[0061] in presence of a suitable solvent like dichloromethane, ethyl acetate, THF or 2-Me-THF, preferably dichloromethane or ethyl acetate, and most preferably dichloromethane, a suitable base like pyridine, triethylamine or diisopropylethylamine, preferably pyridine or triethylamine, and most preferably pyridine, and a suitable dehydrating agent like trifluoroacetic anhydride, trichloroacetyl chloride or Burgess reagent, preferably trifluoroacetic anhydride or tri chloroacetyl chloride, in order to arrive at a compound of formula (1-6)

[0062]

[0063] A process according to claim 6 further comprising the following preceding step:

[0064] the reaction of a compound of formula (I-1)

[0065] o

[0066]

[0067] in presence of a suitable solvent like MeOH, EtOH, zPrOH, THF, 2-Me-THF, TBME or CPME, preferably MeOH or EtOH, and most preferably MeOH, and either (i) NH3 or (ii) a suitable ammonium salt with a suitable base, preferably NH3, in order to arrive at a compound of formula (1-5)

[0068] o

[0069] NH2

[0070]

[0071] (1-5);

[0072] wherein in the above reaction R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

[0073] A process comprising the following steps:

[0074] (a) the reaction of a compound of formula (I-1)

[0075] o

[0076] O'R

[0077]

[0078] (1-1)

[0079] in presence of a suitable solvent like MeOH, EtOH, zPrOH, THF, 2-Me-THF, TBME or CPME, preferably MeOH or EtOH, and most preferably MeOH, and either (i) NH3 or (ii) a suitable ammonium salt with suitable base, preferably NH3, in order to arrive at a compound of formula (1-5)

[0080] O

[0081]

[0082] (b) the reaction of a compound of formula (1-5)

[0083]

[0084] in presence of a suitable solvent like dichloromethane, ethyl acetate, THF or 2-Me-THF, preferably dichloromethane or ethyl acetate, and most preferably dichloromethane, a suitable base like pyridine, triethylamine or diisopropylethylamine, preferably pyridine or triethylamine, and most preferably pyridine, and a suitable dehydrating agent like trifluoroacetic anhydride, trichloroacetyl chloride or Burgess reagent, preferably trifluoroacetic anhydride or tri chloroacetyl chloride, in order to arrive at a compound of formula (1-6)

[0085]

[0086] (c) the reaction of a compound of formula (1-6)

[0087]

[0088] with a suitable reduction agent like H2, Red-Al, LiBH4, LiAlH4, NaBH4, BH3. THF or Et2SiH2, preferably Red-Al, LiBH4or NaBH4, and most preferably Red-Al or LiBH4, in presence of a suitable solvent like THF, 2-Me-THF, CPME, TBME, toluene, methanol or ethanol or a mixture thereof, preferably THF, 2-Me-THF or CPME containing some methanol, and most preferably THF or a mixture of THF and MeOH, and optionally in presence of a suitable additive and / or a suitable catalyst like NiCl6.6H2O, NiCl2, CoCl2, ZnCl2, B(OMe)3, B(OEt)3or Ti(OiPr)4, Ni, Pd / C, PtO2, preferably ZnCl2, in order to arrive at a compound of formula (1-7)

[0089]

[0090] or an acceptable salt thereof like A-acetylleucine, chlocyphos, Mosher’s acid, naproxen, 1,5 -naphthalenedi sulfonic acid, oxalic acid or / ?-toluenesulfonic acid, preferably 1,5-naphthalenedi sulfonic acid, oxalic acid or / ?-toluenesulfonic acid, and most preferably oxalic acid and -toluenesulfonic acid; and

[0091] (d) the reaction of a compound of formula (1-7) NH2

[0092]

[0093] (1-7)

[0094] with a suitable chiral acid like di -,(9’ - -toluyl -tartaric acid, diacetyl-tartaric acid, camphanic acid, binolphosphoric acid, naproxen, camphoric acid, A-acetyl phenylalanine, chlorotartranillic acid, acetyltyrosine, A-acetylleucine, Mosher’s acid, chlocyphos, 5,5-dimethyl-2-hydroxy-4-phenyl-l,3,2-dioxaphophorinan-2-oxide, binaphthyl disulfonimide, / f-carbobenzyl oxy tyrosine, or deoxycholic acid, preferably (A)-chlocyphos, A-acetyl-Z-leucine, (A)-Mosher’s acid or (k)-naproxen, and most preferably (A)-chlocyphos or N-acetyl-Z-leucine, in presence of a suitable solvent like ethanol, methanol, ethyl acetate, butyl acetate, isopropanol, tert-amyl alcohol, toluene, methyl ethyl ketone, methyl isobutyl ketone, diphenyl ether, acetone, CPME, TBME, heptane, cyclohexane or acetonitrile or mixtures thereof, preferably ethanol, ethyl acetate, toluene or acetonitrile, and most preferably with (A)-chlocyphos in ethanol or with A-acetyl-Z-leucine in ethanol, in order to arrive at an acceptable salt of the compound of formula (I)

[0095] NH2

[0096]

[0097] (i);

[0098] wherein in the above reaction R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl. A process comprising the reaction of a compound of formula (1-2)

[0099] o

[0100] O'R

[0101]

[0102] (1-2)

[0103] in presence of a suitable reduction agent like H2, NaBH4, LiBH4, LiAlH4, Red-Al or DIBAL, preferably H2, NaBH4or LiBH4, a suitable solvent like MeOH, EtOH, THF, 2-Me-THF, toluene or a mixture of THF and methanol, preferably MeOH, THF, 2-Me-THF or a mixture of THF and methanol, optionally a catalyst like Ru-MACHO, Ru-MACHO-BH, [RuCl2(Ph2P(CH2)2NH2)2], [RuCl2(Py-CH2NH(CH2)2PPh2)(PPh3)], [RuClH(Py-CH2NH(CH2)2PPh2)(CO)], [RuCl2(Et-SNS)(PPh3)], [RuClH(Et-SNS)(CO)], [RuCl2(Bn-SNS)(PPh3)], [RuCl2(tBu-SNS)(PPh3)], or [RuClH(Cy2P(CH2)2NH(CH2)2PCy2)(CO)], preferably Ru-MACHO, [RuCl2(Ph2P(CH2)2NH2)2], [RuCl2(Et-SNS)(PPh3)], or [RuCl2(Py-CH2NH(CH2)2PPh2)(PPh3)], and optionally an additive like K2CO3, Na3PO4, K3PO4, KOMe, NaOMe, KOEt, NaOEt, NaO / Bu or KOtBu, preferably Na3PO4, NaOMe, KOMe or K3PO4, in order to arrive at a compound of formula (1-8)

[0104]

[0105] (1-8).

[0106] A process comprising the following steps:

[0107] (a) the reaction of a compound of formula (1-2)

[0108] o

[0109] O'R

[0110]

[0111] (1-2)

[0112] in presence of a suitable reduction agent like H2, NaBH4, LiBH4, LiAlH4, Red-Al or DIBAL, preferably H2, NaBH4or LiBH4, a suitable solvent like MeOH, EtOH, THF, 2-Me-THF, toluene or a mixture of THF and methanol, preferably MeOH, THF, 2-Me-THF or a mixture of THF and methanol, optionally a catalyst like Ru-MACHO, Ru-MACHO-BH, [RuCl2(Ph2P(CH2)2NH2)2], [RuCl2(Py-CH2NH(CH2)2PPh2)(PPh3)], [RuClH(Py-CH2NH(CH2)2PPh2)(CO)], [RuCl2(Et-SNS)(PPh3)], [RuClH(Et-SNS)(CO)], [RuCl2(Bn-SNS)(PPh3)], [RuCl2(tBu-SNS)(PPh3)], or [RuClH(Cy2P(CH2)2NH(CH2)2PCy2)(CO)], preferably Ru-MACHO, [RuCl2(Ph2P(CH2)2NH2)2], [RuCl2(Et-SNS)(PPh3)], or [RuCl2(Py-CH2NH(CH2)2PPh2)(PPh3)], and optionally an additive like K2CO3, Na3PO4, K3PO4, KOMe, NaOMe, KOEt, NaOEt, NaOtBu or KOtBu, preferably Na3PO4, NaOMe, KOMe or K3PO4, in order to arrive at a compound of formula (1-8)

[0113]

[0114] (i-8);

[0115] (b) the reaction of a compound of formula (1-8)

[0116]

[0117] (1-8)

[0118] in presence of a suitable solvent like dichloromethane, THF, acetonitrile, EtOAc, DMF, TBME, or 2-Me-THF, preferably acetonitrile or THF, a suitable base like triethylamine, pyridine, diisopropylethylamine, 2,6-dimethylpyridine, NaOH, KOH, K2CO3, Na2CO3, KHCO3, NaHCO3, DMAP, or NMI, preferably NEt3, and a suitable sulfonylating agent like methanesulfonyl chloride, methanesulfonyl anhydride, benzenesulfonyl chloride or 4-toluenesulfonyl chloride in order to arrive at a compound of formula (1-9)

[0119] O...x-O'x

[0120]

[0121] (1-9);

[0122] (c) the reaction of a compound of formula (1-9)

[0123] 9"«Z^O'X

[0124]

[0125] (1-9)

[0126] with a suitable azide reagent like NaN3, LiN3, TMSN3 or NBu4N3, preferably NaN3 or TMSN3, in presence of a suitable solvent like DMF, NMP, NBP, DMAc, cyrene, DMSO, water, THF, Me-THF, MeOH, MeCN, acetone, EtOH, toluene, or ethyl acetate, preferably DMF or Me-THF, in order to arrive at a compound of formula (1-13)

[0127] P'"7^N3

[0128]

[0129] (1-13); and

[0130] (d) the reaction of a compound of formula (1-13)

[0131]

[0132] (M3)

[0133] with a suitable reduction agent like H2, NaBH4, LiBH4, PPh3, LiAlH4, or Et3SiH, preferably H2, optionally in the presence of an additive like Pd / C, Pd(OH)2 / Al2O3, PtCE, N1CI2.6H2O, or InCl3, preferably Pd / C, and in presence of a suitable solvent like THF, DMF, water, PEG400, MeOH, EtOH, MeCN, EtOAc, or 2-Me-THF, preferably THF, in order to arrive at the compound of formula (I) or an acceptable salt thereof

[0134] NH2

[0135]

[0136] (i);

[0137] wherein in the above reaction X is -SO3Me, -SO3Ph or -SO3pTol, and wherein R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

[0138] A process comprising the reaction of a compound of formula (1-9’) or (1-9”)

[0139]

[0140] with NH3, in presence of a suitable solvent like DMF, NMP, NBP, DMAc, cyrene, DMSO, water, THF, Me-THF, MeOH, MeCN, acetone, EtOH, zPrOH, toluene, or ethyl acetate, preferably MeOH or EtOH, in order to arrive at a compound of formula (II-7) or of formula (II-7’)

[0141]

[0142] A process according to embodiment 11 further comprising the following preceding steps: (a) the reaction of a compound of formula (1-2)

[0143] o

[0144]

[0145] (1-2)

[0146] in presence of a suitable reduction agent like H2, NaBH4, LiBH4, LiAlH4, Red-Al or DIBAL, preferably H2, NaBH4or LiBH4, a suitable solvent like MeOH, EtOH, THF, 2-Me-THF, toluene or a mixture of THF and methanol, preferably MeOH, THF, 2-Me-THF or a mixture of THF and methanol, optionally a catalyst like Ru-MACHO, Ru-MACHO-BH, [RuCl2(Ph2P(CH2)2NH2)2], [RuCl2(Py-CH2NH(CH2)2PPh2)(PPh3)], [RuClH(Py-CH2NH(CH2)2PPh2)(CO)], [RuCl2(Et-SNS)(PPh3)], [RuClH(Et-SNS)(CO)], [RuCl2(Bn-SNS)(PPh3)], [RuCl2(tBu-SNS)(PPh3)], or [RuClH(Cy2P(CH2)2NH(CH2)2PCy2)(CO)], preferably Ru-MACHO, [RuCl2(Ph2P(CH2)2NH2)2], [RuCl2(Et-SNS)(PPh3)], or [RuCl2(Py-CH2NH(CH2)2PPh2)(PPh3)], and optionally an additive like K2CO3, Na3PO4, K3PO4, KOMe, NaOMe, KOEt, NaOEt, NaOBu or KOBu, preferably Na3PO4, NaOMe, KOMe or K3PO4, in order to arrive at a compound of formula (1-8)

[0147]

[0148] (1-8); and (b) the reaction of a compound of formula (1-8)

[0149] 9" T^^OH

[0150]

[0151] (1-8)

[0152] in presence of a suitable solvent like di chloromethane, THF, acetonitrile, EtOAc, DMF, TBME, toluene or 2-Me-THF, preferably toluene, acetonitrile or 2-Me-THF, a suitable base like triethylamine, pyridine, diisopropylethylamine, 2,6-dimethylpyridine, NaOH, KOH, K2CO3, Na2CO3, KHCO3, NaHCO3, DMAP, or NMI, preferably NMI or NEt3, and a suitable sulfonylating agent like 4-toluenesulfonyl chloride or benzenesulfonyl chloride in order to arrive at a compound of formula (1-9’) or (1-9”)

[0153]

[0154] wherein in the above reaction R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl; in one particular embodiment the conditions for step (b) are such that the solvent is toluene, the base is NMI and the sulfonylating agent is selected from 4-toluenesulfonyl chloride and benzenesulfonyl chloride.

