CN101941950A - 2-substituted benzo-[d] oxazole-5-propionic acid compound and preparation method and applications thereof - Google Patents
2-substituted benzo-[d] oxazole-5-propionic acid compound and preparation method and applications thereof Download PDFInfo
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Abstract
The invention relates to a 2-substituted benzo-[d] oxazole-5-propionic acid compound and a preparation method and applications thereof in the technical field of drug chemical industry. The compound has a stronger activity restraining function on microbes, in particular to gram-positive bacteria, fungus Candida albicans, staphylococcus aureus, Methicillin-resistant Staphylococcus aureus and bacillus subtilis.
Description
Technical field
What the present invention relates to is a kind of compound and preparation application method thereof of medicine chemical technology field, specifically is that a kind of 2-replaces benzo [d] oxazole-5-phenylpropionic acid compound and preparation and application.
Background technology
Since nineteen twenty-nine, penicillin was found, microbiotic the family member grew stronger day by day.Natural and semisynthetic antibiont, or even the compound of a lot of brand-new synthetic with anti-microbial effect played great contribution in helping the human fight of resisting pathogenic microorganism.Yet in the last few years, the case that infects along with increasing microorganism resistance increased gradually, and it is extremely urgent to develop a kind of novel anti-microbial agents.
As far back as 1981, people such as Elamin I.Elinma reported that at 29 pages " antibacterium of benzoglyoxaline and benzoxazole derivative and anti-mycotic activity " (Antibacterial and AntifungalActivities of Benzimidazole and Benzoxazole Derivatives) literary composition of the 19th the 1st phase of volume of " anti-microbial agents and chemotherapy " the benzoxazole compounds has antimicrobial effect.2008, people such as Sabiha Alper-Hayta 2568 pages of the 43rd volumes of " European pharmaceutical chemistry magazine " " some 2-(substituted-phenyl/benzyl)-5-[(2-cumarone) carbonyl acid amides] benzoxazole synthetic, antimicrobial acivity and pharmacophore analysis " (Synthesis, antimicrobial activity, pharmacophore analysis of some new 2-(substitutedphenyl/cenzyl)-5-[(2-benzofuryl) carboxamido] benzoxazoles) [d] oxazole compounds has the broad spectrum antimicrobial activity, comprising Gram-negative bacteria also to have pointed out benzo in the literary composition, gram-positive microorganism and fungi.
Peroxidase increment activated receptor γ (PPAR γ) agonist is developed as the treatment diabetes B such as thiazolidinediones (TZDs) and non-thiazolidinediones (nTZDs).And in 3255 pages of U.S.'s " pharmaceutical chemistry magazine " the 47th volumes " (2R)-2-ethyl chroman-2-carboxylic acid: as the exploitation of the novel PPAR α/γ dual agonists of conquestio school and high blood cholesterol drug " ((2R)-2-Ethylchromane-2-carboxylic acids:Discovery of NovelPPAR α/γ Dual Agonists as Antihyperglycemic and Hypolipidemic Agents) literary composition, point out that this excitomotor is also at the treatment dyslipidemia according to people such as Hiroo Koyama 2004, hypertension, has certain effect in inflammation and the antitumor field.2009, people such as MichielE point out that troglitazone has the effect that suppresses streptococcus pneumoniae, but do not provide minimal inhibitory concentration (MIC) in the article at " the thiazolidinedione troglitazone reduces pneumonia streptococcus bacteria growing and early stage inflammation in the mouse body " (the The thiazolidinedione ciglitzaone reduces bacterial outgrowth and earlyinflammation during Streptococcuspneumoniae peneumonia in mice) of 614 pages of " critical illness emergency medicine " the 37th volumes.In the present invention, we find that another thiazolidinedione rosiglitazone has good antimicrobial effect equally.The present invention has recorded the minimum inhibition concentration of rosiglitazone to various gram-positive microorganisms and Gram-negative bacteria and fungi.Suppressing intestinal bacteria (Escherichia coli) MIC is 50 μ g/ml, suppressing streptococcus aureus (Staphylococcus aureus) MIC is 25 μ g/ml, suppressing methicillin-resistant Staphylococcus aureus (Methicillin-resistant Staphylococcus aureus) MIC is 25 μ g/ml, suppressing subtilis (Bacillus subtilis) MIC is 25 μ g/ml, and suppressing fungi Candida albicans (Candida albicans) MIC is 200 μ g/ml.
Pass through literature survey, discovery did not have relevant report at present based on the research of the antimicrobial medicine of similar structures exploitation becoming of peroxidase increment activated receptor γ (PPAR γ) agonist, therefore the present invention has designed a class PPAR gamma agonist analogue, and 2-replaces benzo [d] oxazole-5-phenylpropionic acid compound as a kind of novel anti-microbial agents.
Summary of the invention
The present invention is directed to the prior art above shortcomings, provide a kind of 2-to replace benzo [d] oxazole-5-phenylpropionic acid compound and preparation and application.
The present invention is achieved by the following technical solutions:
A kind of 2-replaces benzo [d] oxazole-5-phenylpropionic acid compound, and its structural formula is:
Wherein: m is 0～5 integral multiple, and n is 0～5 integral multiple, R
1Be following any substituting group:
R2, R3 are following any substituting group:
The present invention relates to the preparation method that above-mentioned 2-replaces benzo [d] oxazole-5-propionic acid, comprise the steps:
(1) 4-hydroxy phenylpropionic acid and salpeter solution reaction are obtained further with after strong sulfuric acid response and the reflux obtaining 3-nitro-4-hydroxy-benzenepropanoic acid ethylester behind 3-nitro-4-hydroxy phenylpropionic acid;
Described salpeter solution is a mass percent at 60% aqueous nitric acid;
Described reflux is meant: refluxed 12 hours down at 85 ℃ after 3-nitro-4-hydroxy phenylpropionic acid and the vitriol oil are dissolved in methyl alcohol;
(2) 3-nitro-4-hydroxy-benzenepropanoic acid ethylester being carried out hydrogenation obtains further with behind reaction of 2-chloracetyl imidic acid methyl ester hydrochloride and the secondary back obtaining 3-(2-(chloromethyl) benzo [b] oxazole-5)-methyl propionate behind the 3-amino-4-hydroxy phenylpropionic acid ethyl ester.
Described hydrogenation is meant: the employing concentration ratio is 10% palladium/carbon and 3-nitro-4-hydroxy-benzenepropanoic acid ethylester hydrogenation in methyl alcohol, and temperature of reaction is a room temperature;
Described secondary back is meant: place 70 ℃ methyl alcohol to reflux 1.5 hours 3-amino-4-hydroxy phenylpropionic acid ethyl ester and 2-chloracetyl imidic acid methyl ester hydrochloride.
