Process for preparing derivatives of 1, 1-dialkylethane-1, 2-diols as useful intermediates
阅读说明：本技术 制备作为有用中间体的1，1-二烷基乙烷-1，2-二醇的衍生物的方法 (Process for preparing derivatives of 1, 1-dialkylethane-1, 2-diols as useful intermediates ) 是由 S·沙玛 R·艾哈迈德 S·雷纳 R·A·维什瓦卡尔玛 P·P·辛格 于 2020-03-31 设计创作，主要内容包括：本发明提供了一种合成可用于制备各种含6-硝基-2,3-二氢咪唑并[2,1-b]噁唑的药物的取代二醇中间体1,1-二烷基乙烷-1,2-二醇的新型和实用的路线。具体地,本发明提供了一种用于合成德拉马尼的中间体的新型和实用的路线。(The invention provides a novel and practical route for synthesizing a substituted diol intermediate 1, 1-dialkylethane-1, 2-diol which can be used for preparing various medicines containing 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole. In particular, the present invention provides a novel and useful route for the synthesis of intermediates for delamanit.)
1. A compound of formula (I) or a salt or isomer thereof:
wherein A is substituted or unsubstituted or branched or unbranched C1-C6An 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 substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2.
2. A compound of formula (I) according to claim 1, selected from:
3. a process for the preparation of a diol compound of formula (I),
asymmetric dihydroxylation comprising a compound of formula (IA) in the presence of an asymmetric catalyst
Wherein A is substituted or unsubstituted or branched or unbranched C1-C6An 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 substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from the group consisting of H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2.
4. A compound of formula (IA) or a salt or isomer thereof:
wherein A is substituted or unsubstituted or branched or unbranched C1-C6An 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 substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2.
5. A compound of formula (IA) according to claim 4, selected from:
6. a process for preparing a compound of formula (H):
an intermediate comprising formula (I) or a salt or isomer thereof:
wherein A is substituted or unsubstituted or branched or unbranched C1-C6An 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 substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2.
7. The method of claim 6, wherein the compound of formula (H) is selected from:
8. the process of claims 6 and 7, wherein the process for preparing compounds of formulae (003R) and (003S) comprises:
9. a process as claimed in claims 6 and 7 wherein the process for preparing a compound of formula (VL-2098) comprises:
10. the process of claims 6 and 7, wherein the process for preparing the compound of formula (IIIM-019) comprises:
11. the process of claims 6 and 7, wherein the process for preparing the compound of formula (IIIM-114) comprises:
12. the process of claims 6 and 7, wherein the process for preparing delamanic comprises:
13. a compound selected from the group consisting of:
14. compounds of formulae (003R) and (003S)
15. Antibacterial compounds of formulae (003R) and (003S):
16. a compound according to claim 15 for use in the treatment of a mycobacterial infection.
17. An anti-tubercular pharmaceutical composition of the compound of claim 15.
Technical Field
The present invention relates to the field of the pharmaceutical industry of antibacterial agents. The 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, anti-tuberculosis agents, anti-leishmaniasis agents, and the like, as well as 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 infectious cause of death worldwide. Existing therapies for tuberculosis require lengthy treatment and often require a combination of three or four different drugs (a first-line drug regimen, such as isoniazid, pyrazinamide and rifampin, and several second-line drug regimens, including ethionamide, para-aminosalicylic acid, kanamycin, amikacin, capreomycin, ciprofloxacin, streptomycin, and the like).
Over the past sixty to seventy years, nitroimidazole [ j.med.chem.2017,60,7636-7657] based drugs have played a very important role in combating various types of infections. One of the main results of all these efforts was the discovery and development of delamanic, a nitro-dihydro-imidazooxazole derivative, for the treatment of multidrug resistant tuberculosis (MDR-TB). PCT application WO2004033463a1 reports 2, 3-dihydro-6-nitroimidazo [2,1-b ] oxazoles, including delamanic (compound 1572, page 970 of 1084) and methods for their preparation. In addition to delamanic, several other nitroimidazoles have been studied, such as:
several methods for synthesizing the nitroimidazole molecules described above have been reported. The object 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 process, a nitrohalogenated imidazole or dinitroimidazole is coupled with a three carbon chiral epoxide to produce intermediate (D), which is coupled with a phenol fragment (C) to form intermediate (E) and ultimately converted to the target molecule, as shown below:
in a second approach, a phenol fragment is first coupled with a chiral three-carbon fragment to produce a diol intermediate (F), which is subsequently coupled with an imidazole derivative to form intermediate (E), which is in turn converted to the target molecule, as shown below.
Kuppuswamy Nagrarjan and co-workers (Eur.J.Med.chem.24(1989)631-633) reported the method of the following scheme (I); among them, nitroimidazole derivatives are reported to have anti-tubercular activity. The starting material, 2, 4-dinitroimidazole (I-1), was treated with the epoxy compound (1-2) in hot anhydrous ethanol in the presence of anhydrous sodium acetate to give a separable mixture of isomers (I-3), (I-4) and (1-5) of the nitroimidazole derivative. The 2-nitro group in these reactions serves 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 delamanid. Treating an epoxide compound of formula (II-1) with a phenol of formula (II-2) wherein R1Is hydrogen or lower alkyl, R2Is substituted piperidinyl or substituted piperazinyl, and X1Is a halogen atom or a nitro group 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 radioactive or non-radioactive halogen atoms, reports the treatment of epoxide (III-1) with 4-halophenol (III-2) to provide halogen-containing compound (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 anti-tubercular agents. Treatment of the halonitroimidazole (IV-1) (or the corresponding sulfoxide) with the epoxy-sulfonate (IV-2) affords intermediate (IV-3), which is treated with nucleophile (IV-4) to afford (IV-5), which ultimately affords the target (IV-6).
WO2008/140090 also describes the process of scheme (V) below. Treatment of 1, 4-cyclohexanedione (V-2) with a piperidine derivative (V-1) in the presence of PTSA affords a salt of phenol (V-3). After release of the salt, phenol (V-3) is treated with epoxide (V-4) to give another epoxide (V-5), which when treated with the nitroimidazole derivative (V-6) gives finally (V-7).
