Pleuromutilins, their preparation process, and pharmaceutical composition.

Abstract

The present invention relates to a process for the preparation of a compound of formula ii in the form of a single stereoisomer in crystalline form, comprising deprotecting the amine group in a compound of formula iia lla or in a mixture of a compound of formula iia with a compound of formula iib llb and isolating a compound of formula i from the reaction mixture; compounds and salts of compounds of formula i in crystalline form; pharmaceutical compositions comprising such salts; processes for the preparation of intermediates and intermediates in a process for the preparation of a compound of formula i.

Description

Pleuromutilins, their preparation process, and pharmaceutical composition.

[001] The present invention relates to crystalline 14-O-{[(4-amino-2-hydroxycyclohexyl)sulfanyl]acetyl}mutilin, novel processes for its preparation and crystalline salts thereof. Pleuromutilin, a compound of the formula It is a naturally occurring antibiotic, for example, produced by the basidiomycetes Pleurotus mutilus and P. passeckerianus, see for example, The Merck Index, 12th edition, item 7694.

[002] Several other pleuromutilins having the ring structure of the pleuromutilin principle and being substituted at the primary hydroxy group have been developed, for example, as antimicrobials. Due to their pronounced antimicrobial activity, a group of pleuromutilin derivatives, amino-hydroxysubstituted cyclohexylsulfanylacetylmutilins, as disclosed in WO 2008 / 113089, have been found to be of particular interest. As described in WO2008 / 11089, 14-O{[(4-Amino-2-hydroxy-cyclohexyl)-sulfanyl]-acetyl}-mutilins are particularly useful compounds because they demonstrate activity against Gram-positive and Gram-negative pathogens, for example, associated with respiratory tract infections and skin and skin structure.For the production of substantially pure isomers / diastereomers of this group of compounds, there is a need for a production process that is convenient for use on an industrial scale and that also avoids the use of expensive starting materials, environmentally hazardous reagents and solvents, or demo purification steps. Petition 870260039308, dated 04 / 28 / 2026, page 86 / 176 2 / 70 rads and laborious. The production process described in WO 2008 / 113089 involves chromatographic purification of the prepared compounds according to individual synthesis steps, and the final diastereomers are separated by chiral HPLC chromatography, which cannot be used on an industrial scale.

[003] Surprisingly, crystalline intermediates were found to, on the one hand, exhibit unexpected chemical purification potential, which is important for production processes for pure amino-hydroxy-substituted cyclohexylsulfanylacetylmutilines, avoiding chromatographic purification and separation steps.

[004] It must be pointed out that 14-O-{[(4-amino-2-hydroxycyclohexyl)sulfanyl]acetyl}-mutilins are potential new medicinal substances for the human market with regulatory requirements defined in the corresponding ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines. The ICH guideline on impurities in new medicinal substances (Q3A(R2)) includes the following thresholds: Maximum daily dose Reporting threshold Identification threshold Qualification threshold ^ 2g 0.05% 0.10% 0.15% > 2g 0.03% 0.05% 0.05%

[005] As can be observed from the ICH thresholds above, it is desirable to have all individual unknown impurities below 0.10% of area and elucidated structure impurities below 0.15%, respectively. Processes provided according to the present invention allow the production of APIs (Active Pharmaceutical Ingredients) within the desired specifications and satisfactory ICH requirements.

[006] On the other hand, even more surprisingly, crystalline intermediates allow significant chiral enrichment that Petition 870260039308, dated 04 / 28 / 2026, page 87 / 176 3 / 70 has an immense benefit in producing pure stereoisomers starting from more economical racemic materials or less chirally pure starting materials. The processes described do not involve any chromatographic purification, either normal or chiral phase, unlike the synthetic procedures described in WO2008 / 113089, where it is disclosed, for example, in Example 1, Step B, that 14-O{[(4-amino-2-hydroxycyclohexyl)sulfanyl]acetyl}-mutilins were isolated in the form of diastereomeric mixtures as colorless amorphous foams after normal phase chromatography. The pure chiral diastereomers are described as having been received in WO2008 / 113089, for example, in Example 1A, after subjecting the mixture to chiral chromatography, after which the separated pure diastereomers were isolated in the form of colorless amorphous foams.

[007] Chiral chromatography, however, is not a technology that can be applied on a large industrial scale, and furthermore, no crystalline salt of 14-O-{[(4-amino-2-hydroxy-cyclohexyl)-sulfanyl]-acetyl}mutilins was obtained according to WO2008 / 113089.

[008] In contrast to this, according to the present invention, pharmaceutically acceptable crystalline salts of 14-O-{[(4-amino-2-hydroxycyclohexyl)sulfanyl]acetyl}-mutilins having surprisingly superior properties over the amorphous salts of the prior art disclosed in WO2008 / 113089 were found; for example, surprisingly the chemical stability of the crystalline salts of the present invention is improved over the amorphous salt forms; and also and furthermore, the crystalline salts of the present invention show surprisingly low hygroscopicity.

[009] Processes for the preparation of such crystalline salts in which the salts can be obtained in a single stoichiometric form of 14-O-{[(4-amino-2-hydroxy-cyclohexyl)sulfanyl]-acetyl}-mutilins and processes for the preparation of 14-O-{[(4-amino-2-hydroxy-cyclohexyl)sulfanyl]-acetyl}-mutilins Petition 870260039308, dated 04 / 28 / 2026, p. 88 / 176 4 / 70 hexyl)-sulfanyl]-acetyl}-mutilins stereoisomerically pure in crystalline form as a basis for crystalline salts were also found.

[010] In one aspect, the present invention provides a process for the preparation of a compound of Formula I h2n in the form of a single stereoisomer in crystalline form, comprising deprotecting the amine group in a compound of Formula IIa IIa, or in a mixture of a compound of Formula IIa with a compound of Formula IIb. IIb where R is an amine protecting group, and isolate a compound of Formula I obtained in the form of a single diastereomer in crystalline form directly from the reaction mixture or by recrystallization in an organic solvent.

[011] In another aspect, the present invention provides a Petition 870260039308, dated 04 / 28 / 2026, p. 89 / 176 5 / 70 compound of Formula I as defined above in the form of a single stereoisomer in crystalline form.

[012] Compounds of Formula IIa are novel and also form part of the present invention.

[013] In another aspect, the present invention provides a compound of Formula IIa.

[014] In a compound of Formula I, or IIa, respectively, the carbon atoms of the cyclohexyl ring to which the hydroxyl group, the amine group, and the sulfanyl-acetyl-mutiline group are attached are all in the R configuration, and thus a compound of Formula I, or IIa represents a 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutiline optionally protected by an amine. In contrast, in a compound of Formula Ib or IIb the carbon atoms of the cyclohexyl ring to which the hydroxyl group, the amine group and the sulfanyl-acetyl-mutiline group are attached are all in the S configuration and thus a compound of Formula IIb represents a 14-O-{[(1S,2S,4S)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutiline optionally protected by an amino group.

[015] An amine protecting group includes protecting groups known to a qualified person and which are removable under acidic, basic, hydrogenating, oxidative or reductive methods, for example, by hydrogenolysis, treatment with an acid, a base, a hydride, a sulfide. Suitable amine protecting groups, for example, are described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2007, par. Petition 870260039308, dated 04 / 28 / 2026, page 90 / 176 6 / 70 particularly pp. 696-868.

[016] Amine protection groups that can be conveniently used in a process according to the present invention include, for example - benzyloxycarbonyl (Cbz), removable, for example, by hydrogenolysis, - p-methoxybenzyl carbonyl (Moz or MeOZ), removable, for example, by hydrogenolysis, - tert-butyloxycarbonyl (BOC), removable, for example, by treatment with a strong acid, such as HCl, H3PO4 or CF3COOH, - trifluoroacetyl, removable, for example, by treatment with a base, such as NaOH, K2CO3, Cs2CO3, - 9-fluorenylmethyloxycarbonyl (FMOC), removable, for example, by treatment with a base such as piperidine, - benzyl (Bn), removable, for example, by hydrogenolysis; - p-methoxybenzyl (PMB), removable, for example, by hydrogenolysis; - 3,4-dimethoxybenzyl (DMPM), removable, for example, by hydrogenolysis; - p-methoxyphenyl (PMP), removable for example by treatment with cerium(IV) ammonium nitrate (CAN), - tosyl (Tos), removable for example by treatment with concentrated acid, such as HBr, H2SO4, or by treatment with strong reducing agents, such as sodium in liquid ammonia, sodium naphthalene, - groups that form with amine sulfonamides except TOS-amides, for example, including 2-nitrobenzenesulfonamide (nosyl) or o-nitrophenylsulfenyl (NPS), removable, for example, by treatment with samarium iodide, tributyltin hydride, - benzylidene, removable for example by treatment with Petition 870260039308, dated 04 / 28 / 2026, page 91 / 176 7 / 70 trifluoromethanesulfonic acid, trifluoroacetic acid, dimethyl sulfide; - triphenylmethyl (trityl, Tr), dimethoxytrityl (DMT), for example, removable by treatment with an acid, such as trifluoroacetic acid; preferably trifluoroacetyl or tert-butyloxycarbonyl (BOC).

[017] In the case of trifluoroacetyl, a base, for example, an inorganic base such as NaOH, KOH, Cs2CO3 and K2CO3 or an organic base such as ethanolamine, can be used to effect the deprotection of a compound of Formula IIa and IIb to obtain a compound of Formula I in the form of a single stereoisomer. In a preferred embodiment, an inorganic base such as NaOH and K2CO3 is used.

[018] In the case of tert-butyloxycarbonyl (BOC), an acid, for example, an inorganic acid such as a mineral acid, or an organic acid can be used to effect the deprotection of a compound of Formula IIa and IIb to obtain a compound of Formula I in the form of a single stereoisomer. In a preferred embodiment, an organic acid such as trifluoroacetic acid (TFA) or a mineral acid such as orthophosphoric acid is used.

[019] Alternatively, the nitrogen atom to which R is attached forms a heterocyclic ring, for example, the nitrogen atom attached to the cyclohexyl group is part of a phthalimide ring; removable, for example, by treatment with hydrazine. In this case, the hydrogen on the nitrogen is not present (see example 17).

[020] Deprotection of the compound of Formula IIa leads to the compound of Formula I in the form of a single product. In the case of deprotection of a mixture of a compound of Formula IIa with a compound of Formula IIb, the products obtained are Formulas Ia and Ib. Petition 870260039308, dated 04 / 28 / 2026, p. 92 / 176 8 / 70 are subjected to crystallization / recrystallization and a compound of Formula I is obtained from the mixture.

[021] It was found that during the amine deprotection reaction the stereochemistry of the carbon atoms of the cyclohexyl moiety in which the thio, hydroxy and amino groups, respectively, are attached is maintained as in the protected amine compounds of Formula IIa and IIb used as a starting material.

[022] Surprisingly, it was found that a compound of Formula I can be crystallized after isolation, or directly in the reaction mixture obtained after deprotection of the amine group.For example, a solution of a compound of Formula I in a unique stoichiometric form obtained in an organic solvent, preferably a polar organic solvent such as CH2Cl2, is treated with an antisolvent, such as an ether, for example, diisopropyl ether (DIPE) or tert-butyl methyl ether (MTBE), preferably DIPE; or a solution of a compound of Formula I in a unique stoichiometric form obtained in an organic solvent, preferably a polar organic solvent such as CH2Cl2, is treated after concentration with an organic solvent, preferably an alcohol such as n-butanol; or an isolated crude material of a compound of Formula I in a unique stoichiometric form is absorbed in an organic solvent, such as an ether, for example, tetrahydrofuran (THF), and optionally treated with an antisolvent, such as an ether, for example, DIPE or MTBE. A compound of Formula I in a unique stoichiometric form can crystallize and can be isolated in crystalline form.

[023] Crystallization simplifies the isolation and handling of isolated materials and provides excellent opportunities for further purification of the product.

[024] The crystalline compounds obtained according to the present Petition 870260039308, dated 04 / 28 / 2026, page 93 / 176 9 / 70 of the invention can be subjected to further purification, such as recrystallization, for example, out of an organic solvent, preferably an alcohol, such as n-butanol.

[025] (Re)crystallization can be repeated if desired and can result in high recovery yields and excellent purification.

[026] In TABLE 1 below, the surprisingly high purification potential of the crystalline compound of Formula I is indicated. TABLE 1 Reaction Stage HPLC Purity (% area) of Compound Formula I Impurity RRT 1.32 (% area) Reaction Completion After Deprotection of IIb 87.3 4.2 After DCM / DIPE Crystallization 95.0 2.2 After 1st n-BuOH Crystallization 99.0 0.6 After 2nd n-BuOH Crystallization 3 99.7 < 0.15 RRT = relative retention time in HPLC with respect to there

[027] As can be clearly seen from TABLE 1 above, the purity of a compound of Formula I after deprotection of a compound of Formula IIa was increased from 87.3% to 95.0% after crystallization and isolation from DCM (CH2Cl2) / DIPE. The purity is further increased by (re-)crystallizations of n-butanol to a final purity of the isolated compound of Formula I of up to 99.7%.

[028] TABLE 2 below shows the suppression of selected impurities and overall purification of a compound recovered from Formula I from process precursor liquors after undergoing Petition 870260039308, dated 04 / 28 / 2026, page 94 / 176 10 / 70 a recrystallization of n-butanol: TABLE 2 Initial purity (% area by HPLC) Purity after recrystallization of n-butanol (% area by HPLC) Compound I 96.29 99.03 Impurity 1 0.61 0.14 Impurity 2 1.88 0.54

[029] Crystallization can be enhanced and accelerated by the use of seed crystals. Seed crystals can be obtained by processes as exemplified here. The crystallization and recrystallization process of a compound of Formula I releases the desired purity and is highly useful on an industrial scale. Laborious and expensive purification by chromatography is avoided and makes the process industrially applicable.

[030] Even more surprisingly, crystallization of compound I leads to clear diastereomeric enhancement in favor of a compound of Formula I when starting from a mixture of a compound of Formula I with a compound of Formula Ib. After deprotection of a mixture of a compound of Formula IIa with a compound of Formula IIb and crystallization of the resulting solid in organic solvents or solvent mixtures such as DCM / DIPE results in significant diastereomeric enhancement. The diastereomeric enhancement is even more pronounced if recrystallization out of an organic solvent, preferably an alcohol such as n-butanol, is carried out.

[031] In TABLE 3 below, the chiral enrichment of a compound of Formula I in crystalline form is indicated. TABLE 3 Petition 870260039308, dated April 28, 2026, p. 95 / 176 11 / 70 Chiral purity determined by HPLC chiral (% area) 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutiline (compound I) 14-O-{[(1S,2S,4S)-4Amino-2-hydroxycyclohexylsulfanyl]acetyl}mutiline (compound Ib) DCM / DIPE crystallization 59 41 n-butanol crystallization 93 7 Precursor liquors 16 84

[032] From TABLE 3 it is evident that starting from the diastereomeric mixture of compounds of Formulas IIa and IIb in the deprotection step and isolating the resulting reaction mixture products by means of DCM / DIPE crystallization allows a surprising chiral enhancement of 59:41 in favor of a compound of Formula I. Subjecting the enriched product mixture resulting from a compound of Formula I and a compound of Formula Ib to n-butanol recrystallization results in a massive and even more surprising enrichment in favor of a compound of Formula I in the isolated product (93:7). Unlike the isolated product of the enriched compound of Formula I, the n-butanol precursor liquid contains almost exclusively a compound of Formula Ib (84%).