[0155] A process comprising the following steps:

[0156] (a) the reaction of a compound of formula (1-2)

[0157]

[0158] in presence of a suitable reduction agent like H2, NaBH4, LiBH4, LiAlH4, Red-Al or DIBAL, preferably H2, NaBH4 or LiBH4, a suitable solvent like MeOH, EtOH, THF, 2-Me-THF, toluene or a mixture of THF and methanol, preferably MeOH, THF, 2-Me-THF or a mixture of THF and methanol, optionally a catalyst like Ru-MACHO, Ru-MACHO-BH, [RuCl2(Ph2P(CH2)2NH2)2], [RuCl2(Py-CH2NH(CH2)2PPh2)(PPh3)], [RuClH(Py-CH2NH(CH2)2PPh2)(CO)], [RuCl2(Et-SNS)(PPh3)], [RuClH(Et-SNS)(CO)], [RuCl2(Bn-SNS)(PPh3)], [RuCl2(Bu-SNS)(PPh3)], or [RuClH(Cy2P(CH2)2NH(CH2)2PCy2)(CO)], preferably Ru-MACHO, [RuCl2(Ph2P(CH2)2NH2)2], [RuCl2(Et-SNS)(PPh3)], or [RuCl2(Py-CH2NH(CH2)2PPh2)(PPh3)], and optionally an additive like K2CO3, Na3PO4, K3PO4, KOMe, NaOMe, KOEt, NaOEt, NaO / Bu or KO / Bu, preferably Na3PO4, NaOMe, KOMe or K3PO4, in order to arrive at a compound of formula (1-8)

[0159]

[0160] (1-8);

[0161] (b) the reaction of a compound of formula (1-8)

[0162] OH

[0163]

[0164] (1-8)

[0165] in presence of a suitable solvent like dichloromethane, THF, acetonitrile, toluene, EtOAc, DMF, TBME, or 2-Me-THF, preferably 2-Me-THF or toluene, a suitable base like triethylamine, pyridine, diisopropylethylamine, 2,6-dimethylpyridine, NaOH, KOH, K2CO3, Na2CO3, KHCO3, NaHCO3, DMAP, or NMI, preferably NMI, and a suitable sulfonylating agent like methanesulfonyl chloride, methanesulfonyl anhydride, or 4-toluenesulfonyl chloride in order to arrive at a compound of formula (1-9)

[0166]

[0167] (1-9);

[0168] (c) the reaction of a compound of formula (1-9)

[0169] ox

[0170]

[0171] (1-9)

[0172] with Bn2NH, in presence of a suitable additive like NaI, a suitable base like K2CO3and a suitable solvent like DMF, NMP, NBP, DMAc, cyrene, DMSO, water, THF, Me-THF, MeOH, MeCN, acetone, EtOH, toluene, or ethyl acetate, preferably DMF, in order to arrive at a compound of formula (I- 10)

[0173] o„

[0174]

[0175] (I- 10); and

[0176] (d) the reaction of a compound of formula (I- 10)

[0177]

[0178] (1-10)

[0179] with a suitable reduction agent such as for instance H2 in presence of a suitable solvent such as for instance MeOH or EtOH and a suitable catalyst such as for instance Pd(OH)2 / C or Pd / C in order to arrive at a compound of formula (I)

[0180] NH2

[0181]

[0182] (i);

[0183] or an acceptable salt thereof like salts with N-acetylleucine, chlocyphos, Mosher’s acid, naproxen, 1,5-naphthalenedisulfonic acid, oxalic acid or p-toluenesulfonic acid, preferably 1,5 -naphthalenedi sulfonic acid, oxalic acid or p-toluenesulfonic acid, and most preferably salts with oxalic acid or p-toluenesulfonic acid;

[0184] wherein in the above reaction X is SO3Me, SO3Ph or SO3pTol, and R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

[0185] 14. A process comprising a step selected from (a), (a’) and (a”), and further comprising steps (b) and (c):

[0186] (a) the reaction of a compound of formula (1-2)

[0187] o

[0188]

[0189] (1-2)

[0190] in presence of Bn2NH, a suitable base such as for instance NaOH, LiOH, KOH, NEt3, DIPEA, NMM or NMI, a suitable solvent such as for instance MeOH, EtOH, zPrOH, THF, 2-Me-THF, or EtOAc and a suitable coupling reagent such as for instance T3P, EDC, DIC, pyBOP, COMU, PivCl, PyOxi, PyBOP, or cyanuric chloride in order to arrive at a 26. A compound of formula (I-11)

[0191]

[0192] (I-11);

[0193] in particular in presence of KOH and iPrOH followed by NEt3.HCl, Bn2NH, DIPEA and T3P in order to arrive at a 26. A compound of formula (I-11);

[0194] (a’) the reaction of a compound of formula (1-12)

[0195]

[0196] (I-12)

[0197] in presence of a suitable buffer such as for instance potassium phosphate buffer, a suitable hydrolase (e.g. a suitable lipase, esterase, protease, peptidase or aclyase) and a suitable solvent such as for instance DMSO in order to arrive at a 26. A compound of formula (I-11)

[0198]

[0199] (a”) the reaction of a compound of formula (1-14)

[0200]

[0201] (1-14)

[0202] in presence of Bn2NH, a suitable base such as for instance DIPEA, a suitable coupling reagent such as for instance T3P and a suitable solvent such as for instance EtOAc in order to arrive at a 26. A compound of formula (I-11)

[0203]

[0204] (1-11); and

[0205] (b) the reaction of a 26. A compound of formula (I-11)

[0206]

[0207] in presence of a suitable solvent such as for instance PhMe or CPME and a suitable reduction reagent such as for instance Red- Al or a mixture of PMHS and NaBHEts in order to arrive at a compound of formula (I- 10)

[0208]

[0209] (I- 10); and

[0210] (c) the reaction of a compound of formula (I- 10)

[0211]

[0212] with a suitable reduction agent such as for instance H2 in presence of a suitable solvent such as for instance MeOH or EtOH and a suitable catalyst such as for instance Pd(OH)2 / C or Pd / C in order to arrive at a compound of formula (I)

[0213] NH2

[0214]

[0215] (i); or an acceptable salt thereof like salts with N-acetylleucine, chlocyphos, Mosher’s acid, naproxen, 1,5-naphthalenedisulfonic acid, oxalic acid or p-toluenesulfonic acid, preferably 1,5 -naphthalenedi sulfonic acid, oxalic acid or p-toluenesulfonic acid, and most preferably salts with oxalic acid or p-toluenesulfonic acid;

[0216] wherein in the above reaction R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

[0217] 15. A process according to embodiment 14 further comprising the following preceding step: the reaction of a compound of formula (I-1)

[0218]

[0219] (1-1)

[0220] with a suitable hydrolase (e.g. a suitable lipase, esterase, protease, peptidase or aclyase) with esterase activity and in presence of

[0221] • a suitable buffer selected from potassium phosphate, sodium phosphate, Tris-HCl, sodium acetate, MES, HEPES and PIPES, preferably the buffer is potassium phosphate;

[0222] • optionally a suitable co-solvent selected from TBME, 2-Me-THF, THF, CPME, toluene, anisole, n-heptane, cyclohexane, preferably the co-solvent is 2-MeTHF; and

[0223] • optionally a suitable additive such as for instance (NH4)2SO4

[0224] in order to arrive at a compound of formula (1-2)

[0225]

[0226] (1-2),

[0227] in the above reaction the R is alkyl, in particular ethyl, propyl and isopropyl, and the hydrolase is preferably one of the Amano proteases CES P-1 or P6 SD.

[0228] 16. A process according to embodiment 1, 10, 13, 14 or 15, wherein the compound of formula (I) is isolated in form of an acceptable salt thereof, like salts with N- acetylleucine, chlocyphos, Mosher’s acid, naproxen, 1,5-naphthalenedisulfonic acid, oxalic acid or p-toluenesulfonic acid, preferably 1,5-naphthalenedisulfonic acid, oxalic acid or p-toluenesulfonic acid, and most preferably salts with oxalic acid or p-toluenesulfonic acid.

[0229] A process according to embodiment 1, 10, 13, 14 or 15, wherein the compound of formula (I) is not isolated and is instead telescoped into a further chemical reaction.

[0230] A process according to embodiments 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein R is methyl.

[0231] A process according to embodiments 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein R is ethyl.

[0232] A process according to embodiments 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein R is propyl.

[0233] A process according to embodiments 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein R is isopropyl.

[0234] A process comprising the reaction of a compound of formula (I-1)

[0235] o

[0236]

[0237] with a suitable hydrolase (e.g. a suitable lipase, esterase, protease, peptidase or aclyase) with esterase activity and in presence of

[0238] • a suitable buffer selected from potassium phosphate, sodium phosphate, Tris-HCl, sodium acetate, MES, HEPES and PIPES, preferably the buffer is potassium phosphate; and

[0239] • optionally a suitable co-solvent selected from TBME, 2-Me-THF, THF, CPME, toluene, anisole, n-heptane, cyclohexane, preferably the co-solvent is 2-MeTHF;

[0240] • optionally a suitable additive such as for instance (NH4)2SO4

[0241] in order to arrive at a compound of formula (1-2)

[0242] O

[0243]

[0244] in the above reaction R is alkyl, in particular ethyl, propyl or isopropyl, and the hydrolase is preferably one of the Amano proteases CES P-1 or P6 SD.

[0245] A process comprising the reaction of a compound of formula (I-1-III)

[0246] O I

[0247]

[0248] (I-1-III)

[0249] with a suitable hydrolase (e.g. a suitable lipase, esterase, protease, peptidase or aclyase) with esterase activity and in presence of

[0250] • a suitable buffer selected from potassium phosphate, sodium phosphate, Tris-HCl, sodium acetate, MES, HEPES and PIPES, preferably the buffer is potassium phosphate with a pH between around 6.0 and around 7.9, more preferably with a pH between around 6.4 and around 7.5, most preferably with a pH between around 7.1 and 7.4;

[0251] • a suitable co-solvent selected from water, TBME, 2-Me-THF, THF, CPME, toluene, anisole, n-heptane, cyclohexane, preferably the co-solvent is 2-MeTHF; and

[0252] • a suitable additive such as for instance (NH4)2SO4;

[0253] in order to arrive at a compound of formula (I-2-III)

[0254] O I

[0255] p

[0256]

[0257] (I-2-III),

[0258] in the above reaction the hydrolase is preferably the Amano protease P6 SD, and preferably the temperature in the reaction is kept between around 10 °C and around 30 °C, more preferably between around 20 °C and 25 °C.

[0259] A compound of formula (1-3)

[0260] O

[0261] P" V^NH2

[0262] (1-3).

[0263] A compound of formula (1-4)

[0264]

[0265] (1-4).

[0266] 26. A compound of formula (I-11)

[0267]

[0268] compound selected from the group of compounds of formula (II- 1), (II-2), (II-3), (II-), (II-5) and (II-6)

[0269]

[0270] (II-7’).

[0271]

[0272] (1-9”). 33. A compound of formula (I-2-III)

[0273]

[0274] (I-2-III).

[0275] 34. A compound of formula (I-2-II)

[0276] O

[0277]

[0278] (I-2-II).

[0279] 35. A compound of formula (I-2-I)

[0280]

[0281] (I-2-I).

[0282] General schemes:

[0283] Scheme 1

[0284] step a'

[0285] step b'

[0286] O step c' step d'

[0287]

[0288] step d"

[0289]

[0290] step e"

[0291]

[0292] In the above scheme, R is an alkyl such as for instance methyl, ethyl, propyl and isopropyl.

[0293] In step a, the solvent can be for instance EtOH, iPrOH, toluene, DMSO or a mixture thereof, the base can be for instance potassium hydroxide or triethylamine, and the esterification agent can be for instance ethyl chloroformate, 1 -propyl iodide or 2-propyl iodide. Preferred conditions for R = ethyl are that the solvent is EtOH, the base is potassium hydroxide and the esterification agent is ethyl chloroformate in toluene. Preferred conditions for R = propyl / isopropyl are that the solvent is iPrOH, the base is potassium hydroxide and the esterification agent is 1 -propyl iodide or 2-propyl iodide in DMSO or 2-propyl chloroformate in toluene for R = isopropyl.

[0294] In step a’, the solvent can be for instance EtOH, zPrOH, toluene, DMSO, or a mixture thereof, the base can be for instance potassium hydroxide, K3PO4, K2CO3, or triethylamine, and the esterification agent can be for instance ethyl chloroformate, 1 -propyl iodide or 2-propyl iodide or 2-propyl chloroformate.

[0295] In step b, the solvent of the enzymatic resolution can be for instance aqueous potassium phosphate and 2-Me-THF and an optional additive can be for instance (NH₄)₂SO₄ A suitable hydrolase with esterase activity can be for instance one of the commercially available Amano proteases, CES P-1 or P6 SD. Preferably, R is isopropyl as the isopropyl ester possesses higher hydrolysis stability, since this allows a very robust and efficient enzymatic hydrolysis process at increased temperature (10-30 °C), pH (6.0 -7.5), proper base (NaOH or Na₂CO₃) and therewith at a significantly reduced the enzyme loading. The three key parameters temperature, pH, proper base are dependent on each other and the chemical background hydrolysis is as well impacted of their interplay.

[0296] In steps b’ and c, the solvent can be for instance methanol and the amidation agent can be for instance NH3.

[0297] In steps c’ and d, the solvent can be for instance CH₂Cl₂, or EtOAc. The dehydrating agent can be for instance trifluoroacetic anhydride, or trichloroacetyl chloride. The base can be for instance pyridine, or triethylamine.

[0298] In step d’, the solvent can be for instance aqueous potassium phosphate and DMSO in the presence of a nitrilase or nitrile hydratase. In steps d’ ’ and e, the solvent can be for instance THF, or a mixture of THF and MeOH. The reducing agent can be for instance LiBH4, NaBH4 in the presence of ZnCh, or sodium bis(2-methoxyethoxy)aluminum hydride.

[0299] In step d” ’, the solvent can be for instance toluene. The reducing agent can be for instance sodium bis(2-methoxyethoxy)aluminum hydride.

[0300] In step e”, the solvent can be for instance ethanol. The acid can be for instance (R)-chlocyphos, or N-acetyl-L-leucine.

[0301] Scheme 2

[0302] step a step b

[0303] step e

[0304]

[0305] In the above scheme, R is an alkyl, such as for instance methyl, ethyl propyl or isopropyl.

[0306] In step a, the solvent can be for instance EtOH, iPrOH, toluene, DMSO or a mixture thereof, the base can be for instance potassium hydroxide or triethylamine, and the esterification agent can be for instance 2-propyl chloroformate, ethyl chloroformate, 1 -propyl iodide or 2-propyl iodide. Preferred conditions for R = ethyl are that the solvent is EtOH, the base is potassium hydroxide and the esterification agent is ethyl chloroformate in toluene. Preferred conditions for R = propyl / isopropyl are that the solvent is iPrOH, the base is potassium hydroxide and the esterification agent is 1 -propyl iodide or 2-propyl iodide in DMSO or 2-propyl chloroformate in toluene for R = isopropyl. In step b, the solvent of the enzymatic resolution can be for instance aqueous potassium phosphate and 2-Me-THF and an optional additive can be for instance (NH₄)₂SO₄ A suitable hydrolase with esterase activity can be for instance one of the commercially available Amano proteases CES P-1 or P6 SD. Preferably, R is isopropyl as the isopropyl ester possesses higher hydrolysis stability, since this allows a very robust and efficient enzymatic hydrolysis process at increased temperature (10-30 °C), pH (6.0 -7.5), proper base (NaOH or Na₂CO₃) and therewith at a significantly reduced the enzyme loading. The three key parameters temperature, pH, proper base are dependent on each other and the chemical background hydrolysis is as well impacted of their interplay.

