CN113874341B

CN113874341B - Process for preparing derivatives of 1, 1-dialkylethane-1, 2-diols useful as intermediates

Info

Publication number: CN113874341B
Application number: CN202080027021.6A
Authority: CN
Inventors: S·沙玛; R·艾哈迈德; S·雷纳; R·A·维什瓦卡尔玛; P·P·辛格
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2019-04-01
Filing date: 2020-03-31
Publication date: 2024-05-31
Anticipated expiration: 2040-03-31
Also published as: WO2020202205A1; WO2020202205A4; CN113874341A

Abstract

The present invention provides a novel and useful route to the synthesis of a substituted diol intermediate 1, 1-dialkylethane-1, 2-diol useful in the preparation of various 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazoles containing drugs. In particular, the present invention provides a novel and useful route for the synthesis of intermediates for delamanib.

Description

Process for preparing derivatives of 1, 1-dialkylethane-1, 2-diols useful as intermediates

Technical Field

The present invention relates to the field of pharmaceutical industry of antibacterial agents. The present invention relates in particular to compounds useful as intermediates for the preparation of active pharmaceutical ingredients, such as: antibacterial agents, anticancer agents, anti-HIV agents, antiparasitic agents, antitubercular agents, antileishmaniasis agents, and the like, and imaging agents. More particularly, the present invention relates to 1, 1-dialkylethane-1, 2-diol and a process for the preparation thereof.

Background

Tuberculosis remains a major cause of infectious death worldwide. Existing therapies for tuberculosis require lengthy treatment and often require a combination of three or four different drugs (first-line drug regimens such as isoniazid, pyrazinamide and rifampin, as well as several second-line drug regimens including ethionamide, para-aminosalicylic acid, kanamycin, amikacin, calicheamicin, ciprofloxacin, streptomycin, etc.).

Medicaments based on nitroimidazoles [ j.med.chem.2017,60,7636-7657] have played a very important role in combating various types of infections during the last sixty to seventy years. One of the main outcomes of all these efforts was the discovery and development of delamanib, a nitro-dihydro-imidazo-oxazole derivative, for the treatment of multidrug-resistant tuberculosis (MDR-TB). PCT application WO2004033463A1 reports 2, 3-dihydro-6-nitroimidazo [2,1-b ] oxazoles, including delamanib (Compounds 1572, 1084, page 970) and methods of preparation thereof. In addition to delamanib, several other nitroimidazoles have been studied, such as:

Several methods have been reported for synthesizing the nitroimidazole molecules described above. The aim of all the processes of the prior art is to prepare nitroimidazole molecules by preparing and combining three fragments, namely a halonitroimidazole or dinitroimidazole fragment (a), a central chiral three-carbon fragment (B) as epoxide or as equivalent diol and a phenol fragment (C).

In a first method, a halonitroimidazole or dinitroimidazole is coupled with a three-carbon chiral epoxide to produce an intermediate (D) that is coupled with a phenol fragment (C) to form an intermediate (E) and ultimately converted to a target molecule as shown below:

In the second method, the phenol fragment is first coupled with a chiral three carbon fragment to produce a diol intermediate (F), which is then coupled with an imidazole derivative to form intermediate (E), which in turn is converted to the target molecule, as shown below.

Kuppuswamy Nagrarjan and colleagues (Eur. J. Med. Chem.24 (1989) 631-633) report the following procedure for scheme (I); among them, nitroimidazole derivatives have been reported to have antitubercular activity. The starting material 2, 4-dinitroimidazole (I-1) is treated with epoxide (1-2) in hot absolute ethanol in the presence of anhydrous sodium acetate to give a separable mixture of isomers (I-3), (I-4) and (1-5) of nitroimidazole derivatives. The 2-nitro group in these reactions acts as a leaving group.

WO 2004/033463 and J.Med. Chem.2006,49,7854 describe 2, 3-dihydro-6-nitroimidazo [2,1-b ] oxazole derivatives with emphasis on delamanib. Treating an epoxide compound of formula (II-1) wherein R ¹ is a hydrogen atom or lower alkyl, R ² is a substituted piperidinyl or substituted piperazinyl, and X ¹ is a halogen atom or nitro group with a phenol of formula (II-2) to produce a tertiary alcohol intermediate (II-3) which is converted to the final compound (II-4) as shown in scheme (II).

WO2011/151320, which relates to nitroimidazole derivatives having a radioactive or non-radioactive halogen atom, reports the treatment of epoxide (III-1) with 4-halophenol (III-2) to provide halogen-containing compounds (III-3).

WO2004/035547 describes a process for the preparation of 1-substituted 4-nitroimidazole compounds which are intermediates for various pharmaceuticals and agrochemicals, in particular as intermediates for antitubercular agents. Treatment of the halonitroimidazole (IV-1) (or corresponding sulfoxide) with epoxy-sulfonate (IV-2) affords intermediate (IV-3), which is treated with nucleophile (IV-4) to afford (IV-5) and finally the target (IV-6).

WO2008/140090 also describes the process of scheme (V) below. Treatment of 1, 4-cyclohexanedione (V-2) with piperidine derivative (V-1) in the presence of PTSA gives the salt of phenol (V-3). After liberation of the salt, phenol (V-3) is treated with epoxide (V-4) to give another epoxide (V-5), which when treated with nitroimidazole derivative (V-6) results in (V-7).

WO/2011/093529 describes compounds of formula (VI-4) containing an organic sulfonyloxy group. The diol compound (VI-1) is coupled with the piperidine derivative (VI-2) in toluene in the presence of catalytic amounts of Pd ₂dba₃ and ^t BuXPhos and sodium t-butoxide. The resulting diol (VI-3) is converted to epoxide (VI-5). Coupling of epoxide (VI-5) with halonitroimidazole (VI-6) provides the target molecule (VI-8) via intermediate (VI-7).

WO2016158737A1 also describes a process for the preparation of nitroimidazole derivatives. The 4- (4-trifluoromethoxyphenoxy) piperidine (VII-1) is reacted with hydroquinone (VII-2) at high temperature to give 1- (4-hydroxyphenyl) -4- (4-trifluoromethoxyphenoxy) piperidine (VII-3). Subsequently, treating (VII-3) with ethylene oxide (VII-4) to give diol (VII-5), which is converted to another epoxide (VII-6); it is further converted to the target (VII-9) via intermediate (VII-8).

As described above, the diol intermediate (F) may also be optionally prepared by allylation of the phenol (C) to form an intermediate of type (G) followed by asymmetric dihydroxylation. This type of reaction is the subject of the present invention. (F) The diol compound may be further converted into the target nitrodihydroimidazo-oxazole molecule.

Object of the Invention

The main object of the present invention is to provide a novel and practical route for the synthesis of intermediates and derivatives of 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazoles useful for the treatment of various bacterial and parasitic infections. It is another object of the present invention to provide a synthetic route for the preparation of derivatives of chiral 1, 1-dialkylethane-1, 2-diols. It is another object of the present invention to provide a practical and novel route for the synthesis of delamanib.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (I):

a compound of formula (I) or a salt or isomer thereof:

wherein A is a substituted or unsubstituted or branched or unbranched C ₁-C₆ alkyl group;

W is substituted or unsubstituted carbon, wherein n=0, 1,2 or 3;

Y is a substituted or unsubstituted carbon, nitrogen, oxygen or sulfur atom;

Z is a substituted or unsubstituted alkyl, aryl or heteroaryl group, wherein the substituents are independently selected from H, X, NO ₂,CN,COOH,COOR,OH,OR,OAr,OHetAr,SH,S(O)_n R, SAr, SHETAR, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl groups ,NH₂,NHR,NHAr,NH-HetAr,NR₂,NAr₂,NHetAr₂,CONR₂,OC(O)OR,OC(O)NR;

Wherein the method comprises the steps of

X=f, cl, br or I;

R is a substituted or unsubstituted alkyl group;

Ar is a substituted or unsubstituted aryl group;

HetAr is a substituted or unsubstituted heteroaryl;

and n=0, 1 or 2.