WO/2011/093529 describes compounds of the formula (VI-4) which contain organosulphonyloxy groups. Diol compound (VI-1) and piperidine derivative (VI-2) in catalytic amount of Pd2dba3Andtcoupling in toluene in the presence of BuXPhos and sodium tert-butoxide. The resulting diol (VI-3) is converted to the epoxide (VI-5). Coupling of epoxide (VI-5) with halonitroimidazole (VI-6) affords the target molecule (VI-8) via intermediate (VI-7).
WO2016158737a1 also describes a process for the preparation of nitroimidazole derivatives. 4- (4-trifluoromethoxyphenoxy) piperidine (VII-1) is reacted with hydroquinone (VII-2) at elevated temperature to give 1- (4-hydroxyphenyl) -4- (4-trifluoromethoxyphenoxy) piperidine (VII-3). Subsequently, the (VII-3) is treated with ethylene oxide (VII-4) to give a diol (VII-5) which is converted into another epoxide (VII-6); it is further converted into the target (VII-9) through an intermediate (VII-8).
The diol intermediate (F) may also be prepared by optionally allylating the phenol (C) to form an intermediate of type (G) followed by asymmetric dihydroxylation, as described above. Reactions of this type are the subject of the present invention. (F) The diol compound can be further converted into a target nitrodihydroimidazooxazole 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 ] oxazole useful in 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 delamasib.
Disclosure of Invention
In one aspect, the present invention provides a compound of formula (I) or a salt or isomer thereof:
a compound of formula (I) or a salt or isomer thereof:
wherein A is substituted or unsubstituted or branched or unbranched C1-C6An 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 substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2.
In another aspect, the compound of formula (I) is a1, 1-dialkylethane-1, 2-diol.
In another aspect, the present invention provides a process for the preparation of 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 a diol compound of formula (I) from the corresponding olefin compound of formula (IA) by 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 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 olefinic compound of formula (IA), comprising: the corresponding phenol is alkylated/allylated with 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-dialkylethane-1, 2-diol of formula (I) is selected from the group consisting of compounds of the formula:
in another aspect, the present invention provides the use of a compound of general formula (I) for the preparation of a 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole derivative of the following 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 present invention provides a compound of the formula:
in another aspect, the present invention provides antibacterial compounds of the formula:
in another aspect, the present invention provides compounds of formulae (003R) and (003S) for use in the treatment of mycobacterial infections.
In another aspect, the present invention provides anti-tubercular pharmaceutical compositions of compounds of formulae (003R) and (003S).
Drawings
FIG. 1: HPLC chromatogram of crude reaction mixture of compound of formula (009) for determination of% ee.
FIG. 2: HPLC chromatogram of crude reaction mixture of compound of formula (017) for determining% ee.
FIG. 3: anti-TB in vivo efficacy data for compound 003(R) in a mouse infection model.
Detailed Description
In one aspect, the present invention provides a compound of formula (I) or a salt or isomer thereof:
wherein A is substituted or unsubstituted or branched or unbranched C1-C6An 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 substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from the group consisting of H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2.
In another aspect, Z in formula (I) can be aryl independently substituted with an N-Het group, where N-Het represents and is independently selected from one of an N-containing alkyl or aryl system, such as acridine, azabenzotriazole, azaindole, azepane, aza-cycloheptaneAzetidine, aziridine, benzimidazole, benzotriazole, carbazole, cinnoline, cyclopenta [ b ] or a salt thereof]Pyridine, deazapurine, diazaDihydropyridines, imidazopyridines, imidazoles, imidazolidines, imidazopyridazines, imidazopyridines, imidazopyrimidines, indazoles, indoles, indolizines, isoindoles, isoquinolines, naphthyridines, oxindoles, phenanthrolines, phenazines, phthalazines, piperazines, piperidines, pteridines, purines, pyrazines, pyrazolidines, pyrazolopyridines, pyridazines, pyridines, pyridopyridazines, pyrimidines, pyrrolidines, pyrroles, pyrrolopyrimidines, pyrrolines, pyrrolopyridazines, pyrrolopyrimidines, quinazolines, quinolines, quinolizines, quinoxalines, tetrazoles, triazaphthalenes, triazines, triazoles, triazolopyridines, and isomers thereof, preferably in the para-position.
In one aspect, the present invention provides a compound of general formula (I) selected from the group consisting of:
in another aspect, the compound of formula (I) is a1, 1-dialkylethane-1, 2-diol selected from the group consisting of.
In another aspect, the present invention provides a process for the preparation of 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 a diol compound of formula (I) from the corresponding olefin compound of formula (IA) by an asymmetric dihydroxylation reaction.
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 comprising:
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 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 α [ (DHQ)2PHAL, dihydro quinine and phthalazine adducts]Or AD-mix beta [ (DHQD)2PHAL, dihydro quinidine and phthalazine adducts]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, tert-butanol, and the like, or mixtures thereof. Most preferably, a suitable solvent is a mixture of tert-butanol and water.
Suitable temperatures for the reaction are about-30 ℃ to 40 ℃. Preferably, a suitable temperature range is from-5 ℃ to 25 ℃.
Suitable time periods for the reaction are from 4 hours to 24 hours, although they may vary with respect to the 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 present invention provides the use of a compound of general formula (I) for the preparation of a 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole derivative of the following formula (H):
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 present invention provides a compound of the formula:
in another aspect, the present invention provides antibacterial compounds of the formula:
in another aspect, the present invention provides compounds of formulae (003R) and (003S) for use in the treatment of mycobacterial infections.
In another aspect, the present invention provides anti-tubercular pharmaceutical compositions of compounds of formulae (003R) and (003S).
In another aspect, the present invention provides a process for preparing an olefinic 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 allyl halide (e.g., allyl bromide, allyl chloride, or allyl iodide) derivative 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) at a suitable temperature (60-70 ℃).
The allylation step serves as a protecting group for the phenolic OH group for subsequent reactions, and the attachment of the three-carbon fragment to the molecule, thereby saving the two steps of protection and deprotection that would otherwise be required.
In another aspect, the olefin of formula (IA), e.g., the compounds of formulas ((001), (005), etc.), can be commercially available or can be prepared by simple synthetic methods. Reacting the corresponding phenolic compound with 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 60-70 ℃, for about 6-12 hours;
on the other hand, processes for olefins having formula (IA), such as compounds having formula (008, 011, 016, etc.), can be difficult and require multiple preparation steps.