[033] Optionally, recrystallization can be repeated until a desired optical purity is obtained.

[034] The surprising properties of a compound of Formula I in crystalline form that are shown in TABLES 1, 2 and 3 are extremely useful in the preparation of pharmaceutical compounds. Petition 870260039308, dated 04 / 28 / 2026, p. 96 / 176 12 / 70

[035] The present invention provides a compound of Formula I in a unique stoichiometric form in crystalline form.

[036] Surprisingly, two different crystalline forms of a compound of Formula I were isolated and characterized by X-ray powder diffraction.

[037] In another aspect, the present invention provides 14-O{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin in crystalline form 1, for example, crystalline form 1 being characterized by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2, inter alia): 10.6, 11.1, 12.0, 14.3, 15.1, 16.1,21.1; such as: 10.6, 11.1, 12.0, 14.3, 15.1, 16.1, 18.2, 19.2, 20.7, 21.1, 21.3, 21.8, 22.6, 23.5, 24.7, 28.2, 30.2.

[038] In another aspect, the present invention provides 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in crystalline form 2, obtained as a 1:1 n-butanol solvate, for example, which is characterized by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2, inter alia): 9.8, 11.1, 13.1, 14.1, 17.6, 19.7, 22.2; such as 9.6, 9.8, 11.1, 13.1, 14.1, 16.0, 17.6, 19.7, 22.2; 22.7, 23.0.

[039] The n-butanol content of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in crystalline form 2 is between 10 and 18% w / w, typically between 11 and 14% w / w.

[040] A compound of Formula I is preferably isolated in the form of a salt, such as a pharmaceutically acceptable salt. Such salts are preferably ammonium salts, i.e., acid addition salts of the amino group attached to the cyclohexyl ring, and include acetates, lactates, for example, L-lactates, or maleates, for example, hydrogen maleates.

[041] In another aspect, the present invention provides a Petition 870260039308, dated 04 / 28 / 2026, p. 97 / 176 13 / 70 compound of Formula I in the form of a single stereoisomer and in the form of a salt, for example, a crystalline salt, wherein a compound of Formula I is in the form of a single stereoisomer; the salt is preferably an acetate, lactate, for example, L-lactate or maleate, for example, hydrogen maleate.

[042] Crystalline compounds obtained according to the present invention in a unique stereoisomeric form of Formula I, for example, in the form of a salt, are useful in a pharmaceutical composition.

[043] In another aspect, the present invention provides a pharmaceutical composition comprising crystalline 14-O-{[((1R,2R,4R)-4-amino-2-hydroxy-cyclohexyl)sulfanyl]acetyl}mutilin, or comprising an optionally crystalline acetate, lactate, or hydrogen maleate of 14-O-{[((1R,2R,4R)-4-amino-2-hydroxy-cyclohexyl)sulfanyl]acetyl}mutilin as an active ingredient in combination with pharmaceutically acceptable carrier or diluent.

[044] The compounds of Formula I in free form and in the unique stoichiometric form thus obtained can be converted into a salt by adding an acid to the free base of a compound of Formula I. For example, a compound of Formula I can be dissolved or suspended, or is obtained in dissolved or suspended form, in an organic solvent, preferably a solvent or solvent mixture, such as an alcohol, for example, methanol, ethanol; a halogenated hydrocarbon, for example, dichloromethane; an ether, for example, tetrahydrofuran; an acetate, such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate; a solvent mixture of alcohol with acetate, such as methanol / isopropyl acetate; a solvent mixture of halogenated hydrocarbon with acetate, such as dichloromethane / isopropyl acetate; a solvent mixture of ether with acetate, such as tetrahydrofuran / isopropyl acetate; and for the Petition 870260039308, dated 04 / 28 / 2026, p. 98 / 176 14 / 70 A mixture is obtained by adding an acid, for example, an organic acid or an inorganic (mineral) acid, for example, acetic acid, lactic acid, for example, L-lactic acid, maleic acid. A compound of Formula I, in the form of a salt, for example, a crystalline salt, can be obtained and can be isolated.

[045] It was found that in the salt formation step the stereochemistry of the carbon atoms of the cyclohexyl ring to which a thio, hydroxy or amino group is attached is maintained and remains the same as in a Formula I compound in free form.

[046] Isolation of pharmaceutically active compounds as described in WO2008 / 113089, examples I and Ia, respectively, is advantageous; but isolation according to the present invention in crystalline salt form, such as a compound of Formula I in crystalline salt form, is even more advantageous. For example, improved purity and surprisingly improved stability of the crystalline salt according to the present invention is highly important and useful for the preparation of pharmaceutical compositions intended for veterinary and human use. Crystalline salts of a compound of Formula I demonstrate improved stability over the corresponding amorphous forms and are isolated with chemical and chiral purity of > 90%, for example, up to > 95%.

[047] In the following TABLE 4 comparative stability data of the corresponding crystalline and amorphous salts of compound I are shown. TABLE 4 Percentage of area of ​​14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin (compound I) by HPLC stored at 60°C Acetate (Form B) Acetate L-Lactate L-Lactate Hydrogen maleate Hydrogen maleate crystalline amorphous crystalline amorphous crystalline crystalline Initial 99.5 99.3 99.4 99.5 99.7 99.6 Petition 870260039308, dated 04 / 28 / 2026, page 99 / 176 15 / 70 Percentage of area of ​​14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin (compound I) by HPLC stored at 60°C 28 d 98.9 96.3* 98.3 96.3 98.7 70.9* * the sample did not dissolve completely in water after 28 days (28 d) and therefore the suspension was analyzed

[048] The solubility of active pharmaceutical compounds is an important property for in vivo availability, for example, oral bioavailability. For intravenous application, the solubility of the selected form, for example, salt, is also very crucial, and it is desirable to have formulations without sophisticated technologies or excipients.

[049] The solubility of the crystalline acetate, lactate and (hydrogen)maleate salts of the present invention in water and aqueous-based vehicles such as 0.9% NaCl solution or in biorelevant media such as FaSSIF (Fasting State Simulated Bowel Fluid) and FeSSIF (Fed State Simulated Bowel Fluid) is surprisingly high, which makes the crystalline salts of the present invention even more pharmaceutically viable.

[050] The antimicrobial, for example, antibacterial activity of 14-O-{[(4-amino-2-hydroxycyclohexyl)sulfanyl]-acetyl}-mutilins was described in WO2008 / 113089. For example, the compounds of the present invention, for example, compound of Formula I, show antimicrobial activity, for example, antibacterial activity, against Gram-positive bacteria, such as coagulase-positive Staphylococci, for example, Staphylococcus aureus, and Streptococci, for example, Streptococcus pneumoniae, exhibiting MICs < 0.4 pg / mL against ATCC49951 of Staphylococcus aureus and ATCC49619 of Streptococcus pneumoniae. The minimum inhibitory concentration (MIC) was determined according to CLSI recommendations.

[051] In another aspect, the present invention provides crystalline 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of an acetate in crystalline form A, for example, which Petition 870260039308, dated April 28, 2026, pp. 100-176 16 / 70 is characterized by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2, inter alia): 7.0, 7.7, 11.6, 12.1, 12.6, 13.5, 13.7, 15.4, 15.7, 16.9, 17.3, 19.0, 19.9, 21.1, 23.4, 24.2, 24.4; such as 7.0, 7.7, 11.6, 12.1, 12.6, 13.5, 13.7, 14.1, 15.4, 15.7, 16.5, 16.9, 17.3, 19.0, 19.6, 19.9, 20.1, 21.1, 22.2, 22.5, 23.4, 24.2, 24.4, 26.7, 29.1, 29.6, 31.0.

[052] In another aspect, the present invention provides crystalline 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of an acetate in crystalline form B, for example, which is characterized by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2, inter alia): 10.3, 10.7, 12.7, 14.3, 15.5, 16.0, 17.2, 19.5, 20.6, 22.9; such as 9.0, 10.3, 10.7, 12.7, 14.3, 15.5, 16.0, 17.2, 19.5, 20.6, 21.7, 22.3, 22.7, 22.9, 24.4.

[053] In another aspect, the present invention provides crystalline 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of an L-lactate in crystalline form 1, for example, which is characterized by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2, inter alia): 7.0, 11.6, 12.0, 12.5, 13.4, 13.6, 13.9, 15.3, 16.8, 18.8, 19.5, 19.8, 20.9, 23.3, 23.9, 24.2; such as 7.0, 7.6, 11.6, 12.0, 12.5, 13.4, 13.6, 13.9, 15.3, 15.5, 16.8, 17.2, 18.8, 19.5, 19.8, 20.0, 20.9, 22.0, 22.4, 22.7, 23.3, 23.9, 24.2; 25.3, 28.9, 29.4, 30.8

[054] In another aspect, the present invention provides crystalline 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of a hydrogen maleate in crystalline form 1, for example, which is characterized by a ray powder diffraction pattern Petition 870260039308, dated 04 / 28 / 2026, pp. 101 / 176 17 / 70 X with 2-theta peaks in (degrees, ± 0.2, inter alia): 7.0, 11.3, 11.7, 12.5, 13.5, 13.8, 15.3, 16.7, 18.3, 19.4, 19.7, 21.1,22.2, 23.8, 23.9; such as 7.0, 11.3, 11.7, 12.5, 13.3, 13.5, 13.8, 14.1, 15.3, 16.7, 17.2, 18.0, 18.3, 19.4, 19.7, 20.4, 21.1, 21.9, 22.2, 22.8, 23.8, 23.9, 24.9, 27.1, 27.8, 28.7, 29.3, 30.6, 30.8

[055] A compound of Formula I in the form of a free (crystalline) base exhibits the same order of pharmaceutical activity, such as antimicrobial activity, as a compound of the present invention in the form of a (crystalline) salt.

[056] A compound of Formula IIa in the form of a single stereoisomer or a mixture of a compound of Formula IIa with a compound of Formula IIb may be prepared as appropriate, for example, in accordance with, for example, analogously to a conventional method. Preferably, a compound of Formula IIa in the form of a single stereoisomer or a mixture of the compound of Formula IIa with a compound of Formula IIb is prepared by linking an amino-hydroxy-mercapto-cyclohexane compound of Formula IIIa, or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, wherein the amino group is protected with an amino protecting group with an activated 14-O-acetylmutilin.

[057] In another aspect, the present invention provides a process according to the present invention, in which a compound of Formula IIa, or a mixture of a compound of Formula IIa with a compound of Formula IIb, is obtained by linking a compound of Formula IIIa. OHIIIa, or a mixture of a compound of Formula IIIa with a Petition 870260039308, dated April 28, 2026, pp. 102-176 18 / 70 compound of Formula lllb OH lllbH, respectively where R is as defined above, with an activated 14-O-AKT-acetyl-mutilin of the formula where AKT is an activating group, optionally mesyl, besyl, tosyl, or -OAKT is a halogen; optionally 14-O-AKT-acetylmutilin is a compound of the formula and isolating a compound of formula Ha, or a mixture of a compound of formula Ila with a compound of formula llb obtained from the reaction mixture.

[058] Compounds of Formula IIIa in which R is as defined above are novel and also form part of the present invention.

[059] In another aspect, the present invention provides a compound of Formula 11Ia in a unique stoichiometric form.

[060] In a compound of Formula IIIa the carbon atoms of the cyclohexyl ring to which the hydroxyl group, the amine group and the group Petition 870260039308, dated 04 / 28 / 2026, pp. 103 / 176 19 / 70 thio groups are attached, all in the R configuration, and thus a compound of Formula IIIa represents an optionally amino-protected (1R,2R,4R)-4-amino-2-hydroxy-1-mercaptocyclohexane; and in a compound of Formula IIIb, respectively, the carbon atoms of the cyclohexyl ring to which the hydroxyl group, the amine group, and the thio group are attached are all in the S configuration, and thus a compound of Formula IIIb represents an optionally amino-protected (1S,2S,4S)-4-amino-2-hydroxy-1-mercaptocyclohexane.

[061] The linkage reaction of a compound of Formula IIIa or the mixture of a compound of Formula IIIa with a compound of Formula IIIb, respectively, wherein R is as defined above, with an activated 14-O-AKT-acetylmutilin, wherein AKT is as defined above, to obtain a compound of Formula IIa or a mixture of IIa and IIb, wherein R is as defined above, may be carried out as appropriate, for example, in accordance with, for example, analogously to a conventional method, such as under standard conditions known for those reactions; for example, in the presence of a base, for example, a strong inorganic base, such as a hydroxide such as NaOH, for example, in a two-phase system, and, if the reaction is carried out in a two-phase system, preferably in the presence of a catalyst, such as a phase-transfer catalyst, for example, benzyltributylammonium chloride.The bonding reaction can also be carried out in a single solvent system, for example, in an organic solvent such as a halogenated hydrocarbon, for example, chlorobenzene, dichloromethane, an aromatic solvent such as toluene, a nitrile such as acetonitrile or an ether, for example, tert-butyl-methyl ether, tetrahydrofuran, in the presence of a base, preferably an organic base, such as DBU.

[062] Preferably the bonding reaction is carried out in an organic solvent, for example, a nonpolar solvent such as an ether, by Petition 870260039308, dated 04 / 28 / 2026, pp. 104 / 176 20 / 70 example, tert-butyl methyl ether (MTBE) or polar solvent, such as a halogenated hydrocarbon, for example, dichloromethane; preferably in the presence of an aqueous base solution, such as aqueous NaOH; or in the presence of a base in the organic solvent, such as DBU, DBN, preferably in the presence of a phase transfer catalyst in the case of using an aqueous base solution, such as benzyl tributylammonium chloride.

[063] It was found that during the bonding reaction the stereochemistry of the carbon atoms of the cyclohexyl moiety to which the thio, hydroxyl and amino groups are attached is maintained and remains the same as in a compound of Formula IIIa and a compound of Formula IIIb, respectively, used as a starting material.

[064] A compound of Formula IIIa in the form of a single stereoisomer or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, respectively, may be prepared as appropriate, for example, in accordance with, for example, analogously to a conventional method. Preferably, a compound of Formula IIIa or a mixture of the compound of Formula IIIa with a compound of Formula IIIb, respectively, are prepared by deprotecting the thiol function in an amino-hydroxy-mercaptocyclohexane, wherein the amino group and the thiol group are both protected.

[065] In another aspect, the present invention provides a process according to the present invention, in which a compound of Formula IIIa, or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, is obtained by deprotecting the thiol function in a compound of Formula IVa. OH .'S\ R IVa, or in a mixture of compound IVa with a compound from Petition 870260039308, dated April 28, 2026, pp. 105-176 21 / 70 Formula IVb OH .A,^ε^ R^ IVb N'H, respectively, where R is as defined above and Ri is a thiol protecting group, and isolating a compound of Formula IIIa, or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, respectively, obtained from the reaction mixture.