In another aspect, the compound of formula (I) is 1, 1-dialkyl ethane-1, 2-diol.

In another aspect, the present invention provides a process for preparing a compound of formula (I) or a salt or isomer thereof

Wherein A, W, Y, Z and n are as defined above.

In another aspect, the present invention provides a process for preparing diol compounds of formula (I) from the corresponding olefin compounds of formula (IA) using an asymmetric dihydroxylation reaction.

Wherein A, W, Y, Z and n are as defined above.

In another aspect, the present invention provides a process for preparing a diol compound of formula (I) from the corresponding olefin compound of formula (IA) using Sharpless asymmetric dihydroxylation; wherein the olefin (IA) is reacted with a suitable asymmetric catalyst in a suitable solvent at a suitable temperature for a suitable period of time.

In another aspect, the present invention provides a process for preparing an olefin compound of formula (IA), comprising: the corresponding phenol is alkylated/allylated with a methallyl halide or other suitable allyl halide derivative in the presence of a suitable base and a suitable solvent.

In another aspect, the 1, 1-dialkyl ethane-1, 2-diol of formula (I) is selected from the group consisting of compounds of the following formulas:

In another aspect, the present invention provides the use of a compound of formula (I) for the preparation of a 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole derivative of formula (H):

in another aspect, the 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole derivative of formula (H) is selected from the group consisting of the following compounds, and the like:

In another aspect, the invention provides a compound of the formula:

In another aspect, the invention provides an antimicrobial compound of the formula:

In another aspect, the invention provides compounds of formulas (003R) and (003S) for use in the treatment of a mycobacterial infection.

In another aspect, the invention provides antitubercular pharmaceutical compositions of compounds of formulae (003R) and (003S).

Drawings

Fig. 1: HPLC chromatogram of the crude reaction mixture for determination of% ee of the compound of formula (009).

Fig. 2: HPLC chromatogram of the crude reaction mixture for determining% ee of the compound of formula (017).

Fig. 3: data on the in vivo efficacy of compound 003 (R) against TB in a mouse infection model.

Detailed Description

In one aspect, the present invention provides a compound of formula (I):

W is substituted or unsubstituted carbon, wherein n=0, 1,2 or 3;

Y is a substituted or unsubstituted carbon, nitrogen, oxygen or sulfur atom;

Z is a substituted or unsubstituted alkyl, aryl or heteroaryl group, wherein the substituents are independently selected from the group consisting of H, X, NO ₂,CN,COOH,COOR,OH,OR,OAr,OHetAr,SH,S(O)_n R, SAr, SHETAR, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl groups ,NH₂,NHR,NHAr,NH-HetAr,NR₂,NAr₂,NHetAr₂,CONR₂,OC(O)OR,OC(O)NR;

Wherein the method comprises the steps of

X=f, cl, br or I;

R is a substituted or unsubstituted alkyl group;

Ar is a substituted or unsubstituted aryl group;

HetAr is a substituted or unsubstituted heteroaryl;

and n=0, 1 or 2.

In another aspect, Z in formula (I) may be aryl independently substituted with an N-Het group, wherein N-Het represents and is independently selected from one of the N-containing alkyl or aryl systems, such as acridine, azabenzotriazole, azaindole, azepane, azaAzetidine, aziridine, benzimidazole, benzotriazole, carbazole, cinnoline, cyclopenta [ b ] pyridine, deazapurine, diazaDihydropyridines, imidazopyridines, imidazoles, imidazolidines, imidazopyridazines, imidazopyridines, imidazopyrimidines, indazoles, indoles, indolines, indolizines, isoindoles, isoquinolines, naphthyridines, oxindoles, phenanthrolines, phenazines, phthalazines, piperazines, piperidines, pteridines, purines, pyrazines, pyrazoles, pyrazolidines, pyrazolines, pyrazolopyridines, pyridazines, pyridines, pyridopyridazines, pyrimidines, pyrrolidines, pyrroles, pyrrolopyrimidines, pyrrolopyridazines, pyrrolopyrimidines, quinazolines, quinolines, quinoxalines, tetrazoles, naphthyridines, triazines, triazoles, triazolopyridines, triazolopyrazines, triazolopyridines, and isomers thereof, preferably in the para-position.

In one aspect, the present invention provides a compound of formula (I) selected from the group consisting of:

in another aspect, the compound of formula (I) is 1, 1-dialkyl ethane-1, 2-diol, selected from the group consisting of.

Wherein A, W, Y, Z and n are as defined above.

In another aspect, the present invention provides a compound of formula (IA) selected from the group consisting of:

In another aspect, the present invention provides a process for preparing a diol compound of formula (I) from the corresponding olefin compound of formula (IA) using Sharpless asymmetric dihydroxylation; wherein the olefin (IA) is reacted with a suitable asymmetric catalyst in a suitable solvent at a suitable temperature for a suitable period of time

Wherein A, W, Z and n are as defined above.

Suitable asymmetric catalysts include, but are not limited to, AD-mix alpha [ (DHQ) ₂ PHAL, adducts of dihydroquinine with phthalazine ] or AD-mix beta [ (DHQD) ₂ PHAL, adducts of dihydroquinidine with phthalazine ], and the like.

Suitable solvents include, but are not limited to, polar solvents, preferably polar protic solvents. Preferably suitable solvents include water, acetone, butanone, methanol, ethanol, isopropanol, butanol, t-butanol, and the like, or mixtures thereof. Most preferably, a suitable solvent is a mixture of t-butanol and water.

Suitable temperatures for the reaction are from about-30 ℃ to 40 ℃. Preferably, a suitable temperature range is-5 ℃ to 25 ℃.

Suitable time periods for the reaction are from 4 hours to 24 hours, although they are variable with respect to reactants and reaction conditions.

In another aspect, the 1, 1-dialkylethane-1, 2-diol of formula (I) is a compound of the formula:

in another aspect, the 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole derivative of formula (H) is selected from the group comprising the following compounds, and the like:

In another aspect, the invention provides a compound of the formula:

In another aspect, the present invention provides a process for preparing an olefin compound of formula (IA), comprising: the corresponding phenol is alkylated/allylated with a methallyl halide (e.g., methallyl chloride, methallyl bromide, methallyl iodide) or other suitable allylhalide (e.g., allyl bromide, allyl chloride or allyl iodide) derivative for a suitable period of time (2-4 hours) at a suitable temperature (60-70 ℃) in the presence of a suitable base (e.g., potassium carbonate, cesium carbonate or sodium hydride) and a suitable solvent (e.g., acetonitrile, acetone, DMF).

The allylation step serves as a protecting group for the phenolic OH of the subsequent reaction, as well as the linkage of the three carbon fragment to the molecule, thus saving the two steps of protection and deprotection that would otherwise be required.

In another aspect, olefins of formula (IA), such as compounds of formula ((001), (005), etc.), may be commercially available or may be prepared by simple synthetic methods. Reacting the corresponding phenolic compound with a methallyl halide (or any other allyl halide) in the presence of a suitable base (e.g., potassium carbonate, etc.) in a suitable solvent (e.g., DMF) at about 50-100 ℃, preferably at 60-70 ℃ for about 6-12 hours;

On the other hand, processes for olefins having formula (IA) (e.g., compounds having formulas (008, 011, 016, etc.) can be difficult and require multiple preparation steps.

In another aspect, the phenol compound of formula (007) may be prepared by a cycloaddition reaction between 4-azidophenol (R6) prepared by the azide of 4-aminophenol (R5) and 1- (prop-2-yn-1-yloxy) -4- (trifluoromethoxy) benzene (R4) prepared by the propargylation reaction of 4-trifluoromethoxyphenol (R2) with propargyl halide (R3) and 1- (prop-2-yn-1-yloxy) -4- (trifluoromethoxy) benzene (R4).