[0307] In step c, the solvent can be for instance methanol, or THF. A suitable reducing agent can be for instance NaBH4 and LiCl, or NaBH4, or a combination of Ru-MACHO and H2 with a suitable base such as for instance K2CO3, KOMe, NaOMe, K3PO4, Na₃PO₄ or KOtBu.

[0308] In step d, the solvent can be for instance DCM, MeCN, toluene or Me-THF. The base can be for instance triethylamine, or N-Methylimidazole (NMI), in particular the base is NMI. The sulfonylation agent can be for instance methansulfonylchloride, or / ?-toluenesulfonylchloride or benzensulfonylchloride.

[0309] In step e, the solvent can be for instance DMF and the nucleophile NaNs.

[0310] In step e’, the solvent can be for instance DMF, the additive Nal and the base K2CO3. The nucleophile can be for instance Bn2NH.

[0311] In step e”, the solvent can be for instance MeOH, THF or toluene and the reagent is NH3, in particular the solvent is toluene and the reagent is NH3.

[0312] In step f, the solvent can be for instance THF or MeOH, the reducing agent hydrogen (gas) and the catalyst Pd / C or Pd / AhOs.

[0313] In step f, the solvent can be a suitable alcohol such as for instance, but not limited to, MeOH, or EtOH, the reducing agent hydrogen (gas) and a suitable catalyst could be for instance Pd(OH)2 / C or Pd / C.

[0314] Scheme 3 o step a

[0315] Br

[0316]

[0317] In the above scheme, R is an alkyl such as for instance methyl, ethyl, propyl and isopropyl.

[0318] In step a, the solvent can be for instance EtOH, iPrOH, toluene, DMSO or a mixture thereof, the base can be for instance potassium hydroxide or triethylamine, and the esterification agent can be for instance 2-propyl chloroformate, ethyl chloroformate, 1 -propyl iodide or 2-propyl iodide. Preferred conditions for R = ethyl are that the solvent is EtOH, the base is potassium hydroxide and the esterification agent is ethyl chloroformate in toluene. Preferred conditions for R = propyl / isopropyl are that the solvent is iPrOH, the base is potassium hydroxide and the esterification agent is 1 -propyl iodide or 2-propyl iodide in DMSO or 2-propyl chloroformate in toluene for R = isopropyl.

[0319] In step a’, the solvent can be for instance EtOH, zPrOH, toluene, DMSO, or a mixture thereof, the base can be for instance potassium hydroxide, K3PO4, K2CO3, or triethylamine, and the

[0320] 1 esterification agent can be for instance ethyl chloroformate, 1 -propyl iodide or 2-propyl iodide or 2-propyl chloroformate.

[0321] In step a” and a””, the solvent can be for instance THF, 2-Me-THF, or EtOAc, the base can be for instance NEts, DIPEA, NMM, or NMI, and the coupling reagent can be for instance T3P, EDC, DIC, pyBOP, COMU, PivCl, PyOxi, PyBOP, or cyanuric chloride. The amine can be for instance Bn2NH. Particularly the solvent is EtOAc, the base is DIPEA and the coupling reagent is T3P. In step a’” and c, the solvent is for instance MeOH, EtOH, zPrOH, THF, 2-Me-THF, or EtOAc, the base can be for instance NaOH, LiOH, KOH, NEts, DIPEA, NMM or NMI, the additive can be for instance NEts. HCl, and the coupling reagent can be for instance T3P, EDC, DIC, pyBOP, COMU, PivCl, PyOxi, PyBOP, or cyanuric chloride. The amine can be for instance Bn2NH. Particularly the solvent is iPrOH, the base is KOH, then for the coupling the base is DIPEA, the additive is NEt₃.HCl and the coupling reagent is T3P in EtOAc.

[0322] In step b, the solvent can be for instance aqueous potassium phosphate and 2-Me-THF and an optional additive can be for instance (NH4)2SO4. A suitable esterase can be for instance CES P-1 or P6 SD from Amano. Preferably, R is isopropyl, since this allows a very robust process at increased temperature (10-30 °C), independence of pH (6-7.5), proper base (NaOH or Na2COs) significantly lowering the enzyme loading. The three key parameters temperature, pH, proper base are dependent on each other and the chemical backgound hydrolysis is impacted of their interplay. Preferably, R is isopropyl, since this allows a very robust process at increased temperature, pH, proper base significantly lowering the enzyme loading. The three key parmeter temperature, pH, proper base are dependent on each other and the chemical backgound hydrolysis is impacted of their interplay.

[0323] In step b’, the solvent can be for instance aqueous potassium phosphate and DMSO in the presence of a hydrolase.

[0324] In step d, the solvent can be for instance PhMe or CPME and the reduction reagent can be for instance Red-Al or a mixture of PMHS and NaBHEt₃. Particularly, the solvent is PhMe and the reduction agent is Red-Al. In step e, the solvent can be for instance MeOH, or EtOH, the reducing agent hydrogen (gas) and the catalyst Pd(OH)2 / C or Pd / C. Particularly, the solvent is MeOH or EtOH and the catalyst is about 10% Pd / C.

[0325] Experimental Part

[0326] The following experiments are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. The individual steps may be combined, modified and the sequence altered in order to yield the compound of formula (I) or an intermediate thereof, however the scope of the invention is not limited by the reactions specifically described in the examples but is to be construed in view of the whole disclosure of the present invention including inter alia also the general schemes and common general knowledge.

[0327] Abbreviations:

[0328] ACN = acetonitrile; CAS = chemical abstract service; CPME = cyclopentyl methyl ether; DCM = dichloromethane; DIPEA = N, N-diisopropylethylamine; DMAP = N, N-dimethylaminopyridine; DMF = dimethylformamide; DMSO dimethyl sulfoxide; EtOAc = ethyl acetate; EtOH = ethanol; IPA = 2-propanol; MeCN = acetonitrile; MeOH = methanol; 2-Me-THF = 2-methyl tetrahydrofuran; MEK = methyl ethyl ketone; MIPK = methyl isopropyl ketone; MS = mass spectrometry; MsCl = methanesulfonyl chloride; MsOH = methanesulfonic acid; NEts = triethyl amine; NMI = N-Methylimidazole; NMR = nuclear magnetic resonance; PhMe = toluene; p-TsCl = para-toluenesulfonyl chloride; p-TsOH = para-toluenesulfonic acid; RT = room temperature; SFC = supercritical fluid chromatography; TBME = tert-butyl methyl ether; TEA = tri ethylamine; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran.

[0329] Intermediate 1 - method 1: (rac)-Ethyl oxetane-2-carboxylate

[0330] KOH, EtOH O

[0331]

[0332] then CICO2Et, NEt3

[0333] PhMe / EtOH (rac)-a-Bromo-y-butyrolactone (16.8 mL, 176 mmol; 1.0 eq, CAS number: 5061-21-2) was added dropwise to KOH (28.8 g, 441 mmol, 2.5 eq) in EtOH (300 mL) at 0 °C and warmed to RT overnight. The mixture was filtered, washed with EtOH (150 mL) and concentrated to 100 mL. PhMe (180 mL) and EtOH (90 mL) were added. NEts (46.7 mL, 335 mmol, 1.9 eq) was added dropwise at 15 °C. Ethyl chloroformate (25.4 mL, 265 mmol, 1.5 eq) was added dropwise at 15 °C and warmed to RT overnight. CH₂Cl₂ (200 mL) and saturated aqueous NH₄Cl solution (200 mL) were added. The aqueous phase was separated and extracted with CH₂Cl₂ (135 mL). The combined organic phases were washed with 0.5 M aqueous HCl solution (200 mL) and saturated aqueous NaHCO₃ solution (200 mL) and the solvent was removed under reduced pressure. Purification by distillation afforded the product as a colorless liquid. Yield: 16.7 g (73%).

[0334] ’H NMR (600 MHz, MeOH-d4): 5 5.17 - 5.13 (m, 1H, OCH), 4.72 - 4.68 (m, 1H, OC / 7H), 4.68 - 4.63 m, 1H, OC7 / H), 4.25 - 4.21 (m, 2H, OC / 7H), 3.03 - 2.99 (m, 1H, C H), 2.72 - 2.66 m, 1H, C H), 1.30 - 1.27 (m, 3H, CH3).

[0335] MS (EI+): Calcd. for C₆H₁₀O₃ m / z = 130.1, found m / z = 130.1 [M]+.

[0336] Intermediate 1 - method 2: (rac)-Ethyl oxetane-2-carboxylate

[0337] CICO2Et, NEt3

[0338]

[0339] PhMe / EtOH

[0340] NEts (75.2 mL, 540 mmol, 1.9 eq) was added dropwise to (rac)-oxetane-2-carboxylic acid (29.0 g, 284 mmol, 1.0 eq, CAS 864373-47-7) in PhMe (170 mL) and EtOH (85 mL) at 15 °C. Ethyl chloroformate (40.9 mL, 426 mmol, 1.5 eq) was added dropwise at 15 °C and warmed to RT overnight. CH₂Cl₂ (200 mL) and saturated aqueous NH₄Cl solution (200 mL) were added. The aqueous phase was separated and extracted with CH₂Cl₂ (150 mL). The combined organic phases were washed with 0.5 M aqueous HCl solution (200 mL) and saturated aqueous NaHCO₃ solution (200 mL) and the solvent was removed under reduced pressure. Purification by distillation afforded the product as a colorless liquid. Yield: 24.5 g (65%).

[0341] Analytical data in agreement with the data above for (rac)-ethyl oxetane-2-carboxylate (intermediate 1, as described under method 1). Intermediate 1’: (rac)-l-Propyl oxetane-2-carboxylate

[0342] KOH, / PrOH o

[0343]

[0344] then Prl, DMSO

[0345] (rac)-a-Bromo-y-butyrolactone (1.00 kg, 6.06 mol, 1.0 eq, CAS number: 5061-21-2) was added dropwise to KOH (850 g, 15.2 mol, 2.5 eq) in zPrOH (10.0 L) at 0 °C and stirred at RT. Upon reaction completion, the suspension was filtered and washed twice with zPrOH (2 x 1.5 L). The combined filtrates were concentrated to 2 V under reduced pressure. DMSO (5.0 L) and propyl iodide (3.09 kg, 18.2 mol, 3.0 eq; CAS number: 107-08-4) were added and stirred at RT. Upon reaction completion, the mixture was added to a biphasic mixture of TBME (5.0 L) and 15% aqueous NH4CI solution (8.0 L) at 15 °C. The aqueous phase was separated and extracted with TBME (6.0 L). The combined organic phases were washed with 5% aqueous NaCl solution (6.0 L) and concentrated under reduced pressure. The crude residue was purified by fractional distillation. Yield: 610 g (70%).

[0346] **1**H NMR (400 MHz, CDCl3): δ 5.19 - 5.13 (m, 1H, OCH), 4.76 - 4.71 (m, 2H, OCHH), 4.20 - 4.15 (m, 2H, OCHH), 3.07 - 2.96 (m, 1H, CHH), 2.79 - 2.69 (m, 1H, CHH), 1.77 - 1.66 (m, 2H, CHH), 0.99 - 0.95 (m, 3H, CH3).

[0347] MS (EI+): Calcd. for C7H12O3 m / z = 144.1, found m / z = 144.1 [M]+.

[0348] Intermediate 1” - Method 1: (rac)-2-Propyl oxetane-2-carboxylate

[0349] O KOH, / PrOH

[0350]

[0351] then2-Prl, DMSO

[0352] (rac)-a-Bromo-y-butyrolactone (1.00 kg, 6.06 mol, 1.0 eq, CAS number: 5061-21-2) was added dropwise to KOH (850 g, 15.2 mol, 2.5 eq) in zPrOH (10.0 L) at 0 °C and stirred at RT. Upon reaction completion, the suspension was filtered and washed twice with zPrOH (2 x 1.5 L). The combined filtrates were concentrated to 2 V under reduced pressure. DMSO (5.0 L) and isopropyl iodide (2.06 kg, 12.1 mol, 2.0 eq; CAS number: 75-30-9) were added and stirred at 45 °C. Upon reaction completion, the mixture was added to a biphasic mixture of TBME (65.0 L) and aqueous 10% NH4CI / 5% ascorbic acid solution (6.0 L) at 15 °C. The aqueous phase was separated and extracted with TBME (6.0 L). The combined organic phases were washed with 5% aqueous NaHCO3solution (5.0 L) and concentrated under reduced pressure. The crude residue was purified by fractional distillation. Yield: 520 g (60%).

[0353] ’H NMR (400 MHz, CDCI3): 5 5.19 - 5.08 (m, 2H, OCH), 4.78 - 4.65 (m, 2H, OC / 7H), 3.04 -2.94 (m, 1H, C H), 2.75 - 2.65 m, 1H, C H), 1.29 (d,3. / H.ir = 6.2 Hz, 3H, C#3), 1.28 (d,3JH.ir = 6.4 Hz, 3H, CH3).

[0354] MS (EI+): Calcd. for C7H12O3 m / z = 144.1, found m / z = 144.1 [M]+.

[0355] Intermediate 1” - Method 2: (rac)-2-Propyl oxetane-2-carboxylate

[0356] o KOH, / PrOH

[0357]

[0358] then 2-PrOCOCI,

[0359] Et3N, toluene

[0360] (rac)-a-Bromo-y-butyrolactone (100 g, 0.606 mol, l.eq, CAS number: 5061-21-2) was added dropwise to KOH (85.0 g, 1.52 mol, 2.5 eq) in zPrOH (1.0 L) at 0 °C and stirred at RT. Upon reaction completion, the suspension was filtered and the precipitate washed twice with zPrOH (2 x 200 mL). The combined filtrates were concentrated to 2.5 V under reduced pressure. Toluene (500.0 mL) and triethylamine (160.5 mL, 1.15 mol, 1,9 eq.) were charged. The reaction mixture was cooled to 10 °C and isopropyl chloroformate (111.4 g, 0.91 mol, 1.5 eq.) was added. The reaction was stirred at 22 °C. Upon reaction completion DMAP (7.4 g, 0.061 mol, 0.1 eq.) was added. After complete decomposition of di-isopropyldicarbonate side-product, the reaction mixture was added to a biphasic mixture of dichloromethane (300.0 mL) and aqueous acetic acid 10% (500.0 mL) at 10 - 15 °C. The layers were separated. The aqueous layer was extracted with di chloromethane (400.0 mL) The combined organic layers were washed with aqueous HC10.5 M (500.0 mL) and with aqueous NaHCO3 6%wt (500.0 mL) and concentrated under reduced pressure. The crude residue was purified by fractional distillation. Yield: 63.0 g (72%).