In another aspect, the phenol compound of formula (007) can be prepared by a cycloaddition reaction between 4-azidophenol (R6) and 1- (prop-2-yn-1-yloxy) -4- (trifluoromethoxy) benzene (R4), the 4-azidophenol (R6) being prepared by the azido reaction of 4-aminophenol (R5), and the 1- (prop-2-yn-1-yloxy) -4- (trifluoromethoxy) benzene (R4) being prepared by the propargylation reaction of 4-trifluoromethoxyphenol (R2) with propargyl halide (R3).
In another aspect, the phenolic compound of formula (010) may be prepared by a 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).
On the other hand, the phenol compound having formula (016) can be prepared by allylating the phenol compound having formula (013) using methallyl chloride as allylating agent, followed by CuI-mediated N-arylation using unprotected 4-hydroxypiperidine as amine source to provide the alcohol having formula (015), and finally performing O-arylation under the Mitsunobu reaction condition.
On the other hand, the compound of formula (016) can also be prepared by N-arylation of a compound of formula (014) using commercially available 4- (4- (trifluoromethoxy) phenoxy) piperidine as an amine source.
Scheme for the preparation of compounds of formula (016) by using the commercially available 4- (4- (trifluoromethoxy) phenoxy) piperidine:
figure 1 shows an HPLC chromatogram of the crude reaction mixture of compound of formula (009) for determining% ee. The peak of racemic isomer (RS) of compound of formula (009) is shown in part A of FIG. 1. Part B shows the peaks for the optically pure R-isomer of the compound of formula (009). Section 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 determining% ee. Part a of fig. 2 shows a peak of racemic isomer (RS) of 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 of formula (017).
Table 1: list of compounds
Definition of
The terms used in this disclosure use a number of specific 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" can refer to ± 10% of the number, including the number indicated. 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 also meant a straight or branched chain monovalent hydrocarbon containing up to 1 to 20 carbon atoms;
an "alkyl" group can also be represented by- (CR1R2) n-where R1 and R2 are independently hydrogen or 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 can be independently defined by any one of the alkyl groups, and can be a different group;
the term "substituted alkyl" refers to a straight or branched chain group of 1 to 7 carbons in which one or more hydrogens are replaced with hydroxy, amino, nitro, halo, trifluoromethyl, cyano, -NH (lower alkyl), -N (lower alkyl) 2, lower alkoxy, lower alkylthio, or carboxy; the term "substituted alkyl" refers to groups such as methyl, ethyl, propyl, isopropyl, vinyl, allyl, n-butyl, isobutyl, and tert-butyl, 1-propenyl, isoprenyl, 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 1-4 carbons, wherein one hydrogen is replaced by hydroxy, amino, halogen, trifluoromethyl, cyano, -NH (lower alkyl), -N (lower alkyl)2Lower alkoxy, lower alkylthio or carboxy substitution;
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 chain monovalent hydrocarbons containing 2 to 20 carbon atoms (e.g., C2 to C10 or C2 to C4) and one or more double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, propenylene, allyl, and 1, 4-butadienyl;
the term "substituted alkenyl" refers to a straight or branched chain group of 3-7 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 a straight or branched chain monovalent hydrocarbon containing 2 to 20 carbon atoms (e.g., C2 to C10) and one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-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 lower alkyl as defined above attached to oxygen or sulfur;
the term "acyloxy" refers to the group-O-C (O) -R, where R can 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 the group-n (R) -alkyl, wherein R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
the terms "amido" and "ureido" refer to the groups-NRC (O) R ' and-C (O) NRR ', respectively, where R and R ' may 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-cyclohexylene, 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 include, but are not limited to, pyranyl, dihydrobenzimidazolyl, and 1, 3-dihydrospiro [ benzo [ d ] imidazole-2, 1' -cyclopentan-4-yl;
the term "aryl" refers to phenyl, 1-naphthyl and 2-naphthyl; it also refers to a monovalent 6 carbon monocyclic, 10 carbon bicyclic, 14 carbon tricyclic aromatic ring system. Examples include, but are not limited to, phenyl ("Ph"), naphthyl, pyrenyl, anthracenyl, and phenanthrenyl. The term "aryloxy" refers to-O-aryl;
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-n (R) -aryl, where 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 a monocyclic 5 or 6 atom unsaturated ring containing one or two O and S atoms and/or one to four N atoms, provided that the only other atoms in the 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 through available carbon or nitrogen atoms; and the monocyclic or bicyclic ring may be substituted on an available carbon atom by a lower alkyl group of 1 to 4 carbons, halogen, hydroxy, benzyl or cyclohexylmethyl, or may be substituted on an available nitrogen atom by benzyloxymethyl, p-toluenesulfonyl, 2, 4-dinitrophenyl, a lower alkyl group 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;
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 alkylsulfonamido, arylsulfonamido, hydroxy, halogen, oxo (O ═ thio), thio (S ═) thio, silyl, C1-C10 alkylthio, arylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, and heteroarylthio, Mercapto, amido, thioureido, thiocyanato, sulfonamido, guanidine, ureido (urido), nitro, nitroso, azido, acyl, thioacyl, acyloxy, ureido ((R))carbamido) Carbamoyl (-C (O) NH2), carboxyl (-COOH) and carboxylic acid ester;
on the other hand, possible substituents on the alkyl, alkenyl, alkylene, alkenylene, heteroalkylene, heteroalkenylene, or alkynyl group include all of the above substituents except the C1-C10 alkyl group;
cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also be fused to each other by sharing one or more atoms (e.g., to form a spiro compound);
wherein the R groups, when present, are each 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 is each independently-CH 2-or N, provided that when X is a divalent group in the ring, 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 Synthesis of (S) -2-methylnonane-1, 2-diol (002):
in a 100mL round bottom flask equipped with a magnetic stir bar was placed tert-butanol: water (1:1, 30mL) and AD-mix- α (12 gm). The mixture was stirred at room temperature until two clear phases were produced; the lower (aqueous) phase was bright yellow. Vigorous stirring was required to dissolve all of the AD-mix. The mixture was cooled to 0 ℃ (some dissolved salts precipitated). 2-Methylnon-1-ene (001) (5gm, 35.12mmol) was added and the mixture was stirred vigorously at 0 deg.C (temperature important!), and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at 0 ℃ for 6 hours, and 1.93g (15.3mmol) of sodium sulfite was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Dichloromethane (20mL) and water (40mL) were added sequentially and the reaction mixture was extracted with portions of DCM. The combined organic phases were passed over anhydrous MgSO4Drying, filtering and concentrating under reduced pressure to give a crude oil. The residue was purified by silica gel column chromatography using 4: elution with a gradient of 1 hexane/ethyl acetate gave (002) (S) as a colorless oil. Yield (4.4gm, 71%).