[066] A thiol protecting group, for example, in the sense of Ri in a compound of Formulas IVa and IVb according to the present invention, includes for example, - alkyl (C1-6), wherein alkyl is optionally further substituted, for example, further substituted by aryl (C6-12) such as phenyl, such as a trityl; for example, removable by treatment with strong acid or AgNOa, - Alkyl carbonyl (C1-6), for example, acetyl, for example, removable by base, such as treatment with sodium methoxide, - arylcarbonyl (C6-12), such as a benzoyl, for example, removable by treatment with a reducing agent, such as DIBAL, or by treatment with a base, such as hydrazine, preferably -C(=O)-aryl (C6-12); more preferably benzoyl.

[067] Suitable sulfur protection groups, for example, are described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2007, particularly pp. 647-695.

[068] In a compound of Formula IVa the carbon atoms of the cyclohexyl ring to which the hydroxyl group, the amine group and the Petition 870260039308, dated April 28, 2026, pp. 106-176 22 / 70 thio groups are attached are all in the R configuration, and thus a compound of Formula IVa represents an amine- and thio-protected (1R,2R,4R)-4-amino-2-hydroxy-1-mercaptocyclohexane; and in a compound of Formula IVb the carbon atoms of the cyclohexyl ring to which the hydroxyl group, the amine group, and the thio group are attached are all in the S configuration, and thus a compound of Formula IVb represents an amino- and thio-protected (1S,2S,4S)-4-amino-2-hydroxy-1-mercaptocyclohexane.

[069] It was found that during the thiol deprotection reaction the stereochemistry of the carbon atoms of the cyclohexyl moiety to which the thio, hydroxyl and amino groups are attached is maintained and remains the same as in a compound of Formula IVa and in a compound of Formula IVb, respectively, used as a starting material.

[070] The deprotection of the thiol group is carried out as appropriate, for example, by the use of a cleavage agent, for example, hydrazine hydrate. The deprotection reaction is carried out in an organic solvent, such as a halogenated hydrocarbon, for example, chlorobenzene, dichloromethane, an aromatic solvent such as toluene, a nitrile such as acetonitrile or an ether, for example, tert-butyl methyl ether, tetrahydrofuran. In order to minimize disulfide formation, the deprotection is optionally carried out in the presence of an antioxidant or reducing agent, for example, dithiothreitol (DTT).

[071] A compound of Formula IVa or a mixture of a compound of Formula IVa with a compound of Formula IVb, respectively, may be obtained as appropriate, for example, analogously to a conventional method or as described herein, for example, in the example section.

[072] In another aspect, the present invention provides Petition 870260039308, dated 04 / 28 / 2026, pp. 107 / 176 23 / 70 - a process for producing a compound of Formula I in the form of a single stereoisomer, comprising using a compound of Formula IIa in the form of a single stereoisomer, or a mixture of a compound of Formula IIa with a compound of Formula IIb, respectively, and / or comprising using a compound of Formula IIIa in the form of a single stereoisomer, or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, respectively, and / or using a compound of Formula IVa in the form of a single stereoisomer, or a mixture of a compound of Formula IVa with a compound of Formula IVb, respectively, as an intermediate, and - a compound of Formula IIa in the form of a single stereoisomer, and / or a compound of Formula IIIa in the form of a single stereoisomer, and / or a compound of Formula IVa in the form of a single stereoisomer for use as an intermediate in a process for the production of a compound of Formula I in the form of a single stereoisomer.

[073] In another aspect, the present invention provides a process for producing a compound of Formula I in the form of a single stereoisomer, comprising linking a compound of Formula IIIa in the form of a single stereoisomer, or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, respectively, wherein R is as defined above, with an activated 14-OAKT-acetylmutiline, wherein AKT is an activating group, such as a mesyl, besyl or tosyl group, or -O-AKT is a halogen, preferably AKT is a tosyl group, for example, a compound of Formula Tos-PLEU, to obtain a compound of Formula IIa or a mixture of a compound of Formula IIa with a compound of Formula IIb, respectively, wherein R is as defined above, Petition 870260039308, dated April 28, 2026, pp. 108-176 24 / 70 optionally isolating a compound of Formula IIa in the form of a single stereoisomer, or a mixture of a compound of Formula IIa with a compound of Formula IIb, respectively, wherein R is as defined above, obtained from the reaction mixture, deprotecting the amine function in a compound of Formula IIa in the form of a single stereoisomer, a mixture of a compound of Formula IIa with a compound of Formula IIb, respectively, wherein R is as defined above, obtained, and isolating a compound of Formula I in the form of a single stereoisomer, optionally in the form of a salt; from the reaction mixture optionally by means of recrystallization, and, if desired, converting a compound of Formula I in the form of a single stereoisomer obtained in free form into a compound of Formula I in the form of a salt in the form of a single stereoisomer, or vice versa; wherein optionally a compound of Formula IIIa in the form of a single stereoisomer or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, respectively, wherein R is as defined above, is obtained by deprotection of the thiol function in a compound of Formula IVa in the form of a single stereoisomer, or in a mixture of a compound of Formula IVa with a compound of Formula IVb, wherein R and Ri are as defined above.

[074] As an amine protecting group in a compound of Formula IIa, IIb, IIIa, IIIb, IVa or IVb, conventional amino protecting groups may be used, preferably a trifluoroacetyl or tert-butoxycarbonyl group. If appropriate, the amine protecting group R in a compound of Formula IIa, IIb, IIIa, IIIb, IVa or IVb may be changed, in such a way that the carbon atom of the ring Petition 870260039308, dated April 28, 2026, pp. 109-176 The 25 / 70 cyclohexyl group to which the amine group is attached does not change its configuration, that is, it does not change the stereochemistry, for example, through deprotection of the amine group, followed by protection with a different amine protecting group.

[075] The processes of the present invention allow the isolation of compounds of Formula I in the form of a single stereoisomer in crystalline form. On the one hand, the process controls, when starting from pure chiral starting materials, stereochemistry and produces products in the form of single stereoisomers whereby no sophisticated method such as chromatography, for example, normal phase or chiral phase, for example, chiral HPLC, is necessary to separate mixtures of diastereomers and regioisomers, for example, as described in WO 2008 / 113089, which is a great advantage with respect to an industrially applicable process. The finding of the crystalline compound of Formula I is the key invention and allows perfect control of chemical purity.In combination with the desirable yields observed from the crystalline forms of a compound of Formula I, the processes of the present invention are extremely viable for the production of a pharmaceutical product where a decent / good yield is required from an economic standpoint and purity control is essential for the final quality of the active pharmaceutical ingredient (API).

[076] On the other hand, the processes according to the present invention control the chiral purity of a compound of Formula I even more surprisingly, again by means of surprising properties of the crystalline compound I. The surprising properties of the crystalline compound I allow for the production of much less expensive diastereomeric mixtures. The chiral purity is controlled in the crystalline compound I by means of which the compound I is isolated in the form of a crystalline solid and the unwanted diastereomer is suppressed. Petition 870260039308, dated 04 / 28 / 2026, pp. 110 / 176 26 / 70 mixed with the precursor liquid.

[077] The existence of a compound of Formula I in crystalline form is in no way described in WO 2008 / 113089. In Example 1 Step B of WO 2008 / 113089, the mixture of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin (compound I of the present invention) and 14-O-{[(1S,2S,4S)-4-amino-2-hydroxy-cyclohexylsulfanyl]acetyl}-mutilin is isolated as amorphous foams. Example 1A in WO 2008 / 113089 describes the separation of diastereomers by chiral chromatography, and the separated 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin (compound I of the present invention) and 14-O-{[(1S,2S,4S)-4-amino-2-hydroxy-cyclohexylsulfanyl]acetyl}-mutilin (compound Ib of the present invention) are again isolated as amorphous foams.

[078] The surprising properties of the crystalline compounds I that control the chemical and chiral purity of compound I are extremely valuable for the production of an active pharmaceutical compound to be administered to humans or animals.

[079] The present invention also relates to a new crystalline form of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]acetyl}-mutilin in the form of an acetate, L-lactate or hydrogen maleate. 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}mutilin can be converted to crystalline salt forms using an organic crystallization process with a salt-forming agent. The process for producing the new crystalline salts can be enhanced and accelerated by the use of seed crystals. Seed crystals can be obtained by the processes exemplified.

[080] It has been found that the crystalline salts of the present invention maintain the stereochemistry of a compound of Formula I in free form in the form of a single stereoisomer. The crystalline salts according to the present invention have unexpected advantages. Petition 870260039308, dated 04 / 28 / 2026, page 111 / 176 27 / 70 ras, that is, enhanced stability on the corresponding amorphous salt forms, as is evident from TABLE 4.

[081] Furthermore, and very surprisingly, the hygroscopicity of the crystalline salts of the present invention, preferably the L-lactate salt and the acetate salt in crystalline form B, is small between relevant humidity levels, i.e., between 0 and 80% relative humidity, with a water absorption below 2%, making the salts, in combination with excellent chemical stability, pharmaceutically viable.

[082] The crystalline salts of the present invention are of desired and consistent chemical and chiral purity, have better stability compared to amorphous lyophilized forms, and are advantageous in storage and for the preparation of pharmaceutical compositions. No crystalline salt form of a compound of Formula I has been described before, for example, in WO 2008 / 113089.

[083] Generally, crystalline salt forms of a compound of Formula I have excellent purities and the observed stability was not only superior to the amorphous salt forms but proved to be absolutely pharmaceutically viable within the range of normal storage conditions.

[084] In the form of a single stereoisomer as used herein designates a form in which the compound shows a diastereomeric or enantiomeric excess of > 90% of the indicated stereochemistry.

[085] Particularly preferred compounds of the present invention include the compounds of Examples 1 to 17, for example, a compound selected from the group consisting of [(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]-tert-butyl carbamate, 14-O-{[(1R,2R,4R)-4-tert-Butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin, Petition 870260039308, dated April 28, 2026, pp. 112 / 176 28 / 70 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin, crystal form 1, 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin, crystalline form 2, 2,2,2-Trifluoro-N-[(1R,3R,4R)-3-hydroxy-4-mercapto-cyclohexyl]-acetamide, 14-O-{[(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino]-2-hydroxycyclohexylsulfanyl]acetyl}-mutiline, 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutiline acetate, crystalline form A, 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutiline acetate, crystalline form B, L-lactate of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline, crystalline form 1, hydrogen maleate of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline, crystalline form 1, 14-O-{[(1R,2R,4R)-4-ethoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline, and 14-O-{[(1R,2R,4R)-2-hydroxy-4-(phthalimido-N-yl)-cyclohexylsulfanyl]-acetyl}-mutilin. Description of the Figures

[086] In Figure 1 the Powder Diffractogram of 14-O-{[(1R,2R,4R)4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, Form 1 is shown.

[087] Figure 2 shows the Powder Diffractogram of 14-O{[(1R ,2 ​​R ,4 R )-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, Form 2.

[088] Figure 3 shows the Powder Diffractogram of 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of an acetate, Form A. Petition 870260039308, dated 04 / 28 / 2026, pp. 113 / 176 29 / 70

[089] Figure 4 shows the Powder Diffractogram of 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of an acetate, Form B.

[090] Figure 5 shows the Powder Diffractogram of 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of an L-lactate, Form 1.

[091] Figure 6 shows the Powder Diffractogram of 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of a hydrogen maleate, Form 1.

[092] The process for the synthesis of a compound of Formula I starting from the chiral precursors Ha, IIIa and IVa is summarized in REACTION SCHEME 1 below: REACTION SCHEME 1 solvent-based deprotection agent IVa Sulfur deprotection hU solventHN R HO-AKT-acetyl-mutilinaxr llla ||asolvent deprotection agent Amine deprotection PLEU 3 i'r nh2 Crystalline acetate or crystalline L-lactate or crystalline thiohydrogen maleate Salt formation Acetic acid or L-lactic acid or maleic acid solvent PLEU 3 NH2 I Isolation as a crystalline solid

[093] In REACTION SCHEME 1 R represents an amino protecting group and Ri represents a sulfur protecting group and are as defined above.

[094] The process for the synthesis of a compound of Formula I Petition 870260039308, dated 04 / 28 / 2026, pp. 114 / 176 30 / 70 starting from mixtures of Ila with lib, Illa with lllb and IVa with IVb is summarized in REACTION SCHEME 2 below: REACTION SCHEME 2 solvent-based 14-O-AKT-acetyl lm util ina Connection deprotection agent sokente diastereomeric enrichment _PLEU S Amine deprotection voh HNL R Ha .Pt EU S

[095] In the REACTION SCHEME 2 R represents an amino protecting group and Ri represents a sulfur protecting group (R and Ri as defined above).

[096] Here, including the examples and including REACTION SCHEMES 1, 2, 3, 4, 5 and 6, the following abbreviations are used: °C degrees Celsius 1H NMR nuclear magnetic resonance spectroscopy protoni Petition 870260039308, dated 04 / 28 / 2026, page 115 / 176 31 / 70 ca13C NMR carbon nuclear magnetic resonance spectroscopy [a]D specific optical rotation angle at 589 nm BnBu3NCl benzyltributylammonium chloride BOC tert-butoxycarbonyl d days DCM CH2Cl2 DIBAL diisobutylaluminum hydride DBN 1,5-diazabicyclo[4.3.0]non-5-ene DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIPE diisopropyl ether DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMTF dimethylthioformamide DPPA diphenylphosphoryl azide DTT 1,4-dithio-DL-threitol ESI electrospray ionization EtOAc ethyl acetate GF glass fiber h hours, heptane n -heptane High-Performance Liquid Chromatography (HPLC) KF Karl Fischer M molarity mCPBA metachloroperoxybenzoic acid MTBE methyl tert-butyl ether min minutes MS mass spectrometry m / z mass-to-charge ratio Petition 870260039308, dated 04 / 28 / 2026, pp. 116 / 176 32 / 70 t-BuOH tert-butyl alcohol BU4NCI tetra-n-butylammonium chloride PhCOSH thiobenzoic acid at room temperature TLC thin layer chromatography TEA, Et3N triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Wt weight p / p weight / weight XRPD X-ray powder diffraction

[097] A stripping weight assay as indicated in the examples is defined as follows: The content of an aliquot from a batch or the entire batch is determined by removing the solvent and determining the content by HPLC or NMR using an internal or external standard and / or subtracting known impurities from the compound. In the case of taking an aliquot, a back-extrapolation to the total mass / volume is performed.

[098] An in-line rinse as indicated in the examples is a rinse of the system using an appropriate solvent to minimize losses of product and input materials. Tos-PLEU is a compound of the formula H3C Petition 870260039308, dated 04 / 28 / 2026, pp. 117 / 176 33 / 70

[099] Any compound provided by the present invention is also referred to herein as a compound (according to) the present invention and any process provided by the present invention is referred to herein as a process (according to) the present invention.

[0100] Any compound of the present invention can be obtained as appropriate, for example, analogously to a conventional method or as described herein.

[0101] In the following examples, all temperatures are in degrees Celsius (°C) and were measured without calibration.