[0361] Analytical data in agreement with the data above for (rac)-2-propyl oxetane-2-carboxylate (intermediate 1”). Intermediate 2-1: Ethyl (25)-oxetane-2-carboxylate

[0362] pH 6.5, 15°C, substrate to enzyme ratio 13.3:1, 23 h: yield 35%, ee 97.9%

[0363] CES P-1 potassium phosphate buffer / MeTHF

[0364]

[0365]

[0366] (rac)-Ethyl oxetane-2-carboxylate (5.00 g, 38.4 mmol, 1.0 eq, intermediate 1) was added to 0.4 M potassium phosphate buffer pH 6.5 (225 mL), 2-Me-THF (20 mL) and CES P-1 from Amano (375 mg; CAS#: 9074-07-1; TUB#: 3.4.24.28; EINECS#: 232-991-2) and stirred at 15 °C for 23 hours. The mixture was extracted four times with TBME (4 x 250 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure to afford the product as a colorless liquid. Yield: 1.83 g (35%, 97.9% ee).

[0367] Analytical data in agreement with the data above for (rac)-ethyl oxetane-2-carboxylate (intermediate 1).

[0368] GC (Agilent Cyclosil B (30 m x 250 pm x 0.25 pm); inlet temperature: 200 °C; detector temperature: 280 °C; injection volume: 1 pL, split ratio: 15:1; oven temperature program: 55 °C, hold for 2 min, 20 °C / min to 130 °C, hold for 5 min, 100 °C / min to 250 °C; total run time: 12 min): fa(major) = 5.69 min, fa(minor) = 5.81 min.

[0369] Intermediate 2-II: 1-Propyl (25)-oxetane-2-carboxylate

[0370] pH 6.1, 10 °C, substrate to enzyme ratio 20:1, 23 hours: yield 37%, ee 99.6%

[0371] P6 SD

[0372]

[0373] MES buffer (NH4)2SO4 / MeTHF

[0374] (rac)-l-Propyl oxetane-2-carboxylate (6.00 g, 41.6 mmol, 1.0 eq, intermediate 1’) was added to 0.05 M 2-(A-morpholino)ethanesulfonic acid and 1.0 M (NH₄)₂SO₄U buffer pH 6.1 (20.3 mL) and MeTHF (3.8 mL) and cooled to 10 °C. P6 SD from Amano (200 mg, CAS#: 9074-07-1; TUB#: 3.4.21.63; EINECS#: 232-997-6) was added and stirred at 10 °C for 23 hours keeping the solution at pH 6.1 by addition of 1.0 M NaOH. The reaction was extracted twice with EtOAc (2 x 30 mL). The combined organic phases were dried azeotropically until a water content of 0.4% was achieved. The organic phase was filtered through celite and the solvent was removed under reduced pressure to afford the product as a light yellow liquid. Yield: 2.20 g (37%, 99.6% ee). Analytical data in agreement with the data above for (rac)-l -propyl oxetane-2-carboxylate (intermediate 1’).

[0375] GC (BGB-1765SE (30 m x 250 pm x 0.25 mm); inlet temperature: 160 °C; detector temperature: 250 °C; injection volume: 1 pL, split ratio: 10:1; oven temperature program: 60 °C, hold for 0 min, 10 °C / min to 120 °C, hold for 0 min, 30 °C / min to 210 °C; total run time: 9 min): fa(major) = 4.59 min, tR(minor) = 4.94 min.

[0376] Intermediate 2-III: 2-Propyl (25)-oxetane-2-carboxylate

[0377] a) pH 7.2, 20 °C, substrate to enzyme ratio 80: 1, 23 hours: yield 46%, ee 99.6%

[0378] P6 SD

[0379]

[0380] potassium phosphate buffer

[0381]

[0382] (NH4)2SO4 / MeTHF

[0383] (rac)-2 -Propyl oxetane-2-carboxylate (350.0 g, 2.43 mol, 1.0 eq, intermediate 1”) was added to 0.05 M potassium phosphate and 1.0 M (NH₄)₂SO₄U buffer pH 7.4 (600 mL) and 2-Me-THF (117 mL) and cooled to 20 °C. P6 SD from Amano (4.375 g) was added and stirred at 20 °C for 23 hours keeping the solution at pH 7.2 by addition of 2 M ISfeCCL. The reaction was extracted twice with EtOAc (2 x 575 mL). The combined organic phases were dried azeotropically until a water content of 0.07% was achieved. The organic phase was filtered through celite and the solvent was removed under reduced pressure to afford the product as a colorless liquid. Yield: 161.14 g (46%, 99.6% ee).

[0384] Analytical data in agreement with the data above for (rac)-2-propyl oxetane-2-carboxylate (intermediate 1”).

[0385] GC (BGB-1765SE (30 m x 250 pm x 0.25 mm); inlet temperature: 160 °C; detector temperature: 250 °C; injection volume: 1 pL, split ratio: 10:1; oven temperature program: 60 °C, hold for 0 min, 10 °C / min to 120 °C, hold for 0 min, 30 °C / min to 210 °C; total run time: 9 min): fa(major) = 5.64 min, dminor) = 5.83 min.

[0386] *H NMR (600 MHz, CDC13): 6 ppm 5.12 - 5.18 (m, 1 H), 5.09 - 5.14 (m, 1 H), 4.70 - 4.75 (dd, J=7.9, 7.1 Hz, 2 H), 2.96 - 3.05 (m, 1 H), 2.67 - 2.78 (m, 1 H), 1.31 (d, J=6.0 Hz, 3 H), 1.29 (d, J=5.9 Hz, 3 H). MS (EI+): Calcd. for C7H12O3 mlz = 144.1, mass not found; calcd. for CeHioCh mlz = 130.1, found 129 [M]+; calcd. for C5H8O3 mlz = 116.1, found 115 [M]+; calcd. for C4H6O3 mlz = 102.0, found 102.0 [M]+*; calcd. for C3H8 mlz = 44.1, found 43 [M]+.

[0387] OD (1.00 mg / mL CHCI3, 20°C): -93.3°

[0388] b) pH 7.2, 25°C, substrate to enzyme ratio 90:1, 21.5 hours: yield 39.3, ee 99.7%

[0389] P6 SD

[0390]

[0391] potassium phosphate buffer

[0392]

[0393] (NH4)2SO4 / MeTHF

[0394] (rac)-2 -Propyl oxetane-2-carboxylate (9.0 g, 62.4 mmol; intermediate 1”) was added to 0.05 M potassium phosphate and 1.0 M (NH₄)₂SO₄U buffer pH 7.4 (18 mL) and 2-Me-THF (3 mL) and cooled to 25 °C. P6 SD from Amano (100 mg) was added and stirred at 25 °C for 21.5 hours keeping the solution at pH 7.2 by addition of 2 M Na2CO3. The reaction was extracted twice with EtOAc (2 x 100 mL). The combined organic phases were dried azeotropically until a water content of 0.05% was achieved. The organic phase was filtered through celite and the solvent was removed under reduced pressure to afford the product as a colorless liquid. Yield: 3.54 g (39.3%, 99.7% ee).

[0395] c) pH 7.4, 10 °C, substrate to enzyme ratio 80: 1, 20 hours: yield 42.6%, ee 99.7%

[0396] P6 SD

[0397]

[0398] potassium phosphate buffer

[0399]

[0400] (NH4)2SO4 / MeTHF (rac)-2 -Propyl oxetane-2-carboxylate (25.0 g, 173.4 mmol; intermediate 1”) was added to 0.05 M potassium phosphate and 1.0 M (NH₄)₂SO₄U buffer pH 7.4 (65 mL) and MeTHF (10 mL) and cooled to 10 °C. P6 SD from Amano (100 mg) was added and stirred at 10 °C for 20 hours keeping the solution at pH 7.2 by addition of 2 M Na2COs. The reaction was extracted twice with EtOAc (2 x 100 mL). The combined organic phases were dried azeotropically until a water content of 0.04% was achieved. The organic phase was filtered through celite and the solvent was removed under reduced pressure to afford the product as a colorless liquid. Yield: 10.66 g (42.6%, 99.7% ee).

[0401] Intermediate 3: (25)-Oxetane-2-carboxamide

[0402] NH3O

[0403] MeOH

[0404]

[0405] NH3 (7 M in MeOH, 3.41 mL, 23.9 mmol, 2.00 eq) was added to ethyl (S)-oxetane-2-carboxylate (1.60 g, 11.9 mmol; intermediate 2) and stirred at RT overnight. The solution was cooled to 0 °C and heptane (5 mL) was added. After 3 hours, the precipitate was filtered and washed three times with cold heptane (3 × 5 mL) to afford the product as a white solid. Additional product was obtained by crystallization after concentrating the combined organic phases. Yield: 0.94 g (76%, >99% ee).

[0406] 1H NMR (600 MHz, CDCl3): δ 6.83 (br s, 1H, NHH), 5.84 (br s, 1H, NHH), 5.05 (dd,3JH,H'= 9.3, 6.7 Hz, 1H, OCH), 4.79 - 4.75 (m, 1H, OCHH), 4.67 - 4.63 (m, 1H, OCHH), 3.10 - 3.04 (m, 1H, CHH), 2.74 - 2.68 (m, 1H, CHH).

[0407] MS (EI+): Calcd. for C4H7NO2 m / z = 101.0, found m / z = 101.0 [M]+.

[0408] GC (Agilent Cyclosil B (30 m x 250 pm x 0.25 pm); inlet temperature: 200 °C; detector temperature: 280 °C; injection volume: 1 pL, split ratio: 15:1; oven temperature program: 55 °C, hold for 2 min, 20 °C / min to 130 °C, hold for 5 min, 100 °C / min to 250 °C; total run time: 12 min): fa(major) = 8.86 min, fa(minor) = 9.10 min.

[0409] Intermediate 4 - method 1: (25)-Oxetane-2-carbonitrile o TFAA, pyridine

[0410]

[0411] CH2CI2

[0412] TFAA (1.40 mL, 9.90 mmol, 1.1 eq) was added to (25)-oxetane-2-carboxamide (910 mg, 9.00 mmol; intermediate 3) and pyridine (1.82 mL, 22.5 mmol, 2.5 eq) in CH2CI2 (18 mL) and stirred at 0 °C. After 2 hours, additional TFAA (127 pL, 900 pmol, 0.1 eq) was added and the solution was stirred at RT for 1 hours. Saturated aqueous NH4CI solution (10 mL) was added. The aqueous phase was separated and extracted three times with CH2Q2 (3x5 mL). The combined organic phases were washed twice with 1 M aqueous HC1 solution (10 mL) and 1 M aqueous NaOH solution (10 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford the product as a yellow liquid. Yield: 527 mg (70%, 98.8% ee).

[0413] ’H NMR (600 MHz, CDCI3): 8 5.30 (dd,3JH.ir = 8.7, 6.2 Hz, 1H, OCH), 4.91 - 4.86 (m, 1H, OC7 / H), 4.76 - 4.72 m, 1H, OC / 7H), 3.19 - 3.11 m, 1H, C H), 3.05 - 2.98 (m, 1H, C / 7H). MS (EI+): Calcd. for C4H5NO m / z = 83.0, found m / z = 83.0 [M]+.

[0414] GC (Agilent Cyclosil B (30 m x 250 pm x 0.25 pm); inlet temperature: 200 °C; detector temperature: 280 °C; injection volume: 1 pL, split ratio: 15:1; oven temperature program: 55 °C, hold for 2 min, 20 °C / min to 130 °C, hold for 5 min, 100 °C / min to 250 °C; total run time: 12 min): fa(major) = 4.64 min, fa(minor) = 4.61 min.

[0415] Intermediate 5: (rac)-Oxetane-2-carboxamide

[0416] NH3

[0417] MeOH

[0418]

[0419] NH3 (2 M in MeOH, 122 mL, 245 mmol, 1.35 eq) was added to (rac)-ethyl oxetane-2-carboxylate (24.0 g, 181 mmol; intermediate 1) and stirred at RT overnight. The suspension was cooled to 0 °C and heptane (21 mL) was added. After 4 hours, the precipitate was filtered off and washed three times with cold heptane (3 x 21 mL) to afford the product as a white solid. Additional product was obtained by crystallization after concentrating the combined organic phases. Yield: 17.9 g (98%). Analytical data in agreement with the data above for (25)-oxetane-2-carboxamide (intermediate 3).

[0420] Intermediate 6 - method 1: (rac)-Oxetane-2-carbonitrile

[0421] TFAA, pyridine

[0422]

[0423] CH2CI2

[0424] TFAA (18.4 mL, 131 mmol, 1.1 eq) was added to (rac)-oxetane-2-carboxamide (12.0 g, 119 mmol; intermediate 5) and pyridine (24.0 mL, 297 mmol, 2.5 eq) in CH2Q2 (240 mL) and stirred at 0 °C. After 2 hours, additional TFAA (1.68 mL, 11.9 mmol, 0.1 eq) was added and the solution was stirred at RT for 1 hour. Saturated aqueous NH4CI solution (120 mL) was added. The aqueous phase was separated and extracted three times with CH2Q2 (3 x 60 mL). The combined organic phases were washed with 1 M aqueous HC1 solution (110 mL) and 1 M aqueous NaOH solution (110 mL), dried over ISfeSCU and the solvent was removed under reduced pressure. Purification by distillation afforded the product as a colorless liquid. Yield: 8.18 g (83%).

[0425] Analytical data in agreement with the data above for (25)-oxetane-2-carbonitrile (intermediate 4).

[0426] Intermediate 6 - method 2: (rac)-Oxetane-2-carbonitrile

[0427] O CI3COCI, NEt3N

[0428] EtOAc

[0429]

[0430] Trichloroacetyl chloride (0.59 mL, 5.28 mmol, 1.1 eq) was added to (rac)-oxetane-2-carboxamide (500 mg, 4.80 mmol; intermediate 5) and NEt3(1.34 mL, 9.59 mmol, 2.0 eq) in EtOAc (4 mL) and stirred at 0 °C for 4 hours. The mixture was washed three times with water (3 x 4 mL). The combined aqueous phases were extracted with EtOAc (10 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure to afford the product as a yellow liquid. Yield: 285 mg (72%). Analytical data in agreement with the data above for (25)-oxetane-2-carbonitrile (intermediate 4).

[0431] Intermediate 6 - method 3: (rac)-Oxetane-2-carbonitrile

[0432] O CI3COCI, pyridine

[0433] EtOAc

[0434]

[0435] Trichloroacetyl chloride (118 μL, 1.06 mmol, 1.1 eq) was added to (rac)-oxetane-2-carboxamide (100 mg, 959 μmol; intermediate 5) and pyridine (155 μL, 1.92 mmol, 2.0 eq) in EtOAc (0.8 mL) at 0 °C and stirred at RT for 2 hours. 0.5 M aqueous HCl solution (1 mL) was added and the mixture extracted three times with EtOAc (3 × 1 mL). The combined organic phases were washed with saturated aqueous K2CO3solution, saturated aqueous NaCl solution, dried over Na2SO4and the solvent was removed under reduced pressure to afford the product as a yellow liquid. Yield: 47 mg (59%).