(3) 3-(2-((diethoxy phosphonium mesitoyl base) methyl) benzo [methyl propionate of b] oxazole-5-) will be obtained after 3-(2-(chloromethyl) benzo [b] oxazole-5)-methyl propionate and the triethyl-phosphite Hybrid Heating;
Described Hybrid Heating is meant: at 150 ℃ N, heating is 3 hours in the dinethylformamide;
(4) ([methyl propionate of b] oxazole-5-) and potassium tert.-butoxide mix back and R to 2-((diethoxy phosphonium mesitoyl base) methyl) benzo in organic solvent with 3-
1The CHO aldehyde reaction, and directly be dissolved in reaction product in the methyl alcohol and under platinum dioxide catalysis reduction hydrogenation obtain 3-(2-replace the methyl propionate of benzo [b] oxazole-5-);
Described mixing in organic solvent is meant: stirred 30 minutes in-10 ℃ tetrahydrofuran (THF);
Described R
1CHO aldehyde is meant: R
1Be following any substituting group:
Wherein: R
4Be C
1-C
5Alkyl, nitro, carboxyl, chlorine, bromine, fluorine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, fragrant-oxyl, aromatic base or assorted aromatic base; S is 0～5 integer, and G is O, S or N, R
5And R
6Be following any one: C
1-C
5Alkyl, nitro, carboxyl, chlorine, bromine, fluorine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base or assorted aromatic base;
(5) (2-replaces the methyl propionate hydrolysis of benzo [b] oxazole-5-) and obtains 3-(2-replaces the propionic acid of benzo [b] oxazole-5-) with 3-;
Described hydrolysis is meant: (2-replacement benzo [b] oxazole-5-) methyl propionate reacts down for 25 ℃ in room temperature with aqueous sodium hydroxide solution after being dissolved in ethanol with 3-;
(6) with 3-(2-replace the propionic acid of benzo [b] oxazole-5-) respectively or (S) with (R)-4-sec.-propyl-3-substituted-phenyl third acyl base oxazolidine-2-ketone lithium-4-sec.-propyl-3-substituted-phenyl third acyl base oxazolidine-2-ketone lithium low temperature organic solvent in reaction obtain Evans acid amides (R)-4-sec.-propyl-3-(3-(2-replaces the propionyl of benzo [b] oxazole-5-)) oxazolidine-2-ketone or (S)-4-sec.-propyl-3-(3-(2-replaces the propionyl of benzo [b] oxazole-5-)) oxazolidine-2-ketone;
(7) with the product of step (6) respectively with 1,1,1,3,3,3-hexamethyldisilazane sylvite stirs back and 3-phenyl-2-phenyl sulphonyl-1 in the low temperature organic solvent, 2-is mute, and piperazine carries out the Davis asymmetric oxidation, obtains (R)-3-((R)-2-hydroxyl-3-(2-replaces the propionyl of benzo [b] oxazole-5-)) oxazolidine-2-ketone or (S)-3-((S)-2-hydroxyl-3-(2-replaces the propionyl of benzo [b] oxazole-5-)) oxazolidine-2-ketone respectively;
Described low temperature organic solvent is meant :-78 ℃ tetrahydrofuran (THF);
(8) step (7) product is reacted in alcoholic solution with magnesium methylate respectively, (2-replaces the methyl propionate of benzo [b] oxazole-5-) or (S)-2-hydroxyl-3-, and (2-replaces the methyl propionate of benzo [b] oxazole-5-) to obtain (R)-2-hydroxyl-3-respectively;
Described alcoholic solution is meant: 0 ℃ methyl alcohol;
(9) step (8) product is carried out any one reaction in following two kinds:
9.1) with phenol, triphenylphosphine, di-isopropyl diazonium two carbonic ethers in toluene or tetrahydrofuran (THF) through the Mitsunobu reaction, (2-replaces the methyl propionate of benzo [b] oxazole-5-) or (R)-2-fragrance substituted hydroxy-3-, and (2-replaces the methyl propionate of benzo [b] oxazole-5-) to obtain (S)-2-fragrance substituted hydroxy-3-respectively;
(2-replaces the methyl propionate of benzo [b] oxazole-5-) or (S)-2-alkyl substituted hydroxy-3-, and (2-replaces the methyl propionate of benzo [b] oxazole-5-) 9-2) to obtain (R)-2-alkyl substituted hydroxy-3-respectively with halogenated alkane under the catalysis of silver suboxide;
(10) with step 9.1) and step 9.2) product carry out the secondary hydrolysis reaction and prepare 2-and replace benzo [d] oxazole-5-propionic acid.
Described secondary hydrolysis reaction is meant: with step 9.1) and step 9.2) product place the water-methanol solution that contains lithium hydroxide, V in the described water-methanol solution
Water/ V
Methyl alcohol=3: 2.
The present invention relates to above-mentioned 2-in addition and replaces benzo [d] oxazole-application of 5-propionic acid on microbiostatic activity.
Compared with prior art, the invention has the advantages that: 2-replacement benzo [d] oxazole-5-phenylpropionic acid compound that the present invention relates to is compared existing microbiotic and is had more novel structure; Antibacterium effect with wide spectrum is comprising gram-positive microorganism, Gram-negative bacteria and drug-resistant bacteria.
Description of drawings
Fig. 1 is a synthetic route synoptic diagram of the present invention.
Embodiment
Below embodiments of the invention are elaborated; present embodiment is being to implement under the prerequisite with the technical solution of the present invention; detailed embodiment and concrete operating process have been provided; but protection scope of the present invention is not limited to following embodiment, and following examples are the pairing detailed description of synthetic route among Fig. 1.
Synthesizing of 3-nitro-4-hydroxy-benzenepropanoic acid ethylester (I): (9.83 milliliters in the nitric acid with 60%, 0.144 mmole) be dissolved in 20 milliliters of Glacial acetic acid, under room temperature 15 degree, drop to 4-hydroxy phenylpropionic acid (20 grams in 30 minutes, 0.12 in Glacial acetic acid mmole) (150 milliliters) solution, stirred then one hour.Reaction finishes the back and adds 300 milliliters of frozen water, and water is with 200 milliliters of dichloromethane extractions.Anhydrous sodium sulfate drying is used in organic phase saturated common salt water washing then again.Obtain an xanchromatic solid phase prod 24.6 gram after the filtering and concentrating, this product is dissolved in 300 ml methanol, adds 30 milliliters of the vitriol oils, then reflux 12 hours under 70 degree.Reaction is cooled to 25 degree, concentrates then and remove methyl alcohol.Add 300 milliliters of frozen water subsequently, with 400 milliliters of extracted with diethyl ether, salt solution washing, anhydrous sodium sulfate drying.Be concentrated into and do the back with silicagel column purifying (sherwood oil: ethyl acetate=3: 1), obtain Compound I, 22.8 grams, yield 84%.
1H?NMR(300MHz，CDCl3)δ10.475(s，1H，OH)，7.938-7.930(d，1H，ArH，J＝2.4Hz)，7.460-7.427(dd，1H，ArH，J＝8.4Hz，1.2Hz)，7.101-7.072(d，1H，ArH，J＝8.7Hz)，3.669(s，3H，CH
3)，2.964-2.914(t，2H，CH
2，7.5Hz)，2.658-2.607(t，2H，CH
2，J＝7.7Hz)。MS(ESI?m/z)226.10(M+H)
+。
Embodiment 2
([d] oxazole-5-) methyl propionate (II) is synthetic: with 3-nitro-4-hydroxy-benzenepropanoic acid ethylester (I) (10 grams for 2-(chloromethyl) benzo for 3-, 44.4 mmole) with 10% palladium/carbon (2.3 grams, 2.22 mmole) be dissolved in the methyl alcohol, vigorous stirring is one hour in 1 the atmospheric hydrogen.Filtering and concentrating obtains a white solid to doing then.This white solid and 2-chloracetyl imidic acid methyl ester hydrochloride (7.7 gram, 53.29 mmoles) are dissolved in 150 ml methanol, then reflux 1.5 hours under 70 degree.25 degree backs are reduced in reaction to be concentrated.Residue is used 50 milliliters of saturated sodium bicarbonates, saturated common salt water washing, with anhydrous sodium sulfate drying then successively with 150 milliliters of acetic acid ethyl dissolutions.Obtain thick product after the filtering and concentrating, through silicagel column (sherwood oil: ethyl acetate=10: 1) obtain Compound I I behind the purifying, 10.7 grams, yield 95%.
1H?NMR(300MHz，CDCl3)δ7.548(s，1H，ArH)，7.470-7.440(d，1H，ArH，J＝9.0Hz)，7.246-7.212(dd，1H，ArH，J＝8.4Hz，1.3Hz)，4.732(s，2H，CH
2Cl)，3.659(s，3H，CH
3)，3.089-3.038(t，2H，CH
2，J＝7.7Hz)，2.691-2.640(t，2H，CH
2，J＝7.7Hz)。
3-(2-((diethoxy phosphono) methyl) benzo [methyl propionate (III) of d] oxazole-5-) synthetic: the 3-of 10 grams (39.4 mmole) (2-(chloromethyl) benzo [(13.7 milliliters of methyl propionate (II) of d] oxazole-5-) and triethyl-phosphites; 78.8 mmole) be dissolved in 40 milliliters of N; in the dinethylformamide, under 150 degree, stirred 3 hours then.Concentrate the back with silica gel (sherwood oil: ethyl acetate=2: 1) purifying obtains an orange oil, i.e. compound (III), 9.78 restrain yield 70%.