[0102] The abbreviations used are indicated above (after reaction scheme 2). Example 1 [(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl] tert-butyl carbamate H3C H,C CH O THE .OH SH OO·

[0103] 3.94 kg of {(1R,2R,4R)-4-[(tert-Butoxycarbonyl)-amino]-2-hydroxycyclohexyl}-benzenecarbothioate and 37 L of CH2Cl2 were loaded into a vessel and the resulting mixture was stirred at 15 to 25°C. 0.39 kg of 1,4-dithio-DL-threitol (10% by weight) was added to the mixture and rinsed. Petition 870260039308, dated April 28, 2026, pp. 118-176 34 / 70 mixed with 2 L of CH2Cl2. To the resulting mixture, 0.84 kg of hydrazine monohydrate was added. The resulting mixture was stirred at 18 to 22°C for 3 hours, and the reaction was followed by HPLC. At the conclusion of the reaction, 39 L of 1 M phosphoric acid solution were added, and the resulting mixture was stirred for an additional 15 to 30 minutes. Two phases were formed, and the resulting organic phase was washed with 39 L of 1 M phosphoric acid solution followed by 39 L of 1% aqueous NaCl solution. The resulting organic layer was concentrated under vacuum at <40°C. To the residue of the concentration, 20 L of CH2Cl2 were added, and the resulting mixture was concentrated again. To the residue of the concentration, an additional 8 L of CH2Cl2 was added, and the resulting mixture was concentrated to dryness.

[0104] 2.89 kg of tert-butyl [(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]carbamate in the form of a white solid were obtained. 1H NMR (200 MHz, DMSO-d6, ppm) δ 6.79 (d, J = 7.8 Hz, 1H), 4.99 (d, J = 5.8 Hz, 1H), 3.34 - 3.24 (m, 1H), 3.14 - 3.04 (m, 1H), 2.37 (d, J = 3.8 Hz, 1H), 2.00 -1.89 (m, 1H), 1.87 - 1.82 (m, 1H), 1.73 1.67 (m, 1H), 1.47 - 1.04 (m, 12H) Example 2 22-O-Tosylpleuromutilin

[0105] 22-O-Tosylpleuromutilin is a compound known from the literature. However, a preparation procedure is described below.

[0106] A solution of 13.0 kg of pleuromutilin and 6.57 kg of 4-toluenesulfonyl chloride in 42.1 L of CH2Cl2 at 10 to 15°C was treated with 9.1 L of 5.7 M aqueous NaOH for 20 min, maintaining a temperature <25°C. The resulting yellowish-white suspension was Petition 870260039308, dated April 28, 2026, pp. 119 / 176 A 35 / 70 mixture was heated to reflux for 20 hours. The reaction was followed to completion as determined by HPLC. Upon completion of the reaction, the resulting mixture was cooled to 20-30°C, diluted with 52 L of CH2Cl2, stirred at 15-25°C for 10 min, and the resulting layers were separated. The resulting organic phase was washed several times with 52 L of water until the pH of the aqueous layer was adjusted to < 9. The resulting organic layer was concentrated to 4 volumes and azeotropically dried twice with 52 L of CH2Cl2. To the resulting solution, 52 L of heptane were added dropwise, and the resulting solution was concentrated at <40°C to approximately 4 volumes. To the concentrate obtained, 52 L of heptane were added, and the resulting suspension was stirred at 20 to 25°C for 2 to 2.5 h, filtered, the filter cake obtained was washed with 39 L of heptane and removed dry on the filter.

[0107] The solid was dried under vacuum at <40°C for at least 12 h.

[0108] 16.9 kg of 22-O-tosylpleuromutilin in the form of a white solid were obtained. 1H NMR (200 MHz, DMSO-de, ppm, inter alia) δ 7.81 (d, 2H) 2.41(s, 4H), 1.04 (s, 3H), 0.81 (d, 3H), 0.51 (d, 3H) Example 3 14-O-{[(1R,2R,4R)-4-tert-Butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin SH THE N H CH THE OH .....CH

[0109] 4.75 kg of pleuromutilin tosylate (Tos-PLEU) and 44.4 L Petition 870260039308, dated April 28, 2026, pp. 120-176 36 / 70 of MTBE were loaded into a vessel, and 0.31 kg of benzyltri-n-butylammonium chloride was added to the resulting mixture and rinsed with 2.4 L of MTBE. To this mixture, 20 L of 1 M aqueous NaOH solution and 2.84 kg of tert-butyl [(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]-carbamate were added, and the mixture was stirred at 17 to 23°C for 3 h. At the end of the reaction (determined by HPLC), two layers were separated, and the lower aqueous layer was removed. The resulting organic phase was washed with 19 L of 1 M aqueous NaOH solution, twice with 20 L of 0.1 M phosphoric acid, 20 L of 10% aqueous NaHCO3 solution, and twice with 20 L of water. The organic liquors obtained were concentrated, the concentrate was absorbed in 7.46 kg of 2-propanol, the resulting mixture was concentrated again and dried under vacuum at < 40°C.6.66 kg of 14-O{[(1R,2R,4R)-4-tert-Butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin in the form of a white foam were obtained. 1H NMR (200 MHz, DMSO-d6, ppm, inter alia) δ 6.78 (d, J = 7.8 Hz, 1H), 6.22 - 6.08 (m, 1H), 5.55 (d, J = 7.8 Hz, 1H), 5.13 - 5.02 (m, 2H), 4.95 (d, J = 5 Hz, 1H), 4.52 (d, J = 6 Hz, 1H), 3.36 (AB, J = 15 Hz, 2H), 2.40 (s, wide, 1H), 2.15 - 2.0 (m, 3H), 1.9 - 1.8 (m, 1H), 1.35 (s, 9H), 0.81 (d, J = 7 Hz, 3H), 0.62 (d, J = 6.6 Hz, 3H) MS (ESI, g / mol): m / z 653 [M+2Na]+ Example 4 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, crystalline form 2 Step A: 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin in crystalline form 1

[0110] 6.6 kg of 14-O-{[(1R,2R,4R)-4-tert-Butoxycarbonylamino-2 Petition 870260039308, dated 04 / 28 / 2026, pp. 121 / 176 37 / 70 hydroxycyclohexylsulfanyl acetylmutilin and 13.2 L of isopropanol were loaded into a vessel and stirred at 20–25°C. 11.20 kg of 85% phosphoric acid were added, and the resulting mixture was heated to approximately 50°C for at least 16 h. The resulting mixture was analyzed by HPLC to confirm the reaction. Upon completion of the reaction, the mixture was cooled to 20–25°C, and 52 L of CH2Cl2 were added. The resulting mixture was cooled to 0–5°C, and 51 L of 30% aqueous K2CO3 solution were added for 1 h < 25°C. The resulting mixture was heated to room temperature, stirred for 30 min, and the pH of the aqueous layer was determined. To the resulting mixture, an additional 15 L of 30% aqueous K2CO3 solution was added at < 25°C. The resulting mixture was stirred at 15°C to 25°C for 30 min, and the two phases were separated. The aqueous phase was extracted with 51 L of CH2Cl2, and the combined organic phases were washed with 51 L of purified water.The resulting mixture was concentrated to a volume of 25 L. 33.6 kg of CH2Cl2 were added, and the mixture was concentrated to 25 L. To the resulting concentrate, 33.6 kg of CH2Cl2 were added, and the resulting mixture was concentrated to 10 L. The residue from the concentration was cooled to 18-22°C, and 50 L of diisopropyl ether was added over a period of 1 h. The resulting fluid paste was stirred at 15-25°C for a minimum of 2 h, filtered, and the resulting solid was washed with 10 L of diisopropyl ether and dried.

[0111] 3.79 kg of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin in crystalline form 1 were obtained. Step B: 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin, in crystalline form 2

[0112] For further purification, 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin from Step A and 18.75 L of n-butanol were heated to 88–92°C until complete dissolution and stirred for 30–60 min. The resulting mixture was allowed to cool to 40– Petition 870260039308, dated April 28, 2026, pp. 122-176 38 / 70 The mixture was heated to 45°C for at least 2 hours and stirred at this temperature for 2 hours. The resulting mixture was filtered, and the precipitate was washed with 3.75 L of n-butanol followed by 3.75 L of MTBE. This purification procedure was repeated, and the resulting product was dried under vacuum at < 40°C.

[0113] 3.27 kg of crystalline 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin in crystalline form 2 were obtained in the form of a white solid. 1H NMR (400 MHz, CDCb, ppm, inter alia) δ 6.51 - 6.44 (m, 1H), 5.78 (d, J = 8 Hz, 1H), 5.38 - 5.20 (m, 2H), 3.48 - 3.40 (m, 3, 3, Hz), J = 6.6 1H), 3.25 (AB, J = 15 Hz, 2H), 2.92 - 2.82 (m, 1H), 2.6 - 2.5 (m, 1H), 1.45 (s, 3H), 1.20 (s, 3H), 0.88 (d, J = 7 Hz, 3H), J 3H) MS (ESI, g / mol): m / z 508 [M+H]+ Example 5 14- O-{[(1R ,2 ​​R ,4 R )-4-Amino-2-hydroxy-cyclo-hexylsulfanyl]-acetyl}-mutillin, crystalline form 1

[0114] To a solution of 900 g of 14-O-{[(1R,2R,4R)-4-tert-butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin in 9 L of CH2Cl2 at 15 to 25°C, 1.8 L of TFA at 15 to 25°C was added, and the resulting solution was stirred for 2 h. Following the completion of the reaction, the reaction mixture was concentrated under vacuum, and the residue obtained was azeo-dried to a total of 9 L of CH2Cl2. The resulting concentrate was dissolved in 4.5 L of CH2Cl2, the resulting solution was cooled to 0 to 5°C, and the pH was adjusted to pH 11 with 3.6 L of aqueous K2CO3 solution (2.5 M). The resulting two-phase mixture was heated to 15–20°C and stirred for 5–10 minutes. The resulting layers were then separated. Petition 870260039308, dated April 28, 2026, pp. 123-176 39 / 70 days, the aqueous phase obtained was extracted with 1.8 L of CH2Cl2, the organic phases obtained were combined, washed with 2.3 L of H2O, dried over Na2SO4 and concentrated to dryness under vacuum at < 40°C. 14- Crude {[(1R,2R,4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin was obtained. Yield: 744 g

[0115] For further purification the following procedure was applied:

[0116] 744 g of crude 14-O-{[(1R,2R,4R)-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin were added to 2.23 L of THF and the resulting suspension was stirred at 15 to 25°C for 60 min. To the resulting mixture, 7.44 L of MTBE were added for 15 to 30 min, the resulting suspension was aged for 60 min and filtered under nitrogen. The collected solids were washed with a total of 3 L of MTBE and removed dry on the filter under nitrogen for 1.5 h.

[0117] 626 g of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxy-cyclohexyl sulfanyl]-acetyl}-mutilin in crystalline form 1 were obtained.

[0118] The 1H NMR pattern confirms the structure of 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline. The NMR pattern for 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline is described in Example 4. Example 6 14-O-{[(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)-amino-2-hydroxy-cyclohexyl sulfanyl]-acetyl}-mutilin Procedure 1 THE OH

[0119] 45.3 g of {(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino]-2-hydroxycyclohexyl}benzenecarbothioate and 453 mL of CH2Cl2 were car Petition 870260039308, dated April 28, 2026, pp. 124 / 176 40 / 70 slurries were transferred to a flask and the resulting mixture was degassed at 15–25°C with argon for 25 min. To the resulting mixture, 12.79 g of hydrazine monohydrate were added dropwise, followed by an in-line rinse of 90.6 mL of CH2Cl2. The resulting mixture was stirred at 20–25°C for 2 hours, and the reaction was followed by TLC until completion. At the end of the reaction, the resulting mixture was cooled to 15–20°C and washed with 158.6 mL of 2 M HCl solution. The resulting phases were separated; the resulting aqueous phase was returned to the vessel, 158.6 mL of saturated aqueous NaCl solution were added, and the resulting mixture was back-extracted with 2 x 78.8 mL of CH2Cl2. The combined organic phases obtained were washed with 90.6 mL of saturated aqueous NaCl solution, and the resulting organic layer was concentrated to 2 volumes under vacuum at < 40°C. 226.5 mL of CH2Cl2 were added to the concentrate, and the resulting mixture was concentrated to 2 volumes. 362.4 mL of CH2Cl2 were added to the concentrate.

[0120] A stripping weight assay of the obtained mixture was carried out to determine the content of 2,2,2-trifluoro-N-[(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]-acetamide and a yield of 27.1 g was determined.

[0121] The 2,2,2-trifluoro-N-[(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]-acetamide solution (containing 27.1 g) obtained as described above was degassed with argon. 56.5 g of pleuromutilin tosylate were added, followed by an in-line rinse of 54.3 mL of CH2Cl2, and the resulting mixture was stirred at 20 to 25°C for 15 min. To the resulting mixture, 34.0 g of DBU dissolved in 34 mL of CH2Cl2 were added over 30 min, and the resulting mixture was stirred at 20 to 25°C for 1 h until the reaction was complete. The resulting mixture was washed with 2 x 222.5 mL of 2 M H2SO4 followed by 2 x 222.5 mL of 5% aqueous NaHCO3 solution, and the resulting mixture was concentrated to dryness under vacuum at 40°C. Petition 870260039308, dated April 28, 2026, pp. 125-176 41 / 70

[0122] 72.7 g of 14-O-{[(1R,2R,4R)-[(2,2,2-Trifluoroacetyl)-amino2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of a white-yellowish foam were obtained. 1H NMR (200 MHz, DMSO-d6, ppm, inter alia) δ 9.31 (d, 1H,), 6.15 (dd, J = 17.8 Hz, J = 11.1 Hz, 1H), 5.55 (d, J = 7.8 Hz, 1H), 5.17 - 5.02 (m, 3H, H-20), 5.53 (d, J = 5.8 Hz, 1H), 3.80 - 3.60 (m, 1H), R 6.8 Hz, 3H), 0.63 (d, J = 5.8 Hz, 3H) Procedure 2 OH SH OH F F THE Step A: 2,2,2-Trifluoro-N-[(1R,3R,4R)-3-hydroxy-4-mercapto-cyclohexyl]-acetamide

[0123] 5.79 g of {(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino]-2-hydroxycyclohexyl}benzenecarbothioate were dissolved in 81 mL of dichloromethane, 1.67 g (1.62 mL) of hydrazine hydrate was added, and the resulting solution was stirred at room temperature for 3.5 h. To the resulting mixture, 40 mL of 1 M HCl were added, and the resulting biphasic mixture was vigorously stirred for 10 min. The phases were separated, and the resulting organic phase was washed with 40 mL of 1 M HCl. The resulting combined aqueous layers were saturated with NaCl and washed with 30 mL of DCM; and the resulting combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness.