[0436] Analytical data in agreement with the data above for (25)-oxetane-2-carbonitrile (intermediate 4).

[0437] Intermediate 4 - method 2: (25)-Oxetane-2-carbonitrile

[0438]

[0439] (rac)-Oxetane-2-carbonitrile (1.0 mg, 1.18 mmol; intermediate 6) is added to 0.1 M potassium phosphate buffer pH 7.0 (0.49 mL), DMSO (0.01 mL) and nitrilase or nitrile hydratase (1.0 mg) and stirred at 25 °C for 18 hours. The reaction is diluted with MeCN and analyzed to determine conversion and enantioselectivity.

[0440] Intermediate 7 - method 1: (rac)-(Oxetan-2-yl)methanol o NaBH4

[0441]

[0442] MeOH

[0443] NaBH4 (291 mg, 7.68 mmol, 5.0 eq) was added to (rac)-ethyl oxetane-2-carboxylate (200 mg, 1.54 mmol; intermediate 1) in MeOH (5.0 mL) and stirred at RT overnight. Water (15 mL) was added dropwise and stirred for 15 minutes at RT. The mixture was extracted with CH2Q2 (30 mL) and dried over Na2SO4. Removal of the solvent under reduced pressure afforded the product as a colorless liquid. Yield: 131 mg (68%); NMR shows 30% CH2CI2 in crude material.

[0444] ’H NMR (400 MHz, CDCh): 64.98 - 4.91 (m, 1H, CH), 4.74 - 4.67 (m, 1H, OC / 7H), 4.57 -4.50 (m, 1H, 0C7 / H), 3.80 - 3.74 (m, 1H, 0C7 / H), 3.67 - 3.60 (m, 1H, OC / 7H), 2.73 - 2.56 (m, 2H, C H), 2.33 - 2.25 (m, 1H, OH).

[0445] MS (EI+): Calcd. for C4H8O2 m / z = 88.1, found m / z = 88.1 [M]+.

[0446] Intermediate 7 - method 2: (rac)-(Oxetan-2-yl)methanol

[0447] catalytic reduction

[0448]

[0449] (rac)-Ethyl oxetane-2-carboxylate (10 mg, 76.8 pmol; intermediate 1) and solvent (70 pL) were added to catalyst (1 mol%) and additive (20 mol%). The reaction mixture was placed under 20 bar H2 and stirred at 40 °C overnight, followed by GC analysis.

[0450] entry catalystaadditive solvent alcohol : ester 1 Ru-MACHO K2CO3MeOH 100 : 0 2 Ru-MACHO KOMe MeOH 100 : 0 3 Ru-MACHO KOtBu MeOH 100 : 0 4 Ru-MACHO KOMe THF 100 : 0 5 Ru-MACHO KOtBu THF 100 : 0 6 Ru-MACHO-BH KOtBu MeOH 100 : 0 7 Ru-MACHO-BH KOMe THF 100 : 0 8 Ru-MACHO-BH KOtBu THF 100 : 0 9 [RuCl2(Ph2P(CH2)2NH2)2] KOMe THF 100 : 0 10 [RuClH(Py-CH2NH(CH2)2PPh2)(CO)] K2CO3MeOH 100 : 0 11 [RuClH(Py-CH2NH(CH2)2PPh2)(CO)] KOMe MeOH 100 : 0 12 [RuClH(Py-CH2NH(CH2)2PPh2)(CO)] KOtBu MeOH 100 : 0 13 [RuClH(Py-CH2NH(CH2)2PPh2)(CO)] KOMe THF 100 : 0 14 [RuCl2(Et-SNS)(PPh3)] KOtBu MeOH 100 : 0

[0451]

[0452] 15 [RuCl2(Et-SNS)(PPh3)] KOtBu THF 100 0 16 [RuClH(Et-SNS)(CO)] K2CO3MeOH 100 0 17 [RuClH(Et-SNS)(CO)] KOMe MeOH 100 0 18 [RuClH(Et-SNS)(CO)] KOtBu MeOH 100 0 19 [RuClH(Et-SNS)(CO)] KOMe THF 100 0 20 [RuClH(Et-SNS)(CO)] KOtBu THF 100 0 21 [RuCl2(Bn-SNS)(PPh3)] KOtBu THF 100 0 22 [RuCl2(tBu-SNS)(PPh3)] KOMe THF 100 0 23 [RuClH(Cy2P(CH2)2NH(CH2)2PCy2)(CO)] KOtBu MeOH 100 0 24 [RuClH(Cy2P(CH2)2NH(CH2)2PCy2)(CO)] KOMe THF 100 0

[0453]

[0454] 25 [RuClH(Cy2P(CH2)2NH(CH2)2PCy2)(CO)] KOtBu THF 100 0aCAS numbers for catalysts: Ru-MACHO [1295649-40-9], Ru-MACHO-BH [1295649-41-0], [RuCl2(Ph2P(CH2)2NH2)2] [506417-41-0], [RuCl2(Et-SNS)(PPh3)] [1462397-86-9], [RuClH(Cy2P(CH2)2NH(CH2)2PCy2)(CO)] [1421060-11-6],

[0455] Intermediate 8 - method 1: [(25)-Oxetan-2-yl] methanol

[0456] LiCI, NaBH4

[0457] MeOH / THF

[0458]

[0459] NaBH₄ (57.6 mg, 1.52 mmol, 3.0 eq) was added to ethyl (25)-oxetane-2-carboxylate (66.0 mg, 507 gmol; intermediate 2) and LiCI (64.5 mg, 1.52 mmol, 3.0 eq) in THF (0.53 mL) and MeOH (1.06 mL) at 0 °C and stirred at RT overnight. Saturated aqueous potassium sodium tartrate solution (1.65 mL) was added and stirred for 30 min at RT. The mixture was filtered, diluted with water (1.65 mL) and extracted with EtOAc (5 mL) and CH2CI2 (5 mL). The combined organic phases were dried over Na2SO4 and filtered. Solvent removal under reduced pressure afforded the product as a colorless liquid. Yield: 96.0 mg (47%, 99.0% ee). GC analysis showed a purity of 22% (CH2CI2: 28%, THF: 50%).

[0460] GC (Agilent Cyclosil B (30 m x 250 gm x 0.25 gm); inlet temperature: 200 °C; detector temperature: 280 °C; injection volume: 1 gL, split ratio: 15:1; oven temperature program: 55 °C, hold for 2 min, 20 °C / min to 130 °C, hold for 5 min, 100 °C / min to 250 °C; total run time: 12 min): tR(major) = 4.88 min, tR(minor) = 4.96 min.

[0461] Intermediate 8 - method 2: [(25)-Oxetan-2-yl] methanol Ru-MACHO

[0462] o NaOMe, H2

[0463] OH

[0464]

[0465] MeOH

[0466] NaOMe (25% in MeOH, 23.8 pL, 104 pmol, 1.0 mol%) was added to propyl (25)-oxetane-2-carboxylate (1.50 g, 10.4 mmol; intermediate 2’) and Ru-MACHO (12.6 mg, 20.8 pmol, 0.2 mol%) in MeOH (6 mL) and placed under H2 (20 bar) at 40 °C for 4 hours. The pressure was released and the solvent was removed under reduced pressure. GC analysis showed >99% conversion and >99% ee.

[0467] Intermediate 8 - method 3: [(25)-Oxetan-2-yl] methanol

[0468] Ru-MACHO

[0469] NaOMe, H2

[0470] OH

[0471]

[0472] MeOH

[0473] NaOMe (25% in MeOH, 1.19 mL, 5.20 mmol, 3.0 mol%) was added to 2-propyl (25)-oxetane-2-carboxylate (25.0 g, 173 mmol; intermediate 2”) and Ru-MACHO (211 mg, 247 pmol, 0.2 mol%) in MeOH (100 mL) and placed under H2 (20 bar) at 40 °C for 20 hours. The pressure was released and the solvent was removed under reduced pressure. GC analysis showed >99% conversion and 99.0% ee.

[0474] Intermediate 8 - method 4: [(25)-Oxetan-2-yl] methanol

[0475] Ru-MACHO

[0476] Na3PO4, H2

[0477]

[0478] MeOH

[0479] Na₃PO₄ (114 mg, 694 pmol, 10 mol%) was added to 2-propyl (25)-oxetane-2-carboxylate (1.00 g, 6.94 mmol; intermediate 2”) and Ru-MACHO (4.2 mg, 6.9 pmol, 0.1 mol%) in MeOH (4.0 mL) and placed under H2 (20 bar) at 40 °C for 20 hours. The pressure was released and the solvent was removed under reduced pressure. GC analysis showed >99% conversion and 98.6% ee. Intermediate 9: Methanesulfonic acid |(2. S')-oxetan-2- l| methyl ester

[0480] MsCI, NEt3

[0481] OH OMs

[0482]

[0483] CH2CI2

[0484] MsCI (4.83 mL, 62.4 mmol, 1.1 eq; CAS: 124-63-0) was added over 10 min to [(25)-oxetan-2-yl]methanol (5.00 g, 56.8 mmol; intermediate 8) and NEt3 (9.49 mL, 68.1 mmol, 1.20 eq) in CH2Q2 (50 mL) at 0 °C and warmed to rt overnight. The mixture was diluted with CH2Q2 (150 mL) and washed with water (80 mL), 0.5 M aqueous HC1 solution (80 mL), saturated aqueous NaHCCh solution (80 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford the product as a yellow liquid. Yield: 9.18 g (97%).

[0485] ’H NMR (600 MHz, CDCh): 8 5.05 - 5.00 (m, 1H, OCH), 4.73 - 4.66 (m, 1H, OC / 7H), 4.63 -4.56 m, 1H, OC7 / H), 4.40 - 4.34 m, 2H, OC / 7H), 3.11 (s, 3H, CH3), 2.82 - 2.73 (m, 1H, C H), 2.69 - 2.60 m, 1H, C H).

[0486] Intermediate 9’: 4-Methylbenzenesulfonic acid |(2. S')-oxetan-2- l| methyl ester

[0487] p-TsCI, NMI, DMAP

[0488]

[0489] toluene pTsCl (35.7g, 187.3 mmol, 1.1 eq; CAS: 98-59-9) in toluene (60 mL) was added over 30 min to a solution of [(25)-oxetan-2-yl]methanol (15.0 g, 170.2 mmol; intermediate 8), A-methylimidazole (16.8 g, 204.3 mmol, 1.12 eq., CAS: 616-47-7) and DMAP (2.08 g, 17.0 mmol, 0.10 eq) in toluene (65 mL). The addition line was rinsed with toluene (30 mL) and the reaction mixture was stirred at RT. Upon reaction completion, the mixture was quenched with water (60 mL) and the biphasic mixture was stirred for 2 hours. After layer separation, the organic layer was washed with 7% aqueous NaHCCh solution (75 mL), 20% aqueous. NH4CI solution (75 mL) and with water (60 mL dried over Na2SO4, filtered and the solvent was removed under reduced pressure to afford the product as a light yellow oily liquid. Yield: 37.0 g (89.6%).

[0490] ’H NMR (600 MHz, CDCh): 6 7.84 (d,3JH, H’ = 7.8 Hz, 2H, Ar#), 7.35 (d,3JH, H’ = 7.8 Hz, 2H, Ar#), 4.96 - 4.89 (m, 1H, OCH), 4.64 - 4.57 m, 1H, OC / 7H), 4.54 - 4.47 (m, 1H, OC / 7H), 4.20 - 4.12 m, 2H, OC7 / H), 2.76 - 2.66 (m, 1H, C H), 2.62 - 2.52 m, 1H, C H), 2.45 (s, 3H, CH3). Intermediate 9”: Benzenesulfonic acid |(2. S')-oxetan-2-yl| methyl ester

[0491] PhSO2CI, NMI, DMAP

[0492]

[0493] toluene Benzenesulfonyl chloride (6.61 g, 37.5 mmol, 1.2 eq; CAS: 98-11-3) was added over 5 min to a solution of [(25)-oxetan-2-yl]methanol (3.0 g, 34.1 mmol; intermediate 8), A-methylimidazole (3.35 g, 40.9 mmol; CAS: 616-47-7) and DMAP (416 mg, 3.4 mmol) in toluene (30 mL) and stirred at RT. Upon reaction completion, water (12.0 mL) was added and the layers were separated. The organic layer was washed with 7% aqueous NaHCCL (15.0 mL), 10% aqueous. NH4CI solution 15.0 mL) and water (12.0 mL). The organic layer was dried overNa2SO4, filtered and the solvent was removed under reduced pressure to afford the product as a colorless oil. Yield: 7.37 g (95%).

[0494] ¹H NMR (600 MHz, CDCl₃): δ 7.93 - 7.98 (m, 2H, Ar#), 7.63 - 7.72 (m, 1H, Ar#), 7.53 - 7.0 (m, 2H, Ar#), 4.93 ddt, J = 8.0, 6.5, 3.9, 3.9 Hz, 1H, OCH), 4.60 (ddd, J = 8.7, 7.1, 5.8 Hz, 1H, OC7 / H), 4.44 - 4.54 (m, 1H, OC / 7H), 4.18 (dd, J = 3.8, 1.8 Hz, 2H, OC / 7H), 2.71 (dtd, J = 11.3, 8.3, 8.3, 6.4, 1H, C H), 2.57 (ddt, J = 11.4, 9.1, 6.8, 6.8, 1H, C H).

[0495] Intermediate 10 - method 1: Dibenzyl- [[(25)-oxetan-2-yl] methyl] amine

[0496] Bn2NH

[0497] K2CO3, Nal

[0498] OMs

[0499] DMF

[0500]

[0501] Bn2NH (12.8 mL, 66.3 mmol, 1.2 eq), Nal (828 mg, 5.52 mmol, 0.1 eq) and K2CO3 (9.92 g, 71.8 mmol, 1.3 eq) were added to methanesulfonic acid [(25)-oxetan-2-yl]methyl ester (9.18 g, 55.2 mmol; intermediate 9) in DMF (80 mL) and stirred at 90 °C overnight. The mixture was cooled to RT, filtered and extracted with heptane (300 mL). The heptane phase was washed four times with water (4 x 50 mL; each wash was extracted with heptane (30 mL)), dried over Na? SO4 and the solvent was removed under reduced pressure. Purification by flash column chromatography (EtOAc: heptane = 10:90 to 40:60) afforded the product as a light yellow oil. Yield: 6.97 g (47%). Analytical data in agreement with the data below for dibenzyl-[[(2A')-oxetan-2-yl]methyl]amine (intermediate 10, as described under method 2).

