Novel process for the synthesis of substituted morpholines and thiomorpholines

Abstract

The present invention relates to a process for the preparation heterocyclyl compounds, wherein such heterocyclyl compounds have 2 heteroatoms.

Description

[0001] Docket No. P39344 NOVEL PROCESS FOR THE SYNTHESIS OF SUBSTITUTED MORPHOLINES AND THIOMORPHOLINES BACKGROUNDThe present invention relates to a process for the synthesis of morpholines and thiomorpholines. Morpholines and thiomorpholines are versatile moieties with wide ranges of pharmacological and agrochemical activities (Kumari et al.2020, Asirvatham et al.2021, Chen et al.2023, Wu et al.2023) and are also widely used as starting materials or intermediates in the production of new active pharmaceutical ingredients. The synthesis of morpholines via a three step sequence (N-acylation, cyclisation, reduction) is for example described in Sundeep Dugar et al., Synthesis, 2015, 47, 712-720. The disadvantage of this sequence is the need for a reduction reaction, including the utilization of a reducing agent, contributing to safety risks and environmental impact. Alternatively, a two step sequence (N-alkylation with epoxide, cyclisation) is described in US20005038032. The disadvantages of the N-alkylation reaction are; challenges with controlling regioselectivity which often leads to mixtures of products; difficulty in achieving high chemoselectivity due to competing side reactions; low yields due to side reactions and formation of by-products; utilization of hazardous reagents such as ethylene oxide, contributing to safety risks and environmental impact. Therefore, the objective of this invention is to overcome the advantages described above. Within this application we report an expedient two steps sequence from readily available building blocks for the synthesis of morpholines and thiomorpholines. The process of the present invention has the following advantages: Docket No. P39344 High efficiency: The process of the present invention proceeds in two chemical steps, telescoped in a single process, making the process more efficient and less energy- intensive compared to other methods; Higher yield: The process of the present invention results in high yields of morpholine or thiomorpholines, which enhances its cost-effectiveness and practicality for large-scale production; High selectivity: The process of the present invention results in high selectivity, minimizing the formation of undesired by-products and simplifying product purification; Simplicity: The process of the present invention reduces the number of process steps (e.g. avoiding a reduction step and the use of protection groups) and reduces the need for extensive purification processes; Robustness: The process of the present invention is very robust and suitable for large scale production; Environment impact: The process of the present invention leads to the reduction of hazardous substances, produces no aqueous waste and can be considered as a green chemistry process. References • KUMARI ETAL. = MORPHOLINE AS UBIQUITOUS PHARMACOPHORE IN MEDICINALCHEMISTRY, BIOORGANICCHEMISTRY96 (2020) 103. HTTPS: / / WWW.SCIENCEDIRECT.COM / SCIENCE / ARTICLE / PII / S0045206819318395 • CHEN ET AL. = RESEARCH PROGRESS OF PIPERAZINE AND MORPHOLINE DERIVATIVES IN THE DISCOVERY OF AGRICULTURAL CHEMICALS, J HETEROCYCLIC CHEM.2023;60:1826– 1837HTTPS: / / ONLINELIBRARY.WILEY.COM / DOI / EPDF / 10.1002 / JHET.4689 • WU ETAL= MORPHOLINEDERIVATIVES INAGROCHEMICALDISCOVERY ANDDEVELOPMENT, J. AGRIC. FOOD CHEM.2023, 71, 36, 13197– Docket No. P39344 BRIEF SUMMARY In a first aspect, the invention provides a process for the preparation of compound of formula (I), wherein: R1is hydrogen, aryl, or, R1and R2taken together, form a C4-10cycloalkyl; R2is hydrogen, aryl, C1-6alkyl, or, R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl; R3is hydrogen, C1-6alkyl, or, R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl; R4is hydrogen, C1-6alkyl, wherein C1-6alkyl is optionally substituted with aryl, or, R2and R4taken together, form a C4-10cycloalkyl; R5is hydrogen, or methyl; X is O or S; which comprises reacting compound of formula (II), Docket No. P39344 wherein R1, R2, R3, R4, are as defined above, and X' is -OH or -SH, with compound of formula (III) wherein R5is as described above. In another first aspect, the invention provides a process for the preparation of compound of formula (I), Docket No. P39344 wherein: R1is hydrogen, or aryl; R2is hydrogen, aryl, or C1-6alkyl, R3is hydrogen, or C1-6alkyl; R4is hydrogen, C1-6alkyl, wherein C1-6alkyl is optionally substituted with aryl; R5is hydrogen, or C1-6alkyl; or R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl; X is O or S; which comprises reacting compound of formula (II), wherein R1, R2, R3, R4, are as defined above, and X' is -OH or -SH, with compound of formula (III) Docket No. P39344 wherein R5is as described above. Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: “Amino”, alone or in combination with other groups, refers to NH2. "Aryl" refers to a cyclic aromatic hydrocarbon moiety having a mono-, bi- or tricyclic aromatic ring of 5 to 14 carbon ring atoms (“C5-14-aryl”). Bicyclic aryl ring systems include fused bicyclics having two fused five-membered aryl rings (denoted as 5-5), having a five- membered aryl ring and a fused six-membered aryl ring (denoted as 5-6 and as 6-5), and having two fused six-membered aryl rings (denoted as 6-6). The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. In particular aryl means phenyl. "C1-6alkyl" refers to a saturated linear (i.e. unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-6means one to ten carbon atoms). Particular C1-6alkyl groups are those having 1 to 6 carbon atoms, having 2 to 6 carbon atoms (a “C2-6alkyl”), or having 1 to 4 carbon atoms (a “C1-4alkyl”). Examples of C1-6alkyl group include, but are not limited to, groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n- pentyl, n-hexyl, and the like. "Carbonyl compound" refers to a chemical compound that contains the C=O moiety. Examples of carbonyl compounds are aldehydes and ketones. In particular carbonyl compounds refers to benzaldehyde, phenylacetone acetaldehyde, acetone, MEK, MIBK, cyclohexananone, acetophenone, benzophenone. Docket No. P39344 "Cycloalkyl" refers to a saturated or partially unsaturated carbocyclic moiety having mono-, bi- (including bridged bicyclic and cycloalkyl spiro moieties) or tricyclic rings and 3 to 10 carbon atoms i.e., (C3-C10)cycloalkyl) in the ring. The cycloalkyl moiety can optionally be substituted with one or more substituents. In particular aspects cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular aspects cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl, and bicyclo[1.1.1]pentane. The cycloalkyl moiety can be attached in a “spiro-cycloalkyl” or “cycloalkyl spiro” fashion such as “spirocyclopropyl”. Bicyclic cycloalkyl is in particular indanyl. "Grignard reagent" refers to any compound of formula RMgX, wherein R is an organic radical, and X is a halogen. Examples of Grignard reagents are methylmagnesium chloride, isopropylmagnesiumchloride, or butylmagnesiumchloride. "Halo" or “Halogen” means fluoro, chloro, bromo or iodo, particularly chloro or fluoro. "Haloalkoxy" refers to an alkoxy group in which at least one Halogen takes the place of each H in the hydrocarbon making up the C1-6alkyl moiety of the alkoxy group. An example of a haloalkoxy group is difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3). "Heteroaryl" refers to an aromatic heterocyclic mono-, bi- or tricyclic ring system of 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, more preferably from 5 to 6 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In some aspects, monocyclic heteroaryl rings may be 5-6 membered. Bicyclic heteroaryl ring systems include fused bicyclics having two fused five-membered heteroaryl rings (denoted as 5-5), having a five-membered heteroaryl ring and a fused six-membered heteroaryl ring (denoted as 5-6 and 6-5), and having two fused six-membered heteroaryl rings (denoted as 6-6). The heteroaryl group can be optionally substituted as defined herein. Examples of heteroaryl moieties include indazolyl, indolyl, isoindolinyl, triazolopyridinyl, imidazopyridinyl, imidazopyrazinyl, indolinyl, pyridyl, triazolopyridazinyl, isoquinolinyl, pyridazinyl, triazolopyrazinyl, pyrrolotriazinyl, spirocyclopropaneindolinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, Docket No. P39344 pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, benzothiophenyl, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, and furopyrazinyl. More particularly heteroaryl are pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl. "Heterocycle" or "heterocyclyl" refer to a 3, 4, 5, 6, 7, 8, 9, 10-membered monocyclic, 7, 8, 9 and 10-membered bicyclic (including bridged bicyclic and cycloalkyl spiro moieties) or 10, 11, 12, 13, 14 and 15-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated, and has one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon. In some aspects, the heterocycle is a heterocycloalkyl. In particular aspects heterocycle or heterocyclyl refers to a 4, 5, 6 or 7-membered heterocycle. When used in reference to a ring atom of a heterocycle, a nitrogen or sulfur may also be in an oxidized form, and a nitrogen may be substituted with one or more (C1-C6)C1-6alkyl or groups. The heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any of the heterocycle ring atoms can be optionally substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, without limitation, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, pyrrolidine 1-oxide, N- hydroxypiperidine, 1-methylpyrrolidine N-oxide, diazirinyl and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl. “Hydroxy”, alone or in combination with other groups, refers to -OH. "Hydroxyalkyl" refers to a C1-6alkyl group wherein one or more of the hydrogen atoms of the C1-6alkyl group have been replaced by a hydroxy moiety. Examples include alcohols and diols. Docket No. P39344 "Moiety" and “Substituent” refer to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule. When indicating the number of substituents, the term “one or more” refers to the range from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents, in particular wherein “one or more” refers to one, two or three, most particularly “one or more” refers to one or two. "Optional" or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "aryl group optionally substituted with a C1-6alkyl group" means that the C1-6alkyl may but need not be present, and the description includes situations where the aryl group is substituted with a C1-6alkyl group and situations where the aryl group is not substituted with the C1-6alkyl group. "Optionally substituted" means unsubstituted or substituted. Generally these substituents can be the same or different. “Oxo”, alone or in combination with other groups, refers to =O. "Proton sponge" refers to 1,8-Bis(dimethylamino)naphthalene. "Strong base" refers to a chemical compound that can remove a proton from weak acids, such as water, in an acid base reaction. Examples of strong bases are LiOH, NaOH, KOH, RbOH, CsOH. "Substituted" refers to the replacement of at least one of hydrogen atoms of a compound or moiety with another substituent or moiety. Examples of such substituents include, without