1H?NMR(300MHz，DMSO-d6)δ7.582-7.556(d，1H，ArH，J＝7.8Hz)，7.543(s，1H，ArH)，7.239-7.206(dd，1H，ArH，J＝8.4Hz，1.5Hz)，4.109-4.010(quint，4H，J＝7.4Hz)，3.790(s，1H，O＝PCH
2)，3.717(s，1H，O＝PCH
2)，3.547(s，3H，CH
3)，2.962-2.910(t，2H，J＝7.8Hz)，2.684-2.632(t，2H，J＝7.8Hz)，1.229-1.182(t，6H，J＝7.1Hz)。
(([d] oxazole-5-) methyl propionate (IV) is synthetic: ([(6.47 restrain the methyl propionate (III) of d] oxazole-5-) 2-((diethoxy phosphono) methyl) benzo 3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo 2-3-to drip 3-when-10 spend in 100 milliliters of tetrahydrofuran (THF)s of 2.04 gram potassium tert.-butoxides (18.2 mmole); 18.2 40 milliliters of tetrahydrofuran solutions mmole) continue to stir 30 minutes.(5-methyl-2-Ben Ji oxazole-4-) 40 milliliters of tetrahydrofuran solutions of acetaldehyde (3.66 grams, 18.2 mmoles) splash in the above-mentioned reaction solution with 2-.Reaction is carried out after 10 minutes using ethyl acetate extraction again, with saturated common salt water washing, anhydrous sodium sulfate drying with 50 milliliters of saturated aqueous ammonium chloride cancellation.The crude product that obtains after the filtering and concentrating dissolves with 150 ml methanol, adds three hydration platinum dioxides (0.512 gram, 1.82 mmoles), and vigorous stirring is 12 hours under 1 atmospheric hydrogen; (sherwood oil: ethyl acetate=5: 1) purifying obtains product IV, 2.25 grams, yield 35% with silica gel after the filtering and concentrating.
1H?NMR(300MHz，CDCl3)δ7.975-7.951(m，2H，Ph)，7.464(s，1H)，7.418-7.397(m，3H，Ph)，7.371-7.343(d，1H，ArH，J＝8.40Hz)，7.126-7.098(d，1H，J＝8.4Hz)，3.664(s，3H，OCH
3)，3.065-3.015(t，2H，CH2，J＝7.5Hz)，2.996-2.948(t，2H，CH
2CH
2 CH 2 ，J＝7.20Hz)，2.680-2.632(t，2H，
CH 2 CH
2COOCH
3，J＝7.20Hz)，2.654-2.610(t，2H，
CH 2 CH
2CH
2，J＝6.60Hz)，2.300(s，3H，ArCH
3)，2.300-2.216(quint，2H，CH
2 CH 2 CH
2，J＝7.20Hz，6.90Hz)。
((3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-) propionic acid (V) is synthetic: one one hydronium(ion) oxidation lithium (1.17 grams for 2-for 3-, ((3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [in 30 milliliters of ethanolic solns of the methyl propionate (IV) of d] oxazole-5-), stirs after 1 hour concentrated 2-27.8 20 ml water solution mmole) join the 3-that contains 2.25 grams (5.56 mmole).Water is 3-4 with hcl acidifying to the pH value of 1 mol, uses 50 milliliters of dichloromethane extractions then, with anhydrous sodium sulfate drying.Filtering and concentrating is after to obtain product V behind the diatomite filtration be a yellow solid, 2.117 grams, yield 98%.
1H?NMR(300MHz，DMSO-d6)δ7.878-7.844(m，2H，PhH)，7.514-7.449(m，5H，ArH)，7.182-7.153(d，1H，ArH，J＝8.8Hz)，2.952-2.906(t，2H，CH2，J＝6.9Hz)，2.906-2.860(t，2H，CH2，J＝6.9Hz)，2.585-2.541(t，2H，CH2，J＝6.6Hz)，2.562-2.517(t，2H，CH2，J＝6.8Hz)，2.284(s，3H，ArCH3)，2.131-2.069(quint，2H，CH2，J＝6.2Hz)。
(R)-4-sec.-propyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionyl) oxazolidine-2-ketone (VI of d] oxazole-5-)
1) synthetic: under-78 degree, pivaloyl chloride (0.684 gram, 5.69 mmoles) joined in 30 minutes in 50 milliliters of tetrahydrofuran solutions of compound (V) (2.12 grams, 5.42 mmoles) and triethylamine (0.9 milliliter, 6.5 mmoles).This reaction is warming up to 0 degree back continuation stirring 30 minutes then, is being cooled to-78 degree then.The tetrahydrofuran solution of one-78 20 milliliters of (R)-4-sec.-propyls-3-substituted-phenyl Bing Xian Ji oxazolidine-2-ketone lithium of spending (0.77 gram, 5.9 mmoles) is transferred in above-mentioned-78 degree solution, be warmed up to 25 degree then, continue stirring 30 minutes.After 100 milliliters of saturated aqueous ammonium chloride cancellation, water has 100 milliliters of ethyl acetate extractions, saturated common salt water washing, last anhydrous sodium sulfate drying.(sherwood oil: ethyl acetate=2: 1) purifying obtains yellow solid, VI, 2.27 grams, yield 83% with silicagel column after the filtering and concentrating.
1H?NMR(300MHz，CDCl3)δ7.995-7.964(m，2H，PhH)，7.508(s，2H，ArH)，7.439-7.405(m，3H，PhH)，7.372-7.343(d，1H，ArH，J＝8.7Hz)，7.188-7.156(d，1H，ArH，J＝9.6Hz)，4.439-4.389(m，1H)，4.272-4.166(m，2H)，3.365-3.179(m，2H)，3.097-3.052(t，2H，J＝6.8Hz)，2.995-2.946(t，2H，J＝7.4Hz)，2.665-2.617(t，2H，J＝7.2Hz)，2.376-2.220(m，3H)，2.305(s，3H)，0.905-0.880(d，3H，J＝7.5Hz)，0.836-0.813(d，3H，J＝6.9Hz)。
(S)-4-sec.-propyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionyl) oxazolidine-2-ketone (VI of d] oxazole-5-)
2) synthetic: with reference to embodiment 5; compound (V) with (S)-reaction of 4-sec.-propyl-3-substituted-phenyl Bing Xian Ji oxazolidine-2-ketone lithium obtains (S)-4-sec.-propyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [the propionyl) oxazolidine-2-ketone (VI) of d] oxazole-5-), yield 70%.
1H?NMR(300MHz，CDCl3)δ7.989-7.963(m，2H，PhH)，7.509(s，2H，ArH)，7.423-7.400(m，3H，PhH)，7.370-7.342(d，1H，ArH，J＝8.4Hz)，7.184-7.158(d，1H，ArH，J＝7.8Hz)，4.435-4.387(m，1H)，4.268-4.163(m，2H)，3.391-3.177(m，2H)，3.098-3.051(t，2H，J＝7.0Hz)，2.993-2.944(t，2H，J＝7.4Hz)，2.661-2.614(t，2H，J＝7.0Hz)，2.396-2.218(m，3H)，2.301(s，3H)，0.900-0.879(d，3H，J＝6.3Hz)，0.834-0.811(d，3H，J＝6.9Hz)。
Embodiment 8
(R)-3-((R)-2-hydroxyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionyl of d] oxazole-5-))-4-Yi Bing Ji oxazolidine-2-ketone (VII
1) synthetic: (R)-4-sec.-propyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionyl) oxazolidine-2-ketone (VI of d] oxazole-5-)
1) (2.27 gram, 4.52 mmoles) be cooled to-78 degree after being dissolved in 50 milliliters of tetrahydrofuran (THF)s, with 1,1,1,3,3 of 5.43 milliliters 1 mol, the tetrahydrofuran solution of 3-hexamethyldisilazane sylvite added in 30 minutes, stirred 1 hour then.With the 3-phenyl-2-phenyl sulphonyl-1 of-78 degree, make 6 milliliters of tetrahydrofuran solutions of piperazine (1.4 gram, 4.5 mmoles) of 2-joined in the above-mentioned reaction solution stirring 4 hours.Use 2 milliliters Glacial acetic acid cancellation then, be warmed up to 25 degree.The product that obtains after concentrating dilutes with 100 milliliters of ethyl acetate, uses the saturated common salt water washing, anhydrous sodium sulfate drying.Filtering and concentrating is after silicagel column (sherwood oil: ethyl acetate=2: 1) obtain white solid product VII behind the purifying
1(1.2 grams, yield 52%).