[0502] Intermediate 11 - method 1: (2 )-7V,2V-Dibenzyloxetane-2-carboxamide

[0503] KOH, / PrOH then NEt3. HCI then T3P, DIPEA, EtOAc

[0504]

[0505] Ethyl (25)-oxetane-2-carboxylate (800 mg, 6.15 mmol, 1.2 eq; intermediate 2 (96.2% ee)) was added dropwise to KOH (474 mg, 8.46 mmol, 1.65 eq) in zPrOH (4.0 mL) at 10 °C and stirred at 10 °C for 1 hour before being stirred at RT for 2 hours. NEts. HCl (2.75 g, 20.0 mmol, 3.9 eq) was added and stirred at RT overnight. EtOAc (10.1 mL), Bn2NH (985 pL, 5.13 mmol; CAS number: 103-49-1) and DIPEA (2.68 mL, 15.38 mmol, 3.0 eq) were added and stirred at RT for 30 min. T3P (50% in EtOAc, 4.57 mL, 7.69 mmol, 1.50 eq) was added at 10 °C and stirred at 10 °C for 2 hours. Saturated aqueous KHCO3 solution (10 mL) was added and the mixture warmed to RT. The aqueous phase was separated and extracted twice with EtOAc (2 × 10 mL). The combined organic phases were washed with 1 M aqueous HC1 solution (10 mL) and saturated aqueous NaCl solution (10 mL), dried over Na? SO4 and the solvent was removed under reduced pressure. Purification by flash column chromatography (EtOAc: heptane = 40:60) afforded the product as a light yellow oil. Yield: 1.18 g (82%, 96.1% ee).

[0506] ’H NMR (400 MHz, CDCI3): 8 7.39 - 7.13 m, 10H, Ar#), 5.46 (dd,3. / H.ir = 8.2, 6.9 Hz, 1H OCH), 4.72 - 4.63 m, 2H, OC / 7H), 4.59 (d,2JH.ir = 14.8 Hz, 1H, NC7 / H), 4.54 (d,2. / H.ir = 14.8 Hz, 1H, NC7 / H), 4.39 (d,2 / H.ir = 16.7 Hz, 1H, NC7 / H), 4.35 (d,2 / H.ir = 16.7 Hz, 1H, NC7 / H), 3.22 - 3.12 m, 1H, C H), 2.86 - 2.76 (m, 1H, C / 7H). MS (EI+): Calcd. for C18H19NO2m / z = 281.1, found m / z = 281.1 [M]+.

[0507] HPLC (Daicel Chiralcel OZ-3R (150 mm * 2.1 mm, 3 pm particle size); oven temperature: 25 °C; flow: 0.2 mL / min; mobile phase A: H2O: MeCN = 95:5, mobile phase B: MeCN, mobile phase C: 100 mM ammonium formate buffer pH 9.0; pump program: A: B: C = 20:60:20 for 8 min): fe(major) = 4.58 min, / R(minor) = 5.64 min.

[0508] Intermediate 11 - method 2: (2 )-7V, A-Dibenzyloxetane-2-carboxamide

[0509] KOH, / PrOH then NEt3. HCI then T3P, DIPEA, EtOAc

[0510]

[0511] 1-Propyl (25)-oxetane-2-carboxylate (2.50 g, 17.3 mmol, 1.18 eq; intermediate 2’ (>99.5% ee)) was added to KOH (1.59 g, 24.3 mmol, 1.65 eq) in zPrOH (12.0 mL) at 10 °C and stirred at 10 °C for 1 hour before being stirred at RT for 2 hours. NEts. HCl (3.88 g, 28.2 mmol, 1.9 eq) was added and stirred at RT overnight. The solvent was exchange to EtOAc to give a mixture with 30 mL volume. Bn2NH (2.92 mL, 14.8 mmol; CAS number: 103-49-1) and DIPEA (7.71 mL, 43.4 mmol, 2.94 eq) were added and stirred at RT for 30 min. T3P (50% in EtOAc, 12.9 mL, 21.7 mmol, 1.47 eq) was added at 10 °C and stirred at 10 °C for 2 hours. 0.75 M aqueous KHCO3 solution (35 mL) was added and the mixture warmed to RT. The organic phase was separated and washed with 10% aqueous citric acid solution (30 mL) and water (20 mL) and dried over Na2SO4. Solvent removal under reduced pressure afforded the product as a yellow oil, which was used without further purification. Yield: 4.30 g (quant., >99.5% ee)

[0512] Analytical data in agreement with the data above for (25)-A, A-dibenzyloxetane-2-carboxamide (intermediate 11, as described under method 1).

[0513] Intermediate 10 - method 2: Dibenzyl- [[(25)-oxetan-2-yl] methyl] amine PMHS, NaBHEt3

[0514] CPME

[0515]

[0516] PMHS (average Mn1700 - 3200, 1.03 mL) and NaBHEt3(1.0 M in PhMe, 373 pL, 373 pmol, 10 mol%) was added to (25)-A, A-dibenzyloxetane-2-carboxamide (1.05 g, 3.73 mmol; intermediate 11 (>99.5% ee)) in CPME (10.5 mL) and stirred at 40 °C overnight. The reaction was cooled to RT and water (10 mL) was added dropwise. The organic phase was separated, washed with saturated aqueous NaCl solution (10 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash column chromatography on silica gel (EtOAc: heptane = 40:60) afforded the product as a light yellow liquid. Yield: 520 mg (52%, >99.5% ee)

[0517] ’H NMR (400 MHz, CDC13): 87.40 - 7.29 (m, 8H, Arff), 7.26 - 7.21 (m, 2H, Arff), 5.07 - 4.99 (m, 1H, OCH), 4.66 - 4.60 (m, 1H, OC / 7H), 4.49 - 4.43 (m, 1H, OC / 7H), 3.69 (d,2JH.ir = 13.7 Hz, 2H, NC / 7H), 3.61 (d,2. / H.ir = 13.7 Hz, 2H, NC / 7H), 2.81 (dd,2 / H.ir = 13.7 Hz,3JH.ir = 6.2 Hz, 1H, NC / 7H), 2.70 dd,2 / H.ir = 13.7 Hz,3. / H.ir = 4.8 Hz, 1H, NC / 7H), 2.60 - 2.50 (m, 1H, C H), 2.40 - 2.30 (m, 1H, C H).

[0518] MS (EI+): Calcd. for C18H21NO m / z = 267.2, found m / z = 267.2 [M]+.

[0519] HPLC (Daicel Chiralpak IF-3 (150 mm x 3 mm, 3 pm particle size); oven temperature: 25 °C; flow: 0.4 mL / min; mobile phase A: MeOH, mobile phase B: 100 mM ammonium formate buffer pH 9.0; pump program: A: B = 90:10 for 10 min): fa(major) = 4.24 min, fa(minor) = 4.56 min.

[0520] Intermediate 10 - method 3: Dibenzyl- [[(25)-oxetan-2-yl] methyl] amine

[0521] Red-AI PhMe

[0522]

[0523] (25)-A, A-Dibenzyloxetane-2-carboxamide (11.6 g, 41.3 mmol; intermediate 11 (>99.5% ee)) in PhMe (80 mL) was added to Red- Al (60% in PhMe, 42.9 mL, 132 mmol, 3.2 eq) at 50 °C over 1 hour and stirred at 50 °C for 1.5 hours. The reaction was cooled to 0 °C and saturated aqueous Rochelle salt (100 mL) was added dropwise. The aqueous phase was separated and extracted with PhMe (100 mL). The combined organic phases were washed with saturated aqueous NaHCCL solution (100 mL) and water (50 mL), dried over Na2SC>4 and the solvent was removed under reduced pressure. Yield: 10.6 g (96%, >99.5% ee).

[0524] Analytical data in agreement with the data above for dibenzyl-[[(2, S')-oxetan-2-yl]methyl]amine (intermediate 10, as described under method 2).

[0525] Intermediate 12 - method 1: ( / Y / c)-\.\ l)ibenzyloxet:ine-2-carbox:imide

[0526] T3P, DIPEA

[0527] EtOAc

[0528]

[0529] DIPEA (13.2 mL, 76.0 mmol, 3.0 eq) and Bn2NH (4.87 mL, 25.3 mmol; CAS number: 103-49-1) were added to oxetane-2-carboxylic acid (3.24 g, 31.7 mmol, 1.25 eq; CAS number: 864373-47-7) in EtOAc (50 mL) and stirred atRT for 5 min. T3P (50% in EtOAc, 18.9 mL, 31.7 mmol, 1.25 eq) was added and stirred at RT overnight. Water (35 mL) was added and stirred at RT for 15 min. The organic phase was separated, washed with 1 M aqueous HC1 solution (35 mL) and saturated aqueous NaHCOs solution (35 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash column chromatography (EtOAc: heptane = 40:60) afforded the product as a light yellow oil. Yield: 6.74 g (95%).

[0530] Analytical data in agreement with the data above for (25)-A, A-dibenzyloxetane-2-carboxamide (intermediate 11, as described under method 1).

[0531] Intermediate 12 - method 2: (rm)-\.\ l)ibenzyloxet:ine-2-carbox:imide KOH, EtOH then NEt3. HCI then T3P, DIPEA, EtOAc

[0532]

[0533] (rac)-a-Bromo-y-butyrolactone (1.40 mL, 15.2 mmol, 1.5 eq; CAS number: 5061-21-2) was added dropwise to KOH (1.88 g, 33.5 mmol, 3.3 eq) in EtOH (16 mL) at 0 °C and warmed to RT overnight. NEts. HCl (5.44 g, 39.5 mmol, 3.9 eq) was added and stirred at RT for 6 hours. EtOAc (40 mL), Bn2NH (1.95 mL, 10.1 mmol; CAS number: 103-49-1) and DIPEA (5.30 mL, 30.1 mmol, 3.0 eq) were added and stirred at RT for 30 min. T3P (50% in EtOAc, 9.04 mL, 15.2 mmol, 1.50 eq) was added at 10 °C and stirred at 10 °C overnight. Saturated aqueous KHCO3 solution (40 mL) was added and the mixture warmed to RT. The aqueous phase was separated and extracted twice with EtOAc (2 x 40 mL). The combined organic phases were washed with 1 M aqueous HC1 solution (40 mL) and saturated aqueous NaCl solution (40 mL), dried over Na? SO4 and the solvent was removed under reduced pressure. Purification by flash column chromatography (EtOAc: heptane = 40:60) afforded the product as a light yellow oil. Yield: 2.33 g (82%).

[0534] Analytical data in agreement with the data above for (25)-A, A-dibenzyloxetane-2-carboxamide (intermediate 11, as described under method 1).

[0535] Intermediate 11 - method 3: (2 )-7V,2V-Dibenzyloxetane-2-carboxamide

[0536]

[0537] A mixture of (rac)-A, A-dibenzyloxetane-2-carboxamide (1.0 mg; intermediate 12), 100 mM potassium phosphate buffer at pH 7.0 (0.49 mL), DMSO (0.01 mL) and hydrolase (1.0 mg) was stirred for 18 hours at 25 °C. The reaction was diluted with MeCN for analysis. For instance, the reaction performed with Rabbit Liver Esterase (RLE, Sigma-Aldrich) as the hydrolase yielded 16% conversion and the remaining amide had an enantiomeric excess of 14% for (2R)-N, N-dib enzy 1 oxetane-2-carb oxami de.

[0538] Intermediate 11 - method 4: (2 )-7V,2V-Dibenzyloxetane-2-carboxamide

[0539] T3P, DIPEA

[0540] EtOAc

[0541]

[0542] DIPEA (61.7 mL, 354 mmol, 3.0 eq) and Bn2NH (23.4 mL, 118 mmol; CAS number: 103-49-1) were added to (25 -oxetane-2-carboxylic acid (15.1 g, 148 mmol, 1.25 eq; CAS number: 2241107-29-7) in EtOAc (240 mL) and stirred at RT for 15 min. T3P (50% in EtOAc, 87.8 mL, 148 mmol, 1.25 eq) was added and stirred at RT overnight. The mixture was diluted with EtOAc (180 mL) and washed with water (180 mL), 10% aqueous citric acid (180 mL), saturated aqueous NaHCOs solution (180 mL) and water (50 mL). The organic phase was dried over Na? SO4 and the solvent was removed under reduced pressure. Purification by flash column chromatography (EtOAc: heptane = 40:60) afforded the product as a brown oil. Yield: 34.3 g (quant, >99.5% ee). Analytical data in agreement with the data above for (25)-A, A-dibenzyloxetane-2-carboxamide (intermediate 11, as described under method 1).

[0543] The synthesis of [(25 -oxetan-2-yl]methanamine starting from [(25)-oxetan-2-yl]methanol has been previously described in WO2018109607 via the intermediates [(25)-oxetan-2-yl]methyl methanesulfonate [CAS number: 2230200-71-0] and (25)-2-(azidomethyl)oxetane [CAS number: 2230200-73-2], as well as in WO2019239371 via the intermediates [(25)-oxetan-2-yl]methyl toluenesulfonate [CAS number: 2198942-41-3] and (25)-2-(azidomethyl)oxetane [CAS number: 2230200-73-2], Example 1

[0544] [(25)-Oxetan-2-yl]methanamine hemioxalic acid salt

[0545]

[0546] 2) oxalic acid

[0547] MeOH (1.02 mL, 25.2 mmol, 8.4 eq) was added dropwise to LiBH4 (4.0 M in THF, 3.00 mL, 12.0 mmol, 4.0 eq) at RT. After 15 minutes, (25)-oxetane-2-carbonitrile (254 mg, 3.00 mmol; intermediate 4) in THF (0.25 mL) was added and the solution was stirred at 40 °C for 3 hours. The reaction mixture was diluted with THF (5.0 mL) and saturated aqueous K2HPO4 (5.0 mL) was added slowly. After 2 hours stirring at 40 °C, the suspension was filtered. The filtrate was washed with saturated aqueous K2HPO4 (5.0 mL) and the aqueous layer was extracted with THF (5.0 mL). The combined organic layers were dried over Na2SO4. A solution of oxalic acid (270 mg, 3.0 mmol, 1.0 eq.) in THF (1.0 mL) was added. The resulting suspension was briefly heated and aged for 1 hour at RT. Filtration and drying under reduced pressure afforded the product as a white powder. Yield: 160 mg (40%, 97.3 % ee).

[0548] Analytical data in agreement with the data below for (rac)-oxetan-2-ylmethanamine oxalic acid salt.