limitation, Halogen, -OH, -CN, oxo, alkoxy, C1-6alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl and heterocycle. For example, the term “haloalkyl” refers to the fact that one or more hydrogen atoms of a C1-6alkyl (as defined below) is replaced by one or more Halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, substituted as used herein can refer to replacement of at least one hydrogen atom of a compound or moiety described herein with Halogen or C1-6alkyl. Docket No. P39344 “Superbase” refers to a compound with a particularly high affinity to protons. In particular it refers to species that present a absolute proton affinity (APA = 245.3 kcal / mol) and intrinsic gas phase basicity (GB = 239 kcal / mol) greater than Proton sponge. Examples of superbases are: sodium hydride, potassium hydride, sodium amide, potassium amide, lithium diisopropylamide, lithium diethylamide, lithium bis(trimethylsilyl)amide, or alkyl lithium compounds. BRIEF DESCRIPTION OF THE FIGURES Figures 1 and 2 describe the reaction: DETAILED DESCRIPTION In a another first aspect, the invention provides a process for the preparation of compound of formula (I), wherein: R1is hydrogen, or aryl; R2is hydrogen, aryl, or C1-6alkyl, R3is hydrogen, or C1-6alkyl; R4is hydrogen, C1-6alkyl, wherein C1-6alkyl is optionally substituted with aryl; Docket No. P39344 R5is hydrogen, or C1-6alkyl; or R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl; X is O or S; which comprises reacting compound of formula (II), wherein R1, R2, R3, R4, are as defined above, and X' is -OH or -SH, with compound of formula (III) wherein R5is as described above. In a more particular embodiment, the invention provides a process as hereinabove described, comprising a step of O- or S-alkylation of the compound of formula (II) Docket No. P39344 using a compound of formula (III) to produce a compound of formula (IV): (IV), wherein R1is hydrogen, or aryl; R2is hydrogen, aryl, or C1-6alkyl, R3is hydrogen, or C1-6alkyl; R4is hydrogen, C1-6alkyl, wherein C1-6alkyl is optionally substituted with aryl; Docket No. P39344 R5is hydrogen, or C1-6alkyl; or R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl; X' is -OH or -SH; X is O or S. In a more particular embodiment, the invention provides a process as hereinabove described, comprising a step of cyclization of a compound of formula (IV) to produce a compound of formula (I): . wherein R1is hydrogen, or aryl; R2is hydrogen, aryl, or C1-6alkyl, R3is hydrogen, or C1-6alkyl; Docket No. P39344 R4is hydrogen, C1-6alkyl, wherein C1-6alkyl is optionally substituted with aryl, or, R2and R4taken together, form a C4-10cycloalkyl; R5is hydrogen, or C1-6alkyl; or R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl; X is O or S. In a more particular embodiment, the invention provides a process as hereinabove described, wherein X`=OH and X=O. In a more particular embodiment, the invention provides a process as hereinabove described, comprising a step of O- or S-alkylation of a compound of formula (II) using a compound of formula (II) to produce a compound of formula (IV), which is followed by a step of cyclization of the compound of formula (IV) to produce a compound of formula (I) wherein R1is hydrogen, or aryl; R2is hydrogen, aryl, or C1-6alkyl, R3is hydrogen, or C1-6alkyl; R4is hydrogen, C1-6alkyl, wherein C1-6alkyl is optionally substituted with aryl, or, R2and R4taken together, form a C4-10cycloalkyl; Docket No. P39344 R5is hydrogen, or C1-6alkyl; or R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl; X' is -OH or -SH; X is O or S. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein X`=OH and X=O. The present invention provides the process as described hereinabove, wherein R1is hydrogen, aryl, or, R1and R2taken together, form a C4-10cycloalkyl. In one embodiment, the present invention provides the process as described hereinabove, wherein R1is aryl selected from the group consisting of phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, and azulenyl. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein R1is hydrogen, phenyl, or, R1and R2taken together, form a C4- 10cycloalkyl. In a particular embodiment, the present invention provides the process as described hereinabove, wherein R1is hydrogen or phenyl. In a particular embodiment, the present invention provides the process as described hereinabove, wherein R1and R2taken together, form a C4-10cycloalkyl, wherein the C4-10cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, partially unsaturated (cycloalkenyl) derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl and bicyclo[1.1.1]pentane and cycloalkyl moiety attached in a “spiro-cycloalkyl” or “cycloalkyl spiro” fashion. Docket No. P39344 In a particular embodiment, the present invention provides the process as described hereinabove, wherein R1and R2taken together, form a C4-10cycloalkyl selected from is cyclopentenyl and cyclohexenyl. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein R2is hydrogen, aryl, C1-6alkyl, or, R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl, or ¨ R2and R4taken together, form a C4-10cycloalkyl. In one embodiment, the C4-10cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, partially unsaturated (cycloalkenyl) derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl and bicyclo[1.1.1]pentane and cycloalkyl moiety attached in a “spiro-cycloalkyl” or “cycloalkyl spiro” fashion. In a particular embodiment, R2and R3taken together, form a C4-10cycloalkyl, wherein the cycloalkyl is indanyl. In a particular embodiment, the present invention provides the process as described hereinabove, wherein R1and R2taken together, form a C4-10cycloalkyl selected from, is cyclopentenyl, and cyclohexenyl. In one embodiment, the C4-10heterocycloalkyl is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, pyrrolidine 1-oxide, N-hydroxypiperidine, 1-methylpyrrolidine N-oxide, diazirinyl and quinuclidiny, indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, and tetrahydroquinolinyl. In particular, the C4-10heterocycloalkyl is tetrahydropyranyl. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein R2is hydrogen, phenyl, C1-6alkyl, or, R1and R2taken together, form a C4-10cycloalkyl, or Docket No. P39344 R2and R3taken together, form a C4-10cycloalkyl, a C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein R2is hydrogen, phenyl, C1-3alkyl, or, R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, a C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein R2is hydrogen, phenyl, methyl, or, R1and R2taken together, form a C5-9cycloalkyl, or R2and R3taken together, form a C5-9cycloalkyl, C6heterocycloalkyl, or R2and R4taken together, form a C5cycloalkyl. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein R3is hydrogen, methyl, or R2and R3taken together, form a C5-9cycloalkyl, or a C6heterocycloalkyl. In particular, the C6heterocycloalkyl is indanyl, In a more particular embodiment, the present invention provides the process as described hereinabove, wherein R4is hydrogen, methyl, wherein methyl is optionally substituted with phenyl, or, R2and R4taken together, form a C5cycloalkyl. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein X is O. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein X is S. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein X' is -OH. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein X' is -SH. In one particular embodiment R5is H or C1-6alkyl. Docket No. P39344 In one more particular embodiment R5is H or methyl. In one more particular embodiment, the compound of formula (III) is . In one more particular embodiment X`is O; R1is H or phenyl, R2is H or methyl, R3is H or methyl, R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl. In a more particular embodiment, the present invention provides the process as described hereinabove, in the presence of a superbase. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the superbase is selected from sodium hydride, potassium hydride, sodium amide, potassium amide, lithium diisopropylamide, lithium diethylamide, n-HexLi, t-BuLi, s- BuLi, lithium bis(trimethylsilyl)amide or Grignard reagents, such as MeMgBr, tBuMgBr, iPrMgCl∗LiCl. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the superbase is sodium hydride. In a more particular embodiment, the present invention provides the process as described hereinabove, in presence of a strong base. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the strong base is NaOH, LiOH, KOH, MeONa, EtONa, iPrONa, tBuONa. Docket No. P39344 In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the strong base is NaOH, KOH. In a more particular embodiment, the present invention provides the process as described hereinabove, in presence of a solvent. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the solvent is THF, sulfolane, DMSO, DMF, DMAC, NMP, dimethylsulfone, MeCN, or a combination thereof. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the solvent is THF, or a combination of THF and sulfolane. In one embodiment the present invention provides a process as shown in Scheme 1. Scheme 1 wherein R1, R2, R3, R4, R5, X`and X are as defined herein above. In one particular embodiment the compound of formula (II) is selected from In one particular embodiment, the compound of formula (IV) is selected from Docket No. P39344 The starting materials, reagents and catalysts, which do not have their synthetic route explicitly disclosed herein, are generally available from commercial sources or are readily prepared using methods known to the person skilled in the art. In general, the nomenclature used in this Application is based on AUTONOMTM 2000, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using MDL ISIS™ version 2.5 SP2. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. The following examples are provided for the purpose of further illustration and are not intended to limit the scope of the claimed invention. Docket No. P39344 General process of synthesis All compounds of the present invention were produced following the general procedure herein described (Scheme 2). Scheme 2* Scheme 2 Abbreviations NaH is sodium hydride Eq is equivalent THF is tetrahydrofuran °C is degree Celsius LCMS is liquid chromatography-mass spectrometry Docket No. P39344 DIPEA is N,N-diisopropylethylamine V means volume (unit: mL / g) Tj means jacket temperature BHT is butylated hydroxytoluene (CAS 128-37-0) PTSA.H2O is p-toluenesulfonic acid monohydrate (CAS 6192-52-5) pTSA is p-toluenesulfonic acid (CAS 104-15-4) Ethylene sulfate is KOH is potassium hydroxide General procedure: To a suspension of NaH (1.5eq) in THF (4.5V) were added a solution of Compound (II) (1.0eq) in sulfolane (3.0V) and THF (3.0V) and a THF rinse (0.25V). The mixture was stirred for 1 hour at 70°C and then cooled down to 0°C. Sulfolane (1.0V) was added and a solution of Compound (III) (1.1eq) in THF (7V) was dosed to the mixture over 4 hours. A THF rinse (0.25V) was added and the reaction mixture was stirred at 20°C overnight. Conversion was controlled by LCMS (analytical method described thereafter; with or without derivatization of Intermediate (IV), see derivatization procedure thereafter). KOH flakes (1.5eq) were charged to the reaction mixture and the reaction mixture was stirred at 75°C overnight. The reaction mixture was cooled down and the formation of the Product (I) was confirmed by LCMS (analytical method described thereafter; with or without derivatization, see derivatization procedure thereafter).