1H?NMR(300MHz，CDCl3)δ7.984-7.957(m，2H)，7.520(s，1H)，7.420-7.368(m，4H)，7.234-7.209(d，1H，J＝7.5Hz)，5.288(m，1H)，4.392-4.366(m，1H)，4.325-4.271(m，2H)，3.561(br，1H)，3.284-3.223(dd，2H，J＝13.8，4.5，3.9Hz)，2.991-2.943(t，m，3H，J＝7.2Hz)，2.654-2.605(t，2H，J＝7.3Hz)，2.448-2.391(m，1H)，2.301(s，3H)，2.301-2.212(quint，2H，J＝7.1Hz)，0.927-0.904(d，3H，J＝6.9Hz)，0.892-0.868(d，3H，J＝7.2Hz)。
Embodiment 9
(S)-3-((S)-2-hydroxyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionyl of d] oxazole-5-))-4-Yi Bing Ji oxazolidine-2-ketone (VII
2) synthetic: with reference to embodiment 8, obtain product VII
2, yield 62%.
1H?NMR(300MHz，CDCl3)δ7.986-7.952(m，2H)，7.517(s，1H)，7.438-7.369(m，4H)，7.239-7.211(d，1H，J＝8.4Hz)，5.291(m，1H)，4.393-4.354(m，1H)，4.326-4.273(m，2H)，3.564(br，1H)，3.286-3.227(dd，2H，J＝13.6Hz，3.9Hz，3.9Hz)，2.991-2.918(t，m，3H，J＝6.9Hz)，2.656-2.607(t，2H，J＝7.4Hz)，2.450-2.406(m，1H)，2.302(s，3H)，2.302-2.213(m，2H)，0.929-0.906(d，3H，J＝6.9Hz)，0.894-0.870(d，3H，J＝7.2Hz)。
(R)-2-hydroxyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (VIII of d] oxazole-5-)
1) synthetic: the ethyl magnesium bromide etherate of 2.5 mol joins in 30 ml methanol under-10 degree for 3.7 milliliters.Compound VI I then
1The 15 ml methanol solution of (1.2 grams, 4.6 mmoles) join in the above-mentioned solution, stir after 5 minutes with 50 milliliters of saturated aqueous ammonium chloride cancellation.Product after concentrating dilutes with 50 milliliters of ethyl acetate, and anhydrous sodium sulfate drying is used in the saturated common salt water washing again.Filtering and concentrating is after silicagel column (sherwood oil: ethyl acetate=3: 1) obtain a heavy-gravity product liquid VIII behind the purifying
1, 0.7 gram, yield 71%.
1H?NMR(300MHz，CDCl3)δ7.986-7.955(m，2H)，7.482-7.479(d，1H，J＝0.9Hz)，7.422-7.399(m，3H)，7.381-7.355(d，1H，J＝7.8Hz)，7.155-7.123(dd，1H，J＝8.1Hz，1.5Hz)，4.496-4.463(m，1H)，3.771(s，3H)，3.251-3.190(dd，1H，J＝13.9Hz，4.5Hz，4.2Hz)，3.091-3.025(dd，1H，J＝13.6Hz，6.3Hz，6.0Hz)，2.995-2.944(t，2H，J＝7.6Hz)，2.657-2.609(t，2H，J＝7.2Hz)，2.300(s，3H)，2.300-2.239(m，2H)。
Embodiment 11
(S)-2-hydroxyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (VIII of d] oxazole-5-)
2) synthetic: with reference to embodiment 9, obtain product VII I
1, yield 75%.
1H?NMR(300MHz，CDCl3)δ7.980-7.949(m，2H)，7.482(s，1H)，7.437-7.357(m，4H)，7.156-7.123(dd，1H，J＝8.1Hz，1.4Hz)，4.498-4.465(m，1H)，3.773(s，3H)，3.251-3.190(dd，1H，J＝13.7Hz，4.8Hz，4.5Hz)，3.094-3.026(dd，1H，J＝13.7Hz，7.2Hz，6.3Hz)，2.997-2.947(t，2H，J＝7.5Hz)，2.654-2.607(t，2H，J＝7.0Hz)，2.300(s，3H)，2.300-2.237(m，2H)。
Embodiment 12
(S)-2-(4-tertiary butyl phenoxy group)-3-(3-(2-(methyl propionate (IX of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
1) synthetic: compound (VIII
1) (0.05 gram, 0.119 triphenylphosphine (0.047 gram mmole),, 0.178 mmole) and 4-tert.-butyl phenol (0.178 mmole) be dissolved in 5 milliliters of toluene, 0 degree adds down the tetrahydrofuran solution of the tetrahydrofuran (THF) (0.178 mmole) of 1 milliliter of di-isopropyl diazonium two carbonic ether.Being raised to 25 degree backs stirred 12 hours.After concentrating through silicagel column (sherwood oil: ethyl acetate=8: 1) obtain colourless oily product IX behind the purifying
1, 31 milligrams, yield 47%.
1H?NMR(300MHz，CDCl3)δ7.981-7.956(m，2H)，7.586(s，1H)，7.420-7.397(m，3H)，7.381-7.353(d，1H，J＝8.4Hz)，7.258-7.235(d，1H，J＝6.9Hz)，7.242-7.213(d，2H，J＝8.7Hz)，6.763-6.732(d，2H，J＝9.3Hz)，4.800-4.757(m，1H)，3.731(s，3H)，3.321-3.304(d，2H，J＝5.1Hz)，2.997-2.948(t，2H，J＝7.4Hz)，2.657-2.609(t，2H，J＝7.2Hz)，2.315-2.221(m，2H)，2.294(s，3H)，1.245(s，9H)。MS(ESI?m/z)553.1(M+H)
+。
Embodiment 13
(S)-2-(4-phenyl phenoxy group)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (IX of d] oxazole-5-)
2) synthetic: with reference to embodiment 12, obtain Compound I X
2, yield 51%.
1HNMR(300MHz，CDCl3)δ8.001-7.990(m，2H)，7.611(s，1H)，7.505-7.363(m，10H)，7.309-7.224(m，3H)，6.910-6.882(d，2H，J＝8.4Hz)，4.887-4.847(t，1H，J＝6Hz)，3.750(s，3H)，3.369-3.351(d，2H，J＝5.4Hz)，2.984(m，2H)，2.659(m，2H)，2.306(s，3H，m，2H).MS(ESI?m/z)573.1(M+H)
+。
Embodiment 14
(S)-2-(4-methoxyl group phenoxy group)-3-(3-(2-(methyl propionate (IX of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
3) synthetic: with reference to embodiment 12, obtain Compound I X
3, yield 40%.
1H?NMR(300MHz，CDCl3)δ8.034-8.017(m，2H)，7.644(s，1H)，7.476-7.423(m，4H)，7.288-7.259(d，1H，J＝8.7Hz)，6.813(s，4H)，4.805-4.762(t，1H，J＝6.4Hz)，3.775(s，6H)，3.374-3.354(d，2H，J＝6.0Hz)，3.061-3.012(t，2H，J＝7.4Hz)，2.722-2.675(t，2H，J＝7.0Hz)，2.354-2.306(m，2H)，2.334(s，3H)。
Embodiment 15
(S)-2-(4-fluorophenoxy)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (IX of d] oxazole-5-)
4) synthetic: with reference to embodiment 12, obtain Compound I X
4, yield 46%.