[0124] 3.41 g of 2,2,2-trifluoro-N-[(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]-acetamide in the form of colorless crystals were obtained. 1H NMR (200 MHz, DMSO-d6, ppm, inter alia) δ 9.31 (d, J = 7.2 Hz, 1H), 5.12 (d, J = 5.1 Hz, 1H), 3.82 - 3.6 (m, 1H), 3.24 - 3.09 (m, Petition 870260039308, dated 04 / 28 / 2026, pp. 126 / 176 42 / 70 1H), 2.62 - 2.5 (m, 1H), 2.40 (s, wide, 1H), 2.03 - 1.84 (m, 2H), 1.74 1.71 (m, 1H), 1.47 - 1.21 (m, 3H) Step B: 14-O-{[(1R,2R,4R)-[(2,2,2-Trifluoro-acetyl)-amino]-2-hydroxycyclohexyl-sulfanyl]-acetyl}-mutilin

[0125] 5.91 g of 2,2,2-trifluoro-N-[(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]-acetamide and 11.78 g of pleuromutilin tosylate were dissolved in 82.5 mL of DCM and the resulting solution was degassed with argon for 20 min. To the resulting mixture, 6.91 g of DBU in 27.5 mL of DCM were added over 30 min. At the end of the reaction (TLC control), 25 mL of 2 M HCl were added to the resulting mixture and the mixture was vigorously stirred for 10 min. The resulting phases were separated, the resulting organic phase was washed with 12.5 mL of 2 M HCl and subsequently with 25 mL of 5% sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated from the filtrate obtained under vacuum.

[0126] 16.8 g of 14-O-{[(1R,2R,4R)-4-[(2,2,2-trifluoroacetyl)amino]-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin were obtained in the form of a colorless foam. (the material contained residual DBU tosylate salt and DCM).

[0127] The 1H NMR pattern confirms the structure of 14-O {[(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino]-2-hydroxycyclohexylsulfanyl]acetyl}-mutiline. The NMR pattern for 14-O-{[(1R,2R,4R)-4[(2,2,2-Trifluoroacetyl)amino]-2-hydroxycyclohexylsulfanyl]acetyl}mutiline is described in Example 6, Procedure 1. Example 7 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin, crystalline form 2 Petition 870260039308, dated April 28, 2026, pp. 127-176 43 / 70

[0128] 72.7 g of crude 14-O-{[(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin, 419.9 mL of methanol, and 168 mL of water were charged to a flask, and the resulting mixture was heated to 40–45°C. 67.3 g of K2CO3 were added to the mixture, and the mixture was stirred at 40–45°C for 5 h. The reaction was monitored by HPLC until completion. Upon completion of the reaction, the mixture was cooled to 20–25°C, 588 mL of CH2Cl2 and 588 mL of 2 M phosphoric acid were added, and the mixture was stirred at 20–25°C for 15 min. The resulting mixture was filtered biphasically, separated, and the organic layer obtained was extracted with 588 mL of 1 M phosphoric acid. The resulting phases were separated, and 588 mL of CH2Cl2 were added to the combined aqueous layers (product), and the resulting mixture was cooled to 10–15°C.To the resulting mixture, 6 M NaOH was added dropwise at < 25°C until a pH > 9 was reached (275 mL required). The resulting mixture was filtered biphasically, and the resulting layers were separated. The organic layer (product) was concentrated to approximately 5 volumes under vacuum at < 40°C, 176 mL of CH2Cl2 were added, and the resulting mixture was concentrated again to 2 volumes under vacuum at < 40°C. To the resulting concentrate, 323.5 mL of n-butanol were added dropwise, the resulting mixture was concentrated to 5 volumes under vacuum at < 40°C, and the resulting concentrate was stirred at 20 to 25°C for 2 h. The mixture obtained was filtered, the precipitate obtained was washed with 117.6 mL of n-butanol, and the solid obtained was dried overnight under vacuum at 40°C, yielding 44.2 g of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin in crystalline form 2.

[0129] 44.2 g of crude 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin were loaded into a clean vessel and 221 mL of n-butanol were added. The resulting mixture was heated to 88–92°C, stirred for 40 min, and allowed to cool at this rate. Petition 870260039308, dated 04 / 28 / 2026, pp. 128 / 176 44 / 70 cationic for 3 h until 40 to 45°C and stirred for an additional 2 h. The resulting mixture was filtered, washed with 44.2 mL of n-butanol followed by 44.2 mL of MTBE and dried under vacuum at < 40°C.

[0130] 37.6 g of crystalline 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in crystalline form 2 were obtained as a white crystalline solid.

[0131] The 1H NMR pattern confirms the structure of 14-O {[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline. The NMR pattern for 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline is described in Example 4. Example 8 [(1R,3R,4R)-3-hidroxy-4-mercapto-cyclo-hexyl]-carbamate tert-butyl e [(1S,3S,4S)-3-hidróxi-4-mercapto-ciclo-hexil]-carbamato de terc-butila O O OH SH SH '+ ó „OH

[0132] 7.22 g of a mixture of {(1R,2R,4R)-4-[(tert-Butoxycarbonyl)amino]-2-hydroxycyclohexyl}benzenecarbothioate with {(1S,2S,4S)-4-[(tert-Butoxycarbonyl)amino]-2-hydroxycyclohexyl}benzenecarbothioate and 72 mL of CH2Cl2 were loaded into a flask and the resulting mixture was stirred at 15 to 25°C. The resulting mixture was degassed using argon for a period of 20 minutes. To the resulting mixture, 0.72 g of 1,4-dithio-DL-threitol was added and 1.5 g of hydrazine monohydrate was added dropwise. The reaction was followed by TLC until completion. At the conclusion of the reaction (2.5 h), 72 mL of 1 M phosphoric acid solution were added to the resulting mixture, and the mixture was stirred for 15 min. The resulting phases were separated; the lower organic phase was washed with 72 mL of 1 M phosphoric acid followed by... Petition 870260039308, dated April 28, 2026, pp. 129-176 45 / 70 of 72 mL of 1% NaCl solution, dried over anhydrous magnesium sulfate (10 g), filtered, and the solid rinsed with 2 x 10 mL of CH2Cl2. The resulting mixture was concentrated under vacuum at < 40°C. 5.01 g of a mixture of tert-butyl [(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]-carbamate with tert-butyl [(1S,3S,4S)-3-hydroxy-4-mercaptocyclohexyl]-carbamate in the form of a white solid were obtained. 1H NMR (200 MHz, DMSO-d6, ppm, inter alia) δ 6.79 (d, J = 7.8 Hz, 1H), 5.01 (d, J = 5.6 Hz, 1H), 3.40 - 3.20 (m, 1H), 3.1 - 3.0 (m, 1H), 2.38 (d, J = 3.8 Hz, 1H), 2.01 - 1.78 (m, 2H), 1.73 - 1.61 (m, 1H), 1.47 -1.01 (m, 12H) Example 9 14-O-{[(1R,2R,4R)-4-tert-Butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin and 14-O-{[(1S,2S,4S)-4-tert-Butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilinsCOH SH SH Ç+ ó NH

[0133] 9.68 g of pleuromutilin tosylate and 101 mL of MTBE were loaded into a flask and the resulting mixture was degassed at room temperature using argon for 5 to 10 minutes. To the resulting mixture, 0.64 g of benzyltri-n-butylammonium chloride, 4.72 g of a mixture of tert-butyl [(1R,3R,4R)-3-hydroxy-4-mercaptocyclohexyl]-carbamate with tert-butyl [(1S,3S,4S)-3-hydroxy-4-mercaptocyclohexyl]-carbamate and 40 mL of 1 M aqueous NaOH solution were added with stirring. The resulting mixture was stirred at 20 to 25°C and the reaction was followed by HPLC until completion. At the end of the reaction (1 h) the resulting layers were separated and the lower aqueous layer Petition 870260039308, dated April 28, 2026, pp. 130-176 46 / 70 was removed. The resulting organic phase was washed with 40 mL of 1 M aqueous NaOH solution, 2 x 40 mL of 0.1 M phosphoric acid followed by 40 mL of 10% NaHCO3 solution and 40 mL of H2O. The resulting organic liquors were concentrated and dried under vacuum at < 40°C. 11.88 g of a mixture of 14-O-{[(1R,2R,4R)-4-tert-butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin with 14-O-{[(1S,2S,4S)-4-tert-butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin was obtained in the form of a white foam (not corrected for residual solvent). 1H NMR (200 MHz, DMSO-d6, ppm, inter alia) δ 6.79 (d, J = 7.8 Hz, 1H), 6.22 - 6.07 (m, 1H), 5.55 (d, J = 8 Hz, 1H), 5.12 - 4.96 (m, 3H), 4.54 (d, J = 6 Hz, 1H), 3.55 - 3.24 (m, 4H), 2.54 - 2.50 (m, 1H), 2.41 (s, wide, 1H), 2.23 - 1.80 (m, 5H), 1.71 - 1.56 (m, 3H), 1.56 1.43 (m, 2H), 1.42 - 1.31 (m, 14H), 1.31 - 1.18 (m, 4H), 1.10 - 0.91 (m, 5H), 0.82 (d, J = 6.6 Hz, 3H), 0.63 (d, J = 5.8 Hz, 3H) Example 10 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin, crystalline form 2

[0134] 10.69 g of a mixture of 14-O-{[(1R,2R,4R)-4-tert-Butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin with 14-O-{[(1S,2S,4S)-4-tert-Butoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin (corrected for residual solvent) and 24 mL of isopropanol were placed in a flask and the resulting mixture was shaken. Petition 870260039308, dated April 28, 2026, pp. 131-176 47 / 70 da. To the resulting mixture, 12 mL of 85% phosphoric acid were added, and the mixture was heated to 50°C overnight. Upon completion of the reaction determined by HPLC, the mixture was cooled to room temperature, and 119 mL of CH2Cl2 were added. The mixture was then cooled to 0-5°C, and 119 mL of 30% aqueous K2CO3 solution were added dropwise over 1 hour. The mixture was heated to room temperature and allowed to settle. The formed phases were separated, and the lower organic layer (product) was removed. The aqueous layer (measured at pH 10) was extracted with 119 mL of CH2Cl2, and the combined organic phases were washed with 119 mL of H2O. The resulting organic phase was concentrated to approximately 5 volumes; 59 mL of CH2Cl2 were added, and the mixture was concentrated again to approximately 5 volumes.To the resulting concentrate, 59 mL of dichloromethane were added again, and the resulting mixture was concentrated to 2 volumes. To the resulting concentrate, 119 mL of diisopropyl ether were added dropwise with stirring over a period of 1 hour. A thick oily precipitate was obtained, which turned into white crystals after approximately 1 hour. The resulting mixture was stirred at 15 to 25°C for 2 hours, filtered, and the resulting precipitate was washed with 24 mL of diisopropyl ether and removed dry on the filter. 8.28 g (not corrected for residual solvent) of a mixture of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin with 14-O-{[(1S,2S,4S)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin were obtained in the form of a solid (ratio of 59:41).

[0135] 8.28 g of the crude mixture obtained and 41 mL of n-butanol were charged into a flask and the mixture was heated to 88–92°C with stirring for 30 min. The mixture was allowed to cool to room temperature for approximately 3 h. Precipitation was observed to begin at ~50°C and the mixture was stirred at room temperature. Petition 870260039308, dated April 28, 2026, pages 132 / 176 48 / 70 ambient temperature overnight. The resulting mixture was filtered and the precipitate was washed with 16.6 mL of n-butanol followed by 16.6 mL of MTBE and dried under vacuum at < 40°C. 4.27 g of 14-O-{[(1R,2R,4R)-4Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin in the form of a white crystalline solid in crystalline form 2 were obtained. The optical purity was 93% determined by chiral HPLC and the chemical purity was 99.14% area determined by RP HPLC.

[0136] Furthermore, comparison of the optical rotation of an authentic sample of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin with the optical rotation of 14-O-{[(1R,2R,4R)-4Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin obtained as described above confirmed the chiral purity as well; ([a]D (CHCh) = +24.9° versus +25.9° for the authentic sample)

[0137] The precursor liquors resulting from the recrystallization of n-butanol were evaporated to dryness to provide a white foam. 3.67 g of a mixture of 14-O-{[(1S,2S,4S)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin with 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin were obtained (ratio of 84.0:16.0;

[0138] The 1H NMR pattern confirms the structure of 14-O {[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline. The NMR pattern for 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline is described in Example 4. Example 11 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin acetate, crystal form A

[0139] To a suspension of 615 g of 14-O-{[(1R,2R,4R)-4-amino Petition 870260039308, of 28 / 04 / 2026, p. 133 / 176 49 / 70 2-hydroxycyclohexylsulfanyl]acetyl}mutilin in 12.3 L of methyl acetate at 50-55°C was added to 62 mL of water, and the resulting turbid solution was purified using GF filter paper. The filtrates obtained were heated to 50-55°C (clear solution), 123 mL of acetic acid were added, the resulting mixture was stirred at 50-55°C for 25 minutes, cooled to 15-25°C for 80 minutes, and further cooled to 0-5°C for 60 minutes. The resulting suspension was aged at 0-5°C for 80 minutes, filtered, and the filter cake was washed with 3.08 L of methyl acetate. The filter cake was removed by drying on a filter under nitrogen for 2 hours. 574.1 g of 14-O{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin in the form of an acetate in the form of a fine white crystalline powder in crystalline form A was obtained.

[0140] The 1H NMR pattern confirms the acetate structure of 14O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutiline. The NMR pattern for 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutiline acetate is described in Example 12. Example 12 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin acetate, crystal form B Procedure 1

[0141] To a suspension of 3.260 g of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in 56.8 L of isopropyl acetate, 10 g of 14-O{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin seed crystals in crystalline form B were added. Crystallization also occurs without adding the seed crystals. The resulting suspension was stirred at 20 to 25°C for > Petição 870260039308, de 28 / 04 / 2026, pág. 134 / 176 50 / 70 min. To the resulting mixture, 353 mL of acetic acid were added, and the mixture was stirred at 20 to 25°C for 1 h and tested for completion and polymeric form by XRPD. The resulting suspension was stirred for an additional 1 h at 20 to 25°C, filtered, and the resulting filter cake was washed twice with 2.84 L each of isopropyl acetate. The resulting solid was dried under vacuum at 50°C for at least 12 h.

[0142] 3.15 kg of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin acetate in the form of a white crystalline solid in crystalline form B were obtained. Procedure 2

[0143] 2.00 g of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin were dissolved in 6 mL of methanol. To the resulting mixture, 0.338 mL of acetic acid was added in one portion and the resulting solution was stirred for 15 min. To the resulting mixture, 30 mL of isopropyl acetate were added over 30 min and the resulting suspension was stirred for 30 min. The resulting fluid paste was heated to 30°C, 15 volumes were removed by distillation, and 3 strips (of 3 volumes each) of isopropyl acetate were prepared. The resulting fluid paste was filtered, and the resulting white precipitate was isolated, washed with isopropyl acetate, and dried overnight. 1.74 g of {[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin acetate in the form of a white crystalline solid in crystalline form B was obtained. 1H NMR (500 MHz, in DMSO, ppm, inter alia) δ 6.16 - 6.10 (m, 1 H), 5.54 (d, J = 8.3 Hz, 1H), 5.09 - 5.02 (m, 2H), 3.42 (d, J = 6.6), J = 17 Hz, AB 15 Hz, 2H), 3.29 - 3.25 (m, 1H), 2.77 - 2.67 (m, 1H), 2.55 - 2.5 (m, 1H), 2.40 (s, amplitude, 1H), 2.23 - 2.12 (m, 1H), - 1.95 (m, 1H), 1.94 - 1.85 (m, 1H), 1.77 (s, 3H), 1.77 - 1.71 (m, 1H), 1.7 - 1.57 (m, 2H), 1.36 (s, 3H), 1.37 - 0.96 (m, 10H), 0.81 (d, J = 7 Hz, 3H), 0.62 (d, J = 7 Hz, 3H) Petition 870260039308, of 28 / 04 / 2026, p. 135 / 176 51 / 70 Example 13 L-lactate of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxy-cyclo-hexylsulfanyl]acetyl}-mutilin, crystalline form 1

[0144] 22 g of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin and 1.1 L of EtOAc were loaded into a vessel. The resulting suspension was heated to 50°C and held until dissolved. To the resulting mixture, 1 equivalent of 98% L-lactic acid was added, and the resulting mixture was gradually cooled to 25°C for 3 h.