[0002] Docket No. P39344 Derivatization procedure: Transfer 60 µL of reaction mixture into a 10 mL volumetric flask containing 5 mL of THF, 40 µL of DIPEA and 20 µL of 3-t oluoyl chloride (CAS 1711-06-4) and mix. Dilute to volume with water and mix. Analytical method: System: Acquity UPLC equipped with QDA Detector Stationary phase: Acquity BEH C18 Column: 50 x 2.1 mm - 1.7 µm Column temperature: 50 °C Mobile phase A: Ammonium Formate 5 mM pH 9 Mobile phase B: Acetonitrile Gradient: Time (min) A% B% Initial 97.5 2.5 5.5 0.1 99.9 6.5 0.1 99.9 7 97.5 2.5 Flow rate: 0.75 ml / min Injection volume: 1.0 µL Inlet temperature: 20°C Run time: 7 min PDA detector range: 190-500 nm QDA detector: ES+ / ES- range 50-1250 Da Cone: 20 V Example 2: (-)-1-Amino-2-indanol and ethylene sulfate To a suspension of NaH (1.5eq; 0.40g; 60%w / w mineral oil dispersion) in THF (4.5mL), magnetically stirred in a 40 mL vial, were added a solution of (-)-1-amino-2-indanol (1.0eq; 1.00g) in sulfolane (3.0mL) and THF (3.0mL) and a THF rinse (0.25mL). The mixture was stirred for 1 hour at 70°C and then cooled down to 0°C. Sulfolane (1.0mL) was added and a solution of ethylene sulfate (1.1eq; 0.92g) in THF (7mL) was dosed to the mixture over 4 hours. Docket No. P39344 A THF rinse (0.25mL) was added and the reaction mixture was stirred at 20°C overnight. Conversion was controlled by LCMS: derivatization with 3-toluoyl chloride showed a peak with m / z (M-H) 390. KOH flakes (1.5eq; 0.56g) were charged to the reaction mixture and the reaction mixture was stirred at 75°C overnight. The reaction mixture was cooled down and the formation of product was confirmed by LCMS: derivatization with 3-toluoyl chloride showed a peak with m / z (M+H) 294. Example 9: D-Alaninol and ethylene sulfate To a suspension of NaH (1.5eq; 56.0g; 60%w / w mineral oil dispersion) in THF (315mL), mechanically stirred in a 2L jacketed reactor, were added a solution of D-alaninol (1.0eq; 1.00g) in sulfolane (210mL) and THF (210mL) and a THF rinse (17.5mL). The mixture was stirred for 1 hour at 60°C and then cooled down to 0°C. Sulfolane (70mL) was added and a solution of ethylene sulfate (1.1eq; 127.4g) in THF (350mL) was dosed to the mixture over 4 hours. A THF rinse (17.5mL) was added and the reaction mixture was stirred at 0°C for 14 hours. Conversion was controlled by LCMS: derivatization with 3-toluoyl chloride showed a peak with m / z (M-H) 316. The reaction mixture warmed to 20°C. KOH flakes (1.5eq; 78.4g) were charged to the reaction mixture in six equal portions (one each hour) and the reaction mixture was stirred at 75°C for 10 hours and 20°C for 7 hours. The formation of product was confirmed by LCMS: derivatization with 3-toluoyl chloride showed a peak with m / z (M+H) 220. The reaction suspension was distilled at Tj=50-135°C / 70 mbar. THF was added (3 x 210mL) and distillation continued until the product (R)-3-methylmorpholine was not detected in the residue anymore. The distilled fractions were combined and BHT (0.525g) was added. A solution of PTSA.H2O (1.1eq; 195.3g) in THF (280mL) was added over 30 minutes to the distillate at 20°C. A THF rinse (17.5mL) was added and the suspension was stirred for 30 minutes. The mixture was concentrated to 7.5V at Tj=20-50°C / 60 mbar. The suspension was stirred for 30 minutes, cooled to 0°C and stirred for 18 hours. The solids were filtered and washed with THF (210mL). The wet cake was dried at 40°C under vacuum and 177.6g (R)-3-methylmorpholine pTSA salt was isolated as a white solid (70% yield). The other Examples were produced by analogous procedures. Docket No. P39344 )I(tcud orP ) Hel+ufcolMel( oortz / mn meohct eer28 4 4 dnfhu2 92 32 ao tserSni oln) ) )H H H utMdco cCetgi+ + + nsireM(M M uL cervn( (rttez / z / z / Sy bedhtocm