1H?NMR(300MHz，CDCl3)δ8.111(m，2H)，7.638(s，1H)，7.504(m，3H)，7.455-7.426(d，1H，J＝8.7Hz)，7.277-7.251(d，1H，J＝7.8Hz)，6.987-6.933(m，2H)，6.833-6.792(m，2H)，4.819-4.780(t，1H，J＝5.8Hz)，3.784(s，3H)，3.384-3.365(d，2H，J＝5.7Hz)，3.051(s，2H)，2.763(s，2H)，2.388(s?3H)，2.388-2.297(m，2H).MS(ESIm/z)515.1(M+H)
+。
Embodiment 16
(S)-2-(4-bromine phenoxy group)-3-(3-(2-(methyl propionate (IX of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
5) synthetic: with reference to embodiment 12, obtain Compound I X
5, yield 78%.
1H?NMR(300MHz，CDCl
3)δ7.991-7.965(m，2H)，7.566(s，1H)，7.423-7.363(m，4H)，7.326-7.297(d，2H，J＝8.7Hz)，7.207-7.177(d，1H，J＝9.0Hz)，6.713-6.681(d，2H，J＝9.6Hz)，4.791-4.747(t，1H，J＝6.6Hz)，3.719(s，3H)，3.333-3.310(d，2H，J＝6.9Hz)，3.003-2.955(t，2H，J＝7.2Hz)，2.666-2.619(t，2H，J＝7.1Hz)，2.301(s，3H)，2.301-2.191(m，2H).MS(ESI?m/z)575.0，577.0(M+H)
+。
Embodiment 17
(S)-2-(4-chlorophenoxy)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (IX of d] oxazole-5-)
6) synthetic: with reference to embodiment 12, obtain Compound I X
6, yield 80%.
1H?NMR(300MHz，CDCl
3)δ7.977-7.946(m，2H)，7.572(s，1H)，7.420-7.363(m，4H)，7.213-7.183(d，1H，J＝8.7Hz)，7.183-7.151(d，2H，J＝9.6Hz)，6.757-6.729(d，2H，J＝8.4Hz)，4.790-4.746(t，1H，J＝6.6Hz)，3.721(s，3H)，3.333-3.311(d，2H，J＝6.6Hz)，3.001-2.951(t，2H，J＝7.5Hz)，2.658-2.611(t，2H，J＝7.1Hz)，2.297(s，3H)，2.297-2.243(m，2H)。
Embodiment 18
(S)-2-(4-iodine phenoxy group)-3-(3-(2-(methyl propionate (IX of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
7) synthetic: with reference to embodiment 12, obtain Compound I X
7, yield 80%.
1H?NMR(300MHz，CDCl
3)δ7.976-7.937(m，2H)，7.586(s，1H)，7.507-7.479(d，2H，J＝8.4Hz)，7.146-7.345(m，4H)，7.203-7.175(d，1H，J＝8.4Hz)，6.608-6.580(d，2H，J＝8.4Hz)，4.790-4.748(t，1H，J＝6.3Hz)，3.718(s，3H)，3.330-3.310(d，2H，J＝6.0Hz)，3.000-2.952(t，2H，J＝7.2Hz)，2.663-2.614(t，2H，J＝7.4Hz)，2.298(s，3H)，2.271-2.198(m，2H)。
Embodiment 19
(S)-2-(4-cyano-benzene oxygen)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (IX of d] oxazole-5-)
8) synthetic: with reference to embodiment 12, obtain Compound I X
8, yield 71%.
1H?NMR(300MHz，CDCl
3)δ8.065-8.056(m，2H)，7.624(s，1H)，7.603-7.573(d，2H，J＝9.0Hz)，7.483-7.433(m，4H)，7.263-7.235(d，1H，J＝8.4Hz)，6.942-6.911(d，2H，J＝9.3Hz)，4.952-4.912(t，1H，J＝6.0Hz)，3.797(s，3H)，3.431-3.410(d，2H，J＝6.3Hz)，3.067-3.022(t，2H，J＝6.8Hz)，2.725-2.705(m，2H)，2.373(s，3H，m，2H).MS(ESI?m/z)522.0(M+H)
+。
Embodiment 20
(S)-2-(4-ethanoyl phenoxy group)-3-(3-(2-(methyl propionate (IX of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
9) synthetic: with reference to embodiment 12, obtain Compound I X
9, yield 71%..
1H?NMR(300MHz，CDCl
3)δ7.977-7.947(m，2H)，7.880-7.851(d，2H，J＝8.4Hz)，7.575-7.366(m，4H)，7.219-7.187(d，1H，J＝9.6Hz)，6.869-6.838(d，2H，J＝9.3Hz)，4.928-4.886(t，1H，J＝6.3Hz)，3.725(s，3H)，3.371-3.350(d，2H，J＝6.3Hz)，2.997-2.948(t，2H，J＝7.4Hz)，2.656-2.609(t，2H，J＝7.1Hz)，2.511(s，3H)，2.294(s，3H)，2.294-2.217(m，2H).MS(ESI?m/z)539.1(M+H)
+。
Embodiment 21
(R)-2-(4-4-trifluoromethylphenopendant)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (IX of d] oxazole-5-)
10) synthetic: with reference to embodiment 12, obtain Compound I X
10, yield 60%.
1H?NMR(300MHz，CDCl
3)δ7.985-7.961(m，2H)，7.581(s，1H)，7.500-7.471(d，2H，J＝8.7Hz)，7.419-7.372(m，4H)，7.218-7.194(d，1H，J＝7.2Hz)，6.895-6.867(d，2H，J＝8.4Hz)，4.889-4.848(t，1H，6.1Hz)，3.736(s，3H)，3.369-3.348(d，2H，J＝6.3Hz)，3.003-2.955(t，2H，J＝7.2Hz)，2.661-2.618(d，2H，J＝6.4Hz)，2.300(s，3H)，2.300-2.248(m，2H).MS(ESI?m/z)565.0(M+H)
+。
Embodiment 22
(R)-2-methoxyl group-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (IX of d] oxazole-5-)
11) synthetic: at compound (S)-2-hydroxyl-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (VIII of d] oxazole-5-)
2) (50 milligrams, 0.119 mmole) and silver suboxide (41 milligrams, 0.178 mmole) mix in 2 milliliters of acetonitriles, adds methyl iodide (75 microlitres, 1.19 mmoles) then, with the heating 12 hours under 45 degree of this mixture.Filtering and concentrating is after silicagel column (sherwood oil: ethyl acetate=3: 1) obtain Compound I X behind the purifying
11, 27 milligrams, yield 52%.
1H?NMR(300MHz，CDCl
3)δ7.981-7.964(m，2H)，7.505(s，1H)，7.418-7.402(m，3H)，7.378-7.350(d，1H，J＝8.4Hz)，7.156-7.129(d，1H，J＝8.1Hz)，4.006-3.961(m，1H)，3.728(s，3H)，3.343(s，3H)，3.172-3.023(m，2H)，2.999-2.951(t，2H，J＝7.2Hz)，2.664-2.618(t，2H，J＝6.9Hz)，2.304(s，3H)，2.304-2.247(m，2H).
13CNMR(500MHz，CDCl
3)δ171.9，166.6，158.9，149.3，143.5，141.0，134.3，132.5，129.3，128.1，125.5，125.4，119.5，109.3，81.3，57.9，51.4，38.5，27.4，25.4，24.4，9.7.MS(ESI?m/z)435.1(M+H)
+。
Embodiment 23
(R)-2-isopropoxy-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [methyl propionate (IX of d] oxazole-5-)
12) synthetic: with reference to embodiment 22, obtain Compound I X
12, yield 36%.
1H?NMR(300MHz，CDCl
3)δ7.971-7.947(m，2H)，7.524(s，1H)，7.412-7.395(m，3H)，7.367-7.337(d，1H，J＝8.4Hz)，7.172-7.148(d，1H，J＝7.8Hz)，4.102-4.059(m，1H)，3.715(s，3H)，3.517-3.437(quint，1H，J＝6.0Hz)，3.128-2.998(dd，dd，2H，J＝13.5Hz，4.2Hz，4.5Hz)，2.996-2.947(t，2H，J＝7.3Hz)，2.652-2.606(t，2H，J＝6.9Hz)，2.289(s，3H)，2.289-2.178(m，2H)，1.142-1.122(d，3H，J＝6.0Hz)，0.922-0.901(d，3H，J＝6.3Hz).