In another aspect, the phenol compound of formula (010) can be prepared by cycloaddition reaction between 4-hydroxybenzaldehyde oxime (R11) prepared from 4-hydroxybenzaldehyde (R9) and 1- (prop-2-yn-1-yloxy) -4- (trifluoromethoxy) benzene (R8) prepared by propargylation of 4-trifluoromethoxyphenol (R7) with propargyl halide (R3).

In another aspect, the phenol compound having formula (016) can be prepared by allylating a phenol compound having formula (013) using methallyl chloride as the allylating reagent, then CuI-mediated N-arylation using unprotected 4-hydroxypiperidine as the amine source to provide an alcohol having formula (015), and finally O-arylation under the conditions of the casting reaction (Mitsunobu reaction).

In another aspect, the compound of formula (016) may also be prepared by N-arylation of the compound of formula (014) using commercially available 4- (4- (trifluoromethoxy) phenoxy) piperidine as an amine source.

Scheme for preparing compounds of formula (016) by using commercially available 4- (4- (trifluoromethoxy) phenoxy) piperidine:

Figure 1 shows an HPLC chromatogram of a crude reaction mixture for determining% ee of a compound of formula (009). Part a of fig. 1 shows peaks for the racemate isomer (RS) of the compound of formula (009). Part B shows the peak of the optically pure R-isomer of the compound of formula (009). Part C shows the main peak of the optically pure S-isomer of the compound of formula (009).

FIG. 2 shows an HPLC chromatogram of a crude reaction mixture of the compound of formula (017) for determination of% ee. Part a of fig. 2 shows peaks for the racemate isomer (RS) of the compound of formula (017). Part B shows the peak of the optically pure R-isomer of the compound having formula (017). part-C shows the main peak of the optically pure S-isomer of the compound having formula (017).

Table 1: list of compounds

Definition of the definition

The terms used in this disclosure use a number of special terms defined as follows:

as used herein, the modifier "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "about 1 to about 4" also discloses the range "1 to 4". When used to modify a single number, the term "about" may refer to ± 10% of the number, including the indicated number. For example, "about 10%" may cover a range of 9% to 11%, and "about 1" means 0.9-1.1.

As used herein, the term "alkyl" refers to an organic group derived from an alkane. By itself or as part of another substituent is meant also a straight or branched monovalent hydrocarbon containing up to 1 to 20 carbon atoms;

An "alkyl" group may also be represented as- (CR 1R 2) n-, where R1 and R2 are independently hydrogen or are independently absent, and for example, m is 1 to 8, and such representation also includes saturated and unsaturated alkyl groups;

the numerical indicator represents the number of carbon atoms in any substituent, e.g., C1-C20 means 1 to 20 carbon atoms;

Variables or substituents such as Rl, R2, R3, R4, R5, wherein each R group may be independently defined by any one of the alkyl groups, and may be a different group;

The term "substituted alkyl" refers to a straight or branched chain group of 1 to 7 carbons wherein one or more hydrogens are replaced with a hydroxyl, amino, nitro, halogen, trifluoromethyl, cyano, -NH (lower alkyl), -N (lower alkyl) 2, lower alkoxy, lower alkylthio, or carboxyl group; the term "substituted alkyl" refers to groups such as methyl, ethyl, propyl, isopropyl, vinyl, allyl, n-butyl, isobutyl, and t-butyl, 1-propenyl, prenyl, ethynyl, 1-propynyl, 2-propynyl, 1, 3-butadienyl, penta-1, 3-dienyl, penta-1, 4-dienyl, hex-1, 3, 5-trienyl, and the like. The term "lower alkyl" refers to a straight or branched chain group having 1 to 4 carbon atoms;

The term "substituted lower alkyl" refers to a straight or branched chain group having 1 to 4 carbons wherein one hydrogen is replaced by hydroxy, amino, halogen, trifluoromethyl, cyano, -NH (lower alkyl), -N (lower alkyl) ₂, lower alkoxy, lower alkylthio or carboxy;

The term "alkenyl" refers to a straight or branched chain group of 3 to 7 carbon atoms having one or two double bonds; it also refers to straight or branched monovalent hydrocarbons containing 2 to 20 carbon atoms (e.g., C2-C10 or C2-C4) and one or more double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, propenylidene, allyl, and 1, 4-butadienyl;

the term "substituted alkenyl" refers to a straight or branched chain group of 3 to 7 carbons having one or two double bonds wherein hydrogen is replaced by hydroxy, amino, halogen, trifluoromethyl, cyano, -NH (lower alkyl), -N (lower alkyl) 2, lower alkoxy, lower alkylthio or carboxy;

The term "alkynyl" refers to straight or branched chain monovalent hydrocarbons containing 2 to 20 carbon atoms (e.g., C2-C10) and one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl and 2-butynyl, and 1-methyl-2-butynyl;

The term "alkoxy" refers to an-O-alkyl group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy;

The terms "lower alkoxy" and "lower alkylthio" refer to a lower alkyl group as defined above attached to oxygen or sulfur;

the term "acyloxy" refers to an-O-C (O) -R group, wherein R may be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

the term "amino" refers to NH2, alkylamino or arylamino;

the term "alkylamino" refers to an-N (R) -alkyl group, wherein R may be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

The terms "amido" and "ureido" refer to the-NRC (O) R ' and-C (O) NRR ' groups, respectively, where R and R ' can each independently be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

The term "cycloalkyl" refers to a saturated ring of 3 to 7 carbon atoms; it also refers to monovalent saturated hydrocarbon ring systems having 3 to 30 carbon atoms (e.g., C3-C12). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1, 4-cyclohexylidene, cycloheptyl, cyclooctyl, and adamantyl;

The term "cycloalkenyl" refers to a monovalent non-aromatic hydrocarbon ring system having 3 to 20 carbons (e.g., C3-C20) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, fluorenyl, and cycloheptenyl;

The term "heterocycloalkyl" refers to a monovalent non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S or Se). Examples include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, 4-tetrahydropyranyl, and tetrahydrofuranyl;

The term "heterocycloalkenyl" refers to a monovalent non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S or Se) and one or more double bonds; examples of heterocycloalkenyl groups include, but are not limited to, pyranyl, dihydrobenzimidazolyl, and 1, 3-dihydrospiro [ benzo [ d ] imidazol-2, 1' -cyclopentane ] -4-yl;

The term "aryl" refers to phenyl, 1-naphthyl and 2-naphthyl; it also refers to monovalent 6 carbon monocyclic, 10 carbon bicyclic, 14 carbon tricyclic aromatic ring systems. Examples include, but are not limited to, phenyl ("Ph"), naphthyl, pyrenyl, anthryl, and phenanthryl. The term "aryloxy" refers to an-O-aryl group;

The term "substituted aryl" refers to phenyl, 1-naphthyl; and a 2-naphthyl substituent having a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, hydroxy, trifluoromethyl, amino, -NH (lower alkyl) and-N (lower alkyl) 2, di-and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl, wherein the substituent is selected from the group consisting of methyl, methoxy, methylthio, halogen, hydroxy, and amino;

The term "arylamino" refers to the radical —n (R) -aryl, wherein R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

The term "heteroaryl" refers to phenyl, 1-naphthyl and 2-naphthyl; it also refers to monovalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring systems having one or more heteroatoms (e.g. O, N, S or Se). Examples of heteroaryl groups include pyridyl, pyrrolyl, furyl, imidazolyl, indazolyl, benzimidazolyl, pyrimidinyl, thienyl, oxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, and thiazolyl. In other words, the term refers to an unsaturated monocyclic ring of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms, provided that the only other atoms in the monocyclic ring are C atoms and the total number of O, S and N atoms is 4 or less, and bicyclic rings in which a five-or six-membered ring as defined above is fused to a phenyl or pyridyl ring, the heteroaryl ring being linked by an available carbon or nitrogen atom; and the mono-or bicyclic ring may be substituted on the available carbon atoms by lower alkyl of 1 to 4 carbons, halogen, hydroxy, benzyl or cyclohexylmethyl, or may be substituted on the available nitrogen atoms by benzyloxymethyl, p-toluenesulfonyl, 2, 4-dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl or benzhydryl;

the term "form" as used herein refers to a polymorphic form of a compound or a salt form of a compound, or both polymorphic and salt forms;

the term "halogen" or "halo" refers to chlorine, bromine, fluorine and iodine;