m m ) VI(etaidemretnI)el fH-ucolMelo ( ortz / mn meocdht eno 8 0 0 nfhttia7 9 3 l 3 3 3 aonyn) ) )erSiutMdkcCeloH H Hta-isr- - -eM M M urtL ceO yteevn(o z / (z / (z / S b dht cm m m )IfIeIt(a etetfl afafodues ] lrn3 us ] l3us ]3 ue -n 3e -n 3e -n 3 utopel5-2el5-2el5-. c1uretm y olS Cht70 y E1[ht70 y 2 E1[ht70 E1[baTnilnlo -1 ona-lw n d yo)IhIicn h ]i- ]tes f( ylsodngl0y -2- 0 o7- ni er i3m- 4-2- ]ol5- uuone8- m6nio 8ntocp h 3iup- 1a- 54 mna6-tartmo)66 1- S C -( 5[ )6 - 2 (1[A- p 2or42 p1[mrofeln pri 1embearelxm Eu obn 1 2 3 MaT Docket No. P39344 06 6 2 4 67 80 ) 2)2)3)H+ H+ H+ H+ M(M(M(M z / z / z / (z / m m m m 65 2 2 4 3 43 7 0 ))3)4)H-H-H-H- M(M M M z / (z / (z / (z / m m m meta elta etfl a etf fl afus ]e3] ] l ]-us3 us3 us3n 3el5e --n 3 5e --n 3 5e --n 3 5-y 2ht7el2el2el2 0 y 70 y 70 y 70 E1[htE1[htE1[htE1[l- H l o o n2n a-tol eronaanxednadn e p y h ol]hahtr]il ]t e7yh0- olcc ]yc5-etm)l -0 - 2-te -52-)yc8- o 3 1- oy-2-6 omy8-4R,2o 6nn 1- i1ni8 m4-n 07nix o 38Ri1(m1 m 3 A9[A- 39A-ar0 m 2 28[4(y p7[Ar-d 63 2y h1[5 6 7 Docket No. P39344 60 02 02 28 2 2)2)2)2 2 ) 2)H+ H+ H+ H+ H+ M(M M M z / (z / (z / (M z / (z / m m m m m 20 6 6 8 3 1 1 7 81 ) 3)3)3)3)H-H-H-H-H- M(M M M M z / (z / (z / (z / (z / m m m m meta etetetetfl afl afl afafus ]e3-us ]3-us ] l3-us ] l3us ]3n 3el5e-n 3 el5e-n 3 el5e --n 3 el5e --n 3 el5-y 27 y 27 y 2 y 2 y 2ht0 E1[ht0 E1[ht70 E1[ht70 7 E1[ht0 E1[)lyhlteoihemni ]oltenm] l1- ]nal5- o 3l3- ioh o] ac6- hteo 3ni2- o ni1 m Ana4- na(la3 o]1-l02 n1a- lhl9 -a9y-8ni3t14A- 35A47 hzpne6 m 52A--0 E1[D3[ -L2[lab7[26[9 01 11 21 Docket No. P39344 20)87)82)6)1)deHsi1de1de11de+t)aHsi+t)aHsi )si+taHtaMvi(reMvir vi+ rvird(eM d(eM(ez / nz / nz / dnz / dn mu(mu(mu(mu(61 29 24 0 3 3 3 ))3)3)H-H-H-H- M(M M / (M zz / (z / (z / m m m m -eta ete-,22fl atfl afl ,2,eus ]us ]u]31 na]e3- e3- s3- -l l8-n 3l5n 3en 3 yoi e3e-y 2el5-2el5-2 htehtadi8-9ht70 y E1[ht70 y 70 xx 86 E1[htE1[M- 4oidoid5[lolneo anhatnie)m) htoal ly nio hen t)eo nimaal ]htmy m 1el ]2 xe ]al ]yht-e3y8z -3orni5- y1- ddil3 ht3 M - (- 9ne6- yo6- e8- 0B40 Hrr89 M 90 21[ -N1[(- 2y p4[(- 21[41 51 61 Docket No. P39344 W -lM69 6 6 4 6 yd 8 69 16 4 8 oe4 5 0 34 6 ul zi 3 3 3 31 ott . . . .3.-a 18 3 3 9 5 3vi2 9 3 5 4 re2 2 2 2 D lo nat l lhtcelo - o yna1-l ln y oatundn hnanedei-texp orh2- eh olPp- 2- om- oni2- - olccycnim o a-nl2 i o -n)yco a Ronim 1 mp2,nim A- - 2)-(A- 2orR p1(m AA- 2 - 2,- 2,- 2,- 2 - 2)I2 2 2,2,2 II ene e e e(edanan n n vl lalalalnitaoihoihoioioiut ththth ovpira a a atamex o doix oix oix oix oD- e,D- eD- eDe iDeC2 di3,x2 di2 di -2di -di1oi ,x d3,1oi ,d3,x 1oi ,d3,x 1oi2,d3,x 1oid el lo o vitn naal avio pxrenea lorh p- ollco d)hto n 1- yn IIelya(ndlycath oneden n hi-t nip up-2e-mm olop2--o oni2-A- cycmonim o 2 ni-)o niC ma- R - 1 m2,m A-2)-(A- R 21(A- 2 elpremb am 1 2 3 4 5 xu E n2elbaT Docket No. P39344 42 3 85 8 6 5 5 8 97 9 3.2.7 5 0 02.7 92.9 3 2 12 12 -l lH2-o-o-ol erondna1-1-adnanayhah nip p ottre lyor rehep ptm o)l-tenio o niniy-2- 4- om mniniyalm mm x oA-A-An -a4rmorna2- 2-)(y pA- d 2y hht )ES(R(-2,-22,- 22,- 2,- 2,e e2 e 2 e 2nlneaoialnalnanahoihoi lhoi loitat ththtxaxa a aoi eoix oix oix oiD-,D- eD- eD- eD- e2 di3,x2 di2 di2 di2 di1oi ,d3,x 1oi ,d3,x 1oi ,d3,x 1oi ,d3,x 1oid-naryp- l lH o-no2e anorndapap doroy nrha lilp-py1- -rtoetn- htenio1-ooah2- enm minminiteo mmniyxalm oAA-)lmorna -2A-24(y- 4A- d 2y hht-)-)ER(S(7 8 9 01 Docket No. P39344 ) 6d)ed)d 8z1i ezez3.2t1 0a i8tit1vir7a8a1vir21vi22edern de(n d uu(n u(elnid l oloily o z nlnaneoiht are))hrty lep b hto))ly yenhnta io nihteehtm mealmam olo ylhyzyx-aoniteorhnih plmoaA( cmnMeb d l y aA- 2(- 2(- 2 - 2H(- 2,- 22,- 22,- 2,- 2,ene2 e 2 e 2 e aln oialnalnalnalhoitahoitahoit hoit htx oixaxaxax D- eoi2,diD- eoidD- eoidD- eoidD- ed ,2, i2, i2, i2, i3x 1oid3,x 1oid3,x 1oid3,x 1oid3,x 1oid leynizd