13CNMR(300MHz，CDCl
3)δ173.5，167.2，159.6，149.9，144.0，141.6，135.2，133.7，129.8，128.8，128.0，126.2，126.1，120.4，109.8，78.5，72.7，52.1，39.8，28.1，26.1，25.1，22.7，21.5，10.3.MS(ESI?m/z)463.1(M+H)
+。
Embodiment 24
(S)-2-(4-tertiary butyl phenoxy group)-3-(3-(2-(propionic acid (X of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
1) synthetic: room temperature 25 degree are down, 1 milliliter of lithium hydroxide monohydrate aqueous solution (19 milligrams, 0.443 mmole) is joined 78 milligrams of (S)-2-(4-tertiary butyl phenoxy group)-3-(3-(2-(methyl propionate (IX of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
1) in the ethanolic soln (2 milliliters) of (0.147 mmole), stirred 4 hours.Remove ethanol under reduced pressure,, filter to pH=4 with 3 mol hcl acidifyings, drying obtains solid (S)-2-(4-tertiary butyl phenoxy group)-3-(3-(2-(propionic acid (X of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
1) 60 milligrams, yield 78%;
1H NMR (300MHz, DMSO-d6) δ 7.874-7.850 (m, 2H), 7.586 (s, 1H), and 7.534-7.507 (d, 1H, J=8.1Hz), 7.462-7.440 (m, 3H), 7.278-7.247 (d, 1H, J=9.3Hz), and 7.223-7.194 (d, 2H, J=8.7Hz), 6.736-6.708 (d, 2H, J=8.4Hz), 4.903-4.864 (m, 1H), and 3.254-3.163 (m, 2H), 2.953-2.904 (t, 2H, J=7.4Hz), 2.582-2.533 (t, 2H, J=7.4Hz), 2.276 (s, 3H), 2.139-2.068 (quint, 2H, J=7.1Hz), 1.177 (s, 9H).
Embodiment 25
(S)-2-(4-phenyl phenoxy group)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionic acid (X of d] oxazole-5-)
2) synthetic: with reference to embodiment 24, obtain compounds X
2, yield 79%;
1H NMR (300MHz, DMSO-d6) δ 7.867-7.846 (m, 2H), 7.615 (s, 1H), and 7.552-7.506 (m, 5H), 7.463-7.440 (m, 3H), 7.407-7.355 (m, 2H), and 7.305-7.265 (m, 2H), 6.926-6.897 (d, 2H, J=8.7Hz), 5.048-5.005 (m, 1H), 3.339-3.259 (m, 2H), 2.959-2.910 (t, 2H, J=7.4Hz), 2.586-2.539 (t, 2H, J=7.1Hz), 2.275 (s, 3H), 2.120-2.070 (quint, 2H, J=7.5Hz).
Embodiment 26
(S)-2-(4-methoxyl group phenoxy group)-3-(3-(2-(propionic acid (X of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
3) synthetic: with reference to embodiment 24, obtain compounds X
3, yield 80%;
1H NMR (300MHz, DMSO-d6) δ 7.879-7.854 (m, 2H), 7.581 (s, 1H), and 7.539-7.511 (d, 1H, J=8.4Hz), 7.466-7.448 (m, 3H), 7.273-7.246 (d, 1H, J=8.1Hz), 6.798-6.726 (m, 4H), and 4.851-4.811 (m, 1H), 3.304 (s, 3H), 3.238-3.196 (m, 2H), 2.961-2.912 (t, 2H, J=7.4Hz), 2.589-2.539 (t, 2H, J=7.5Hz), 2.283 (s, 3H), 2.142-2.072 (quint, 2H, J=7.0Hz).
Embodiment 27
(S)-2-(4-fluorophenoxy)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionic acid (X of d] oxazole-5-)
4) synthetic: with reference to embodiment 24, obtain compounds X
4, yield 87%.
1H?NMR(300MHz，DMSO-d6)δ7.877-7.852(m，2H)，7.589(s，1H)，7.538-7.509(d，1H，J＝8.7Hz)，7.467-7.450(m，3H)，7.278-7.249(d，1H，J＝8.7Hz)，7.075-7.015(t，2H，J＝9.0Hz)，6.852-6.807(m，2H)，4.961-4.917(m，1H)，3.321-3.168(m，2H)，2.959-2.911(t，2H，J＝7.2Hz)，2.588-2.540(t，2H，J＝7.2Hz)，2.280(s，3H)，2.142-2.070(quint，2H，J＝7.2Hz)。
Embodiment 28
(S)-2-(4-bromine phenoxy group)-3-(3-(2-(propionic acid (X of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
5) synthetic: with reference to embodiment 24, obtain compounds X
5, yield 78%;
1H NMR (300MHz, DMSO-d6) δ 7.875-7.849 (m, 2H), 7.583 (s, 1H), and 7.534-7.506 (d, 1H, J=8.4Hz), 7.464-7.442 (m, 3H), 7.392-7.362 (d, 2H, J=9.0Hz), and 7.269-7.244 (d, 1H, J=7.5Hz), 6.815-6.785 (d, 2H, J=9.0Hz), 5.015-4.975 (m, 1H), 3.278-3.176 (m, 2H), 2.955-2.908 (t, 2H, J=7.1Hz), 2.584-2.535 (t, 2H, J=7.4Hz), 2.275 (s, 3H), 2.140-2.067 (quint, 2H, J=7.3Hz).
Embodiment 29
(S)-2-(4-chlorophenoxy)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionic acid (X of d] oxazole-5-)
6) synthetic: with reference to embodiment 24, obtain compounds X
6, yield 80%;
1H NMR (300MHz, DMSO-d6) δ 7.876-7.846 (m, 2H), 7.587 (s, 1H), and 7.534-7.507 (d, 1H, J=8.1Hz), 7.463-7.441 (m, 3H), 7.269-7.242 (d, 3H, J=8.1Hz), and 6.864-6.835 (d, 2H, J=8.7Hz), 5.017-4.978 (m, 1H), 3.329-3.182 (dd, dd, 2H, J=14.1Hz, 5.1Hz, 8.7Hz), 2.956-2.908 (t, 2H, J=7.2Hz), 2.584-2.537 (t, 2H, J=7.1Hz), 2.277 (s, 3H), 2.141-2.048 (quint, 2H, J=7.0Hz).
Embodiment 30
(S)-2-(4-iodine phenoxy group)-3-(3-(2-(propionic acid (X of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
7) synthetic: with reference to embodiment 24, obtain compounds X
7, yield 80%;
1H NMR (300MHz, DMSO-d6) δ 7.877-7.851 (m, 2H), 7.577 (s, 1H), 7.534-7.506 (d, 3H, J=8.4Hz), 7.464-7.450 (m, 3H), 7.266-7.239 (d, 1H, J=8.1Hz), 6.689-6.661 (d, 2H, J=8.4Hz), 4.998-4.958 (m, 1H), 3.274-3.171 (m, 2H), 2.957-2.909 (t, 2H, J=7.2Hz), 2.585-2.539 (t, 2H, J=6.9Hz), 2.278 (s, 3H), 2.119-2.071 (quint, 2H, J=7.2Hz).
Embodiment 31
(S)-2-(4-cyano-benzene oxygen)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionic acid (X of d] oxazole-5-)
8) synthetic: with reference to embodiment 24, obtain compounds X
8, yield 71%;
1H NMR (300MHz, DMSO-d6) δ 7.873-7.841 (m, 2H), 7.713-7.682 (d, 2H, J=9.3Hz), 7.626 (s, 1H), 7.595-7.565 (d, 1H, J=9.0Hz), 7.554-7.447 (m, 3H), and 7.280-7.253 (d, 1H, J=8.1Hz), 7.017-6.986 (d, 2H, J=9.3Hz), 5.223-5.182 (m, 1H), 3.373-3.215 (m, 2H), 2.955-2.906 (t, 2H, J=7.4Hz), 2.582-2.536 (t, 2H, J=6.9Hz), 2.273 (s, 3H), 2.137-2.066 (quint, 2H, J=7.1Hz).