The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, amino, aryl, and heteroaryl groups include substituted and unsubstituted moieties;

Possible substituents on amino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl include, but are not limited to, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10 alkylamino, arylamino, C1-C10 alkylimino, arylimino, C1-C10 alkylsulfonimino, arylsulfonimino hydroxy, halogen, oxo (o=), thio (s=), thio, silyl, C1-C10 alkylthio, arylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, mercapto, acylamino, thiourea, thiocyanate, sulfonamide, guanidine, ureido (urideo), nitro, nitroso, azido, acyl, sulfonyl, acyloxy, ureido (carbamido), carbamoyl (-C (O) NH 2), carboxyl (-COOH) and carboxylate;

On the other hand, possible substituents on the alkyl, alkenyl, alkylene, alkenylene, heteroalkylene, heteroalkenylene or alkynyl group include all of the above substituents except for C1-C10 alkyl;

cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl can also be fused to each other (e.g., to form a spiro compound) through sharing one or more atoms;

Wherein each R group, when present, is independently selected from the following substituents: -F, -Cl, -Br, -I, -CH3, -OH, -SH, -SCH3, -NH2, NHR ', -NR ' R "(wherein R ' and R" are each independently H or C1-3 alkyl, -CN, -NO2, -och3. Alkyl, substituted aryl, heteroaryl and substituted heteroaryl as defined herein); x, Y, Z are each independently-CH 2-or N, provided that when X in the ring is a divalent group, at least one of X, Y and Z is N and X is O, S or NH.

Detailed Description

Detailed description of the most preferred aspects:

example I, step 1 (S) -2-methylnonane-1, 2-diol (002) synthesis:

t-butanol was placed in a 100mL round bottom flask equipped with a magnetic stir bar: water (1:1, 30 mL) and AD-mix- α (12 gm). Stirring the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase is bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 ℃ (some dissolved salts precipitated). 2-methylnon-1-ene (001) (5 gm,35.12 mmol) was added and the mixture was stirred vigorously at 0℃C (temperature is important |) and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at 0deg.C for 6 hours, and 1.93g (15.3 mmol) of sodium sulfite was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Dichloromethane (20 mL) and water (40 mL) were added sequentially and the reaction mixture was extracted with a portion of DCM. The combined organic phases were dried over anhydrous MgSO ₄, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by column chromatography on silica gel using 4: gradient elution with 1 hexane/ethyl acetate gives (002) as a colorless oil (S). Yield (4.4 gm, 71%).

Synthesis of (R) -2-methylnonane-1, 2-diol (002) (R):

T-butanol was placed in a 100mL round bottom flask equipped with a magnetic stir bar: water (1:1, 30 mL) and AD-mix- β (5.5 gm). Stirring the mixture at room temperature until two clear phases are produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 ℃ (some of the dissolved salts may precipitate). 2-methylnon-1-ene (001) (2 gm,35.12 mmol) was added and the mixture was stirred vigorously at 0℃C (temperature is important |) and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at 0deg.C for 6 hours, and 1.93g (15.3 mmol) of sodium sulfite was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Dichloromethane (20 mL) and water (40 mL) were added sequentially and the reaction mixture was partially extracted with DCM. The combined organic phases were dried over anhydrous MgSO ₄, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by column chromatography on silica gel using 4: gradient elution with 1 hexane/ethyl acetate gives a colorless oil (002). Yield (1.6 gm, 58%).

Step 2 (R) -Synthesis of 2-heptyl-2-methyl-oxirane (002-EPR):

In a 100mL round bottom flask, (R) -2-methylnonane-1, 2-diol 002 (1.6 gm,2 mmol) was added to DCM solvent and triethylamine (0.960 mL,4 mmol) was added followed by dropwise methanesulfonyl chloride (280. Mu.L, 2.2 mmol) at 0deg.C and stirred at room temperature for 2 hours. The solvent was then evaporated and extracted with ethyl acetate and aqueous layer. The organic solvent was evaporated to give the methanesulfonylation product as a gum-like material, which was used as such in the next reaction. In the next step, the methanesulfonylated compound was dissolved in ethyl acetate, and DBU (300 μl,4 mmol) was added, the reaction mixture was stirred for 2 hours, then water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was evaporated under a rotary evaporator, then ethyl acetate: hexane (40:60) was purified on 100-200 silica gel as eluent to give compound 002-EP as a brown gum-like liquid. (1.4 gm, 85% yield).

Synthesis of (S) -2-heptyl-2-methyl oxirane (002-EPS):

In a 100mL round bottom flask, (S) -2-methylnonane-1, 2-diol 002S (800 mg,2 mmol) was added to DCM solvent and triethylamine (0.480 mL,4 mmol) was added followed by dropwise methanesulfonyl chloride (140. Mu.L, 2.2 mmol) at 0deg.C and stirred at room temperature for 2 hours. The solvent was then evaporated and extracted with ethyl acetate and aqueous layer. The organic solvent was evaporated to give the methanesulfonylation product as a gum-like material, which was used as such in the next reaction. In the next step, the methanesulfonylated compound was dissolved in ethyl acetate, and DBU (150 μl,4 mmol) was added, the reaction mixture was stirred for 2 hours, then water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was evaporated under a rotary evaporator, then ethyl acetate: hexane (40:60) was purified on 100-200 silica gel as eluent to give compound 002-EPS as a brown gum-like liquid. (700 mg, 82% yield).

Step 3 (R) -Synthesis of 1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methylnon-2-ol and 2-heptyl-2-methyl-6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole (003R):

A solution of 2-chloro-4-nitro-1H-imidazole (1.0 g,8.2 mmol), epoxide 002-EP (S) (1.32 g,9.86 mmol) and triethylamine (2.28 mL,16.4 mmol) in ethyl acetate (4.0 mL) was heated at 60-65℃for 6H. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the uncyclized intermediate. TLC (EtOAc: hexane 4:6): rf=0.20; yield: 69%. The intermediate (1.0 gm,3 mmol) was then dissolved in anhydrous DMF, cesium carbonate (2.2 gm,6 mmol) was added and the reaction mixture was stirred at 50℃for 2 hours. Water (20 mL) was added sequentially and the reaction mixture was partially extracted with ethyl acetate. The combined organic phases were dried over anhydrous MgSO ₄, filtered and concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography on silica gel using 4: gradient elution with 1 hexane/ethyl acetate was performed as a pale yellow solid product (003R). Yield (61%).

Synthesis of (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methylnon-2-ol and 2-heptyl-2-methyl-6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole (003S):

A solution of 2-chloro-4-nitro-1H-imidazole (1.0 g,8.2 mmol), epoxide 002-EP (R) (660 mg,9.86 mmol) and triethylamine (1.14 mL,16.4 mmol) in ethyl acetate (2.0 mL) was heated at 60-65℃for 6H. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the uncyclized intermediate. TLC (EtOAc: hexane 4:6): rf=0.20; yield: 69%. The intermediate (1.0 gm,3 mmol) was then dissolved in anhydrous DMF, cesium carbonate (2.2 gm,6 mmol) was added and the reaction mixture was stirred at 50℃for 2 hours. Water (20 mL) was added sequentially and the reaction mixture was partially extracted with ethyl acetate. The combined organic phases were dried over anhydrous MgSO ₄, filtered and concentrated under reduced pressure to give the crude material. The residue was purified by column chromatography on silica gel using 4: gradient elution with 1 hexane/ethyl acetate afforded the product (003S) as a pale yellow solid. Yield (57%).