Synthesis of (R) -2-methylnonane-1, 2-diol (002) (R):
in a 100mL round bottom flask equipped with a magnetic stir bar was placed tert-butanol: water (1:1, 30mL) and AD-mix-. beta.5.5 gm. The mixture was stirred at room temperature until two clear phases were produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring was required to dissolve all of the AD-mix. The mixture was cooled to 0 ℃ (some dissolved salts may precipitate). 2-Methylnon-1-ene (001) (2gm, 35.12mmol) was added and the mixture was stirred vigorously at 0 deg.C (temperature important!), and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at 0 ℃ for 6 hours, and 1.93g (15.3mmol) of sodium sulfite was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Dichloromethane (20mL) and water (40mL) were added sequentially and the reaction mixture was extracted with portions of DCM. The combined organic phases were washed with anhydrous MgSO4Dried, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by silica gel column chromatography using 4: elution with a gradient of 1 hexane/ethyl acetate gave a colorless oil (002). Yield (1.6gm, 58%).
Step 2 (R) -2-heptyl-2-methyloxirane (002-EPR) synthesis:
in a 100mL round bottom flask, (R) -2-methylnonane-1, 2-diol 002(1.6gm, 2mmol) was added to DCM solvent and triethylamine (0.960mL, 4mmol) was added, followed by methanesulfonyl chloride (280. mu.L, 2.2mmol) dropwise at 0 ℃ 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 mesylated product as a gummy material and used as such in the next reaction. In the next step, the mesylated compound was dissolved in ethyl acetate and DBU (300 μ L, 4mmol) 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 and then with ethyl acetate: hexane (40: 60) was purified as eluent over 100-200 silica gel to give compound 002-EP as a brown gummy liquid. (1.4gm, 85% yield).
Synthesis of (S) -2-heptyl-2-methyloxirane (002-EPS):
in a 100mL round bottom flask, (S) -2-methylnonane-1, 2-diol 002S (800mg, 2mmol) was added to DCM solvent and triethylamine (0.480mL, 4mmol) was added, followed by methanesulfonyl chloride (140. mu.L, 2.2mmol) dropwise at 0 ℃ and stirring at room temperature for 2 h. The solvent was then evaporated and extracted with ethyl acetate and aqueous layer. The organic solvent was evaporated to give the mesylated product as a gummy material and used as such in the next reaction. In the next step, the mesylated compound was dissolved in ethyl acetate and DBU (150 μ L, 4mmol) 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 and then with ethyl acetate: hexane (40: 60) was purified as eluent over 100-200 silica gel to give compound 002-EPS as a brown colloidal liquid. (700mg, yield 82%).
Step 3 Synthesis of (R) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methylnonan-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 (1.0g, 8.2mmol), epoxide 002-EP (S) (1.32g, 9.86mmol) and triethylamine (2.28mL, 16.4mmol) in ethyl acetate (4.0mL) 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 acyclic intermediate. TLC (EtOAc: hexane 4:6) Rf 0.20; yield: and 69 percent. The intermediate (1.0gm, 3mmol) was then dissolved in anhydrous DMF, cesium carbonate (2.2gm, 6mmol) was added, and the reaction mixture was stirred at 50 ℃ for 2 hours. Water (20mL) was added in order, and the reaction mixture was extracted with a portion of ethyl acetate. The combined organic phases were washed with anhydrous MgSO4Dried, filtered and concentrated under reduced pressure to give the crude material. The residue was purified by silica gel column chromatography using 4: the product eluted with a gradient of 1 hexane/ethyl acetate as a pale yellow solid (003R). Yield (61%).
Synthesis of (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methylnonan-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 (1.0g, 8.2mmol), epoxide 002-EP (R) (660mg, 9.86mmol) and triethylamine (1.14mL, 16.4mmol) in ethyl acetate (2.0mL) 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 acyclic intermediate. TLC (EtOAc: hexane 4:6) Rf 0.20; yield: and 69 percent. The intermediate (1.0gm, 3mmol) was then dissolved in anhydrous DMF, cesium carbonate (2.2gm, 6mmol) was added, and the reaction mixture was stirred at 50 ℃ for 2 hours. Water (20mL) was added in order, and the reaction mixture was extracted with a portion of ethyl acetate. The combined organic phases were washed with anhydrous MgSO4Dried, filtered and concentrated under reduced pressure to give the crude material. The residue was purified by silica gel column chromatography using 4: elution with a gradient of 1 hexanes/ethyl acetate afforded the product as a pale yellow solid (003S). Yield (57%).
0031H 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):
starting material 4-trifluoromethoxyphenol (004) (5gm, 28mmol, 1 eq.) and K2CO3(7.8gm, 56mmol, 2 equiv.) is suspended in DMF. Methallyl chloride (3mL, 36.4mmol, 1.3 equivalents) 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. Over MgSO4Drying, filtration and rotary evaporation gave the crude material. Silica gel column chromatography stoneThe residue was separated with oil 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):
in a 100mL round bottom flask equipped with a magnetic stir bar was placed tert-butanol: water (1:1, 30mL) and AD-mix- α (4 gm). The mixture was stirred at room temperature until two clear phases were produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring was required to dissolve all of the AD-mix. The mixture was cooled to 0 ℃ (some dissolved salts may precipitate). 1- ((2-Methylallyl) oxy) -4- (trifluoromethoxy) benzene (005) (1gm, 4.31mmol) was added and the mixture was stirred vigorously at 0 ℃ to room temperature (temperature important!), and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at room temperature for 6-12 hours, and 1.93g (15.3mmol) of sodium sulfite was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. DCM (20mL) and water (40mL) were then added sequentially and the reaction mixture was extracted with portions of DCM. The combined organic phases were washed with anhydrous MgSO4Dried, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by silica gel column chromatography using 4: gradient elution with 1 hexanes/ethyl acetate afforded colorless oily material (006) (R). Yield 1.0g (88%).