[0145] Optionally, seed crystals of 14-O{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin L-lactate were added. Crystallization also occurs without seed crystals.

[0146] The resulting suspension was stirred at 20 to 25°C overnight and further cooled to 5°C for 1 h. The precipitate obtained was isolated by filtration and dried under vacuum at 40°C overnight.

[0147] 23.7 g of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin L-lactate in crystalline form 1 were obtained. 1H NMR (400 MHz, DMSO-de, ppm, inter alia) δ 6.13 (dd, J = 11 and 18 Hz, 1H), 5.54 (d, J = 8 Hz, 1H), 5.10 - 5.01 (m, 2H), 4.53 (d, broad, 1H), 3.60 (dd, J = 7 e 14 Hz, 1H), 3.40 (AB, J = 15 Hz, 2H), 2.93 (m, 1H), 2.55 - 2.48 (m, 1H), 2.39 (s, wide, 1H), 1.36 (s, 3H), 1.09 (d, J = 7 Hz, 3H), 1.04 (s, 3H), 0.81 (d, J = 7 Hz, 3H), 0.61 (d, J = 7 Hz, 3H). Example 14 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin hydrogen maleate, crystalline form 1 Petition 870260039308, dated April 28, 2026, pp. 136-176 52 / 70

[0148] 5.5 g of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin and 110 mL of EtOAc were charged into a flask. The resulting suspension was heated to 80°C and held until dissolved. 10.8 mL of 1 M maleic acid in THF were added to the resulting mixture, and the mixture was allowed to cool to room temperature overnight with stirring.

[0149] Optionally, 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}mutilin hydrogen maleate seed crystals were added. Crystallization also occurs without seed crystals.

[0150] 6.16 g of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in the form of a crystalline hydrogen maleate salt in crystalline form 1 were isolated by filtration and dried for 6 h vacuum. 1H NMR (400 MHz, DMSO-d-6, ppm, inter alia) δ 6.13 (dd, J = 11 and 18 Hz, 1H), 6.00 (s, 2H), 5.54 (d, J = 8 Hz, 1H), 5.10 - 5.01 (m, 2H), 4.54 (d, J = 6 Hz, 1H), 3.40 (AB, J = 15 Hz, 2H), 3.05 (m, 1H), 2.56 - 2.49 (m, 1H), 2.40 (s, wide, 1H), 1.36 (s, 3H), 1.05 (s, 3H), 0.81 (d, J = 7 Hz, 3H), 0.61 (d, J = 7 Hz, 3H).

[0151] The process for exchanging the protecting group of amine R in a compound of Formula I is shown in REACTION SCHEME 3 below: REACTION SCHEME 3ir,.--PLEUPLEU I J. ,OH amine protective agent LJ baseI I solvent nh2Jh I

[0152] In the REACTION SCHEME 3 R represents an amino protecting group as defined above. Petition 870260039308, dated April 28, 2026, pp. 137-176 53 / 70 Example 15 14- O-{[(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin h2n F

[0153] 1 g of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin and 10 mL of DCM were charged to a flask at room temperature and the resulting mixture was stirred. To the resulting mixture, 0.41 mL of triethylamine was added dropwise, followed by 0.29 mL of trifluoroacetic anhydride, and the resulting mixture was stirred until the reaction was complete (determined by TLC). The resulting mixture was washed with 10 mL of 0.1 M HCl followed by 10 mL of 5% NaHCO3 and 10 mL of water and concentrated to dryness.

[0154] 1.20 g of 14-O-{[(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutilin was obtained in the form of a foam.

[0155] The 1H NMR pattern confirms the structure of 14-O {[(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline. The NMR pattern for 14-O-{[(1R,2R,4R)-4[(2,2,2-Trifluoroacetyl)-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}mutiline is described in Example 6. Example 16 14-O-{[(1R,2R,4R)-4-ethoxycarbonylamino-2-hydroxy-cyclohexyl-sulfanyl]acetyl}-mutilin HN

[0156] 1 g of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexyl] Petition 870260039308, dated 28 / 04 / 2026, p. 138 / 176 54 / 70 sulfanil]-acetyl}-mutilin and 10 mL of DCM were charged to a flask at room temperature and the resulting mixture was shaken. To the resulting mixture, 0.41 mL of triethylamine was added dropwise, followed by 0.2 mL of ethyl chloroformate, and the mixture was shaken until the reaction was complete (determined by TLC). The resulting mixture was washed with 10 mL of 0.1 M HCl followed by 10 mL of 5% NaHCO3 and 10 mL of water, and concentrated to dryness.

[0157] 1.05 g of 14-O-{[(1R,2R,4R)-4-ethoxycarbonylamino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin was obtained in the form of a foam. 1H NMR (400 MHz, DMSO-d-6, ppm, inter alia) δ 7.07 (d, J = 7.6 Hz, 1H), 6.16 (dd, J = 17.6 Hz, J = 11.0 Hz, 1H), 5.55 (d, 1H, J = 8.0 Hz), 5.13 - 4.96 (m, 3H) 1.40 - 0.88 (m, 17H), 0.82 (d, J = 6.8 Hz, 3H), 0.63 (d, J = 5.8 Hz, 3H) Example 17 14- O-{[(1R,2 R,4R)-2-hydroxy-4-(phthalimido-N-yl)-cyclohexyl-sulfanyl]acetyl}-mutilin

[0158] 1 g of 14-O-{[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin and 40 mL of toluene were charged to a flask at room temperature and the resulting mixture was stirred. To the resulting mixture, 0.41 mL of triethylamine was added dropwise, followed by 0.30 g of phthalic anhydride, and the resulting mixture was heated to reflux and the water was removed under Dean-Stark conditions until the reaction was complete (determined by HPLC). The resulting mixture was washed with 10 Petition 870260039308, dated April 28, 2026, pp. 139-176 55 / 70 mL of 0.1 M HCl followed by 10 mL of 5% NaHCO3 and 10 mL of water, dried over sodium sulfate and concentrated to dryness.

[0159] 0.87 g of 14-O-{[(1R,2R,4R)- 2-hydroxy-4-(phthalimido-N-yl)cyclohexylsulfanyl]-acetyl}-mutilin was obtained in the form of opaque white crystals. 1H NMR (400 MHz, DMSO-d-6, ppm, inter alia) δ 7.9 - 7.7 (m, 4H), 6.17 (dd, J = 17.6 Hz, J = 11.2 Hz, 1H), 5.58 (d, 1H, J = 7.8 Hz), 5.16 - 5.06 (m, 3H), 4.54 (d, 1H, J = 6.0 Hz), 4.13 - 4.01 (m, 1H), 3.62 - 3.29 (m, 4H), 2.69 - 2.60 (m, 1H), 2.43 (m, 1H), 2.30 - 1.80 (m, 8H), 1.80 - 1.15 (m, 12H), 1.1 - 0.9 (m, 4H), 0.83 (d, J = 6.6 Hz, 3H), 0.65 (d, J = 5.8 Hz, 3H)

[0160] The process for the starting material of Formula IVa useful for the production of compounds of Formula IIIa is summarized in Reaction Scheme 4 below. REACTION SCHEME 4

[0161] In the REACTION SCHEME 4 R represents an amino protecting group and Ri represents a sulfur protecting group and are as defined above. Petition 870260039308, dated April 28, 2026, pp. 140-176 56 / 70 Example 18 {(1R,2R,4R)-4-[(tert-Butoxycarbonyl)-amino]-2-hydroxycyclohexyl}benzenecarbothioate Step A: tert-butyl cyclohex-3-enyl-1(R)-carbamate A. Formation of cyclohex-3-ene-1-carboxylic acid salt. OCH3 + í| j^ OH+HN^J^ O rj^^p^O HN^^^I

[0162] 1000 g of racemic cyclohex-3-ene-1-carboxylic acid were charged to a flask and 5 volumes of acetone were added. The resulting mixture was stirred, heated to 55–60°C and stirred for 30 min. To the resulting mixture, 960.5 g of (S)-(-)-α-methylbenzylamine in 2 volumes of acetone were added dropwise over approximately 25 min. A clear, orange solution was obtained and cooled slowly. Crystallization began at 53°C (after 30 min). Total crystallization occurred after ~1 h at 49°C. The resulting mixture was cooled to room temperature for an additional 3 h in an ice bath, then stirred at room temperature for an additional 1.5 h. The resulting precipitate was separated by filtration and washed with acetone. An α-methylbenzylamine salt of cyclohex-3-ene-1-carboxylic acid, as shown in the reaction scheme above, was obtained. Yield (wet): 1966.9 g; optical rotation: 20[α]ο = +8.05° (c = 1, MeOH) B. Dissolution of the salt

[0163] 1966.9 g (wet) of a salt as presented under step A and 3.8 volumes of acetone were charged to a 10 L vessel and the resulting mixture was heated to 55–60°C. When the product dissolved, the resulting mixture was stirred for an additional 15 min and then cooled slowly to room temperature. The crystallization Petition 870260039308, dated April 28, 2026, pp. 141-176 57 / 70 The reaction began after 1 h 10 min (53°C). The resulting mixture was cooled to 20–25°C for 4.5 h and stirred at room temperature for an additional 1.5 h. The precipitate obtained was separated by filtration and washed with acetone. An α-methylbenzylamine salt of cyclohex-3-ene-1-carboxylic acid in which the R isomer was enriched was obtained. Yield (wet): 1143 g; optical rotation: 20[a]D = +20.65° (c = 1, MeOH)

[0164] Step B. was repeated until a required optical rotation (20[a]D > 40°) was obtained. C. Cyclohex-3-ene-1(R)-carboxylic acid ° CH3 í|^p^OH HN^^jj^lj HO^^O

[0165] 579.6 g of (S)-(-)-α-methylbenzylamine salt of cyclohex-3-ene-1(R)-carboxylic acid and 5 volumes of MTBE were charged to a flask at 20-25°C and the resulting mixture was stirred. 10 volumes of 1 M HCl were added to the mixture, which was stirred for 5-10 min, and two layers were formed. The layers were separated, and the aqueous layer was extracted with MTBE. The organic layers were combined and washed with brine. The organic phase was dried over Na2SO4, filtered, and the filter cake was washed with MTBE. The solvent was removed from the filtrate under vacuum. Cyclohex-3-ene-1(R)-carboxylic acid in the form of a clear oil was obtained. Yield: 301.78 g Optical rotation20[a]D = +83.1° (c = 1, CHCb)

[0166] Cyclohex-3-ene-1(R)-carboxylic acid can be obtained by analogy to the method disclosed in Schwartz, HM; et al. JACS 1978, 100, 5199-5203. Petition 870260039308, dated April 28, 2026, pp. 142-176 58 / 70 D. Curtius transposition to obtain tert-butyl cyclohex-3-enyl-(R)-carbamate HH,C. .O^ ,NHHC yhoO Ch, O

[0167] 305 g of cyclohex-3-ene-1(R)-carboxylic acid and 10 volumes of toluene were charged to a flask at 20-25°C and the resulting mixture was stirred. To the resulting mixture, 1.1 equivalents of triethylamine were added dropwise over 15 min and the mixture was stirred for an additional 20 min. To the resulting mixture, 1.05 equivalents of DPPA were added dropwise over approximately 20 min and the temperature was raised to 95°C (exothermic reaction) with vigorous gas evolution. The resulting mixture was stirred for 15 min and heated to reflux. The progress of the reaction was monitored by 1H NMR measurements until completion. The resulting mixture was cooled to 80°C for 35 min and 5 equivalents of tert-butanol were added dropwise over 10 min, followed by 7.65 g of CuCl. The resulting mixture was heated to 100°C and stirred for an additional 40 minutes. The progress of the reaction was monitored by 1H NMR measurements until completion.The resulting mixture was cooled, and 5 volumes of saturated aqueous NaHCO3 solution were added over 10 minutes. The mixture was stirred for 20 minutes and left overnight. The mixture was filtered, and the residual solid was washed twice with toluene. The organic layers were separated, and the aqueous layer was washed twice with toluene. All the organic layers obtained were combined, washed with H2O, and the solvent was removed under vacuum. tert-butyl cyclohex-3-enyl-1(R)-carbamate was obtained as a light brown solid. Gross yield: 479.7 g.