003 (Koku) ¹H NMR:¹NMR(400MHz,CDCl₃)δ7.47(s,1H),4.02(d,J＝10.2Hz,1H),3.91(d,J＝10.2Hz,1H),1.85-1.76(m,3H),1.57(s,3H),1.29-1.16(m,10H),0.81(t,J＝6.1Hz).sss13C NMR(CDCl3)δ156.07(s),147.27(s),112.60(s),95.89-95.69(m),54.01(s),40.11(s),31.63(s),29.47(s),28.98(s),25.54(s),23.26(s),22.54(s),13.98(s).

Example II, step 1: synthesis of 1- ((2-methylallyl) oxy) -4- (trifluoromethoxy) benzene (005):

The starting material 4-trifluoromethoxyphenol (004) (5 gm,28mmol,1 eq.) and K ₂CO₃ (7.8 gm,56mmol,2 eq.) were suspended in DMF. Methallyl chloride (3 ml,36.4mmol,1.3 eq.) was then added and the reaction was heated to 70 ℃ for a period of 12 hours. After cooling, the mixture was diluted with ethyl acetate and transferred to a separatory funnel. The organic phase was washed twice with water and once with brine. Dried over MgSO ₄, filtered, and rotary evaporated to give the crude material. The residue was separated by column chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as eluent to give the corresponding allyl ether product (005). (yield 93%).

Example II, step 2: synthesis of (R) -2-methyl-3- (4-trifluoromethoxy) phenoxy) propane-1, 2-diol (006) (R):

T-butanol was placed in a 100mL round bottom flask equipped with a magnetic stir bar: water (1:1, 30 mL) and AD-mix- α (4 gm). Stirring the mixture at room temperature until two clear phases are produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 ℃ (some of the dissolved salts may precipitate). 1- ((2-methallyloxy) -4- (trifluoromethoxy) benzene (005) (1 gm,4.31 mmol) was added and the mixture was stirred vigorously at 0℃to room temperature (temperature is important |) with the progress of the reaction being followed by TLC. The resulting mixture was stirred vigorously at room temperature for 6-12 hours, and 1.93g (15.3 mmol) of sodium sulfite was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. DCM (20 mL) and water (40 mL) were then added sequentially, and the reaction mixture was partially extracted with DCM. The combined organic phases were dried over anhydrous MgSO ₄, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by column chromatography on silica gel using 4: gradient elution with 1 hexane/ethyl acetate afforded colorless oily substance (006) (R). Yield 1.0g (88%).

Step 3: epoxidation

Synthesis of (R) -2-methyl-2- ((4- (trifluoromethoxy) phenoxy) methyl) oxirane (006-EP):

In a 100mL round bottom flask, (R) -2-methyl-3- (4- (trifluoromethoxy) phenoxy) propane-1, 2-diol 006 (0.360 gm,2 mmol) was added to DCM solvent and triethylamine (0.240 mL,4 mmol) was added, then methanesulfonyl chloride (70. Mu.l, 2.2 mmol) was added dropwise at 0deg.C and stirred at room temperature for 2 hours. The solvent was then evaporated and extracted with ethyl acetate and aqueous layer. The organic solvent was evaporated to give the methanesulfonylation product as a gum-like material, which was used as such in the next reaction. In the next step, the methanesulfonylated compound was dissolved in ethyl acetate, and DBU (60 μl,4 mmol) was added, the reaction mixture was stirred for 2 hours, then water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was evaporated under a rotary evaporator, then ethyl acetate: hexane (40:60) was purified on 100-200 silica gel as eluent to give compound 006-EP (R) as a brown gum-like liquid. (0.240 gm, 85% yield).

Step 4: ring opening and cyclization

Synthesis of (R) -2-methyl-6-nitro-2- ((4- (trifluoromethoxy) phenoxy) methyl) -2, 3-dihydroimidazo [2,1-b ] oxazole (VL-2098):

A mixture of epoxide 006-EP (R) (240 mg,1 mmol), 2-bromo-4-nitro-1H-imidazole (190 mg,1 mmol) and DIPEA (2.0 mL) was placed in a sealed tube and heated at 115℃for 2 hours. After cooling the reaction mixture, dichloromethane was added and evaporated to give the crude product which was used for the next reaction. Cesium carbonate was added to the anhydrous DMF stirred solution of the crude product and the reaction mixture was stirred at 50 ℃ for 2 hours, then after the reaction was completed, water was added and the reaction mixture was extracted with ethyl acetate. The solvent was then evaporated and the reaction mixture was purified with silica gel 100-200, with 40% ethyl acetate: elution with methylene chloride afforded compound VL-2098 as a white solid (172 mg, 48%). [ alpha ] D ²⁵ +7° (c 1, chloroform)

¹H NMR(400MHz,CDCl₃)δ7.53(s,1H),7.11(d,J＝8.8Hz,2H),6.81(d,J＝9.1Hz,2H),4.46(d,J＝10.3Hz,1H),4.19(d,J＝10.1Hz,1H),4.05(dd,J＝10.0,8.0Hz,2H),1.75(s,3H).LC-MS(ESI+):m/z Calculated value (m+h) ⁺ 360.20.

Example III, synthesis of 1- (4- ((2-methylallyl) oxy) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazole, (008):

The starting materials 4- (4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) phenol (007) (5 gm,14.24mmol,1 eq.) and K ₂CO₃ (4 gm,28.48mmol,2 eq.) were suspended in DMF. Methallyl chloride (1.7 ml,18.15mmol,1.3 eq.) was then added and the reaction was heated to 70 ℃ for a period of 2 hours. After cooling, the mixture was diluted with EtOAc and transferred to a separatory funnel. The organic phase was washed twice with H ₂ O and once with brine. Dried over MgSO ₄, filtered, and rotary evaporated to give the crude material. The residue was separated by column chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as eluent to give the corresponding allyl ether product (008). (yield 86%).

Example III, step 2: synthesis of (S) -2-methyl-3- (4- (4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) phenoxy) propane-1, 2-diol (009):

t-butanol was placed in a100 mL round bottom flask equipped with a magnetic stir bar: water (1:1, 40 mL) and AD-mix- β (gm). Stirring the mixture at room temperature until two clear phases are produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 ℃, some of the dissolved salts may precipitate). 1- (4- ((2-methallyloxy) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazole (008) (1 gm,2.47 mmol) was added and the reaction progress was followed by TLC with vigorous stirring at 0℃C (temperature is important. The resulting mixture was vigorously stirred at 0deg.C for 6 hours, and 19g (15.3 mmol) of sodium sulfide was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Dichloromethane (20 mL) and water (40 mL) were then added sequentially and the reaction mixture was extracted with a portion of DCM. The combined organic phases were dried over anhydrous MgSO ₄, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by column chromatography on silica gel using 4: gradient elution with 1 hexane/ethyl acetate was performed as brown gummy solid (009) (S). Yield (950 mg, 88%).

Synthesis of (R) -2-methyl-3- (4- (4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) phenoxy) propane-1, 2-diol (009) (R):

T-butanol was placed in a 100mL round bottom flask equipped with a magnetic stir bar: water (1:1, 40 mL) and AD-mix- α (2.81 gm). Stirring the mixture at room temperature until two clear phases are produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 ℃, some of the dissolved salts may precipitate). 1- (4- ((2-methallyloxy) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazole (008) (4 gm,9.87 mmol) was added and the reaction progress was followed by TLC with vigorous stirring at 0℃C (temperature is important. The resulting mixture was vigorously stirred at 0deg.C for 6 hours, and 19g (15.3 mmol) of sodium sulfide was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Dichloromethane (20 mL) and water (40 mL) were then added sequentially and the reaction mixture was extracted with a portion of DCM. The combined organic phases were dried over anhydrous MgSO ₄, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by column chromatography on silica gel using 4: gradient elution with 1 hexane/ethyl acetate was performed as brown gummy solid (009) (R). Yield (3.9 gm, 90%).