[0549] GC (Agilent Cyclosil B (30 m x 250 pm x 0.25 pm); inlet temperature: 200 °C; detector temperature: 280 °C; injection volume: 1 pL, split ratio: 15:1; oven temperature program: 55 °C, hold for 2 min, 20 °C / min to 130 °C, hold for 5 min, 100 °C / min to 250 °C; total run time: 12 min): / R(major) = 4.39 min, / R(minor) = 4.52 min.

[0550] Example 2 - step 1, method 1

[0551] (rac)-Oxetan-2-ylmethanamine hemioxalic acid salt

[0552] N 1) LiBH4, MeOH, THF O

[0553] 2) oxalic acid

[0554]

[0555] MeOH (1.02 mL, 25.2 mmol, 8.4 eq) was added dropwise to LiBH4(4.0 M in THF, 3.00 mL, 12.0 mmol, 4.0 eq) at RT. After 15 minutes, (rac)-oxetane-2-carbonitrile (254 mg, 3.00 mmol; intermediate 6) in THF (0.25 mL) was added and the solution was stirred at 40 °C for 3 hours. The reaction mixture was diluted with THF (5.0 mL) and saturated aqueous K2HPO4 (5.0 mL) was added slowly. After 2 hours stirring at 40 °C, the suspension was filtered. The filtrate was washed with saturated aqueous K2HPO4 (5.0 mL) and the aqueous layer was extracted with THF (5.0 mL). The combined organic layers were dried over Na2SO4. A solution of oxalic acid (270 mg, 3.0 mmol, 1.0 eq.) in THF (1.0 mL) was added. The resulting suspension was briefly heated and aged for 1 hour at RT. Filtration and drying under reduced pressure afforded the product as a white powder. Yield: 120 mg (30%).

[0556] 1H NMR (400 MHz, DMSO-d6): 57.64 (br s,

[0557]

[0558] 4H, + H), 4.92 - 4.85 (m, 1H, OCH), 4.58 - 4.42 (m, 2H, OC / 7H), 3.11 (dd,2JH.ir = 13.3 Hz,3JH.ir = 6.6 Hz, NC7 / H), 3.02 dd,2. / H.ir = 13.3 Hz,3. / n.ir = 4.2 Hz, NC7 / H), 2.72 - 2.62 (m, 1H, C H), 2.53 - 2.43 (m, 1H, C H).

[0559] Example 2 - step 1, method 2

[0560] (rac)-Oxetan-2-ylmethanamine hemioxalic acid salt

[0561] 1) NaBH4, ZnCI2, MeOH, THF

[0562]

[0563] 2) oxalic acid

[0564] MeOH (0.51 mL, 12.6 mmol, 4.2 eq) was added dropwise to NaBH4 (227 mg, 6.00 mmol, 2.0 eq) in 2-Me-THF at RT. After 15 minutes, ZnCh (1.9 M in 2-Me-THF, 0.32 mL, 600 pmol, 0.2 eq) was added. After 15 min, (rac)-oxetane-2-carbonitrile (254 mg, 3.00 mmol; intermediate 6) was added and the solution was stirred at 40 °C for overnight. The reaction mixture was diluted with 2-Me-THF (5.0 mL) and saturated aqueous K2HPO4 (5.0 mL) was added slowly. After 2 hours stirring at 40 °C, the suspension was filtered. The filtrate was washed with saturated aqueous K2HPO4 (5.0 mL) and the aqueous layer was extracted with 2-Me-THF (5.0 mL). The combined organic layers were dried over Na2SO4. A solution of oxalic acid (270 mg, 3.0 mmol, 1.0 eq.) in 2-Me-THF (1.0 mL) was added. The resulting suspension was briefly heated and aged for 1 hour at RT. Filtration and drying under reduced pressure afforded the product as a white powder. Yield: 260 mg. Analytical data in agreement with the data above for (rac)-oxetan-2-ylmethanamine hemioxalic acid salt.

[0565] Example 2 - step 1, method 3

[0566] (rac)-Oxetan-2-ylmethanamine / i-toluenesulfonic acid salt

[0567] 1) LiBH4, MeOH, THF

[0568] 2) pTsOH

[0569]

[0570] MeOH (1.02 mL, 25.2 mmol, 8.4 eq) is added dropwise to LiBH4(4.0 M in THF, 3.00 mL, 12.0 mmol, 4.0 eq) at RT. After 15 minutes, (rac)-oxetane-2-carbonitrile (254 mg, 3.00 mmol; intermediate 6) in THF (0.25 mL) is added and the solution is stirred at 40 °C for 3 hours. The reaction mixture is diluted with THF (5.0 mL) and saturated aqueous K2HPO4 (5.0 mL) is added slowly. After 2 hours stirring at 40 °C, the suspension is filtered. The filtrate is washed with saturated aqueous K2HPO4 (5.0 mL) and the aqueous layer is extracted with THF (5.0 mL). The combined organic layers are dried over Na2SO4. A solution of / ?-TsOH monohydrate (514 mg, 3.0 mmol, 1.0 eq.) in THF (1.0 mL) is added. The resulting suspension is briefly heated and aged for 1 hour at RT. Filtration and drying under reduced pressure affords the product as a white powder.

[0571] Example 2 - step 1, method 4

[0572] (rac)-Oxetan-2-ylmethanamine

[0573] H2, Ni, NH3

[0574]

[0575] MeOH

[0576] NH3 (7.0 M in MeOH, 0.43 mL, 3.01 mmol, 5.0 eq) and a sponge Nickel catalyst (Type A-5009 by Johnson Matthey, 50 mg, previously washed twice with water and 5 times with MeOH) were added to (rac)-oxetane-2-carbonitrile (50 mg, 602 pmol, intermediate 6) in MeOH (4.0 mL). The reactor was sealed, made inert with Argon and pressurized to 50 bar H2. The reactor was shaken at 60 °C for 18 hours. After this time, the reactor was cooled to RT and the reaction mixture analyzed, confirming product formation. The product was not isolated and we only showed its formation by GC and NMR.

[0577] Example 2 - step 1, method 5

[0578] (rac)-Oxetan-2-ylmethanamine hemioxalic acid salt

[0579] 1 ) Red-AI, THF o

[0580]

[0581] 2) oxalic acid o

[0582] (rac)-Oxetane-2-carbonitrile (254 mg, 3.00 mmol; intermediate 6) in THF (0.25 mL) was added to sodium bis(2-methoxyethoxy)aluminum hydride (60% in PhMe, 1.94 mL, 6.00 mmol, 2.0 eq) in THF (1.0 mL) at 0 °C and stirred for 30 min. The mixture was diluted with THF (5 mL) and water (0.43 mL, 24 mmol, 8.0 eq) was added. The suspension was filtered, washed with THF (3 mL), dried over Na2SO4and filtered. Oxalic acid (270 mg, 3.00 mmol, 1.0 eq) in THF (1 mL) was added. The resulting suspension was briefly heated and aged for 2 hour at RT. Filtration and drying under reduced pressure afforded the product as a white powder. Yield: 328 mg.

[0583] Analytical data in agreement with the data above for (rac)-oxetan-2-ylmethanamine hemioxalic acid salt.

[0584] Example 2 - step 2

[0585] [(25)-Oxetan-2-yl]methanamine salt screening

[0586]

[0587] (rac)-Oxetan-2-ylmethylamine (10.0 mg, 115 pmol) and chiral acid (68.9 pmol, 0.6 eq) in solvent were stirred at 50 °C for 1.5 hours and then cooled to RT for 1.5 hours. This cycle was repeated three times before the suspension was stirred at 0 °C overnight. The solvent was removed using a filter paper or by filtration and the residue was analyzed by SFC. Selected results are shown below.

[0588]

[0589] entry acid solvent ee" 1 (R)-Chlocyphos EtOH (10 vol) 78% 2 (R)-Chlocyphos PhMe (10 vol) 74%

[0590] 3 (R)-Chlocyphos EtOAc(10 vol) 73%

[0591] 4 (R)-Chlocyphos BuOAc (10 vol) 66%

[0592] 5 Ac-D-Leu-OH MIBK (10 vol) -61%

[0593] 6 Ac-D-Leu-OH EtOH (10 vol) -55%

[0594] 7 Ac-D-Leu-OH MEK (10 vol) -50%

[0595] 8 Ac-D-Leu-OH CPME (10 vol) -46%

[0596] 9 Ac-D-Leu-OH iPrOH (10 vol) -40%

[0597] 10 (A)-Mosher’s acid (0.6 eq) MeCN (lO vol) 54%

[0598] 11 (A)-Mosher’s acid (0.6 eq) PhMe (lO vol) 49%

[0599] 12 (A)-Mosher’s acid (0.6 eq) CPME (10 vol) 37%

[0600]

[0601] 13 (S)-Naproxen (0.6 eq) PhMe (10 vol) 22%

[0602] apositive values indicate that the (5)-enantiomer was favored.

[0603] Example 3

[0604] In a second screening with [(25)-ox etan-2 -yl]methanamine following a similar procedure as above, crystalline solids of the ammonium salt were obtained from / ?-Toluenesulfonic acid ( / ? TsOH), oxalic acid, or 1,5-naphthalenedisulfonic acid from BuOH, EtOAc, 2-Me-THF, or THF.

[0605] (25)-Oxetan-2-ylmethanamine / >-toluenesulfonic acid salt

[0606] pTsOH

[0607]

[0608] / ?-Toluenesulfonic acid monohydrate (1.09 g, 5.74 mmol, 1.0 eq) was added to l-[(25)-oxetan-2-yl]methanamine (500 mg, 5.74 mmol) in EtOH (5.0 mL). The solvent was exchanged to 2-Me- THF under reduced pressure and stirred at RT for 4 hours. The precipitate was filtered off and washed with EtOAc (1.5 mL) to afford an off-white solid. Yield: 518 mg (35%).

[0609] ’H NMR (400 MHz, DMSO-d6): 5 7.87 (br s, 3H,3), 7.50 - 7.45 (m, 2H, Ar#), 7.14 - 7.09 (m, 2H, ArJT), 4.92-4.83 (m, 1H, OCH), 4.60-4.53 m, 1H, OC / 7H), 4.51 -4.43 m, 1H, OC / 7H), 3.13 (dd, 1H,2JH, H’ = 13.3 Hz,3. / H.ir = 6.8 Hz, NC7 / H), 3.03 (dd, 1H,2JH, H’ = 13.4 Hz,3JH.ir = 3.8 Hz, NC7 / H), 2.73 - 2.63 (m, 1H, C H), 2.53 - 2.42 (m, 1H, C H), 2.29 (s, 3H, ArC#3). Example 4

[0610] (rac)-Oxetan-2-ylmethanamine hemioxalic acid salt

[0611] 1 ) Red-AI, THF

[0612] ?~~r ~N H2 HOH

[0613]

[0614] 2) oxalic acid

[0615] (rac)-Oxetane-2-carboxamide (250 mg, 2.40 mmol; intermediate 5) in PhMe (3.0 mL) was added to sodium bis(2-methoxyethoxy)aluminum hydride (60% in PhMe, 1.56 mL, 4.80 mmol, 2.0 eq) in THF (2.0 mL) at RT and stirred for 2 hours. Additional sodium bis(2-methoxyethoxy)aluminum hydride (60% in PhMe, 0.39 mL, 1.20 mmol, 0.5 eq) was added to the mixture at RT and stirred for 60 min. Saturated aqueous K2HPO4 (1.5 mL) was added slowly. The suspension was filtered through Na2SO4 and washed with THF (2.0 mL). A solution of oxalic acid (216 mg, 2.4 mmol, 1.0 eq.) in THF (1.0 mL) was added and stirred overnight at RT. Filtration and drying under reduced pressure afforded the product as a light yellow solid. Yield: 270 mg.

[0616] Analytical data in agreement with the data above for (rac)-oxetan-2-ylmethanamine hemioxalic acid salt.

[0617] Example 5

[0618] (25)-Oxetan-2-ylmethanamine / >-toluenesulfonic acid salt

[0619] S

[0620]

[0621] 4-Methylbenzenesulfonic acid [(25)-oxetan-2-yl]methyl ester (10.00 g, 41.27 mmol, 1.00 eq, intermediate 9’) was dissolved in toluene (29 mL) in an autoclave. NH3 (112.5 g, 6603 mmol, 160 eq) was added to the reactor at -10 °C and the reactor was then sealed and heated to 75 °C for at least 8 hours. The reaction mixture was cooled to RT, the autoclave opened to release the gas and then opened. The resulting mixture was diluted with MeOH (100 mL) and transferred to a glass reactor to be concentrated at 30 °C and reduced pressure (180-100 mbar) to reach a total volume of 20 mL. The mixture was then diluted with EtOH (40 mL) and concentrated at 30 °C and reduced pressure (180-100 mbar) to reach a volume of 20 mL and this operation was performed twice. The resulting mixture was then cooled to RT and stirred in these conditions for at least 1 hour to then be filtered. To the filtered solution was added 2-MeTHF (20 mL), followed by crystals of (2S)-Oxetan-2-ylmethanamine p-toluenesulfonic acid salt (50 mg) to induce crystallization of the product. Finally, additional 2-MeTHF (80 mL) was added within 1 hours and the resulting suspension was stirred at RT for at least 2 hours to be then cooled to 0 °C within at least 1 hour and then be stirred under these conditions for at least 8 hours. The resulting suspension was filtered and the filtered cake was washed with 2-MeTHF (4 mL) and dried at 40 °C under reduced pressure (< 20 mba) for at least 6 hours to afford the product as a white solid. Yield: 9.11 g (85%).

[0622] Analytical data in agreement with the data above for (2A')-oxetan-2-ylmethanamine p-toluenesulfonic acid salt.

[0623] Example 5 - alternative procedure

[0624] (25)-Oxetan-2-ylmethanamine / >-toluenesulfonic acid salt

[0625]

[0626] Continuous Process'. 4-Methylbenzenesulfonic acid [(25)-oxetan-2-yl]methyl ester (5.00 g, 20.6 mmol) was dissolved in 7 M NH3 in MeOH (88.2 g, 38.0 equiv, 784 mmol). The light-yellow solution was pumped in a heated plug flow reactor (PFR, 2.5 mL, stainless steal) with an HPLC pump. Optimal reaction conditions were as follows: residence time: 5 minutes; Flow rate: 0.5 mL / min; Jacket temperature: 170 °C; Internal pressure of PFR: 30 Bar. The yellow solution was collected after plug flow reactor and back pressure regulator (BPR) in a 250 mL batch reactor. Batch Isolation: The collected light yellow organic phase was evaporated to the dryness. The solid residue was dissolved in ethanol (20 mL, 4 V) and insoluble part was filtered off. The clear solution was concentrated to ca. 6 mL (1.2 V) volume. Tetrahydrofuran (50 mL, 10.0 V) was added, light suspension was formed. The suspension was stirred overnight and filtered via G3 filter at ambient temperature. The filter cake was washed with THF (2 x 5.6 mL) to afford 3.93 g white solid (73%, 95.5 % LC-CAD purity).