ne lilb olo or)lnanry ylhtt ah p h eoihe) te))ly mtoeo h n otenina inih m t mam y me l(yalx A-lo hyzoraonitend hh mey poaclaAM B H l - 2(- 2(- 2(- 2 21 31 41 51 Docket No. P39344)dezitavirednu(lo nahte)o nimalyhteM(- 2 - -22,,2 3, e1n -lalyhoitehta ediM- x 4oix doid lo nahte)o nimalyhteM(- 2 Docket No. P39344 Clauses Clause 1. A process for the preparation of compound of formula (I), wherein: R1is hydrogen, aryl, or, R1and R2taken together, from a C4-10cycloalkyl; R2is hydrogen, aryl, C1-6alkyl, or, R1and R2taken together, from a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl; R3is hydrogen, C1-6alkyl, or, R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl; R4is hydrogen, C1-6alkyl, wherein C1-6alkyl is optionally substituted with aryl, or, R2and R4taken together, form a C4-10cycloalkyl; R5is hydrogen, or methyl; X is O or S; which comprises reacting compound of formula (II), Docket No. P39344 (II) wherein R1, R2, R3, R4, are as defined above, and X' is -OH or -SH, with compound of formula (III) c(III) wherein R5is as described above. Clause 2. The process for the preparation of clause 1 wherein R1is hydrogen, phenyl, or, R1and R2taken together, from a C4-10cycloalkyl. Clause 3. The process for the preparation of clause 1 or 2 wherein R2is R2is hydrogen, phenyl, C1-3alkyl, or, R1and R2taken together, from a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl. Clause 4. The process for the preparation of any one of clauses 1 to 3 wherein R2is R2is R2is hydrogen, phenyl, methyl, or, R1and R2taken together, from a C5-9cycloalkyl, or R2and R3taken together, form a C5-9cycloalkyl, C6heterocycloalkyl, or R2and R4taken together, form a C5cycloalkyl. Claims 5. The process for the preparation of any one of clauses 1 to 4 wherein R3is hydrogen, methyl, or R2and R3taken together, form a C5-9cycloalkyl, or a C6heterocycloalkyl. Claim 6. The process for the preparation of any one of clauses 1 to 5 wherein R4is hydrogen, methyl, wherein methyl is optionally substituted with phenyl, or, R2and R4taken together, form a C5cycloalkyl. Clause 7. The process for the preparation of any one of clauses 1 to 6 wherein X is O. Docket No. P39344 Clause 8. The process for the preparation of any one of clauses 1 to 6 wherein X is S. Clause 9. The process for the preparation of any one of clauses 1 to 7 wherein X' is -OH. Clause 10. The process for the preparation of any one of clauses 1-6 or 8 wherein X' is -SH. Clause 11. The process for the preparation of any one of clauses 1 to 10 in the presence of a superbase. Clause 12. The process for the preparation of any one of clauses 1 to 11 wherein the superbase is selected from sodium hydride, potassium hydride, sodium amide, potassium amide, lithium diisopropylamide, lithium diethylamide, n-HexLi, t-BuLi, s-BuLi, lithium bis(trimethylsilyl)amide or Grignard reagents, such as MeMgBr, tBuMgBr, iPrMgCl∗LiCl. Clause 13. The process for the preparation of any one of clauses 1 to 12 wherein the superbase is sodium hydride. Clause 14. The process for the preparation of any one of clauses 1 to 13 in presence of a strong base. Clause 15. The process for the preparation of any one of clauses 1 to 14 wherein the strong base is NaOH, LiOH, KOH, MeONa, EtONa, iPrONa, tBuONa. Clause 16. The process for the preparation of any one of clauses 1 to 15 wherein the strong base is NaOH, KOH. Clause 17. The process for the preparation of any one of clauses 1 to 16 in presence of a solvent. Clause 18. The process for the preparation of any one of clauses 1 to 17 wherein the solvent is THF, sulfolane, DMSO, DMF, DMAC, NMP, dimethylsulfone, MeCN, or a combination thereof. Clause 19. The process for the preparation of any one of clauses 1 to 18 wherein the solvent is THF, or a combination of THF and sulfolane.