[0168] Crude tert-butyl cyclohex-3-enyl-1(R)-carbamate obtained Petition 870260039308, dated April 28, 2026, pages 143 / 176 59 / 70 was subjected to chromatography. For 160 g of crude product, the column was packed with 1.5 kg of silica gel, using 2.5 L of cyclohexane, and covered with sand. The crude product was loaded into 0.8 L of 5% EtOAc / cyclohexane. The column was scintillated with the following gradient system, a separate fraction being collected at a time: EtOAc / cyclohexane at 2% (9 x 0.8 L fractions) EtOAc / cyclohexane at 5% (7 x 0.8 L fractions) EtOAc / cyclohexane at 10% (4 x 0.8 L fractions) Overall yield after chromatography: 81.3% of theory 1H NMR (CDCb, 500 MHz, ppm): δ 5.64 - 5.67 (m, 1H), 5.56 - 5-60 (m, 1H), 4.54 (s, wide, 1H), 3.77 (s, wide, 1H), 2.32 - 2.34 (m, 1H), 2.07 - 2.17 (m, 2H), 1.81 - 1.87 (m, 2H), 1.48 - 1.56 (m, 1H), 1.44 (s, 9H)13C NMR (CDCle, 500 MHz, ppm):): δ 155.3, 126.9, 124.5, 79.1,45.7, 32.1, 28.4, 23.6 Step B: (1R,3R,6S)-(7-oxa-bicyclo[4,1,0]hept-3-yl)-tertbutylcarbamate

[0169] 4500 g of mCPBA (70%) and 24 L of CH2Cl2 were loaded into a vessel and the resulting mixture was cooled to 15°C. 3000 g of tert-butyl cyclohex-3-enyl-1(R)-carbamate in 4.5 L of CH2Cl2 were added dropwise over approximately 30 min, maintaining the temperature at 15 to 25°C. To the resulting mixture, 1.5 L of CH2Cl2 was added and the mixture was stirred at 20 to 25°C for 1 h and heated to reflux (40°C) for 2 h. At the conclusion of the reaction (1H NMR control), the mixture was cooled to -5 to 0°C, stirred for Petition 870260039308, dated April 28, 2026, pages 144 / 176 60 / 70 at night and the solid precipitate obtained was separated by filtration and washed with CH2Cl2. The resulting filtrate was washed with 10% aqueous sodium thiosulfate solution to remove peroxides, 10% aqueous NaHCO3 solution until a pH > 7 was obtained in the aqueous phase, and water. The organic phase obtained was concentrated to the minimum volume and 15 L of toluene were added and the mixture obtained was concentrated again to the minimum volume. This stripping process was repeated two more times, yielding 2.63 kg (2.05 kg corrected yield for residual mCBA and toluene) of tert-butyl (1R,3R,6S)(7-oxa-bicyclo[4,1,0]hept-3-yl)-carbamate in the form of a toluene solution. 1H NMR (200 MHz, CDCh, ppm) δ 4.85 (d, J = 7 Hz, 1H), 3.6 - 3.54 (m, 1H), 3.10 (s, broad, 2H), 2.23 - 1.99 (m, 2H), 1.92 1.67 (m, 2H), 1.54 - 1.27 (m, 11H) Step C: {(1R,2R,4R)-4-[(tert-Butoxycarbonyl)-amino]-2-hydroxycyclohexyl}-benzene-carbothioate THE H.O OH H3C^^O^____NH HC^^O^_,NH HC^JH H.C''!H3ch3o ch3o

[0170] 2630 g (corrected to 2050 g) of tert-butyl (1R,3R,6S)-(7-oxabicyclo[4,1,0]hept-3-yl)-carbamate in the form of a toluene solution (solution weight: 15.44 kg) from step B above and 3.1 L of toluene were charged into a vessel and the resulting mixture was stirred at 15 to 25°C. To the resulting mixture, 1.44 L of thiobenzoic acid (10%) was added dropwise. The temperature was maintained below 30°C. In addition, 1.9 L of toluene and 85.3 g of tetrabutylammonium chloride monohydrate were added in one portion, the external temperature control was stopped, and the resulting mixture was subjected to Petition 870260039308, dated 04 / 28 / 2026, pages 145 / 176 61 / 70 to the exothermic reaction. The resulting mixture was heated to 40-45°C and stirred for 4 h. Upon completion of the reaction (TLC and 1H NMR control), the mixture was cooled to 15-20°C and washed twice with 5% aqueous NaHCO3 solution followed twice with H2O. The resulting organic layer was concentrated under vacuum to the minimum volume. 10.25 L of toluene were added and the mixture was again concentrated to the minimum volume. This process was repeated and the dry weight obtained was determined. All subsequent re-pasting volumes are linked to this weight.

[0171] To the crude concentration residue obtained, 0.5 volumes of toluene were added under stirring, and the resulting mixture was stirred at 15 to 25°C for 30 min. To the resulting mixture, 0.5 volumes of heptane were added dropwise over 15 min, and the resulting mixture was stirred at 15 to 25°C for 40 min. The resulting solid was filtered and washed with 0.25 volumes of toluene-heptane (1:1), followed by a fluid paste wash with 0.5 volumes of toluene-heptane (1:1), followed by a displacement wash with 0.25 volumes of toluene-heptane (1:1). This procedure reduced the amount of undesirable regioisomer and thiobenzoic acid to undetectable levels (by 1H NMR). The resulting solid was isolated and dried under vacuum at 30°C.

[0172] 1090 g of {(1R,2R,4R)-4-[(tert-Butoxycarbonyl)-amino]-2-hydroxycyclohexyl}-benzene-carbothioate in the form of a white solid were obtained. 1H NMR (200 MHz, DMSO-d6, ppm) δ 7.92 - 7.87 (m, 2H), 7.71 - 7.63 (m, 1H), 7.58 - 7.49 (m, 2H), 6.85 (d, J = 8 Hz, 1H), 5.11 (d, J = 5.6 Hz, 1H), 3.49 - 3.25 (m, 3H), 2.12 - 1.95 (m, 2H), 1.79 1.69 (m, 1H), 1.54 - 1.14 (m, 12H)

[0173] An alternative process (telescoping) for obtaining the starting material of Formula IVa that is useful for the production of compounds of Formula IIIa is summarized in REACTION SCHEME 5 Petition 870260039308, dated 04 / 28 / 2026, pages 146 / 176 62 / 70 below: REACTION SCHEME 5 O^^OH Villa DPPA TEA pHCl HR CuCl pHCl PhCl mCPBA R1^ S C^^OH R1SH Bu4NCl PhCl .»O HN. R Va HN. R IVa where R represents an amino protecting group and Ri represents a sulfur protecting group and are defined as above. Example 19 {(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino]-2-hydroxycyclohexyl}benzenecarbothioate "OH" Step A: N-(Cyclohex-3-en-1( R )-yl)-2,2,2-trifluoro-acetamide

[0174] 50 g of 3-cyclohexene-1(R)-carboxylic acid and 425 mL of chlorobenzene were placed in a flask at 20-25°C and the resulting mixture was shaken. To the resulting mixture, 110 mL of triethylamine were added dropwise followed by 25 mL of chlorobenzene. The mixture Petition 870260039308, dated April 28, 2026, pages 147 / 176 The 63 / 70 mixture obtained was heated to 78–82°C, and 109.2 g of DPPA were added in a controlled dose, maintaining the temperature at 80–90°C and steady-state gas evolution. A 20 mL in-line rinse of chlorobenzene was then provided. The resulting mixture was stirred at 78–82°C for 1 h until completion determined by TLC. The resulting mixture was then cooled to approximately 70°C, and 226 g of trifluoroacetic acid in 34 mL of chlorobenzene were added dropwise, maintaining the temperature at 70–80°C, followed by 1.57 g of CuCl and a 25 mL in-line rinse of chlorobenzene. The resulting mixture was stirred at 90–95°C for 2 h, and the reaction was followed by TLC until completion. The resulting mixture was cooled to 15-25°C, and 375 mL of a 20% aqueous K2CO3 solution was added. The mixture was then stirred for 15 minutes. The resulting layers were separated, and 375 mL of a 20% aqueous K2CO3 solution was added to the upper organic layer.The resulting mixture was filtered through Celite to remove residual solids, and the Celite was washed with 50 mL of chlorobenzene. The resulting layers were separated. The combined lower aqueous layers were back-extracted with 250 mL of chlorobenzene, and the resulting combined organic phases were washed with 500 mL of 0.5 M phosphoric acid. The resulting aqueous layer was back-extracted with 300 mL of chlorobenzene, and the resulting combined organic phases were washed with 500 mL of 5% aqueous NaCl solution.

[0175] A stripping weight assay was performed to determine the content of N-(cyclohex-3-en-1(R)-yl)-2,2,2-trifluoroacetamide for use in the epoxidation step B below.

[0176] The chlorobenzene solution obtained contained 69.52 g of N(cyclohex-3-en-1(R)-yl)-2,2,2-trifluoroacetamide. 1H NMR (200 MHz, D6-DMSO, ppm) δ 9.33 (d, 1H), 5.69 5.56 (m, 2H), 3.82 (s, broad, 1H), 2.25 - 1.96 (m, 4H), 1.81 - 1.74 Petition 870260039308, dated April 28, 2026, pp. 148-176 64 / 70 (m, 1H), 1.66 - 1.58 (m, 1H) MS (ESI, g / mol): m / z 194 [M+H]+ Step B: 2,2,2-Trifluoro-N-(1R,3R,6S)-(7-oxa-bicyclo[4,1,0]hept-3-yl)acetamide

[0177] 106.5 g of m-chloroperbenzoic acid (70%) were loaded into portions of the vessel containing the cooled solution (10 to 15°C) of 69.5 g of N-(cyclohex-3-en-1(R)-yl)-2,2,2-trifluoroacetamide from step A, maintaining the temperature < 30°C, and rinsed with 69.5 mL of chlorobenzene. The resulting mixture was stirred at 20 to 25°C for 1 hour, and the reaction was followed by TLC until completion. At the end of the reaction, the resulting mixture was cooled to 0 to -5°C, stirred for 30 min, and the resulting solid precipitate (mCBA) was separated by filtration and washed with 2 x 34.8 mL of chlorobenzene. The resulting filtrate was washed with 347.6 mL of 10% sodium thiosulfate solution to remove peroxides, and the resulting aqueous layer was back-extracted with 208.6 mL of chlorobenzene. The combined organic layers obtained were washed with 347.6 mL of 5% sodium bicarbonate solution to ensure a pH > 7 of the aqueous phase, and the resulting aqueous layer was back-extracted with 208.6 mL of chlorobenzene.The combined organic layers were washed with 347.6 mL of water.

[0178] A stripping weight assay was performed to determine the content of 2,2,2-trifluoro-N-(1R,3R,6S)-(7-oxa-bicyclo[4,1,0]hept-3yl)-acetamide.

[0179] The chlorobenzene solution obtained contained 58.64 g of 2,2,2-trifluoro-N-(1R,3R,6S)-(7-oxa-bicyclo[4,1,0]hept-3-yl)-acetamide containing approximately 11% anti-epoxide (trans) and the organic solution was used for step C below (ring opening). 1H NMR (400 MHz, D6-DMSO, ppm) δ 9.21 (d, J = 7.2 Hz, 1H), 3.80 - 3.52 (m, 1H), 3.10 - 3.09 (m, 2H), 2.22 - 1.66 (m, 4H), Petition 870260039308, dated 04 / 28 / 2026, pp. 149 / 176 65 / 70 2.03 - 2.10 (m, 1H), 1.91 - 1.78 (m, 1H), 1.76 - 1.68 (m, 1H), 1.52 1.30 (m, 2H) MS (ESI, g / mol): m / z 208 [MH]- Step C: {(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino]-2-hydroxycyclohexyl}benzenecarbothioate

[0180] The chlorobenzene solution from step B containing 58.64 g of 2,2,2-trifluoro-N-(1R,3R,6S)-(7-oxa-bicyclo[4,1,0]hept-3-yl)-acetamide was concentrated to approximately 5 volumes based on the epoxide. The resulting concentrate was degassed at 15 to 25°C with argon for 30 min and the temperature was adjusted to 15 to 20°C. To the resulting mixture, 58.1 g of thiobenzoic acid (90%) were added dropwise, ensuring a temperature below 30°C. To the resulting mixture, 17.6 mL of chlorobenzene were added to the vessel as an in-line rinse, and 2.49 g of tetrabutylammonium chloride monohydrate were added in portions at < 30°C. The resulting mixture was heated to 40–45°C, stirred, and the reaction was followed by TLC until completion. Upon completion of the reaction, the resulting mixture was cooled to 0–5°C, stirred for 1 hour, filtered, and the resulting filter cake was washed with 2 x 58.64 mL of chlorobenzene. The resulting solid was dried under vacuum at <40°C.45.5g of {(1R,2R,4R)-4-[(2,2,2-Trifluoroacetyl)amino]-2-hydroxycyclohexyl}-benzenecarbothioate were obtained in solid form. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.38 (s, 1H), 7.91 (m, 2H), 7.68 (m, 1H), 7.55 (m, 2H), 5.23 (s, 1H), 3.80 (m, 1H), 3.55 - 3.49 (m, 1H), 3.41 - 3.34 (m, 1H), 2.13 - 2.03 (m, 2H), 1.82 - 1.79 (m, 1H), 1.60 - 1.38 (m, 3H). MS (ESI, g / mol): m / z 348.0 [M+H]+

[0181] The process for the starting material of the mixture of compound of Formula IVa with a compound of Formula IVb useful for the production of the mixture of compound of Formula IIIa with a compound of Formula IIIb is summarized in REACTION SCHEME 6 below: Petition 870260039308, dated April 28, 2026, pages 150 / 176 66 / 70 REACTION SCHEME 6 where R represents an amino protecting group and R1 represents a sulfur protecting group, and are as defined above. Example 20 {(1R,2R,4R)-4-[(ferc-Butoxycarbonyl)-amino]-2-hydroxycyclohexyl}benzenecarbothioate and {(1S,2S,4S)-4-[(ferc-Butoxycarbonyl)-amino]-2-hydroxycyclohexyl}benzenecarbothioate Step A: tert-butyl cyclohex-3-enyl-1(R)-carbamate and tert-butyl cyclohex-3-enyl-1(S)-carbamate

[0182] 50.0 g of 3-cyclohexene-1-carboxylic acid and 500 mL of toluene were loaded into a 2 L flask at 20 to 25°C, the resulting mixture was stirred and 60.7 mL of triethylamine were added dropwise over 15 min followed by the dropwise addition of 89.7 mL of DPPA du Petition 870260039308, dated April 28, 2026, pp. 151-176 67 / 70 during 20 min (gas evolution, exothermic at ~50°C). To the resulting mixture, 50 mL of toluene were added as an in-line rinse. The resulting mixture was heated to reflux and stirred until the reaction was complete, determined by TLC and 1H NMR. The reaction was shown to be complete after 1 h. The resulting mixture was cooled to 80°C and 186 mL of t-BuOH were added dropwise over 10 min, followed by 1.26 g of CuCl, and the resulting mixture was heated to reflux. The reaction was followed by 1H NMR and shown to be complete after 1 h. The resulting mixture was cooled to 20-25°C and 250 mL of saturated NaHCO3 solution were added over 5-10 min. The resulting mixture was stirred for 30 min, filtered to remove residual solids, and the solids were rinsed with 25 mL of toluene. The layers were separated, and the aqueous layer was extracted with 2 x 150 mL of toluene. The organic layers were combined, washed with 150 mL of water, and concentrated under vacuum.79.8 g of a mixture of tert-butyl cyclohex-3-enyl-1(R)-carbamate and tert-butyl cyclohex-3-enyl-1(S)-carbamate were obtained in the form of a brown solid. Optical rotation: [a]D (CHCh) = 0° Purification by column chromatography:

[0183] The crude mixture of tert-butyl cyclohex-3-enyl-1(R)-carbamate and tert-butyl cyclohex-3-enyl-1(S)-carbamate was purified by column chromatography (eluent: cyclohexane / EtOAc 9:1).