Step 4: epoxidation

Synthesis of (R) -1- (4- ((2-methyl-oxiran-2-yl) methoxy) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazole (009-EP):

in a 100mL round bottom flask, (R) -2-methyl-3- (4- (4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) phenoxy) propane-1, 2-diol 009 (3.6 gm,2 mmol) was added to DCM solvent and triethylamine (2.4 mL,4 mmol) was then added dropwise methanesulfonyl chloride (0.684 mL,2.2 mmol) at 0deg.C and stirred at room temperature for 2 hours. The solvent was then evaporated and extracted with ethyl acetate and aqueous layer. The organic solvent was evaporated to give the methanesulfonylation product as a gum-like material and used as such in the next reaction. In the next step, the methanesulfonylated compound was dissolved in ethyl acetate, and DBU (0.596 ml,4 mmol) was added, the reaction mixture was stirred for 2 hours, then water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was evaporated under a rotary evaporator, then ethyl acetate: hexane (40:60) was purified on 100-200 silica gel as eluent to give compound 009-EP (R) as a brown gum-like liquid. (2.4 gm, 85% yield).

Step 5: ring opening and cyclization

Synthesis of (R) -2-methyl-6-nitro-2- ((4- (4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) phenoxy) methyl) -2, 3-dihydroimidazo [2,1-b ] oxazole (IIIM-019):

A mixture of epoxide 009-EP (R) (2.4 g,5 mmol), 2-bromo-4-nitro-1H-imidazole (730 mg,5 mmol) and DIPEA (2.0 mL) was placed in a sealed tube and heated at 115℃for 2 hours. After cooling the reaction mixture, dichloromethane was added and evaporated to give the crude product which was used for the next reaction. Cesium carbonate was added to the stirred anhydrous DMF solution of the crude product and the reaction mixture was stirred at 50 ℃ for 2 hours, then after the reaction was completed, water was added and the reaction mixture was extracted with ethyl acetate. The solvent was then evaporated and the reaction mixture was purified with silica gel 100-200, with 40% ethyl acetate: elution with methylene chloride afforded the final compound IIIM-019 as a white solid (300 mg, 48%). [ alpha ] D ²⁵ +7° (c 1, chloroform)

Example IV, step 1: synthesis of 5- (4-fluorophenethyl) -3- (4- ((2-methallyl) oxy) phenyl) isoxazole (011):

The starting materials 4- (5- ((4-fluorophenoxy) methyl) isoxazol-3-yl) phenol (010) (5 gm,17.55mmol,1 eq.) and K ₂CO₃ (4.8 gm,35.1mmol,2 eq.) were suspended in DMF. Methallyl chloride (2.04 ml,22.75mmol,1.3 eq.) was then added and the reaction heated to 70 ℃ for a period of 2 hours. After cooling, the mixture was diluted with EtOAc and transferred to a separatory funnel. The organic phase was washed twice with water and once with brine. Dried over MgSO ₄, filtered, and rotary evaporated to give the crude material. The residue was separated by chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as eluent to give the corresponding allyl ether product (oil). (5.5 gm, 93% yield).

Example IV, step 2: synthesis of (R) -3- (4- (5- (4-fluorophenylethyl) isoxazol-3-yl) phenoxy) -2-methylpropane-1, 2-diol (012) (R):

t-butanol was placed in a 100mL round bottom flask equipped with a magnetic stir bar: water (1:1, 40 mL) and AD-mix- α (13.45 gm). Stirring the mixture at room temperature until two clear phases are produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 ℃, some of the dissolved salts may precipitate). 5- ((4-fluorophenoxy) methyl) -3- (4- ((2-methallyloxy) phenyl) isoxazole (011) (4 gm,11.79 mmol) and continued to vigorously stir the mixture at 0deg.C (temperature critical. The resulting mixture was stirred vigorously at 0deg.C for 6 hours and 19g (15.3 mmol) of sodium sulfide were added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Then 20 ml of DCM and 40ml of water were added sequentially and the reaction mixture was extracted with portions of DCM. The combined organic phases were dried over anhydrous MgSO ₄, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by column chromatography on silica gel using 4: gradient elution with 1 hexane/ethyl acetate was performed as brown gum product (012) (R). Yield (4.0 gm, 90%).

Step 4: epoxidation

Synthesis of (R) -5- ((4-fluorophenoxy) methyl) -3- (4- ((2-methylethyloxy-2-yl) methoxy) phenyl) isoxazole (012-EP (R)):

In a 100mL round bottom flask ((R) -3- (4- (5- ((4-fluorophenoxy) methyl) isoxazol-3-yl) phenoxy) -2-methylpropan-1, 2-diol 012 (1.8 gm,2 mmol) was dissolved in DCM solvent and triethylamine (1.2 mL,4 mmol) was added, then methanesulfonyl chloride (0.3492 mL,2.2 mmol) was added dropwise at 0deg.C and stirred at room temperature for 2h then the solvent was evaporated and extracted with ethyl acetate and aqueous layer the organic solvent was evaporated to give the methanesulfonylated product as a gum material and used as such in the next reaction step, the methanesulfonylated compound was dissolved in ethyl acetate and DBU (0.596 mL,4 mmol) was added, the reaction mixture was stirred for 2h, then water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was evaporated with ethyl acetate: hexane (40:60) as eluent on 100-200 to give compound O12 as a gum yield (EP 1.81%).

Step 5: ring opening and cyclization

Synthesis of (R) -2- ((4- (5- ((4-fluorophenoxy) methyl) isoxazol-3-yl) phenoxy) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole (IIIM-114):

A mixture of epoxide 012-EP (R) (2.4 g,5 mmol), 2-bromo-4-nitro-1H-imidazole (1.4 g,5 mmol) and DIPEA (4.0 mL) was placed in a sealed tube and heated at 115℃for 2 hours. After cooling the reaction mixture, dichloromethane was added and evaporated to give the crude product which was used for the next reaction. Cesium carbonate was added to the stirred anhydrous DMF solution of the crude product and the reaction mixture was stirred at 50 ℃ for 2 hours, then after the reaction was completed, water was added and the reaction mixture was extracted with ethyl acetate. The solvent was then evaporated and the reaction mixture was purified with silica gel 100-200, with 40% ethyl acetate: elution with methylene chloride afforded the final compound IIIM-114 as a white solid (0.800 gm, 48%).

Example V, step 1: synthesis of 1-iodo-4- ((2-methallyl) oxy) benzene (014):

The starting materials 4-iodophenol (013) (20 gm,91mmol,1 eq.) and K ₂CO₃ (182 mmol,2 eq.) were suspended in DMF. Methallyl chloride (118.3 mmol,1.3 eq.) was then added and the reaction heated to 70 ℃ for a period of 2 hours. After cooling, the mixture was diluted with EtOAc and transferred to a separatory funnel. The organic phase was washed twice with H ₂ O and once with brine. Dried over MgSO ₄, filtered, and rotary evaporated to give the crude material. The residue was separated by column chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as eluent to give the corresponding allyl ether product (014). (24 gm, 97% yield).

Example V, synthesis of 1- (4- ((2-methylallyloxy) phenyl) piperidin-4-ol (015):

TABLE 2N optimization of general reaction conditions for arylation

Numbering device

Solvent(s)

Catalyst

Ligand

Alkali

Temperature (temperature)

Time of

Yield%

1.

Toluene (toluene)

Pd(OAc)₂

Rac-Binap

Cs₂CO₃

100℃

24hrs

40

2.

DMSO

CuI

Phenanthroline(s)

Cs₂CO₃

80℃

24hrs

55

3.