Embodiment 32
(S)-2-(4-ethanoyl phenoxy group)-3-(3-(2-(propionic acid (X of 3-(5-methyl-2-benzene base oxazole-4-) propyl group) benzo [d] oxazole-5-)
9) synthetic: with reference to embodiment 24, obtain compounds X
9, yield 71%;
1H NMR (300MHz, DMSO-d6) δ 7.872-7.848 (m, 2H), 7.821-7.793 (d, 2H, J=8.4Hz), 7.588 (s, 1H), 7.513-7.484 (d, 1H, J=8.7Hz), 7.462-7.446 (m, 3H), and 7.276-7.249 (d, 1H, J=8.1Hz), 6.894-6.865 (d, 2H, J=8.7Hz), 4.916 (m, 1H), 3.352-3.150 (dd, dd, 2H, J=14.4Hz, 8.7Hz, 3.6Hz), 2.947-2.898 (t, 2H, J=7.4Hz), 2.579-2.532 (t, 2H, J=7.1Hz), 2.477 (s, 3H), 2.434 (s, 3H), and 2.131-2.062 (quint, 2H, J=6.9Hz).
Embodiment 33
(R)-2-(4-4-trifluoromethylphenopendant)-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionic acid (X of d] oxazole-5-)
10) synthetic: with reference to embodiment 24, obtain compounds X
10, yield 60%.
1H?NMR(300MHz，DMSO-d6)δ7.874-7.843(m，2H)，7.602(s，2H)，7.571(s，1H)，7.540-7.513(d，1H，J＝8.1Hz)，7.464-7.443(m，3H)，7.292-7.259(dd，1H，J＝8.7Hz，1.5Hz)，7.027-6.998(d，2H，J＝8.7Hz)，5.174-5.131(m，1H)，3.372-3.221(dd，dd，2H，J＝14.1Hz，8.1Hz，3.9Hz)，2.956-2.907(t，2H，J＝7.4Hz)，2.582-2.536(t，2H，J＝6.9Hz)，2.273(s，3H)，2.142-2.070(quint，2H，J＝7.2Hz)。
Embodiment 34
(S)-2-methoxyl group-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionic acid (X of d] oxazole-5-)
11) synthetic: with reference to embodiment 24, obtain compounds X
11, yield 60%.
1H?NMR(300MHz，DMSO-d6)δ7.886-7.853(m，2H)，7.515-7.447(m，5H)，7.178-7.146(dd，1H，J＝8.4Hz，2.1Hz)，3.974-3.932(m，1H)，3.207(s，3H)，3.082-3.019(dd，1H，J＝13.8Hz，4.2Hz)，2.985-2.914(m，3H)，2.594-2.546(t，2H，J＝7.2Hz)，2.290(s，3H)，2.148-2.076(quint，2H，J＝7.2Hz)。
Embodiment 35
(S)-2-isopropoxy-3-(3-(2-(3-(5-methyl-2-Ben Ji oxazole-4-) propyl group) benzo [propionic acid (X of d] oxazole-5-)
12) synthetic: with reference to embodiment 24, obtain compounds X
12, yield 70%.
1H?NMR(300MHz，DMSO-d6)δ7.887-7.856(m，2H)，7.512-7.448(m，5H)，7.189-7.16(d，1H，J＝8.4Hz)，4.088-4.045(m，1H)，3.516-3.434(quint，1H，J＝6.2Hz)，3.046-2.850(m，5H)，2.595-2.548(t，2H，J＝7.1Hz)，2.478(s，3H)，2.151-2.080(quint，2H，J＝7.1Hz)，1.032-1.014(d，3H，J＝5.4Hz)，0.852-0.831(d，3H，J＝6.3Hz)。
Embodiment 36
The anti-microbial activity minimum inhibition concentration MIC of compound adopts 96 orifice plate broth dilution methods to record.
1) microbial culture
Intestinal bacteria (Escherichia coli), streptococcus aureus (Staphylococcus aureus), methicillin-resistant staphylococcus aureus (Methicillin-resistant Staphylococcus aureus) and subtilis (Bacillus subtilis) all use the beef soup agar slant to cultivate; Fungi Candida albicans (Candida albicans) uses potato soup agar glucose slant culture.
2) medicine preparation
All compounds are mixed with the solution that maximum concentration is 5 mg/ml with methyl-sulphoxide, are diluted to 400 mcg/ml with aseptic beef soup nutrient solution and aseptic potato soup nutrient solution respectively then, and in-20 ℃ of preservations, for repeatedly using.
3) 96 orifice plate broth dilution method determination anti-microbial activity minimum inhibition concentration MIC
With sterilized water bacterium on the nutrient agar and fungi are washed, then respectively with beef soup substratum and the dilution of potato soup dextrose culture-medium.Bacterial concentration is controlled at 10
5About individual bacterium colony units per ml, fungi concentration is controlled at 10
4About individual bacterium colony units per ml.Use the volley of rifle fire,, then the medicine of 400 mcg/ml of 100 microlitres is joined the 1st row of 96 hollow plates, blow and beat repeatedly 6 to 8 times at 96 aerial each aerial above-mentioned nutrient solution that carry disease germs that add 100 microlitres.This moment, the 1st row drug level was 200 mcg/ml.Draw 100 microlitre band medicine nutrient solutions with the volley of rifle fire from above-mentioned the 1st row and join in the 2nd row, blow and beat repeatedly 6 to 8 times, this moment, the drug level of the 2nd row was 100 mcg/ml.From the 2nd row, get 100 microlitres to the, 3 row again according to aforesaid operations, piping and druming repeatedly, this moment, the drug level of the 3rd row was 50 mcg/ml.Same operation continues up to the 10th row.This moment the 1st, row to the 10th row drug level was followed successively by 200,100,50,25,12.5,6.25,3.12,1.56,0.78 and 0.39 mcg/ml.In the incubator of 37 degree, cultivate after 24 hours, observe the clarity of each concentration.Can make empty clarification lowest concentration of drug be anti-microbial activity minimum inhibition concentration MIC value, the gained result is referring to table 1.
Table 1.2-replaces benzo [d] oxazole-5-propionic acid antimicrobial acivity test
Table 1. explanation: 1) all compounds are stronger than Gram-negative bacteria (intestinal bacteria) to the restraining effect of gram-positive microorganism (streptococcus aureus, methicillin-resistant staphylococcus aureus, subtilis); 2) all compound to the minimum inhibition concentration MIC of fungi Candida albicans all more than 200 mcg/ml; 3) compounds X
1, X
2Anti-streptococcus aureus (Staphylococcus aureus) minimum inhibition concentration MIC is 1.56 mcg/ml, and it suppresses activity and is better than positive control rosiglitazone (25 mcg/ml) greatly; Double than cefotaxime and penicillin inhibition active (3.12 mcg/ml); But suppress active low one times than ceftazidime; 4) at methicillin-resistant staphylococcus aureus resistance (Methicillin-resistantStaphylococcus aureus), compounds X
1, X
2, X
7Minimum inhibition concentration MIC is 1.56 mcg/ml; Compounds X
5And X
10Minimum inhibition concentration MIC is 3.12 mcg/ml, more than the inhibition activity of 5 compounds all be better than all positive controls; 5) compounds X
1, X
2Best to the inhibition activity of subtilis (Bacillus subtilis) in the compound of all tests, be 3.12 mcg/ml; But to hang down twice than positive control cefotaxime (Cefotaxime) and penicillin (Penicillin).All in all, compounds X
1, X
2, X
5, X
7And X
10In the bacteria test of being tested, show than obvious inhibiting activity.