And 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(0.360gm, 2mmol) was added to DCM solvent and triethylamine (0.240mL, 4mmol) was added, followed by dropwise addition of methanesulfonyl chloride (70. mu.L, 2.2mmol) at 0 ℃ 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 mesylated product as a gummy material and used as such in the next reaction. In the next step, the mesylated compound was dissolved in ethyl acetate and DBU (60 μ L, 4mmol) 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 and then with ethyl acetate: hexane (40: 60) was purified as eluent over 100-200 silica gel to give compound 006-EP (R) as a brown gummy liquid. (0.240gm, 85% yield).
And 4, 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) (240mg, 1mmol), 2-bromo-4-nitro-1H-imidazole (190mg, 1mmol) and DIPEA (2.0mL) was placed in a sealed tube and heated at 115 deg.C 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. To a stirred solution of the crude product in anhydrous DMF was added cesium carbonate and the reaction mixture was stirred at 50 ℃ for 2 hours, then after completion of the reaction, water was added and the reaction mixture was extracted with ethyl acetate. The solvent was then evaporated and the reaction mixture was purified over silica gel 100-: elution with dichloromethane provided compound VL-2098 as a white solid (172mg, 48%). [ alpha ] to]D25+7 ° (c1, chloroform)
1H NMR(400MHz,CDCl3) δ 7.53(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 +): calculated M/z (M + H)+360.20。
Example III, step 1 Synthesis of 1- (4- ((2-methylallyl) oxy) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazole, (008):
starting material 4- (4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) phenol (007) (5gm, 14.24mmol, 1 eq.) and K2CO3(4gm, 28.48mmol, 2 equiv.) is suspended in DMF. Methallyl chloride (1.7mL, 18.15mmol, 1.3 equivalents) was then added and the reaction heated to 70 ℃ for 2 hoursThe time period of (a). After cooling, the mixture was diluted with EtOAc and transferred to a separatory funnel. The organic phase is treated with H2Wash twice with brine. Over MgSO4Drying, filtration and rotary evaporation gave the crude material. The residue was separated by silica gel column chromatography 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):
in a 100mL round bottom flask equipped with a magnetic stir bar was placed tert-butanol: water (1:1, 40mL) and AD-mix-. beta.s (gm). The mixture was stirred at room temperature until two clear phases were produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring was required to dissolve all of the AD-mix. The mixture was cooled to 0 ℃, and some dissolved salts could precipitate). 1- (4- ((2-methylallyl) oxy) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazole (008) (1gm,2.47mmol) was added and the mixture was stirred vigorously at 0 deg.C (temperature important!) and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at 0 ℃ for 6 hours, and 19g (15.3mmol) of sodium sulfide was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Dichloromethane (20mL) and water (40mL) were then added sequentially and the reaction mixture was extracted with portions of DCM. The combined organic phases were washed with anhydrous MgSO4Dried, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by silica gel column chromatography using 4: elution was with a gradient of 1 hexane/ethyl acetate as a brown gummy solid (009) (S). Yield (950mg, 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):
in a 100mL round bottom flask equipped with a magnetic stir bar was placed tert-butanol: water (1:1, 40mL) and AD-mix- α (2.81 gm). The mixture was stirred at room temperature until two clear phases were produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring was required to dissolve all of the AD-mix. Cooling the mixture to 0 ℃, -. -Some dissolved salts may precipitate). 1- (4- ((2-methylallyl) oxy) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) -1H-1,2, 3-triazole (008) (4gm, 9.87mmol) was added and the mixture was stirred vigorously at 0 deg.C (temperature important!) and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at 0 ℃ for 6 hours, and 19g (15.3mmol) of sodium sulfide was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Dichloromethane (20mL) and water (40mL) were then added sequentially and the reaction mixture was extracted with portions of DCM. The combined organic phases were washed with anhydrous MgSO4Dried, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by silica gel column chromatography using 4: elution was with a gradient of 1 hexanes/ethyl acetate as a brown gummy solid (009) (R). Yield (3.9gm, 90%).
And 4, step 4: epoxidation
Synthesis of (R) -1- (4- ((2-methyloxiran-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(3.6gm, 2mmol) was added to DCM solvent and triethylamine (2.4mL, 4mmol) was added, followed by methanesulfonyl chloride (0.684mL, 2.2mmol) dropwise at 0 ℃ and stirring at room temperature for 2 hours. The solvent was then evaporated and extracted with ethyl acetate and aqueous layer. Evaporation of the organic solvent gave the mesylated product as a gummy material and used as such in the next reaction. In the next step, the mesylated compound was dissolved in ethyl acetate and DBU (0.596mL, 4mmol) was added and the reaction mixture 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 and then washed with ethyl acetate: hexane (40: 60) was purified as eluent over 100-200 silica gel to give compound 009-EP (R) as a brown gummy liquid. (2.4gm, 85% yield).
And 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) (2.4g,5mmol), 2-bromo-4-nitro-1H-imidazole (730mg,5mmol) and DIPEA (2.0mL) was placed in a sealed tube and heated at 115 deg.C 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. To the stirred dry DMF solution of the crude product was added cesium carbonate 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 over silica gel 100-: elution with dichloromethane gave final compound IIIM-019 as a white solid (300mg, 48%). [ alpha ] to]D25+7 ° (c1, chloroform)
Example IV, step 1: synthesis of 5- (4-fluorophenethyl) -3- (4- ((2-methylallyl) oxy) phenyl) isoxazole (011):
starting material 4- (5- ((4-fluorophenoxy) methyl) isoxazol-3-yl) phenol (010) (5gm, 17.55mmol, 1 eq.) and K2CO3(4.8gm, 35.1mmol, 2 equivalents) was suspended in DMF. Methallyl chloride (2.04mL, 22.75mmol, 1.3 equivalents) 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 water and once with brine. Over MgSO4Drying, filtration and rotary evaporation gave the crude material. The residue was separated by silica gel chromatography using petroleum ether/ethyl acetate (9: 1) as eluent to give the corresponding allyl ether product (oil). (5.5gm, 93% yield).