DMF

CuI

L-proline

Cs₂CO₃

rt

24hrs

80

4.

DMF

CuI

L-proline

------

rt

24hrs

85

5.

DMF

CuI

Bipyridine (P)

------

rt

24hrs

60

6.

DMF

CuI

Pyrrolidine compounds

------

rt

24hrs.

35

Table 3: optimization of N-arylation catalyst and ligand mol%

Numbering device	Solvent(s)	CuI mol％	L-proline mol%	Temperature (temperature)	Time of	Yield%
							1.	DMF	10	10	rt	24hrs	40
2.	DMF	10	20	rt	24hrs	48
							3.	DMF	20	30	rt	24hrs	55
4.	DMF	20	40	rt	24hrs	85
							5.	DMF	40	80	rt	24hrs	78

The oven dried flask was charged with copper iodide (5 gm,0.3 mmol) and L-proline (6.0 gm,0.6 mmol). The flask was evacuated with a high N ₂ atmosphere and then fitted with a rubber septum. DMSO (80 mL) was then added, along with aryl iodide (014) (25 gm,91 mmol) added at this stage. The resulting blue solution was stirred for 10 minutes, then 4-hydroxypiperidine (27.3 gm,273.0 mmol) was added. The resulting mixture was stirred at room temperature until completion (12-36 hours). After completion, the reaction mixture was diluted with 70ml of 1m aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the desired pure product (015) as a solid (20 gm, 88% yield).

Example V, step 3: synthesis of 1- (4- ((2-methylallyloxy) phenyl) -4- (4- (trifluoromethoxy) phenoxy) piperidine (016):

Table 4: optimization of general reaction conditions for O-arylation

To a solution of the 4-hydroxypiperidine derivative (015) (10 g,40 mmol) in THF (60 mL) was added PPh ₃ (15 g,60 mmol), and a solution of 4-trifluoromethoxyphenol (5.6 mL,44 mmol) and DEAD (9.8 mL) was further added dropwise thereto under ice cooling, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the resulting residue was added aqueous sodium hydroxide solution, followed by extraction with EtOAc. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane: etoac=4:1 (V/V)) to give 1- (4- ((2-methallyl) oxy) phenyl) -4- (4- (trifluoromethoxy) phenoxy) piperidine (016) (10 gm, yield 63%).

Example V, step 4: synthesis of (R) -2-methyl-3- (4- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) phenoxy) propane-1, 2-diol (017) (R)

T-butanol was placed in a 100mL round bottom flask equipped with a magnetic stir bar: water (1:1, 30 mL) and AD-mix- α (12 gm). Stirring the mixture at room temperature until two clear phases are produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 ℃, some of the dissolved salts may precipitate). 1- (4- ((2-methallyloxy) phenyl) -4- (4- (trifluoromethoxy) phenoxy) piperidine (016) (5 gm,12.28 mmol) was added and the mixture was stirred vigorously at 0deg.C (temperature is important |) and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at 0deg.C for 6 hours, 1.93g (15.3 mmol) of sodium sulfide was added, the reaction mixture was warmed to room temperature, stirred for 1 hour, then 20mL of DCM and 40mL of water were added sequentially, the reaction mixture was partially extracted with DCM, the combined organic phases were dried over anhydrous MgSO ₄, filtered, concentrated under reduced pressure to give a crude oil, and the residue was purified by silica gel column chromatography, purified with 4: gradient elution with 1 hexane/ethyl acetate was performed as a brown gum material (017) (R). Yield (4.4 gm, 86%). The enantiomeric excess can be determined by chiral HPLC techniques using a chiral packed column.

Step 5: epoxidation

Synthesis of (R) -2-hydroxy-2-methyl-3- (4- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) phenoxy) propylmethanesulfonate and (R) -1- (4- ((2-methyl-oxiran-2-yl) methoxy) phenyl) -4- (4-trifluoromethoxy) phenoxy) (O17-EP):

In a 100mL round bottom flask, (R) -2-methyl-3- (4- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) phenoxy) propane-1, 2-diol 017 (0.9 gm,2 mmol) was added to DCM solvent and triethylamine (0.570 mL,4 mmol) was added followed by dropwise methanesulfonyl chloride (0.170 mL,2.2 mmol) at 0deg.C and stirring at room temperature for 2 hours. The solvent was then evaporated and extracted with ethyl acetate and aqueous layer. The organic solvent was evaporated to give the methanesulfonylation product as a gum-like material, which was used as such in the next reaction. In the next step, the methanesulfonylated compound was dissolved in ethyl acetate, and DBU (0.596 ml,4 mmol) was added, the reaction mixture was stirred for 2 hours, then water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was evaporated under a rotary evaporator, then ethyl acetate: hexane (40:60) was purified on 100-200 silica gel as eluent to give compound 017-EP (R) as a brown gum-like liquid. (0.7 gm, 82% yield).

Step 6: ring opening and cyclization

Synthesis of 1- (2-bromo-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (4- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) phenoxy) propan-2-ol and 2-methyl-6-nitro-2- ((4- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) phenoxy) methyl) -2, 3-dihydroimidazo [2,1-b ] oxazole (delamanib):

table 5: optimization of general reaction conditions for epoxide opening

Sequence number	Solvent(s)	Alkali	Temperature..degree.C	Yield%
					1	Acetic acid ethyl ester	Et₃N	70	NR
2	---	Et₃N	80	Micro-quantity
					3	---	DBU	100	NR
4	DMF	Cs₂CO₃	100	Micro-quantity
					5	---	DIPEA	115	89

A mixture of epoxide 017-EP (R) (424 mg,1 mmol), 2-bromo-4-nitro-1H-imidazole (190 mg,1 mmol) and DIPEA (2.0 mL) was placed in a sealed tube and heated to 115℃for a period of 12H. After cooling the reaction mixture, dichloromethane was added and evaporated to dryness under reduced pressure, the residue was purified on silica gel 100-200, then eluted with 0.5% etoac/CH2Cl2 to give the desired compound (552 mg) in 90% yield. Cesium carbonate was added to a stirred solution of the uncyclized compound (307 mg,0.5 mol) in anhydrous DMF and the reaction mixture was stirred at 50 ℃ for 2 hours, then after the reaction was completed, water was added and extracted with ethyl acetate. The solvent was then evaporated and the reaction mixture was purified on silica gel 100-200 eluting with 40% ethyl acetate: dichloromethane to give the compound delamanib as a white solid (185mg,70％).Mp 195-196℃.¹NMR(CDCl₃)δ7.58(s,1H),7.17-7.15(d,J＝8.0Hz,2H),6.84-6.91(m,4H),6.81-6.78(d,J＝12.0Hz,2H),4.53-4.50(d,J＝12.0Hz,1H),4.46-4.41(1H,m),4.21-4.18(d,J＝10.2Hz,1H),4.07-4.04(dd,J＝12.0Hz,2H),3.41-3.35(m,2H),3.04-2.98(m,2H),2.14-2.09(m,2H),1.99-1.93(m,2H),1.78(s,3H);¹⁹F NMR(CDCl₃,376MHz)：δ-58.32;¹³C NMR(101MHz,CDCl₃)δ155.92,151.71,146.89,122.50,119.29(q,JC-F＝256.54Hz,)118.56,116.84,115.57,112.54,93.24,72.70,72.23,51.43,47.86,30.57,23.16;[α]D25-12°(c1, chloroform); HRMS (esi+) for C ₂₅H₂₅F₃N₄O₆ calculated 535.180 ([ m+h ] +) found 535.179.