[0184] The required clean fractions were identified and combined. Concentration under vacuum yielded the required product. 60.88 g of a mixture of tert-butyl cyclohex-3-enyl-1(R)-carbamate with tert-butyl cyclohex-3-enyl-1(S)-carbamate were obtained as a white solid. Optical rotation: [a]D (CHCh) = 0°1H NMR (200 MHz, CDCb, ppm) δ 5.69 - 5.53 (m, 2H), 4.55 (s, wide, 1H), 3.76 (s, wide, 1H), 2.41 - 2.30 (m, 1H), 2.12 - 2.08 (m, Petition 870260039308, dated April 28, 2026, pp. 152-176 68 / 70 2H), 1.91 - 1.76 (m, 2H), 1.6 - 1.48 (m, 1H), 1.43 (s, 9H) Step B: (1R,3R,6S)-(7-oxa-bicyclo[4,1,0]hept-3-yl)-tert-butyl carbamate and (1S,3S,6R)-(7-oxa-bicyclo[4,1,0]hept-3-yl)-tert-butyl carbamate + H3C H,C ch3O H H

[0185] 45 g of m-chloroperbenzoic acid (70%) and 240 mL of CH2Cl2 were charged to a 1 L flask and the resulting mixture was cooled to 10–15°C. To the resulting mixture, 30.0 g of tert-butyl cyclohex-3-enyl-1(R)-carbamate and tert-butyl cyclohex-3-enyl-1(S)-carbamate in 45 mL of CH2Cl2 were added dropwise over approximately 30 min, ensuring a temperature below 25°C. To the resulting mixture, 15 mL of CH2Cl2 were added as an in-line rinse and the resulting mixture was stirred at room temperature for 1 h, heated to reflux (40°C) for 2 h, followed by HPLC and TLC until the reaction was complete. At the conclusion of the reaction, the resulting mixture was cooled to 0-5°C, stirred for 30 min, and the resulting solid precipitate (m CBA) was separated by filtration and washed with 2 x 15 mL of CH2Cl2.The resulting filtrate was washed with 3 x 150 mL of 10% aqueous sodium thiosulfate solution to remove peroxides, followed by 3 x 150 mL of saturated sodium bicarbonate solution to ensure a pH > 7 (recorded pH = 8-9), followed by 2 x 150 mL of water. The resulting organic layer was concentrated, 150 mL of toluene were added, and the resulting mixture was concentrated again. To the resulting concentrate, 150 mL of toluene were added, the resulting mixture was concentrated to dryness, toluene was added to approximately 2 volumes, and the resulting mixture was kept in a refrigerator before use in the next step. Petition 870260039308, dated April 28, 2026, pages 153 / 176 69 / 70

[0186] 25.73 g of a mixture of (1R,3R,6S)-(7-oxabicyclo[4,1,0]hept-3-yl)-tert-butyl carbamate and (1S,3S,6R)-(7-oxabicyclo[4,1,0]hept-3-yl)-tert-butyl carbamate were obtained (the entire batch was evaporated to dryness, weighed, and the epoxide, mCBA, and toluene contents were determined by NMR analysis). The material still contained mCBA and toluene.

[0187] The syn:anti ratio is 100:0 and determined by 1H NMR. Optical rotation: [a]D (CHCh) = 0°1H NMR (200 MHz, CDCle, ppm) δ 4.82 (s, wide, 1H), 3.63 - 3.54 (m, 1H), 3.13 (s, 2H) 2.26 - 2.03 (m, 2H), 1.96 - 1.70 (m, 2H), 1.49 - 1.28 (m, 11H) Step C: {(1R,2R,4R)-4-[(tert-Butoxycarbonyl)amino]-2-hydroxycyclohexyl}-benzenecarbothioate and {(1S,2S,4S)-4-[(tert-Butoxycarbonyl)amino]-2-hydroxycyclohexyl}-benzenecarbothioate ...Ή 3' 3' H H £ £ ch3o h3c h3c CH o THE h3c h3c CH3o THE OH £ £ CH o

[0188] The product solution obtained in Step B containing 20.1 g of tert-butyl (1R,3R,6S)-(7-oxa-bicyclo[4,1,0]hept-3-yl)-carbamate and tert-butyl (1S,3S,6R)-(7-oxa-bicyclo[4,1,0]hept-3-yl)-carbamate and 60 mL of toluene were charged into a flask, the resulting mixture was stirred at 15 to 25°C and 15 mL of thiobenzoic acid were melted and added dropwise to the resulting mixture, ensuring a temperature below 30°C. 18 mL of toluene were then added as an in-line rinse to the resulting mixture, 0.8 g of tetrabutylammonium chloride monohydrate was added in one portion, the external temperature control was stopped, and the resulting mixture was left until exothermic. The resulting mixture was heated to 40–45°C and the reaction was monitored by TLC until completion. At the end of the reaction (3 h), the resulting mixture was cooled. Petition 870260039308, dated April 28, 2026, pages 154 / 176 70 / 70 until room temperature and washed twice with 2 x 101 mL of 5% sodium bicarbonate solution followed by 2 x 101 mL of water. The resulting organic layer was concentrated under vacuum to the minimum volume. 101 mL of toluene were then added and the batch concentrated again to the minimum volume. This process was repeated and another 101 mL of toluene were added to the resulting mixture and the mixture was concentrated to ~40 mL. The water content was analyzed by KF (0.04%). To the resulting mixture, 101 mL of toluene were added and the resulting mixture was concentrated to dryness.

[0189] Yield of raw material: 35.29 g.

[0190] To the crude material obtained, 17.6 mL of toluene were added, and the resulting mixture was cooled to 10–15°C with stirring, at which point a solid precipitated. The resulting fluid paste was stirred for 45 min. To the resulting mixture, 17.6 mL of heptane were added dropwise, and the mixture was stirred for 1 h. The resulting mixture was filtered, the resulting solid was left to dry, and a displacement wash with toluene-heptane (1:1, 8.8 mL) was performed, followed by a fluid paste wash with toluene-heptane (1:1, 17.6 mL), which reduced the amount of the undesirable regioisomer until it was undetectable by NMR analysis. The resulting solid was dried under vacuum at <40°C. 8.24 g of a mixture of {(1R,2R,4R)-4-[(tert-Butoxycarbonyl)-amino]2-hydroxycyclohexyl}-benzene-carbothioate with {(1S,2S,4S)-4-[(tert-Butoxycarbonyl)-amino]-2-hydroxycyclohexyl}-benzene-carbothioate were obtained in the form of a yellowish-white solid. Rotação óptica: [a]D (CHCla) = 01H NMR (200 MHz, DMSO-de, ppm) δ 7,91 - 7,87 (m, 2H), 7,70 - 7,50 (m, 3H), 6,85 (d, J = 6 Hz, 1H), 5,13 (d, J = 5,6 Hz, 1H), 3,50 - 3,26 (m, 3H), 2,13 - 1,96 (m, 2H), 1,79 - 1,69 (m, 1H), 1,54 1,15 (m, 12H)

Claims

1. Compound, characterized in that it has Formula I: in the form of a single stereoisomer in crystalline form, selected from the group consisting of: 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]acetyl}-mutiline, in Crystalline Form 1, which is defined by an X-ray powder diffraction pattern exhibiting at least two 2theta peaks at (degrees, ± 0.2): 10.6, 11.1, 12.0, 14.3, 15.1, 16.1 or 21.1; 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin acetate salt, in Crystalline Form A, which is defined by an X-ray powder diffraction pattern exhibiting at least four 2-theta peaks at (degrees, ± 0.2): 7.0, 7.7, 11.6, 12.1, 12.6, 13.5, 13.7, 15.4, 15.7, 16.9, 17.3, 19.0, 19.9, 21.1, 23.4, 24.2 or 24.4;14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin acetate salt, in Crystalline Form B, which is defined by an X-ray powder diffraction pattern exhibiting at least four 2-theta peaks at (degrees, ± 0.2): 10.3, 10.7, 12.7, 14.3, 15.5, 16.0, 17.2, 19.5, 20.6 or 22.9; L-lactate salt of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutilin in Crystalline Form 1, which is defined by an X-ray powder diffraction pattern with at least two 2-theta peaks at (degrees, ± 0.2): 7.0, 11.6, 12.0, 12.5, 13.4, 13.6, 13.9, 15.3, 16.8, 18.8, 19.5, 19.8, 20.9, 23.3, 23.9 or 24.2;and Petition 870260039308, dated 04 / 28 / 2026, page 156 / 176 2 / 8 hydrogen maleate salt of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxycyclohexylsulfanyl]-acetyl}-mutiline, in Crystalline Form 1, which is defined by an X-ray powder diffraction pattern with at least two 2-theta peaks at (degrees, ± 0.2): 7.0, 11.3, 11.7, 12.5, 13.5, 13.8, 15.3, 16.7, 18.3, 19.4, 19.7, 21.1, 22.2, 23.8 or 23.9.; 2. Compound according to claim 1, characterized in that it is 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutiline, in Crystalline Form 1, defined by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2): 10.6, 11.1, 12.0, 14.3, 15.1, 16.1 and 21.

1.

3. Compound according to claim 2, characterized in that it is in Crystalline Form 1, defined by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2): 10.6, 11.1, 12.0, 14.3, 15.1, 16.1, 18.2, 19.2, 20.7, 21.1, 21.3, 21.8, 22.6, 23.5, 24.7, 28.2 and 30.

2.

4. Compound according to claim 1, characterized in that it is in the form of a unique stereoisomer in the form of a crystalline salt.

5. Compound according to claim 4, characterized in that the crystalline salt is an acetate, lactate or hydrogen maleate.

6. Compound according to claim 1, characterized in that it is an acetate of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, in Crystalline Form A, defined by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2): 7.0, 7.7, 11.6, 12.1, 12.6, 13.5, 13.7, 15.4, 15.7, 16.9, 17.3, 19.0, 19.9, 21.1, 23.4, 24.2, and 24.

4.

7. Compound according to claim 6, characterized in that the acetate, in Crystalline Form A, is defined by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2): 7.0, 7.7, 11.6, 12.1, 12.6, 13.5, 13.7, 14.1, 15.4, 15.7, 16.5, 16.9, 17.3, 19.0, 19.6, 19.9, 20.1, 21.1, 22.2, 22.5, 23.4, 24.2, 24.4, 26.7, 29.1, 29.6 and 31.

0.

8. Compound according to claim 1, characterized in that it is an acetate of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, in crystalline form B, defined by an X-ray powder diffraction pattern with 2theta peaks at (degrees, ± 0.2): 10.3, 10.7, 12.7, 14.3, 15.5, 16.0, 17.2, 19.5, 20.6, and 22.

9.

9. Compound according to claim 8, characterized in that the acetate, in Crystalline Form B, is defined by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2): 9.0, 10.3, 10.7, 12.7, 14.3, 15.5, 16.0, 17.2, 19.5, 20.6, 21.7, 22.3, 22.7, 22.9, and 24.

4.

10. Compound according to claim 1, characterized in that it is an L-lactate of 14-O-{[(1R,2R,4R)-4amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, in Crystalline Form 1, defined by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2): 7.0, 11.6, 12.0, 12.5, 13.4, 13.6, 13.9, 15.3, 16.8, 18.8, 19.5, 19.8, 20.9, 23.3, 23.9, and 24.

2.

11. Compound according to claim 10, characterized in that L-lactate, in Crystalline Form 1, is defined by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2): 7.0, 7.6, 11.6, 12.0, 12.5, 13.4, 13.6, 13.9, 15.3, 15.5, 16.8, 17.2, 18.8, 19.5, 19.8, 20.0, 20.9, 22.0, 22.4, 22.7, 23.3, 23.9, 24.2; 25.3, 28.9, 29.4, and 30.

8.

12. Compound, according to claim 1, characterized in that it is a hydrogen maleate of 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, in Crystalline Form 1, defined by a powder diffraction pattern of Petition 870260039308, dated 04 / 28 / 2026, p. 158 / 176 4 / 8 os X with 2-theta peaks at (degrees, ± 0.2): 7.0, 11.3, 11.7, 12.5, 13.5, 13.8, 15.3, 16.7, 18.3, 19.4, 19.7, 21.1, 22.2, 23.8, and 23.

9.

13. Compound according to claim 12, characterized in that hydrogen maleate, in Crystalline Form 1, is defined by an X-ray powder diffraction pattern with 2-theta peaks at (degrees, ± 0.2): 7.0, 11.3, 11.7, 12.5, 13.3, 13.5, 13.8, 14.1, 15.3, 16.7, 17.2, 18.0, 18.3, 19.4, 19.7, 20.4, 21.1, 21.9, 22.2, 22.8, 23.8, 23.9, 24.9, 27.1, 27.8, 28.7, 29.3, 30.6, and 30.

8.

14. Pharmaceutical composition, characterized in that it comprises a compound, as defined in claims 1, 2, 6, 8, 10 or 12, as an active ingredient, in combination with a pharmaceutically acceptable vehicle or diluent.

15. Process for preparing a compound of Formula I, as defined in claim 1, in the form of a single stereoisomer in crystalline form, said process being characterized in that it comprises: deprotecting the amine group in a compound of Formula IIa, IIa, or Petition 870260039308, dated 04 / 28 / 2026, page 159 / 176 5 / 8 compound of Formula IIa with a mixture of a Ilb in which R is an amine protecting group; and isolating a compound of Formula I, obtained in the form of a single diastereomer, in crystalline form directly from the reaction mixture or by means of recrystallization in an organic solvent; wherein the crystalline form is as defined in claim 1;and whereby the isolation step of the compound of Formula I, in the form of a single diastereomer in crystalline form, comprises one of the following steps: (a) treating a solution of a compound of Formula I in a single stereoisomeric form obtained in the polar organic solvent CH2CU with an antisolvent selected from diisopropyl ether (DIPE) or methyl tert-butyl ether (MTBE), preferably DIPE; (b) treating a solution of a compound of Formula I in a single stereoisomeric form obtained in the polar organic solvent CH2Cl2, after concentration with an alcohol, such as n-butanol; (c) taking an isolated crude material of a compound of Formula I in a single stereoisomeric form, in an ether, for example, tetrahydrofuran (THF), and optionally treating it with an antisolvent selected from DIPE or MTBE;(d) obtain a compound of Formula I in the form of a single crystalline diathereomer via (re-)crystallization in an organic solvent, wherein the organic solvent is an alcohol, such as n-butanol.

16. Process according to claim 15, characterized in that it further comprises the step of: (e) recrystallizing a crystalline compound obtained from an alcohol, such as n-butanol.

17. Process, according to claim 15 or 16, characterized in that a compound of Formula IIa, or a mixture of a compound of Formula IIa with a compound of Formula IIb, is obtained by coupling, or a compound of Formula IIIa, a mixture of a compound of Formula IIIa with a compound of Formula IIIb, IIIb, respectively, wherein R is as defined in claim 15, with an activated 14-O-AKT-acetylmutiline, wherein AKT is an activating group, optionally mesyl, besyl, tosyl, or -O-AKT is a halogen, optionally 14-O-AKT-acetylmutiline is a compound of Formula Petition 870260039308, dated 04 / 28 / 2026, page 161 / 176 7 / 8 h3c; and isolate a compound of Formula IIa, or a mixture of a compound of Formula IIa with a compound of Formula IIb, respectively, obtained from the reaction mixture.

18. Process according to claim 17, characterized in that a compound of Formula IIIa, or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, is obtained by deprotecting the thiol function in a compound of Formula IVa, R1 IVa, or in a mixture of compound IVa with a compound of Formula IVb, OH / \^δχR. ,.£j R1 IVb N' H , respectively, wherein R is as defined in claim 15, and R1 is a thiol protecting group; and isolating a compound of Formula IIIa, or a mixture of a compound of Formula IIIa with a compound of Formula IIIb, respectively, obtained from the reaction mixture.

19. Process, according to any of the claims 15 to 18, characterized by the fact that R, in a compound of Formula IIIa, is tert-butoxycarbonyl or trifluoroacetyl.

20. Process, according to any one of claims 15 to 19, characterized in that it further comprises the step of converting the compound of Formula I into a salt by the addition of an acid, and isolating the compound in the form of a crystalline salt.

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