Example IV, step 2: synthesis of (R) -3- (4- (5- (4-fluorophenethyl) isoxazol-3-yl) phenoxy) -2-methylpropan-1, 2-diol (012) (R):
in a 100mL round bottom flask equipped with a magnetic stir bar was placed tert-butanol: water (1:1, 40mL) and AD-mix- α (13.45 gm). The mixture was stirred at room temperature until two clear phases were produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring was required to dissolve all of the AD-mix. The mixture was cooled to 0 ℃, and some dissolved salts could precipitate). 5- ((4-fluorophenoxy) methyl) -3- (4- ((2-methylallyl) oxy) phenyl) isoxazole (011) (4gm, 11.79mmol) was added and the mixture was stirred vigorously at 0 deg.C (temperature important!), and the progress of the reaction was monitored by TLC. The resulting mixture was stirred vigorously at 0 ℃ for 6 hours and 19g (15.3mmol) of sodium sulfide were added. The reaction mixture was warmed to room temperature and stirred for 1 hour. Then 20ml of DCM and 40ml of water are added successively and the reaction mixture is extracted with a portion of DCM. The combined organic phases were washed with anhydrous MgSO4Dried, filtered and concentrated under reduced pressure to give a crude oil. The residue was purified by silica gel column chromatography using 4: elution with a gradient of 1 hexane/ethyl acetate gave product (012) (R) as a brown gum. Yield (4.0gm, 90%).
And 4, step 4: epoxidation
Synthesis of (R) -5- ((4-fluorophenoxy) methyl) -3- (4- ((2-methyloxiran-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-methylpropane-1, 2-diol 012(1.8gm, 2mmol) was dissolved in DCM solvent and triethylamine (1.2mL, 4mmol) was added, then methanesulfonyl chloride (0.342mL, 2.2mmol) was added dropwise at 0 ℃ and stirred at room temperature for 2h, then the solvent was evaporated and extracted with ethyl acetate and an aqueous layer the organic solvent was evaporated to give the methanesulfonylated product as a gum and used as such for the next reaction in the next step, the methanesulfonylated compound was dissolved in ethyl acetate and DBU (0.596mL, 4mmol) 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 under a rotary evaporator and then washed with ethyl acetate: hexane (40: 60) was purified as eluent over 100-200 silica gel to give compound O12-EP (R) as a brown gummy liquid. (1.2gm, 81% yield).
And 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) (2.4g,5mmol), 2-bromo-4-nitro-1H-imidazole (1.4g,5mmol), and DIPEA (4.0mL) was placed in a sealed tube and heated at 115 deg.C 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. To the stirred dry DMF solution of the crude product was added cesium carbonate 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 over silica gel 100-: elution with dichloromethane afforded final compound IIIM-114 as a white solid (0.800gm, 48%).
Example V, step 1: synthesis of 1-iodo-4- ((2-methylallyl) oxy) benzene (014):
starting material 4-iodophenol (013) (20gm, 91mmol, 1 eq.) and K2CO3(182mmol, 2 equivalents) was suspended in DMF. Methallyl chloride (118.3mmol, 1.3 equivalents) 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 is treated with H2Wash twice with brine. Over MgSO4Drying, filtration and rotary evaporation gave the crude material. The residue was separated by silica gel column chromatography using petroleum ether/ethyl acetate (9: 1) as eluent to give the corresponding allyl ether product (014). (24gm, yield 97%).
Example V, step 2 Synthesis of 1- (4- ((2-methylallyl) oxy) phenyl) piperidin-4-ol (015):
TABLE 2 optimization of general N-arylation reaction conditions
Numbering
Solvent(s)
Catalyst and process for preparing same
Ligands
Alkali
Temperature of
Time
Yield%
1.
Toluene
Pd(OAc)2
Rac-Binap
Cs2CO3
100℃
24hrs
40
2.
DMSO
CuI
Phenanthroline
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
------
rt
24hrs
60
6.
DMF
CuI
Pyrrolidine as a therapeutic agent
------
rt
24hrs.
35
Table 3: n-arylation catalyst and optimization of ligand mol%
Numbering
Solvent(s)
CuI mol％
L-proline mol%
Temperature of
Time
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 (5gm, 0.3mmol) and L-proline (6.0gm, 0.6 mmol). Using high N in flask2The atmosphere was evacuated and then a rubber septum was fitted. DMSO (80mL) was then added, along with aryl iodide (014) (25gm, 91mmol) added at this stage. The resulting blue solution was stirred for 10 minutes, then 4-hydroxypiperidine (27.3gm, 273.0mmol) 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 give the desired pure product (015) as a solid (20gm, 88% yield).
Example V, step 3: synthesis of 1- (4- ((2-methylallyl) oxy) phenyl) -4- (4- (trifluoromethoxy) phenoxy) piperidine (016):
table 4: optimization of general reaction conditions for O-arylation
To a solution of 4-hydroxypiperidine derivative (015) (10g, 40mmol) in THF (60mL) was added PPh3(15g, 60mmol), and a solution of 4-trifluoromethoxyphenol (5.6mL, 44mmol) and DEAD (9.8mL) 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 silica gel column chromatography (eluent: hexane: EtOAc ═ 4:1(V/V)) to give 1- (4- ((2-methylallyl) oxy) phenyl) -4- (4- (trifluoromethoxy) phenoxy) piperidine (016) (10gm, 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)
In a 100mL round bottom flask equipped with a magnetic stir bar was placed tert-butanol: water (1:1, 30mL) and AD-mix- α (12 gm). The mixture was stirred at room temperature until two clear phases were produced; the lower layer (water) is correspondingly bright yellow. Vigorous stirring was required to dissolve all of the AD-mix. The mixture was cooled to 0 ℃, and some dissolved salts could precipitate). 1- (4- ((2-methylallyl) oxy) phenyl) -4- (4- (trifluoromethoxy) phenoxy) piperidine (016) (5gm,12.28mmol) was added and the mixture was stirred vigorously at 0 deg.C (temperature important!) and the progress of the reaction was followed by TLC. The resulting mixture was stirred vigorously at 0 ℃ for 6h, 1.93g (15.3mmol) of sodium sulfide was added, the reaction mixture was warmed to room temperature, stirred for 1h, then 20mL of DCM and 40mL of water were added in order, the reaction mixture was extracted with a portion of DCM, and the combined organic phases were over anhydrous MgSO4Drying, filtering, and concentrating under reduced pressure to obtain crude oilThe residue was purified by silica gel column chromatography using a 4: the gradient 1 hexane/ethyl acetate eluted as a brown gum (017) (R). Yield (4.4gm, 86%). The enantiomeric excess can be determined by chiral HPLC techniques using a chiral packed column.