Biological evaluation:

in vitro Activity against Mycobacterium tuberculosis H ₃₇ RV

The method comprises the following steps: the MIC of one of Mycobacterium tuberculosis (M.tuberculosis) H ₃₇R_v (ATCC 27294; american type culture Collection, manassas, va., USA), mycobacterium tuberculosis (M.tuberculosis) MDR (isoniazid and rifampicin resistant) and laboratory-generated mutant Mycobacterium tuberculosis Rif ^R (rifampicin resistant) ¹⁰ was determined by broth dilution, using a micro-broth dilution method. Bacterial strains were grown in Middlebrook 7H9 broth (Difco Laboratories, detroit, mich.) supplemented with 0.5% (v/v) glycerol, 0.25% (v/v) tween 80 (Himedia, mumbai India) and 10% adc (albumin glucose catalase, becton Dickinson, sparks, MD) for 10 to 15 days under shaking conditions at 37 ℃ and 5% co ₂ to promote exponential phase growth of organisms. Bacterial suspensions were prepared by suspending Mycobacterium tuberculosis growths in physiological saline containing 0.5% tween 80 and adjusting the turbidity to 1MCFARLAND (MCF) standard, which corresponds to 1.0X10 ⁷ cfu/mL. 2-fold serial dilutions of compounds were prepared in Middle brook 7H9 (Difco laboratories) for M.tuberculosis at 100. Mu.L/well in 96-well U-bottom microtiter plates (Tarson, mumbai, india). The bacterial suspension described above was further diluted 1:10 in growth medium and 100. Mu.L volume of this diluted inoculum was added to each well of the plate, yielding a final inoculum in the well of 1.0X10 ⁶ CFU/mL and a final concentration of compound ranging from 0.015 to 32. Mu.g/mL. Plates were incubated in 5% CO2 for 7 days at 37 ℃. For evaluation of the results (Resaurin micro titer assay), the REMA method was used. After incubation, 15 μl of 0.04% resazurin and 12.5 μl of 20% tween 80 were added to each well of the plate including the medium and growth control. After 48 hours incubation, the plates were read visually and the minimum concentration of compound that showed no color change was recorded as MIC.

Results:

a compound of formula 003 as claimed wherein said compound exhibits an in vitro antitubercular activity of MIC of 0.25-0.015 μg/ml against H ₃₇ RV mycobacterium tuberculosis and a compound of formula (003R) exhibits a significant in vitro activity of MIC of 0.015 μg/ml.

^a MIC minimum inhibitory concentration

H ₃₇R_V toxic strains of Mycobacterium tuberculosis;

in vivo efficacy study of compound 003R:

Dose preparation:

The compound of formula 003R was dissolved in a minimum amount of DMSO and then mixed in alcohol, 5% ethanol and 95% peg400 (v/v) to final volume. The compound was dissolved to give a final concentration of 25mg/kg while isoniazid was prepared at the same concentration of 25 mg/kg. The corresponding doses for a total of 200 μl volume were administered orally (oral gavage) to each group in a biosafety cabinet. The placebo group was given the same volume of the mixture, i.e. 5% ethanol and 95% peg400 (v/v). One group of mice was not dosed as a control.

The method comprises the following steps:

In this particular study we prepared nine groups and each group was equipped with four BALB/c mice with an average body weight of 18-22 grams. Mycobacterium tuberculosis H37Rv was grown in 7H9 medium supplemented with 10% ADC. After 14 days, the cultures were diluted to a final strength of 1 McF. 20 μl of the culture was administered by the left nasal route. Dosing was started after the first day of infection, and three mice from the early control were also dissected simultaneously, which allowed for counting of mycobacteria established in the lungs. Two weeks later, mice in the late control and treatment groups were sacrificed and the left lung was removed. It allows monitoring of post-treatment reductions in bacillus load and comparison with early and late controls. The left lung was removed during dissection and distributed in 1ml NST and the samples were homogenized. Individual samples were serially diluted (up to 10-6). Each dilution of 20m1 was spotted on 7H10 agar plates supplemented with 10% ADC and PANTA antibiotics. After 28 days the Mycobacterium tuberculosis growth was observed and CFU was measured.

Results:

The in vivo efficacy of compound 003R in a intranasal mouse model of Balb/c mice acute infection was evaluated. After one week following MTB infection, the compounds were orally administered at 25mg/kg once a day for two weeks. Compounds of formula 003R showed a significant 1.2log reduction in CFU (colony forming units) compared to untreated controls (late control, no drug treated parallel run group) and a 1.8log reduction in colony forming units compared to early control (group at the start of treatment).

THE ADVANTAGES OF THE PRESENT INVENTION

The present invention relates to a novel process for the preparation of chiral 1, 1-dialkylethane-1, 2-diols of formula (I), which chiral 1, 1-dialkylethane-1, 2-diols are useful intermediates for the synthesis of 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole related compounds.

In order to introduce the only chiral center in useful 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole related compounds, the present invention employs Sharpless dihydroxylation, which has many advantages over Sharpless epoxidation (commonly used in the prior art), such as simple formulation (single commercial reagent mixture), reaction conditions (near room temperature rather than-40 to-10 ℃ for epoxidation), reaction time (2-12 hours versus about 2 days), solvent advantages (water/t-butanol mixture versus anhydrous DCM and absolute anhydrous conditions), and ease of handling. The present invention provides a concise route to key intermediates of the TB drug delamanib while reducing the number of reaction steps and improving the cost effectiveness of the drug molecule.

The present invention eliminates the need for protecting groups for halophenols and 4-hydroxypiperidine segments. The halophenols are allylated with methallyl chloride, which essentially serves as a protecting group and linkage of the three carbon fragments. The Cu-mediated N-arylation process allows the use of unprotected piperidines, does not require the use of expensive and toxic palladium-based catalysts, and also does not require long periods of high temperature reaction conditions.

The present invention provides novel compounds such as 1- (4- ((2-methylallyl) oxy) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazole (008), (R) -2-methyl-3- (4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) phenoxy) propane-1, 2-diol (009), 5- ((4-fluorophenoxy) methyl) -3- (4- ((2-methylallyl) oxy) phenyl) isoxazol (011), (R) -3- (4- (5- ((4-fluorophenoxy) methyl) isoxazol-3-yl) phenoxy) -2-methylpropan-1, 2-diol (012), 1- (4- ((2-methallyl) oxy) phenyl) piperidin-4-ol (015) and 1- (4- ((2-methallyl) oxy) phenyl) -4- (4- (trifluoromethoxy) phenoxy) piperidine (016); (R) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methylnon-2-ol and 2-heptyl-2-methyl-6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole (003R and 003S) and the like.

Claims

1.A glycol compound selected from the group consisting of:

2. a process for preparing a diol compound of formula (I),

Comprising asymmetric dihydroxylation of a compound of formula (IA) in the presence of an asymmetric catalyst

W is substituted or unsubstituted carbon, wherein n=0, 1,2 or 3;

Y is a substituted or unsubstituted carbon, nitrogen, oxygen or sulfur atom;

Wherein the method comprises the steps of

X=f, cl, br or I;

R is a substituted or unsubstituted alkyl group;

Ar is a substituted or unsubstituted aryl group;

HetAr is a substituted or unsubstituted heteroaryl;

And n=0, 1 or 2;

Wherein the asymmetric catalyst is selected from AD-mix alpha [ (DHQ) 2PHAL, an adduct of dihydroquinine and phthalazine ] or AD-mix beta [ (DHQD) ₂ PHAL, an adduct of dihydroquinidine and phthalazine ]; and

Wherein the diol compound of formula (I) is selected from:

and the compound of formula (IA) is selected from:

3. An olefinic compound selected from the group consisting of:

4. use of a diol compound according to claim 1 for the preparation of a 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole derivative selected from the group consisting of:

5. The use of claim 4, wherein the process for preparing the compound of formula (IIIM-019) comprises:

6. the use of claim 4, wherein the process for preparing the compound of formula (IIIM-114) comprises:

7. A compound selected from the group consisting of:

8. use of compounds of formulae 002-EP (R) and 002-EP (S) as set forth in claim 7 for the preparation of compounds of formulae (003R) and (003S):