Claims (14)
1. a 2-replaces benzo [d] oxazole-5-phenylpropionic acid compound, it is characterized in that its structural formula is:
Wherein: m is 0～5 integral multiple, and n is 0～5 integral multiple, R
1Be following any substituting group:
2. the preparation method of 2-replacement benzo [d] oxazole according to claim 1-5-propionic acid is characterized in that, comprises the steps:
(1) 4-hydroxy phenylpropionic acid and salpeter solution reaction are obtained further with after strong sulfuric acid response and the reflux obtaining 3-nitro-4-hydroxy-benzenepropanoic acid ethylester behind 3-nitro-4-hydroxy phenylpropionic acid;
(2) 3-nitro-4-hydroxy-benzenepropanoic acid ethylester being carried out hydrogenation obtains further with behind reaction of 2-chloracetyl imidic acid methyl ester hydrochloride and the secondary back obtaining 3-(2-(chloromethyl) benzo [b] oxazole-5)-methyl propionate behind the 3-amino-4-hydroxy phenylpropionic acid ethyl ester;
(3) 3-(2-((diethoxy phosphonium mesitoyl base) methyl) benzo [methyl propionate of b] oxazole-5-) will be obtained after 3-(2-(chloromethyl) benzo [b] oxazole-5)-methyl propionate and the triethyl-phosphite Hybrid Heating;
(4) ([methyl propionate of b] oxazole-5-) and potassium tert.-butoxide mix back and R to 2-((diethoxy phosphonium mesitoyl base) methyl) benzo in organic solvent with 3-
1The CHO aldehyde reaction, and directly be dissolved in reaction product in the methyl alcohol and under platinum dioxide catalysis reduction hydrogenation obtain 3-(2-replace the methyl propionate of benzo [b] oxazole-5-);
(5) (2-replaces the methyl propionate hydrolysis of benzo [b] oxazole-5-) and obtains 3-(2-replaces the propionic acid of benzo [b] oxazole-5-) with 3-;
(6) with 3-(2-replace the propionic acid of benzo [b] oxazole-5-) respectively or (S) with (R)-4-sec.-propyl-3-substituted-phenyl third acyl base oxazolidine-2-ketone lithium-4-sec.-propyl-3-substituted-phenyl third acyl base oxazolidine-2-ketone lithium low temperature organic solvent in reaction obtain Evans acid amides (R)-4-sec.-propyl-3-(3-(2-replaces the propionyl of benzo [b] oxazole-5-)) oxazolidine-2-ketone or (S)-4-sec.-propyl-3-(3-(2-replaces the propionyl of benzo [b] oxazole-5-)) oxazolidine-2-ketone;
(7) with the product of step (6) respectively with 1,1,1,3,3,3-hexamethyldisilazane sylvite stirs back and 3-phenyl-2-phenyl sulphonyl-1 in the low temperature organic solvent, 2-is mute, and piperazine carries out the Davis asymmetric oxidation, obtains (R)-3-((R)-2-hydroxyl-3-(2-replaces the propionyl of benzo [b] oxazole-5-)) oxazolidine-2-ketone or (S)-3-((S)-2-hydroxyl-3-(2-replaces the propionyl of benzo [b] oxazole-5-)) oxazolidine-2-ketone respectively;
(8) step (7) product is reacted in alcoholic solution with magnesium methylate respectively, (2-replaces the methyl propionate of benzo [b] oxazole-5-) or (S)-2-hydroxyl-3-, and (2-replaces the methyl propionate of benzo [b] oxazole-5-) to obtain (R)-2-hydroxyl-3-respectively;
(9) step (8) product is carried out any one reaction in following two kinds:
9.1) with phenol, triphenylphosphine, di-isopropyl diazonium two carbonic ethers in toluene or tetrahydrofuran (THF) through the Mitsunobu reaction, (2-replaces the methyl propionate of benzo [b] oxazole-5-) or (R)-2-fragrance substituted hydroxy-3-, and (2-replaces the methyl propionate of benzo [b] oxazole-5-) to obtain (S)-2-fragrance substituted hydroxy-3-respectively;
9.2) (2-replaces the methyl propionate of benzo [b] oxazole-5-) or (S)-2-alkyl substituted hydroxy-3-, and (2-replaces the methyl propionate of benzo [b] oxazole-5-) to obtain (R)-2-alkyl substituted hydroxy-3-respectively with halogenated alkane under the catalysis of silver suboxide;
(10) with step 9.1) and step 9.2) product carry out the secondary hydrolysis reaction and prepare 2-and replace benzo [d] oxazole-5-propionic acid.
3. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that, described salpeter solution is a mass percent at 60% aqueous nitric acid.
4. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that described reflux is meant: refluxed 12 hours down at 85 ℃ after 3-nitro-4-hydroxy phenylpropionic acid and the vitriol oil are dissolved in methyl alcohol.
5. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that, described hydrogenation is meant: the employing concentration ratio is 10% palladium/carbon and 3-nitro-4-hydroxy-benzenepropanoic acid ethylester hydrogenation in methyl alcohol, and temperature of reaction is a room temperature.
6. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that described secondary back is meant: place 70 ℃ methyl alcohol to reflux 1.5 hours 3-amino-4-hydroxy phenylpropionic acid ethyl ester and 2-chloracetyl imidic acid methyl ester hydrochloride.
7. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that described Hybrid Heating is meant: at 150 ℃ N, heating is 3 hours in the dinethylformamide.
8. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that described mixing in organic solvent is meant: stirred 30 minutes in-10 ℃ tetrahydrofuran (THF).
9. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that described R
1CHO aldehyde is meant: R
1Be following any substituting group:
Wherein: R
4Be C
1-C
5Alkyl, nitro, carboxyl, chlorine, bromine, fluorine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, fragrant-oxyl, aromatic base or assorted aromatic base; S is 0～5 integer, and G is O, S or N, R
5And R
6Be following any one: C
1-C
5Alkyl, nitro, carboxyl, chlorine, bromine, fluorine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base or assorted aromatic base.
10. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that described hydrolysis is meant: (2-replacement benzo [b] oxazole-5-) methyl propionate reacts down for 25 ℃ in room temperature with aqueous sodium hydroxide solution after being dissolved in ethanol with 3-.
11. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that described low temperature organic solvent is meant :-78 ℃ tetrahydrofuran (THF).
12. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that, described secondary hydrolysis reaction is meant: with step 9.1) and step 9.2) product place the water-methanol solution that contains lithium hydroxide, V in the described water-methanol solution
Water/ V
Methyl alcohol=3: 2.
13. 2-according to claim 2 replaces the preparation method of benzo [d] oxazole-5-propionic acid, it is characterized in that described alcoholic solution is meant: 0 ℃ methyl alcohol.
14. one kind according to arbitrary described 2-replacement benzo [d] oxazole-5-propionic acid among the claim 1-13, it is characterized in that, be used to suppress the biological activity of gram-positive microorganism, fungi Candida albicans, streptococcus aureus, methicillin-resistant staphylococcus aureus and subtilis.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019702A1 (en) * | 1990-06-14 | 1991-12-26 | Pfizer Inc. | 3-aryl-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents |
| US5232945A (en) * | 1992-07-20 | 1993-08-03 | Pfizer Inc. | 3-aryl-2-hydroxypropionic acid derivatives and analogs as antihypertensives |
| CN101830894A (en) * | 2010-06-01 | 2010-09-15 | 上海交通大学 | Benzo[d]oxazole compounds and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019702A1 (en) * | 1990-06-14 | 1991-12-26 | Pfizer Inc. | 3-aryl-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents |
| US5306726A (en) * | 1990-06-14 | 1994-04-26 | Pfizer Inc. | 3-aryl-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents |
| US5232945A (en) * | 1992-07-20 | 1993-08-03 | Pfizer Inc. | 3-aryl-2-hydroxypropionic acid derivatives and analogs as antihypertensives |
| CN101830894A (en) * | 2010-06-01 | 2010-09-15 | 上海交通大学 | Benzo[d]oxazole compounds and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《Antimicrobial Agents and Chemotherapy》 19810131 Elamin I. Elnima, et al. Antibacterial and Antifungal Activities of Benzimidazole and Benzoxazole Derivatives 29-32 1-14 第19卷, 第1期 2 * |
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