Claims

Docket No. P39344 CLAIMS 1. A process for the preparation of compound of formula (I),wherein: R1is hydrogen, or aryl; R2is hydrogen, aryl, or C1-6alkyl, R3is hydrogen, or C1-6alkyl; R4is hydrogen, C1-6alkyl, wherein C1-6alkyl is optionally substituted with aryl; R5is hydrogen, or C1-6alkyl; or R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, or a C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl; X is O or S; which comprises reacting compound of formula (II),Docket No. P39344wherein R1, R2, R3, R4, are as defined above, and X' is -OH or -SH, with compound of formula (III)wherein R5is as described above.

2. The process for the preparation of claim 1 wherein R1is hydrogen, phenyl, or, R1and R2taken together, form a C4-10cycloalkyl.

3. The process for the preparation of claim 1 or 2 wherein R2is R2is hydrogen, phenyl, C1-3alkyl, or, R1and R2taken together, form a C4-10cycloalkyl, or R2and R3taken together, form a C4-10cycloalkyl, C4-10heterocycloalkyl, or R2and R4taken together, form a C4-10cycloalkyl.

4. The process for the preparation of any one of claims 1 to 3 wherein R2is R2is R2is hydrogen, phenyl, methyl, or, R1and R2taken together, form a C5-9cycloalkyl, orDocket No. P39344 R2and R3taken together, form a C5-9cycloalkyl, C6heterocycloalkyl, or R2and R4taken together, form a C5cycloalkyl.

5. The process for the preparation of any one of claims 1 to 4 wherein R3is hydrogen, methyl, or R2and R3taken together, form a C5-9cycloalkyl, or a C6heterocycloalkyl.

6. The process for the preparation of any one of claims 1 to 5 wherein R4is hydrogen, methyl, wherein methyl is optionally substituted with phenyl, or, R2and R4taken together, form a C5cycloalkyl.

7. The process for the preparation of any one of claims 1 to 6 wherein X is O.

8. The process for the preparation of any one of claims 1 to 6 wherein X is S.

9. The process for the preparation of any one of claims 1 to 7 wherein X' is -OH.

10. The process for the preparation of any one of claims 1-6 or 8 wherein X' is -SH.

11. The process for the preparation of any one of claims 1-10, wherein R5is H or methyl.

11. The process for the preparation of any one of claims 1 to 10 in the presence of a superbase.

13. The process for the preparation of any one of claims 1 to 12 wherein the superbase is selected from sodium hydride, potassium hydride, sodium amide, potassium amide, lithium diisopropylamide, lithium diethylamide, n-HexLi, t-BuLi, s-BuLi, lithium bis(trimethylsilyl)amide or Grignard reagents, such as MeMgBr, tBuMgBr, iPrMgCl∗LiCl.

14. The process for the preparation of any one of claims 1 to 13 wherein the superbase is sodium hydride.

15. The process for the preparation of any one of claims 1 to 14 in presence of a strong base.

16. The process for the preparation of any one of claims 1 to 15 wherein the strong base is NaOH, LiOH, KOH, MeONa, EtONa, iPrONa, tBuONa.

17. The process for the preparation of any one of claims 1 to 16 wherein the strong base is NaOH, KOH.

18. The process for the preparation of any one of claims 1 to 17 in presence of a solvent.Docket No. P39344 19. The process for the preparation of any one of claims 1 to 18 wherein the solvent is THF, sulfolane, DMSO, DMF, DMAC, NMP, dimethylsulfone, MeCN, or a combination thereof.

20. The process for the preparation of any one of claims 1 to 19 wherein the solvent is THF, or a combination of THF and sulfolane.

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