[0627] Analytical data in agreement with the data above for (25)-oxetan-2-ylmethanamine p-toluenesulfonic acid salt.

[0628] Example 6

[0629] (25)-Oxetan-2-ylmethanamine benzenesulfonic acid salt

[0630] NH toluene

[0631]

[0632] Benzenesulfonic acid [(25)-oxetan-2-yl]methyl ester (2.23 g, 9.77 mmol, 1.00 eq, intermediate 9”) was dissolved in toluene (7 mL) in an autoclave. NH3 (26.62 g, 1563 mmol, 160 eq) was added to the reactor at -10 °C and the reactor was then sealed and heated to 75 °C for 18 hours. The reaction mixture was cooled to RT, the autoclave opened to release the gas and then opened. The resulting mixture was diluted with MeOH (22 mL) and transferred to a glass reactor to be concentrated at 30 °C and reduced pressure (180-100 mbar) to reach a total volume of 5 mL. The mixture was then diluted with EtOH (9 mL) and concentrated at 30 °C and reduced pressure (180— 100 mbar) to reach a volume of 5 mL and this operation was performed twice. To the resulting mixture was added over 30 min THF (22 mL) and the resulting mixture was stirred at RT for 2 hours to be then cooled to 0 °C and then be stirred under these conditions for 48 hours. The resulting suspension was filtered and the filtered cake was washed with THF (4 mL) and dried at 40 °C under reduced pressure (< 20 mbar) for 18 hours to afford the product as a white solid. Yield: 2.25 g (94%).

[0633] ’H NMR (600 MHz, DMSO-d6): 5 7.91 (br s, 3H,3), 7.62 - 7.58 (m, 2H, Ar#), 7.34 - 7.31 (m, 2H, Ar#), 7.30 (br d, J= 1.2 Hz, Ar#), 4.88 (dtd, 1H, J= 7.8, 6.8, 3.8 Hz, OCH), 4.55 (ddd, 1H, J= 8.6, 7.2, 5.8 Hz, OC / 7H), 4.77 (dd, 1H, J= 9.1, 6.0 Hz, OC / 7H), 3.12 (br s, 1H, NC / 7H), 3.08 - 3.00 m, 1H, NC / 7H), 2.67 (did, 1H, J= 11.4, 8.3, 6.3 Hz, OCH2CZ / H), 2.48 - 2.44 (m, 1H, OCH2C H).

[0634] Example 6

[0635] (25)-Oxetan-2-ylmethanamine

[0636] Pd(OH)2 / C, H2

[0637] MeOH

[0638]

[0639] 20% Pd(OH)2 / C (Pearlman, 3.0 mg) was added to dibenzyl-[[(25)-ox etan-2 -yl]methyl]amine (50.0 mg, 187 pmol, intermediate 10) in MeOH (1.0 mL). The reactor was sealed, made inert with Argon and pressurized to 3 bar H2. The reactor was shaken at 40 °C for 18 hours. After this time, the reactor was cooled to RT and the reaction mixture analyzed, confirming product formation. The product was not isolated and we only showed its formation by GC and NMR.

[0640] Example 7

[0641] (25)-Oxetan-2-ylmethanamine oxalic acid salt

[0642] 1) Pd / C, EtOH, H2

[0643] 2) oxalic acid

[0644] O

[0645]

[0646] 10% Pd / C (EVONIK Noblyst P1065, 20.0 mg) was added to dibenzyl-[[(25)-oxetan-2-yl]methyl]amine (1.00 g, 3.74 mmol, intermediate 10) in EtOH (5.0 mL). The reactor was sealed and made inert with argon. The reactor was heated to 50 °C and pressurized to 10 bar H2 and stirred for 18 hours. The reaction was cooled to RT and filtered. Oxalic acid (337 mg, 3.74 mmol, 1.00 eq) and EtOH (20 mL) were added and the mixture stirred at RT for 1 hour. The precipitate was filtered, washed with EtOH (2 x 2.5 mL) and dried under reduced pressure to afford the product as a white solid. Yield: 514 mg (78%).

[0647] 1H NMR (400 MHz, DMSO-d6): 57.66 (br s, 4H,3+ OH), 4.93 - 4.85 (m, 1H, OCH), 4.58 -4.42 (m, 2H, OC / 7H), 3.13 - 3.06 (m, 1H, NC7 / H), 3.13 - 3.06 (m, 1H, NC7 / H), 3.05 - 2.99 (m, 1H, NC7 / H), 2.72 - 2.62 (m, 1H, C H), 2.53 - 2.43 (m, 1H, C / 7H).

[0648] Example 8

[0649] (25)-Oxetan-2-ylmethanamine / i-toluenesulfonic acid salt

[0650] 1) Pd / C, EtOH, H2

[0651] 2) pTsOH

[0652]

[0653] 10% Pd / C (EVONIK Noblyst® P1065, 18.2 mg) was added to dibenzyl-[[(25)-oxetan-2-yl]methyl]amine (910 mg, 3.40 mmol, intermediate 10) in EtOH (4.55 mL). The reactor was sealed and made inert with argon. The reactor was heated to 50 °C and pressurized to 10 bar H2 and stirred for 18 hours. The reaction was cooled to RT, 4-methylbenzene-l -sulfonic acid monohydrate (583 mg, 3.06 mmol, 0.90 eq) was added and stirred for 10 min at RT before the reaction was filtered. The reaction was concentrated and MeTHF (15 mL) was added. The precipitate was filtered, washed with MeTHF (2 × 1 mL) and dried under reduced pressure to afford the product as a white solid. Yield: 716 mg (81%).

[0654] Analytical data in agreement with the data above for (25)-oxetan-2-ylmethanamine p-toluenesulfonic acid salt.

Claims

Claims1. A process comprising the reaction of a compound of formula (1-4)(1-4)with a suitable reduction agent in presence of a suitable solvent and optionally in presence of a suitable additive and / or a suitable catalyst in order to arrive at a compound of formula(I)or an acceptable salt thereof.

2. A process according to claim 1 further comprising the following preceding step:the reaction of a compound of formula (1-3)O(1-3)in presence of a suitable solvent, a suitable base and a suitable dehydration agent in order to arrive at a compound of formula (1-4)3. A process according to claim 2 further comprising the following preceding step:the reaction of a compound of formula (1-2)O(1-2)in presence of a suitable solvent and either (i) NH3or (ii) a suitable ammonium salt with a suitable base, in order to arrive at a compound of formula (I-3)(i-3);wherein in the above reaction R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

4. A process according to claim 3 further comprising the following preceding step:the reaction of a compound of formula (I-1)o(1-1)in presence of a suitable solvent, a suitable buffer and suitable hydrolase in order to arrive at a compound of formula (1-2)(1-2),wherein in the above reaction R is alkyl, preferably R is ethyl, propyl or isopropyl, more preferably R is isopropyl.

5. A process according to claim 1 further comprising the following preceding step:the reaction of a compound of formula (1-6)Oin presence of a suitable solvent, a suitable buffer and a suitable nitrilase or nitrile hydratase in order to arrive at a compound of formula (1-4)A process according to claim 5 further comprising the following preceding step:the reaction of a compound of formula (1-5)in presence of a suitable solvent, a suitable base and a suitable dehydration agent in order to arrive at a compound of formula (1-6)(1-6).

7. A process according to claim 6 further comprising the following preceding step:the reaction of a compound of formula (I-1)oin presence of a suitable solvent and either (i) NH3or (ii) a suitable ammonium salt with a suitable base, in order to arrive at a compound of formula (I-5)oNH2(I-5);wherein in the above reaction R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

8. A process comprising the following steps:(a) the reaction of a compound of formula (I-1)oin presence of a suitable solvent and NH3or a suitable salt thereof in order to arrive at a compound of formula (I-5)O(b) the reaction of a compound of formula (1-5)(1-5)in presence of a suitable solvent, a suitable base and a suitable dehydration agent in order to arrive at a compound of formula (1-6)(1-6);(c) the reaction of a compound of formula (1-6)(1-6)with a suitable reduction agent in presence of a suitable solvent and optionally in presence of a suitable additive and / or a suitable catalyst in order to arrive at a compound of formula (1-7)or an acceptable salt thereof; and(d) the reaction of a compound of formula (1-7)(1-7)with a suitable chiral acid in presence of a suitable solvent in order to arrive at an acceptable salt of the compound of formula (I)NH2wherein in the above reaction R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

9. A process comprising the reaction of a compound of formula (1-2)in presence of a suitable reduction agent and a suitable solvent in order to arrive at a compound of formula (1-8)10. A process comprising the following steps:(a) the reaction of a compound of formula (1-2)o(1-2)in presence of a suitable reduction agent and a suitable solvent in order to arrive at a compound of formula (1-8)(i-8);(b) the reaction of a compound of formula (1-8)(1-8)in presence of a suitable solvent, a suitable base and a suitable (9-sulfonylation reagent in order to arrive at a compound of formula (1-9)n> X(1-9);(c) the reaction of a compound of formula (1-9)r(1-9)with a suitable azide reagent in presence of a suitable solvent in order to arrive at a compound of formula (1-13)P'"y^N3(1-13); and(d) the reaction of a compound of formula (1-13)(I-13)with a suitable reduction agent and in presence of a suitable solvent and optionally a catalyst in order to arrive at the compound of formula (I) or an acceptable salt thereof(i);wherein in the above reaction X is -SO3Me, -SO3Ph or -SO3pTol, and R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

11. A process comprising the reaction of a compound of formula (1-9’) or (1-9”)with NH3, in presence of a suitable solvent in order to arrive at a compound of formula (II- 7) or a compound of formula (II-7’)12. A process according to claim 11 further comprising the following preceding steps:(a) the reaction of a compound of formula (1-2)o(1-2)in presence of a suitable reduction agent and a suitable solvent in order to arrive at a compound of formula (1-8)(b) the reaction of a compound of formula (1-8)in presence of a suitable solvent, a suitable base and a suitable (9-sulfonylation reagent in order to arrive at a compound of formula (1-9’) or (1-9”)(1-9’) (1-9”);wherein in the above reaction R is alkyl.

13. A process comprising the following steps:(a) the reaction of a compound of formula (1-2)o(1-2)in presence of a suitable reduction agent and a suitable solvent in order to arrive at a compound of formula (1-8)(b) the reaction of a compound of formula (1-8)(1-8)in presence of a suitable solvent, a suitable base and a suitable (9-sulfonylation reagent in order to arrive at a compound of formula (1-9)n> X(1-9);(c) the reaction of a compound of formula (1-9)(1-9)with Bn2NH, in presence of a suitable base, a suitable solvent, and optionally a suitable additive, in order to arrive at a compound of formula (I- 10)(I- 10); and(d) the reaction of a compound of formula (I- 10)(1-10)with a suitable reduction agent in presence of a suitable solvent and a suitable catalyst in order to arrive at a compound of formula (I)NH2or an acceptable salt thereof,wherein in the above reaction X is -SO3Me, -SO3Ph or -SO3pTol, and R is alkyl; preferably R is methyl, ethyl, propyl or isopropyl.

14. A process comprising a step selected from (a), (a’) and (a”), and further comprising steps (b) and (c):(a) the reaction of a compound of formula (1-2)in presence of Bn2NH, a suitable solvent, a suitable base and a suitable coupling reagent in order to arrive at a compound of formula (I-11)(a’) the reaction of a compound of formula (1-12)(I-12)in presence of a suitable buffer, a suitable hydrolase and a suitable solvent in order to arrive at a 26. A compound of formula (I-11)(I-11);(a”) the reaction of a compound of formula (1-14)(1-14)in presence of Bn2NH, a suitable base and a suitable solvent in order to arrive at a compound of formula (I-11)(I-11); and(b) the reaction of a 26. A compound of formula (I-11)(1-11)in presence of a suitable solvent and at least one suitable reduction reagent in order to arrive at a compound of formula (I- 10)o„(I- 10); and(c) the reaction of a compound of formula (I- 10)o„with a suitable hydrogenation agent in presence of a suitable solvent in order to arrive at a compound of formula (I)NH2(i);wherein in the above reaction R is alkyl.

15. A process according to claim 14 further comprising the following preceding step:the reaction of a compound of formula (I-1)oin presence of a suitable solvent, a suitable buffer and a suitable hydrolase in order to arrive at a compound of formula (1-2)(1-2),wherein in the above reaction R is alkyl, preferably R is ethyl, propyl or isopropyl, more preferably R is isopropyl.

16. A process according to claim 1, 10, 12, 13 or 14, wherein the compound of formula (I) is isolated in form of an acceptable salt thereof, like salts with N-acetylleucine, chlocyphos, Mosher’s acid, naproxen, 1,5-naphthalenedisulfonic acid, oxalic acid or / ?-toluenesulfonic acid, preferably 1,5-naphthalenedisulfonic acid, oxalic acid or / ?-toluenesulfonic acid, and most preferably salts with oxalic acid or / ?-toluenesulfonic acid.

17. A process according to claim 1, 10, 12, 13 or 14, wherein the compound of formula (I) is not isolated and is instead telescoped into a further chemical reaction.

18. A process according to claims 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14,15, 16 or 17, wherein R is methyl.

19. A process according to claims 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14,15, 16 or 17, wherein R is ethyl.

20. A process according to claims 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14,15, 16 or 17, wherein R is propyl.

21. A process according to claims 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14,15, 16 or 17, wherein R is isopropyl.

22. A process comprising the reaction of a compound of formula (I-1)with suitable hydrolase and in presence of• a suitable buffer,• optionally a suitable co-solvent; and• optionally a suitable additive;in order to arrive at a compound of formula (1-2)in the above reaction R is alkyl, in particular ethyl, propyl or isopropyl.

23. A process comprising the reaction of a compound of formula (I-1-III)(I-1-III)with a suitable hydrolase and in presence of• a suitable buffer;• a suitable co-solvent; and• a suitable additive;in order to arrive at a compound of formula (I-2-III)(I-2-III).

24. A compound of formula (1-3)(1-3).

25. A compound of formula (1-4)(1-4).

26. A 26. A compound of formula (I-11)27. A compound selected from the group of compounds of formula (II- 1), (II-2), (II-3), (II- 4), (II-5) and (II-6)28. A compound of formula (II-2)29. A compound of formula (II-5)30. A compound of formula (II-6)31. A compound of formula (II-7’)(II-7’).

32. A compound of formula (1-9”)33. A compound of formula (I-2-III)(I-2-III).

34. A compound of formula (I-2-II)O(I-2-II).

35. A compound of formula (I-2-I)

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