And 5: epoxidation
Synthesis of (R) -2-hydroxy-2-methyl-3- (4- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) phenoxy) propyl methanesulfonate and (R) -1- (4- ((2-methyloxiran-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(0.9gm, 2mmol) was added to DCM solvent and triethylamine (0.570mL, 4mmol) was added, followed by dropwise addition of methanesulfonyl chloride (0.170mL, 2.2mmol) at 0 ℃ 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 mesylated product as a gummy material and used as such in the next reaction. In the next step, the mesylated compound was dissolved in ethyl acetate and DBU (0.596mL, 4mmol) was added and the reaction mixture 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 and then washed with ethyl acetate: hexane (40: 60) was purified as eluent over 100-200 silica gel to give the compound 017-EP (R) as a brown gummy liquid. (0.7gm, yield 82%).
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 (delamanic):
table 5: optimization of general reaction conditions for epoxide opening
Serial number
Solvent(s)
Alkali
Temperature of
Yield%
1
Ethyl acetate
Et3N
70
NR
2
---
Et3N
80
Micro-scale
3
---
DBU
100
NR
4
DMF
Cs2CO3
100
Micro-scale
5
---
DIPEA
115
89
A mixture of epoxide 017-EP (R) (424mg, 1mmol), 2-bromo-4-nitro-1H-imidazole (190mg, 1mmol) and DIPEA (2.0mL) 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, and the residue was purified on silica gel 100-200, then eluted with 0.5% EtOAc/CH2Cl2 to give the desired compound (552mg) in 90% yield. To a stirred solution of the uncyclized compound (307mg, 0.5mol) in anhydrous DMF was added cesium carbonate and the reaction mixture was stirred at 50 ℃ for 2 hours, then after completion of the reaction, water was added and extracted with ethyl acetate. The solvent was then evaporated and the reaction mixture was purified using silica gel 100-200, eluting with 40% ethyl acetate: dichloromethane, to give the compound Delamani 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); c25H25F3N4O6HRMS (ESI +) calculation of (535.180) [ M + H ]](+) measured value 535.179.
Biological evaluation:
anti-mycobacterium tuberculosis H37In vitro activity of RV
The method comprises the following steps: determination of anti-mycobacterium tuberculosis (m.tuberculosis) H by broth dilution method37Rv(ATCC 27294(ii) a American type culture Collection, Manassas, VA, USA), Mycobacterium tuberculosis (M.tuberculosis) MDR (isoniazid and rifampicin resistant), and laboratory-produced mutant Mycobacterium tuberculosis RifR(Rifampicin resistance)10MIC of one, using 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.) at 37 ℃ and 5% CO2For 10 to 15 days under shaking conditions to promote exponential growth of the organism. Bacterial suspensions were prepared by suspending M.tuberculosis growths in physiological saline containing 0.5% tween 80 and adjusting turbidity to 1McFarland (McF) standard, which corresponds to 1.0X 107cfu/mL. 2-fold serial dilutions of the compounds were prepared in 96-well U-bottom microtiter plates (Tarson, Mumbai, India) at 100 μ L/well in Middle brook 7H9(Difco laboratories) for mycobacterium tuberculosis. The above bacterial suspension was further diluted 1:10 in growth medium and a volume of 100. mu.L of this diluted inoculum was added to each well of the plate, resulting in a 1.0X 10 in the well6CFU/mL of final inoculum, and final concentration of compound ranging from 0.015 to 32 μ g/mL. Plates were incubated at 37 ℃ in 5% CO2 for 7 days. To evaluate the results (Resaurin microtitre assay), REMA method was used. After incubation, 15 μ L of 0.04% resazurin and 12.5 μ L of 20% tween 80 were added to each well of the plate including the medium and growth controls. After 48 hours of incubation, the plates were read visually and the minimum concentration of compound showing no color change was recorded as the MIC.
As a result:
the compound of formula 003 as claimed, wherein the compound is para H37RV M. tuberculosis shows in vitro antitubercular activity with MIC of 0.25-0.015. mu.g/ml, and the compound of formula (003R) shows significant in vitro activity with MIC of 0.015. mu.g/ml.
aMIC minimum inhibitory concentration and
H37RVtoxic strains of Mycobacterium tuberculosis;
in vivo efficacy studies of compound 003R:
preparation of dosage:
the compound of formula 003R was dissolved in a minimal amount of DMSO and then mixed in alcohol with 5% ethanol and 95% PEG400(v/v) to reach final volume. The compound was dissolved to a final concentration of 25mg/kg while isoniazid was prepared at the same concentration of 25 mg/kg. A total of 200 μ L volumes of the respective doses 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 and served 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 culture was diluted to a final strength of 1 McF. 20 μ l of this culture was administered by the left nasal route. Dosing was started after the first day of infection and three mice from early controls were also dissected simultaneously, which allowed counting of mycobacteria established in the lungs. Two weeks later, mice from the late control and treatment groups were sacrificed and the left lung was removed. It allows monitoring of the reduction of bacillary load after treatment and comparison with early and late controls. The left lung was removed during dissection and partitioned in 1ml NST and the sample was 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 pana antibiotics. After 28 days, growth of Mycobacterium tuberculosis was observed and CFU was measured.
As a result:
compound 003R was evaluated for in vivo efficacy in an intranasal mouse model of acute Balb/c mouse infection. One week after MTB infection, compounds were administered orally at 25mg/kg once daily for two weeks. The compound having formula 003R showed a significant 1.2log reduction in CFU (colony forming units) compared to the untreated control (late control, parallel run without drug treatment) and 1.8log reduction in colony forming units compared to the 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) as useful intermediates for the synthesis of 6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole related compounds.
To introduce a unique 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 commercially available 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/tert-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 as well as 4-hydroxypiperidine fragments. The halophenol is allylated with methallyl chloride, which essentially serves as a protecting group and the linkage of the three carbon fragment. The Cu-mediated N-arylation process allows the use of unprotected piperidine, does not require the use of expensive and toxic palladium-based catalysts, and also does not require long-term 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- ((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) isoxazole (011), (R) -3- (4- (5- ((4-fluorophenoxy) methyl) isoxazole-3-yl) Phenoxy) -2-methylpropane-1, 2-diol (012), 1- (4- ((2-methylallyl) oxy) phenyl) piperidin-4-ol (015), and 1- (4- ((2-methylallyl) oxy) phenyl) -4- (4- (trifluoromethoxy) phenoxy) piperidine (016); (R) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methylnonan-2-ol and 2-heptyl-2-methyl-6-nitro-2, 3-dihydroimidazo [2,1-b ] oxazole (003R and 003S), and the like.
The claims (modification according to treaty clause 19)
1. A compound of formula (I) or a salt or isomer thereof:
wherein A is substituted or unsubstituted or branched or unbranched C1-C6An alkyl group;
w is substituted or unsubstituted carbon, wherein n ═ 0, 1,2, or 3;
y is a substituted or unsubstituted nitrogen, oxygen or sulfur atom;
z is substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2;
wherein when said Z is aryl independently substituted with an N-Het group, said N-Het is independently selected from one of the following alkyl or aryl groups: acridine, azabenzotriazole, azaindole, azepane, azaAzetidine, aziridine, benzimidazole, benzotriazole, carbazole, cinnoline, cyclopenta [ b ]]Pyridine, deazapurine, diazaDihydropyridines, imidazopyridines, imidazoles, imidazolidines, imidazopyridazines, imidazopyridines, imidazopyrimidines, indazoles, indoles, indolizines, isoindoles, isoquinolines, naphthyridines, oxindoles, phenanthrolines, phenazines, phthalazines, piperazines, piperidines, pteridines, purines, pyrazines, pyrazolidines, pyrazolopyridines, pyridines, pyridopyridazines, pyrimidines, pyrrolidines, pyrroles, pyrrolopyrimidines, pyrrolines, pyrrolopyridazines, pyrrolopyrimidines, quinazolines, quinolines, quinolizines, quinoxalines, tetrazoles, triazaphthalenes, triazines, triazoles, triazolopyridines, and isomers thereof, preferably in the para-position.
2. A compound of formula (I) according to claim 1, selected from:
3. a process for the preparation of a diol compound of formula (I),
asymmetric dihydroxylation comprising a compound of formula (IA) in the presence of an asymmetric catalyst
Wherein A is substituted or unsubstituted or branched or unbranched C1-C6An 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 substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from the group consisting of H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2;
wherein the asymmetric catalyst is selected from the group consisting of AD-mix alpha [ (DHQ)2PHAL, an adduct of dihydroquinine and phthalazine]Or AD-mix beta [ (DHQD)2PHAL, dihydro quinidine and phthalazine adducts]。
4. A compound of formula (IA) or a salt or isomer thereof:
wherein A is substituted or unsubstituted or branched or unbranched C1-C6An alkyl group;
w is substituted or unsubstituted carbon, wherein n ═ 0, 1,2, or 3;
y is a substituted or unsubstituted oxygen atom;
z is substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2;
wherein when said Z is aryl independently substituted with an N-Het group, said N-Het is independently selected from one of the following alkyl or aryl groups: acridine, azabenzotriazole, azaindole, azepane, azaAzetidine, aziridine, benzimidazole, benzotriazole, carbazole, cinnoline, cyclopenta [ b ]]Pyridine, deazapurine, diazaDihydropyridines, imidazopyridines, imidazoles, imidazolidines, imidazopyridazines, imidazopyridines, imidazopyrimidines, indazoles, indoles, indolizines, isoindoles, isoquinolines, naphthyridines, oxindoles, phenanthrolines, phenazines, phthalazines, piperazines, piperidines, pteridines, purines, pyrazines, pyrazolidines, pyrazolopyridines, pyridines, pyridopyridazines, pyrimidines, pyrrolidines, pyrroles, pyrrolopyrimidines, pyrrolines, pyrrolopyridazines, pyrrolopyrimidines, quinazolines, quinolines, quinolizines, quinoxalines, tetrazoles, triazaphthalenes, triazines, triazoles, triazolopyridines, and isomers thereof, preferably in the para-position.
5. A compound of formula (IA) according to claim 4, selected from:
6. a compound of formula (H):
wherein X is nitrogen;
the compound of formula H is prepared using a compound of formula (I), as defined in claim 1, or a salt or isomer thereof:
wherein A is substituted or unsubstituted or branched or unbranched C1-C6An 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 substituted or unsubstituted alkyl, aryl or heteroaryl, wherein the substituents are independently selected from H, X, NO2，CN，COOH，COOR，OH，OR，OAr，OHetAr，SH，S(O)nR, SAr, SHEtAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH2，NHR，NHAr，NH-HetAr，NR2，NAr2，NHetAr2，CONR2，OC(O)OR，OC(O)NR；
Wherein
X ═ F, Cl, Br, or I;
r is substituted or unsubstituted alkyl;
ar is a substituted or unsubstituted aryl group;
HetAr is substituted or unsubstituted heteroaryl;
and n is 0, 1 or 2;
wherein when said Z is aryl independently substituted with an N-Het group, said N-Het is independently selected from one of the following alkyl or aryl groups: acridine, azabenzotriazole, azaindole, azepane, azaAzetidine, aziridine, benzimidazole, benzotriazole, carbazole, cinnoline, cyclopenta [ b ]]Pyridine, deazapurine, diazaDihydropyridines, imidazopyridines, imidazoles, imidazolidines, imidazopyridazines, imidazopyridines, imidazopyrimidines, indazoles, indoles, indolizines, isoindoles, isoquinolines, naphthyridines, oxindoles, phenanthrolines, phenazines, phthalazines, piperazines, piperidines, pteridines, purines, pyrazines, pyrazolidines, pyrazolopyridines, pyridines, pyridopyridazines, pyrimidines, pyrrolidines, pyrroles, pyrrolopyrimidines, pyrrolines, pyrrolopyridazines, pyrrolopyrimidines, quinazolines, quinolines, quinolizines, quinoxalines, tetrazoles, triazaphthalenes, triazines, triazoles, triazolopyridines, and isomers thereof, preferably in the para-position.
7. The compound of claim 6, wherein the compound of formula (H) is selected from:
8. the compound of claims 6 and 7, wherein the process for preparing the compounds of formulae (003R) and (003S) comprises:
9. a compound as claimed in claims 6 and 7 wherein the process for preparing a compound of formula (VL-2098) comprises:
10. the product of claims 6 and 7, wherein the process for preparing the compound of formula (IIIM-019) comprises:
11. the product of claims 6 and 7, wherein the process for preparing the compound of formula (IIIM-114) comprises:
12. a process for preparing delamanib comprising:
13. a compound selected from the group consisting of:
14. compounds of formulae (003R) and (003S)
15. Antibacterial compounds of formulae (003R) and (003S):
16. a compound according to claim 15 for use in the treatment of a mycobacterial infection.
17. An anti-tubercular pharmaceutical composition of the compound of claim 15.